TETRACYCLIC INDOLE DERIVATIVES FOR TREATING HEPATITIS C VIRUS INFECTION

DERIVES D'INDOLES TETRACYCLIQUES POUR LE TRAITEMENT D'UNE INFECTION PAR LE VIRUS DE L'HEPATITE C

English Abstract

Tetracyclic indole derivatives of formula (I), pharmaceutically acceptable salts and the pharmaceutical compositions thereof are provided, wherein A, A', G, R1, R15, U, V, V, W, W, X, X', Y, Y' are as defined in the invention. Use of these derivatives for treating hepatitis C virus (HCV) infection is also provided.

French Abstract

La présente invention concerne des dérivés d'indoles tétracycliques de formule (I), leurs sels pharmaceutiquement acceptables et leurs compositions pharmaceutiques, dans laquelle A, A', G, R1, R15, U, V, V, W, W, X, X', Y, Y' sont tels que définis dans l'invention. L'invention concerne également l'utilisation desdits dérivés pour le traitement d'une infection par le virus de l'hépatite C (VHC).

Claims

513

CLAIMS

1. A compound having the formula:
Image
or a pharmaceutically acceptable salt thereof, wherein:
A and A' are each independently a 5 or 6-membered monocyclic
heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl
group can
be optionally fused to an aryl group; and wherein said 5 or 6-membered
monocyclic
heterocycloalkyl group can be optionally and independently substituted on one
or more
ring carbon atoms with R13, such that any two R13 groups on the same ring,
together with
the carbon atoms to which they are attached, can join to form a fused, bridged
or
spirocyclic 3 to 6-membered cycloalkyl group or a fused, bridged or
spirocyclic 4 to 6-
membered heterocycloalkyl group, wherein said 5 or 6-membered monocyclic
heterocycloalkyl contains from 1 to 2 ring heteroatoms, each independently
selected from
N(R4), S, O and Si(R16)2;
G is selected from -C(R3)2-O-, -C(R3)2-N(R5)-, -C(O)-O-, -C(O)-N(R5)-,
-C(O)-C(R3)2-, -C(R3)2-C(O)-, -C(=NR5)-N(R5)-, -C(R3)2-SO2-, -SO2-C(R3)2-, -
SO2N(R5)-, -C(R3)2-C(R3)2-, -C(R14)=C(R14)- and -C(R14)=N-;
U is selected from N and C(R2);
V and V' are each independently selected from N and C(R15);
W and W' are each independently selected from N and C(R1);
X and X' are each independently selected from N and C(R10);
Y and Y' are each independently selected from N and C(R10);
R1 is selected from H, C1-C6 alkyl, 3 to 6-membered cycloalkyl, halo, -OH,
-O-(C1-C6 alkyl), C1-C6 haloalkyl and -O-(C1-C6 haloalkyl);




514
each occurrence of R2 is independently selected from H, C1-C6 alkyl, 3 to
6 membered cycloalkyl, -O-(C1-C6 alkyl), C1-C6 haloalkyl -O-(C1-C6 haloalkyl);
halo, -
OH, aryl, and heteroaryl;
each occurrence of R3 is independently selected from HC1-C6 alkyl, C 1 -
C6 haloalkyl, -(C1-C6 alkylene)-O-(C1-C6 alkyl), -(C1-C6 alkylene)-O-(3 to 6
membered
cycloalkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
aryl, 5 or 6-
membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl and
benzyl,
wherein said aryl group, said 5 or 6-membered monocyclic heteroaryl group,
said 9 or
10-membered bicyclic heteroaryl group or the phenyl moiety of said benzyl
group can be
optionally substituted with up to 3 groups, which can be the same or
different, and are
selected from C1-C6 alkylC1-C6 haloalkyl, -O-(C1-C6 alkyl), -O(C1-C6
haloalkyl), halo, -
(C1-C6 alkylene)-O-(C1-C6 alkyl) and -CN and wherein two R3 groups attached to
the
same carbon atom, together with the common carbon atom to which they are
attached,
can join to form a carbonyl group, a 3 to 6-membered spirocyclic cycloalkyl
group or a 3
to 6-membered spirocyclic heterocycloalkyl group;
each occurrence of R4 is independently selected from -[C(R7)2]q N(R6)2,-
C(O)R11, -C(O)-[C(R7)2]q N(R6)2, -C(O)-[C(R7)2]q-R11, -C(O)-[C(R7)2]q
N(R6)C(O)-R11, -
C(O) [C(R7)2] q N(R6)SO2-R11, -C(O)- [C(R7)2] q N(R6)C(O)O-R11, -C(O)-
[C(R7)2] q C(O)O-
R11 an -alkylene-N(R6)-[C(R7)2]q-N(R6)-C(O)O-R11;
each occurrence of R5 is independently selected from HC1-C6 alkyl, -(C1-
C6 alkylene)-O-(C1-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered
heterocycloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl and benzyl,
wherein said
aryl group, said 5 or 6-membered monocyclic heteroaryl group or the phenyl
moiety of
said benzyl group can be optionally substituted with up to 3 groups, which can
be the
same or different, and are selected from C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-
C6 alkyl), -
O-(C1-C6 haloalkyl), halo, -(C1-C6 alkylene)-O-(C1-C6 alkyl) and -CN;
each occurrence of R6 is independently selected from H, C1-C6 alkyl, 3 to
6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6-
membered
monocyclic heteroaryl, wherein said 3 to 6-membered cycloalkyl group, said 4
to 6-
membered heterocycloalkyl group, said aryl group and said 5 or 6-membered
monocyclic
heteroaryl group can be optionally and independently substituted with up to
two R8

515



groups, and wherein two R6 groups that are attached to the same nitrogen atom,
together



with the common nitrogen atom to which they are attached, can join to form a 4
to 6-



membered heterocycloalkyl group;



each occurrence of R7 is independently selected from H, C1-C6 alkyl, C1-



C6 haloalkyl, -alkylene-O-(C1-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-
membered



heterocycloalkyl, aryl and 5 or 6-membered monocyclic heteroaryl, wherein said
3 to 6-



membered cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said
aryl



group and said 5 or 6-membered monocyclic heteroaryl group can be optionally



substituted with up to three R8 groups;



each occurrence of R8 is independently selected from H, C1-C6 alkyl, halo,



-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -OH, -C(0)NH-(C1-C6 alkyl), -C(0)N(C1-C6




alkyl)2, -O-(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 and -
NHC(O)-(C1-C6



alkyl);



each occurrence of R9 is independently selected from H, C1-C6 alkyl, C1-C6



haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl
and 5 or



6-membered monocyclic heteroaryl;



C6 haloalkyl, halo, -OH, -O-(C1-C6 alkyl) and -CN;



each occurrence of R10 is independently selected from H, C1-C6 alkyl, C1-
each occurrence of R11 is independently selected from H, C1-C6 alkyl, C1-



C6 haloalkyl, C1-C6 hydroxyalkyl, 3 to 6-membered cycloalkyl and 4 to 6-
membered



heterocycloalkyl;



each Occurrence of Ri2 is independently selected from C1-C6 alkyl, C1-C6



haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl
and 5 or



6-membered monocyclic heteroaryl;



each occurrence of R13 is independently selected from H, halo, C1-C6 alkyl,



C1-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
-CN, -



OR9, -N(R9)2, -C(O)R12, -C(O)OR9, -C(O)N(R9)2, -NHC(O)R12, -NHC(O)NHR9, -



NHC(O)OR9, -OC(O)R12, -SR9 and -S(O)2R12, wherein two R12 groups together with
the



carbon atom(s) to which they are attached, can optionally join to form a 3 to
6-membered



cycloalkyl group or 4 to 6-membered heterocycloalkyl group;

516

each occurrence of R14 is independently selected from H, halo, C1-C6 alkyl,
-(C1-C6 alkylene)-O-(C1-C6 alkyl), 3 to 6-membered cycloalkyl, C1-C6
haloalkyl, aryl, 5
or 6-membered monocyclic heteroaryl and benzyl, wherein said aryl group, said
5 or 6-
membered monocyclic heteroaryl group or the phenyl moiety of said benzyl group
can be
optionally substituted with up to 3 groups, which can be the same or
different, and are
selected from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -O-(C1-C6 alkyl), -(C1-
C6
alkylene)-O-(C1-C6 alkyl) and -O-(C1-C6 haloalkyl);
each occurrence of R15 is independently selected from H, C1-C6 alkyl, 3 to
6-membered cycloalkyl, halo, -OH, -O-(C1-C6 alkyl), C1-C6 haloalkyl and -O-(C1-
C6
haloalkyl);
each occurrence of R16 is independently selected from H, halo, C1-C6 alkyl
and 3 to 6-membered cycloalkyl, wherein two R16 groups that are attached to a
common
silicon atom can join to form a -(CH2)4- or a -(CH2)5- group; and
each occurrence of q is independently an integer ranging from 0 to 4,
provided that the compound of formula (I) is other than:

517


Image




518
2. The compound of claim 1 having the formula:
Image
and pharmaceutically acceptable salts thereof, wherein:
A and A' are each independently a 5-membered monocyclic
heterocycloalkyl, wherein said 5-membered monocyclic heterocycloalkyl group
can be
optionally and independently substituted on one or more ring carbon atoms with
R13, such
that any two R13 groups on the same ring, together with the carbon atoms to
which they
are attached, can join to form a fused, bridged or spirocyclic 3 to 6-membered
cycloalkyl
group or a fused, bridged or spirocyclic 4 to 6-membered heterocycloalkyl
group,
wherein said 5-membered monocyclic heterocycloalkyl contains from 1 to 2 ring
heteroatoms, each independently selected from N(R4) and Si(R16)2;
G is selected from-C(R3)2-O-, or -C(R3)2-C(R3)2-
R1 represents an optional ring substituent on the phenyl ring to which R1 is
attached, wherein said substituent is selected from C1-C6 alkyl, -OC1-C6 alkyl
and halo;
each occurrence of R2 is independently selected from H, halo C1-C6 alkyl,
3 to 6 membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-
membered
monocyclic heteroaryl, benzyl, -O-(C1-C6 alkyl), C1-C6 haloalkylene -O-(C1-C6
haloalkyl); -(C1-C6 alkylene)C(=O)NH-alkyl, -(C1-C6 alkylene)aryl, and -(C1-C6

alkylene)heteroaryl, wherein said aryl group, said 5 or 6-membered monocyclic
heteroaryl group or the phenyl group of said benzyl group can be optionally
substituted
with up to 3 groups, which can be the same or different, and are selected from
halo, -CN,
C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -(C1-C6 alkylene)-O-C1-C6 alkyl
and -O-(C1-C6 haloalkyl);

519

each occurrence of R3 is independently selected from H, C1-C6 haloalkyl,
C1-C6 alkyl, 3 to 6 membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
aryl, 5 or 6-
membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl, benzyl, -
O-(C1-
C6 alkyl), C1-C6 haloalkylene haloalkyl); alkylene)C(=O)NH-alkyl,
alkylene)aryl, and -(C1-C6 alkylene)heteroaryl, wherein said aryl group, said
5 or
6-membered monocyclic heteroaryl group, said 9 or 10-membered bicyclic
heteroaryl
group or the phenyl group of said benzyl group can be optionally substituted
with up to 3
groups, which can be the same or different, and are selected from halo, -CN,
C1-C6 alkyl,
C1-C6 haloalkyl, -O-C1-C6 alkyl, -(C1-C6 alkylene)-O-C1-C6 alkyl and -O-(C1-C6

haloalkyl);
each occurrence of R4 is independently -C(O)-[C(R7)2]N(R6)C(O)O-R11;
each occurrence of R6 is independently selected from H and C1-C6 alkyl;
each occurrence of R7 is independently selected from C1-C6 alkyl, C1-C6
haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl
and 5 or
6-membered monocyclic heteroaryl, wherein said 3 to 6-membered cycloalkyl
group,
said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-
membered
monocyclic heteroaryl group can be optionally and independently substituted
with up to
three R8 groups;
each occurrence of R8 is independently selected from H, C1-C6 alkyl, halo,
-C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -OH, -C(O)NH-(C1 -C6 alkyl), -C(O)N(C1-
C6
alkyl)2, -O-(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2 and -
NHC(O)-(C1-C6
alkyl);
each occurrence of R10 is independently selected from H and halo;
each occurrence of R11 is independently C1-C6 alkyl;
each occurrence of R13 is independently selected from H and halo, wherein
two R13 groups, together with the carbon atom(s) to which they are attached,
can
optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-membered
heterocycloalkyl group;
each occurrence of R14 is independently selected from H, halo C1-C6 alkyl,
3 to 6 membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-
membered
monocyclic heteroaryl, benzyl, -O-(C1-C6 alkyl), C1-C6 haloalkylene




520
haloalkyl); -(C1-C6alkylene)C(=O)NH-alkyl, -(C1-C6alkylene)aryl, and -(C1-C6
alkylene)heteroaryl, wherein said aryl group, said 5 or 6-membered monocyclic
heteroaryl group or the phenyl group of said benzyl group can be optionally
substituted
with up to 3 groups, which can be the same or different, and are selected from
halo, -CN,
C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -(C1-C6 alkylene)-O-C1-C6 alkyl
and -O-
(C1-C6 haloalkyl);
each occurrence of R15 is independently selected from H, halo C1-C6 alkyl,
3 to 6 membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl, 5 or 6-
membered
monocyclic heteroaryl, benzyl, -O-(C1-C6 alkyl), C1-C6 haloalkylene
haloalkyl); -(C1-C6alkylene)C(=O)NH-alkyl, -(C1-C6alkylene)aryl, and -(C1-C6
alkylene)heteroaryl, wherein said aryl group, said 5 or 6-membered monocyclic
heteroaryl group or the phenyl group of said benzyl group can be optionally
substituted
with up to 3 groups, which can be the same or different, and are selected from
halo, -CN,
C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -(C1-C6 alkylene)-O-C1-C6 alkyl
and -O-
(C1-C6 haloalkyl); and
each occurrence of R16 is independently selected from C1-C6 alkyl.
3. The compound of claim 1 or 2 wherein the group:
Image
has the structure:
Image
4. The compound of claim 1 or 2, wherein the group:

521


Image


has the structure:


Image


5. The compound of any one of claims 1 to 4, wherein A and A' are
each independently selected from:



Image



6. The compound of claim 5, wherein A and A' are each
independently selected from:

522



Image



7. The compound of any one of claims 1 to 6, wherein A and A' are
each

Image

wherein each occurrence of Z is independently -Si(R13)2-, -C(R13)2- or -S-,
and each occurrence of R13 is independently H, Me, F or two R13 groups
together with Z,
can combine to form a spirocyclic 3 to 6-membered cycloalkyl group or a
spirocyclic 3 to
6-membered silyl-containing heterocycloalkyl group.

8. The compound of any one of claims 1 to 6, wherein each
occurrence of R4 is independently -C(O)C(R7)2NHC(O)O-R11 or -C(O)C(R7)2NR6)2.

9. The compound of any one of claim 8, wherein each occurrence of
R4 is independently -C(O)CH(alkyl)-NHC(O)Oalkyl, C(O)CH(cycloalkyl)-
NHC(O)Oalkyl, C(O)CH(heterocycloalkyl)-NHC(O)Oalkyl, C(O)CH(aryl)-
NHC(O)Oalkyl or C(O)CH(aryl)-N(alkyl)2.

10. The compound of claim 1 having the formula:

523



Image



or a pharmaceutically acceptable salt thereof, wherein:


R2 is H or F;


each occurrence of R3 is independently selected from H, C1-C6 alkyl,


C6 haloalkyl, 3 to 6 membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
aryl, 5 or


6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl, -O-(C1-
C6


alkyl), C1-C6 haloalkylene -O-(C1-C6 haloalkyl); -(C1-C6alkylene)C(=O)NH-
alkyl, -(C1-


C6 alkylene)aryl, and -(C1-C6alkylene)heteroaryl, wherein said aryl group,
said 5 or 6-


membered monocyclic heteroaryl group, said 9 or 10-membered bicyclic
heteroaryl


group or the phenyl group of said benzyl group can be optionally substituted
with up to 3


groups, which can be the same or different, and are selected from halo, -CN,
C1-C6 alkyl,


C1-C6 haloalkyl, -O-Ci1C6 alkyl, -(C1-C6 alkylene)-O-C1-C6 alkyl and -O-(C1-C6



haloalkyl);


each occurrence of R4 is independently selected from -C(O)O-(C1-C6


alkyl), -C(O)-CH(R7)N(R6)2 and -C(O)-CH(R7)C(O)O-R11;


each occurrence of R6 is independently H or C1-C6alkyl;


each occurrence of R7 is independently selected from C1-C6alkyl, phenyl,


4 to 6-membered heterocycloalkyl and 3 to 6 membered cycloalkyl;



each occurrence of R13a is independently H, Me or F; or two R13a groups


that are attached to the same carbon atom, together with the common carbon
atom to


which they are attached, combine to form a spirocyclic 3 to 6 membered
cycloalkyl group;


each occurrence of R13b is independently H, or one or both R13b groups and
each occurrence of R11 is independently C1-C6alkyl;

an R13a group that are attached to same ring, together with the ring carbon
atoms to


which they are attached, can combine to form a fused 3 to 6 membered
cycloalkyl group;


and

R x is H or F, or R w and R x, together with the ring carbon atoms to which



524

R15 represents up to 2 substituents, each independently selected from H,
halo, C1-C6 alkyl, C1-C6haloalkyl, 3 to 6 membered cycloalkyl, 4 to 6-membered

heterocycloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl, benzyl, -O-(C1-
C6 alkyl),
C1-C6 haloalkylene -O-(C1-C6 haloalkyl) -(C1-C6alkylene)C(=O)NH-alkyl, -(C1-C6

alkylene)aryl, and -(C1-C6alkylene)heteroaryl, wherein said aryl group, said 5
or 6-
membered monocyclic heteroaryl group or the phenyl group of said benzyl group
can be
optionally substituted with up to 3 groups, which can be the same or
different, and are
selected from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -O-C1-C6 alkyl, -(C1-C6
alkylene)-
O-C1-C6 alkyl and -O-(C1-C6 haloalkyl).

11. The compound of claim 1 having the formula:



Image



or a pharmaceutically acceptable salt thereof,
wherein:
R30 is C1-C6 alkyl, aryl, 5 or 6-membered monocyclic heteroaryl or 9-
membered bicyclic heteroaryl;
R w is H, or R w and le, together with the ring carbon atoms to which they
are attached, combine to form a fused 3 to 6-membered cycloalkyl group;

they are attached, combine to form a fused 3 to 6-membered cycloalkyl group;
R y is H, or R y and R z, together with the ring carbon atoms to which they
are attached, combine to form a fused 3 to 6-membered cycloalkyl group; and

they are attached, combine to form a fused 3 to 6-membered cycloalkyl group.

R z is H or F, or R y and R z, together with the ring carbon atoms to which

525


12. A compound of Table 1 or Table 2 of the above specification or a
stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising an effective amount of
the compound of any of claims 1 to 12 and a pharmaceutically acceptable
carrier.

14. The pharmaceutical composition according to claim 13 further
comprising a second therapeutic agent selected from the group consisting of
HCV
antiviral agents, immunomodulators, and anti-infective agents.

15. The pharmaceutical composition according to claim 14, further
comprising a third therapeutic agent selected from the group consisting of HCV
protease
inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.

16. The use of the compound according to any of claims 1 to 12 for
inhibiting HCV replication or for treating infection by HCV in a patient in
need thereof.

17. A method of treating a patient infected with HCV comprising the
step of administering an amount of (i) the compound according to any of claims
1 to 10
or (ii) the composition according to any of claims 13 to 15 effective to treat
infection by
HCV in said patient.
18. The method according to claim 17, further comprising the step of
administering pegylated-interferon alpha and an HCV protease to said patient.

19. The method according to claim 17 or 18, further comprising the
step of administering ribavirin to said patient.

20. The method according to claim 17 or 18, further comprising the
step of administering from one to three additional therapeutic agents to said
patient,




526
wherein the additional therapeutic agents are each independently selected from
HCV
protease inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
21. The method according to claim 20, wherein the one to three
additional therapeutic agents comprises MK-5172.
22. The method according to claim 21 or 22, wherein the one to three
additional therapeutic agents comprises PSI-7977.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 504
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
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VOLUME
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NOTE: For additional volumes, please contact the Canadian Patent Office
NOM DU FICHIER / FILE NAME:
NOTE POUR LE TOME / VOLUME NOTE:

CA 02811662 2013-03-19
WO 2012/041014 1
PCT/CN2011/001638
TETRACYCLIC INDOLE DERIVATIVES FOR TREATING
HEPATITIS C VIRUS INFECTION
FIELD OF THE INVENTION
The present invention relates to novel Tetracyclic Indole Derivatives,
compositions comprising at least one Tetracyclic Indole Derivative, and
methods of
using the Tetracyclic Indole Derivatives for treating or preventing HCV
infection in a
patient.
BACKGROUND OF THE INVENTION
Hepatitis C virus (HCV) is a major human pathogen. A substantial
fraction of these HCV-infected individuals develop serious progressive liver
disease,
including cirrhosis and hepatocellular carcinoma, which are often fatal. HCV
is a (+)-
sense single-stranded enveloped RNA virus that has been implicated as the
major
causative agent in non-A, non-B hepatitis (NANBH), particularly in blood-
associated
NANBH (BB-NANBH) (see, International Publication No. WO 89/04669 and
European Patent Publication No. EP 381 216). NANBH is to be distinguished from

other types of viral-induced liver disease, such as hepatitis A virus (HAV),
hepatitis B
virus (HBV), delta hepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-
Barr
virus (EBV), as well as from other forms of liver disease such as alcoholism
and
primary biliar cirrhosis.
It is well-established that persistent infection of HCV is related to
chronic hepatitis, and as such, inhibition of HCV replication is a viable
strategy for
the prevention of hepatocellular carcinoma. Current therapies for HCV
infection
include a-interferon monotherapy and combination therapy comprising a-
interferon
and ribavirin. These therapies have been shown to be effective in some
patients with
chronic HCV infection, but suffer from poor efficacy and unfavorable side-
effects and
there are currently efforts directed to the discovery of HCV replication
inhibitors that
are useful for the treatment and prevention of HCV related disorders.
Current research efforts directed toward the treatment of HCV includes
the use of antisense oligonucleotides, free bile acids (such as
ursodeoxycholic acid
and chenodeoxycholic acid) and conjugated bile acids (such as
tauroursodeoxycholic

CA 02811662 2013-03-19
WO 2012/041014
PCT/CN2011/001638
2
acid). Phosphonoformic acid esters have also been proposed as potentially
useful for
the treatment of various viral infections, including HCV. Vaccine development,

however, has been hampered by the high degree of viral strain heterogeneity
and
immune evasion and the lack of protection against reinfection, even with the
same
inoculum.
In light of these treatment hurdles, the development of small-molecule
inhibitors directed against specific viral targets has become a major focus of
anti-
HCV research. The determination of crystal structures for NS3 protease, NS3
RNA
helicase, NS5A, and NS5B polymerase, with and without bound ligands, has
provided
important structural insights useful for the rational design of specific
inhibitors.
Recent attention has been focused toward the identification of
inhibitors of HCV NS5A. HCV NS5A is a 447 amino acid phosphoprotein which
lacks a defined enzymatic function. It runs as 56kd and 58kd bands on gels
depending on phosphorylation state (Tanji, et al. J. Virol. 69:3980-3986
(1995)).
HCV NS5A resides in replication complex and may be responsible for the switch
from replication of RNA to production of infectious virus (Huang, Y, et al.,
Virology
364:1-9 (2007)).
Multicyclic HCV NS5A inhibitors have been reported. See U.S. Patent
Publication Nos. US20080311075, US20080044379, US20080050336, US20080044380,
US20090202483 and US2009020478. HCV NS5A inhibitors having fused tricyclic
moieties are disclosed in International Patent Publication Nos. WO 10/065681,
WO
10/065668, and WO 10/065674.
Other HCV NS5A inhibitors and their use for reducing viral load in
HCV infected humans have been described in U.S. Patent Publication No.
US20060276511.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides Compounds of Formula

CA 02811662 2013-03-19
WO 2012/041014
PCT/CN2011/001638
3
A / X
R15
jcw X'¨Y'
N
H '
v A
__________________________________________ i.
R1 -
(I)
or a pharmaceutically acceptable salt thereof, wherein:
A and A' are each independently a 5 or 6-membered monocyclic
heterocycloalkyl, wherein said 5 or 6-membered monocyclic heterocycloalkyl
group
can be optionally fused to an aryl group; and wherein said 5 or 6-membered
monocyclic heterocycloalkyl group can be optionally and independently
substituted
on one or more ring carbon atoms with R13, such that any two R13 groups on the
same
ring, together with the carbon atoms to which they are attached, can join to
form a
fused, bridged or spirocyclic 3 to 6-membered cycloalkyl group or a fused,
bridged or
spirocyclic 4 to 6-membered heterocycloalkyl group, wherein said 5 or 6-
membered
monocyclic heterocycloalkyl contains from 1 to 2 ring heteroatoms, each
independently selected from N(R4), S, 0 and Si(R16)2;
G is selected from ¨C(R3)2-0-, ¨C(R3)2-N(R5)-, -C(0)-0-, -C(0)-
N(R5)-, -C(0)¨C(R3)2-, -C(R3)2-C(0)-, -C(=NR5)-N(R5)-, ¨C(R3)2-S02-, -S02-
C(R3)2-,
-SO2N(R5)-, ¨C(R3)2¨C(R3)2-, ¨C(R14)=c(¨K14-
) and _c(R.14)=N_;
U is selected from N and C(R2);
V and V' are each independently selected from N and C(R15);
W and W' are each independently selected from N and C(R1);
X and X' are each independently selected from N and C(R10);
Y and Y' are each independently selected from N and C(R10);
R1 is selected from H, C1-C6 alkyl, 3 to 6-membered cycloalkyl, halo, -
OH, -0-(C1-C6 alkyl), C1-C6 haloalkyl and ¨0-(C1-C6 haloalkyl);
each occurrence of R2 is independently selected from H, C1-C6 alkyl, 3
to 6 membered cycloalkyl, -0-(C1-C6 alkyl), Ci-C6 haloalkyl ¨0-(C1-C6
haloalkyl);
halo, -OH, aryl, and heteroaryl;
each occurrence of R3 is independently selected from H, C1-C6 alkyl,
Ci-C6 haloalkyl, -(C1-C6 alkylene)-0-(Ci-C6 alkyl), -(C1-C6 alkylene)-0-(3 to
6
membered cycloalkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered

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4
heterocycloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl, 9 or 10-
membered
bicyclic heteroaryl and benzyl, wherein said aryl group, said 5 or 6-membered
monocyclic heteroaryl group, said 9 or 10-membered bicyclic heteroaryl group
or the
phenyl moiety of said benzyl group can be optionally substituted with up to 3
groups,
which can be the same or different, and are selected from C1-C6 alkyl, Ci-C6
haloalkyl,
-0-(C1-C6 alkyl), -0(C1-C6 haloalkyl), halo, ¨(C1-C6 alkylene)-0-(Ci-C6 alkyl)
and ¨
CN and wherein two R3 groups attached to the same carbon atom, together with
the
common carbon atom to which they are attached, can join to form a carbonyl
group, a
3 to 6-membered spirocyclic cycloalkyl group or a 3 to 6-membered spirocyclic
heterocycloalkyl group;
each occurrence of R4 is independently selected from -[C(R7)21qN(R6)2,
-C(0)R1 1, -C(0)1C(117)2LN(R6)2, -C(0)-[C(R7)2]q-R1 1, -C(0)4C(R7)2]qN(R6)C(0)-

R11, -C(0)[C(R7)2]1N(R6)S02-R11, -C(0)1C(R7)2]qN(R6)C(0)0-R11, -C(0)-
[C(R7)2]qC(0)0-R11 and -alkylene-N(R6)-[C(R7)2L-N(R6)-C(0)0-R11;
each occurrence of R5 is independently selected from H, Ci-C6 alkyl, -
(Ci-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-membered
heterocycloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl and benzyl,
wherein
said aryl group, said 5 or 6-membered monocyclic heteroaryl group or the
phenyl
moiety of said benzyl group can be optionally substituted with up to 3 groups,
which
can be the same or different, and are selected from C1-C6 alkyl, C1-C6
haloalkyl, -0-
(C1-C6 alkyl), -0-(C1-C6 haloalkyl), halo, ¨(C1-C6 alkylene)-0-(Ci-C6 alkyl)
and ¨
CN;
each occurrence of R6 is independently selected from H, C1-C6 alkyl, 3
to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl and 5 or 6-
membered monocyclic heteroaryl, wherein said 3 to 6-membered cycloalkyl group,

said 4 to 6-membered heterocycloalkyl group, said aryl group and said 5 or 6-
membered monocyclic heteroaryl group can be optionally and independently
substituted with up to two R8 groups, and wherein two R6 groups that are
attached to
the same nitrogen atom, together with the common nitrogen atom to which they
are
attached, can join to form a 4 to 6-membered heterocycloalkyl group;
each occurrence of R7 is independently selected from H, C1-C6 alkyl,
C1-C6 haloalkyl, -alkylene-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, 4 to 6-

membered heterocycloalkyl, aryl and 5 or 6-membered monocyclic heteroaryl,
wherein said 3 to 6-membered cycloalkyl group, said 4 to 6-membered

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heterocycloalkyl group, said aryl group and said 5 or 6-membered monocyclic
heteroaryl group can be optionally substituted with up to three R8 groups;
each occurrence of R8 is independently selected from H, C1-C6 alkyl,
halo, -Ci-C6 haloalkyl, Ci-C6 hydroxyallcyl, -OH, -C(0)NH-(Ci-C6 alkyl), -
C(0)N(C1-
C6 alky1)2, -0-(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alky1)2 and -
NHC(0)-
(C 1-C6 alkyl);
each occurrence of R9 is independently selected from H, C1-C6 alkyl,
C1-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
aryl
and 5 or 6-membered monocyclic heteroaryl;
each occurrence of R1 is independently selected from H, C1-C6 alkyl,
C1-C6 haloalkyl, halo, -OH, -0-(C i-C6 alkyl) and ¨CN;
each occurrence of R11 is independently selected from H, Ci-C6 allcyl,
C1-C6 haloalkyl, C1-C6 hydroxyalkyl, 3 to 6-membered cycloalkyl and 4 to 6-
membered heterocycloalkyl;
each occurrence of R12 is independently selected from C1-C6 alkyl, CI-
C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
aryl
and 5 or 6-membered monocyclic heteroaryl;
each occurrence of R13 is independently selected from H, halo, C1-C6
alkyl, C1-C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered
heterocycloalkyl, -CN, -0R9, -N(R9)2, -C(0)R12, -C(0)0R9, -C(0)N(R9)2, -
NHC(0)R12, -NHC(0)NHR9, -NHC(0)0R9, -0C(0)R12, -SR9 and ¨S(0)2R12,
wherein two R12 groups together with the carbon atom(s) to which they are
attached,
can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-
membered
heterocycloalkyl group;
each occurrence of R14 is independently selected from H, halo, C1-C6
alkyl, -(Ci-C6 allcylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, Ci-C6
haloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl and benzyl, wherein
said aryl
group, said 5 or 6-membered monocyclic heteroaryl group or the phenyl moiety
of
said benzyl group can be optionally substituted with up to 3 groups, which can
be the
same or different, and are selected from halo, -CN, Ci-C6 alkyl, C1-C6
haloalkyl, -0-
(C1-C6 alkyl), ¨(C1-C6 alkylene)-0-(Ci-C6 alkyl) and -0-(C1-C6 haloalkyl);
each occurrence of R15 is independently selected from H, C1-C6 alkyl,
3 to 6-membered cycloalkyl, halo, -OH, -0-(C1-C6 alkyl), C1-C6 haloalkyl and
¨0-
(C1-C6 haloalkyl);

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6
each occurrence of R16 is independently selected from H, halo, C1-C6
alkyl and 3 to 6-membered cycloalkyl, wherein two R16 groups that are attached
to a
common silicon atom can join to form a -(CH2)4- or a -(CH2)5- group; and
each occurrence of q is independently an integer ranging from 0 to 4,
provided that the compound of formula (I) is other than:
al, 0 PI3
it 0 /
CH3 CH3L -I CH3
---01 CH3
/ /-NH CH30`r.
0
NH 0 ON-* .1,
ON NH
0 Fi\r0
rsk e , v
/7-NH CH3 ' r-
0,..pi
'/7"-NH N /
N 0 / 11
--- I \ 111 1
/ H \ N \ N
I \ iii
N
N Nair \ '/ 1µ.r.' )\---0
\---0 N
CH0-13
I 3
0 CH3
---CµCH3
MN CH3 CH3
/
0
CN404CH3'\.0
/ CH3 CH
r13 0ro
HN....../\
CH3 C--)--1 I
N F N HN gi \ H
--- 0 T3 N..7,-ON
0
41
CcINH
IN
1.1 N\ 1, NYN
\ /
---0 N OID
CH3 di,
9 9
/NI
N
(--._õ, 1 ,C>-.KN \ rh
H \ # / N
L-4 õ 40 \ it , N HN.--/0
Ct)11...0
N\ HN-11. 411111114 N il
FIN--".
1.-D ,
C. Ci--- CH3 0
CH3 NH 0 0 1 3
0 CH3 . 0),N
0
p CH37XNH
HN y-CF1'
CH3
CH3 0,LO --'c.. CH
0 0 s
I
CH, , CH3 3
N
N 1 \
0-.H 5 '
Q.61-11 all N H
N \ = \ I
N N 6: 1 0 c25-0 0./N----
/
0.13 CH3-CE13 FIN-i,
CH3
CH3 o 3-CH3
FIN ' ,C/
CH3 NH
0 0 CH3 CH3
p
CH3 00 \
CH3 cH3
, ,
F F
N N
CNI \ 41 \ = _________________ 0õ, \
\
1./1 \
N H N \ /N
N',, n
o
0
HN___,,, \__
0./ N
y0 \--0 H
N--./
0...j 7---CH3
HN) "'"(CH3
- / 0 CH3 C)0 C-(13-Cli, HN2 ""( ,,,,. CH3
CH
CH3 0 0 CiF13 C(L 3
\
CH3 63
s

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7
N N
\ NI
H
n
N\--o= \
o N
o 9
or
The Compounds of Formula (I) (also referred to herein as the
"Tetracyclic Indole Derivatives") and pharmaceutically acceptable salts
thereof can be
useful, for example, for inhibiting HCV viral replication or replicon
activity, and for
treating or preventing HCV infection in a patient. Without being bound by any
specific theory, it is believed that the Tetracyclic Indole Derivatives
inhibit HCV viral
replication by inhibiting HCV NS5A.
Accordingly, the present invention provides methods for treating or
preventing HCV infection in a patient, comprising administering to the patient
an
effective amount of at least one Tetracyclic Indole Derivative.
The details of the invention are set forth in the accompanying detailed
description below.
Although any methods and materials similar to those described herein
can be used in the practice or testing of the present invention, illustrative
methods and
materials are now described. Other embodiments, aspects and features of the
present
invention are either further described in or will be apparent from the ensuing
description, examples and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel Tetracyclic Indole Derivatives,
compositions comprising at least one Tetracyclic Indole Derivative, and
methods of
using the Tetracyclic Indole Derivatives for treating or preventing HCV
infection in a
patient.
Definitions and Abbreviations
The terms used herein have their ordinary meaning and the meaning of
such terms is independent at each occurrence thereof. That notwithstanding and

except where stated otherwise, the following definitions apply throughout the
specification and claims. Chemical names, common names, and chemical
structures

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8
may be used interchangeably to describe the same structure. If a chemical
compound
is referred to using both a chemical structure and a chemical name and an
ambiguity
exists between the structure and the name, the structure predominates. These
definitions apply regardless of whether a term is used by itself or in
combination with
other terms, unless otherwise indicated. Hence, the definition of "alkyl"
applies to
"alkyl" as well as the "alkyl" portions of "hydroxyalkyl," "haloalkyl," "-O-
alkyl," etc...
As used herein, and throughout this disclosure, the following terms,
unless otherwise indicated, shall be understood to have the following
meanings:
A "patient" is a human or non-human mammal. In one embodiment, a
patient is a human. In another embodiment, a patient is a chimpanzee.
The term "effective amount" as used herein, refers to an amount of
Tetracyclic Indole Derivative and/or an additional therapeutic agent, or a
composition
thereof that is effective in producing the desired therapeutic, ameliorative,
inhibitory
or preventative effect when administered to a patient suffering from a viral
infection
or virus-related disorder. In the combination therapies of the present
invention, an
effective amount can refer to each individual agent or to the combination as a
whole,
wherein the amounts of all agents administered are together effective, but
wherein the
component agent of the combination may not be present individually in an
effective
amount.
The term "preventing," as used herein with respect to an HCV viral
infection or HCV-virus related disorder, refers to reducing the likelihood of
HCV
infection.
The term "alkyl," as used herein, refers to an aliphatic hydrocarbon
group having one of its hydrogen atoms replaced with a bond. An alkyl group
may be
straight or branched and contain from about 1 to about 20 carbon atoms. In one

embodiment, an alkyl group contains from about 1 to about 12 carbon atoms. In
different embodiments, an alkyl group contains from 1 to 6 carbon atoms (Ci-C6
alkyl)
or from about 1 to about 4 carbon atoms (C1-C4 alkyl). Non-limiting examples
of
alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,
isobutyl,
tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. An
alkyl
group may be unsubstituted or substituted by one or more substituents which
may be
the same or different, each substituent being independently selected from the
group
consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -0-
alkyl,
-0-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(allcyl), -N(alkyl)2, -
NH(cycloalkyl),

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9
-0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)0H and ¨C(0)0-alkyl. In
one embodiment, an alkyl group is linear. In another embodiment, an alkyl
group is
branched. Unless otherwise indicated, an alkyl group is unsubstituted.
The term "alkenyl," as used herein, refers to an aliphatic hydrocarbon
group containing at least one carbon-carbon double bond and having one of its
hydrogen atoms replaced with a bond. An alkenyl group may be straight or
branched
and contain from about 2 to about 15 carbon atoms. In one embodiment, an
alkenyl
group contains from about 2 to about 12 carbon atoms. In another embodiment,
an
alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting
examples
of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-
pentenyl, octenyl and decenyl. An alkenyl group may be unsubstituted or
substituted
by one or more substituents which may be the same or different, each
substituent
being independently selected from the group consisting of halo, alkenyl,
alkynyl, aryl,
cycloallcyl, cyano, hydroxy, -0-alkyl, -0-aryl, -alkylene-O-alkyl, alkylthio, -
NH2, -
NH(alkyl), -N(alkyl)2, -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-
cycloalkyl, -C(0)0H and ¨C(0)0-alkyl. The term "C2-C6 alkenyl" refers to an
alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an
alkenyl group is unsubstituted.
The term "alkynyl," as used herein, refers to an aliphatic hydrocarbon
group containing at least one carbon-carbon triple bond and having one of its
hydrogen atoms replaced with a bond. An alkynyl group may be straight or
branched
and contain from about 2 to about 15 carbon atoms. In one embodiment, an
alkynyl
group contains from about 2 to about 12 carbon atoms. In another embodiment,
an
alkynyl group contains from about 2 to about 6 carbon atoms. Non-limiting
examples
of alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An

alkynyl group may be unsubstituted or substituted by one or more substituents
which
may be the same or different, each substituent being independently selected
from the
group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -
0-alkyl,
-0-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl)2, -
NH(cycloalkyl),
-0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)0H and ¨C(0)0-alkyl. The

term "C2-C6 alkynyl" refers to an alkynyl group having from 2 to 6 carbon
atoms.
Unless otherwise indicated, an alkynyl group is unsubstituted.
The term "alkylene," as used herein, refers to an alkyl group, as
defined above, wherein one of the alkyl group's hydrogen atoms has been
replaced

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with a bond. Non-limiting examples of alkylene groups include ¨CH2-, -CH2CH2-,
-
CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH(CH3)- and -
CH2CH(CH3)CH2-. In one embodiment, an alkylene group has from 1 to about 6
carbon atoms. In another embodiment, an alkylene group is branched. In another

embodiment, an alkylene group is linear. In one embodiment, an alkylene group
is -
CH2-. The term "Ci-C6 alkylene" refers to an alkylene group having from 1 to 6

carbon atoms.
The term "aryl," as used herein, refers to an aromatic monocyclic or
multicyclic ring system comprising from about 6 to about 14 carbon atoms. In
one
embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An
aryl
group can be optionally substituted with one or more "ring system
substituents" which
may be the same or different, and are as defined herein below. In one
embodiment,
an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group.
Non-
limiting examples of aryl groups include phenyl and naphthyl. In one
embodiment,
an aryl group is phenyl. Unless otherwise indicated, an aryl group is
unsubstituted.
The term "arylene," as used herein, refers to a bivalent group derived
from an aryl group, as defined above, by removal of a hydrogen atom from a
ring
carbon of an aryl group. An arylene group can be derived from a monocyclic or
multicyclic ring system comprising from about 6 to about 14 carbon atoms. In
one
embodiment, an arylene group contains from about 6 to about 10 carbon atoms.
In
another embodiment, an arylene group is a naphthylene group. In another
embodiment, an arylene group is a phenylene group. An arylene group can be
optionally substituted with one or more "ring system substituents" which may
be the
same or different, and are as defined herein below. An arylene group is
divalent and
either available bond on an arylene group can connect to either group flanking
the
arylene group. For example, the group "A-arylene-B," wherein the arylene group
is:
OVVV.
9
is understood to represent both:

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11
A
and SSA
In one embodiment, an arylene group can be optionally fused to a
cycloalkyl or cycloalkanoyl group. Non-limiting examples of arylene groups
include
phenylene and naphthalene. In one embodiment, an arylene group is
unsubstituted.
In another embodiment, an arylene group is:
'III- -PPP
'"or
Unless otherwise indicated, an arylene group is unsubstituted.
The term "cycloalkyl," as used herein, refers to a non-aromatic mono-
or multicyclic ring system comprising from about 3 to about 10 ring carbon
atoms. In
one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon
atoms.
In another embodiment, a cycloalkyl contains from about 3 to about 7 ring
atoms. In
another embodiment, a cycloalkyl contains from about 5 to about 6 ring atoms.
The
term "cycloalkyl" also encompasses a cycloalkyl group, as defined above, which
is
fused to an aryl (e.g., benzene) or heteroaryl ring. Non-limiting examples of
monocyclic cycloallcyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl,
cycloheptyl and cyclooctyl. Non-limiting examples of multicyclic cycloalkyls
include
1-decalinyl, norbornyl and adamantyl. A cycloalkyl group can be optionally
substituted with one or more "ring system substituents" which may be the same
or
different, and are as defined herein below. In one embodiment, a cycloalkyl
group is
unsubstituted. The term "3 to 6-membered cycloalkyl" refers to a cycloalkyl
group
having from 3 to 6 ring carbon atoms. Unless otherwise indicated, a cycloalkyl
group
is unsubstituted. A ring carbon atom of a cycloalkyl group may be
functionalized as a
carbonyl group. An illustrative example of such a cycloalkyl group (also
referred to
herein as a "cycloalkanoyl" group) includes, but is not limited to,
cyclobutanoyl:
0

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12
The term "cycloalkenyl," as used herein, refers to a non-aromatic
mono- or multicyclic ring system comprising from about 4 to about 10 ring
carbon
atoms and containing at least one endocyclic double bond. In one embodiment, a

cycloalkenyl contains from about 4 to about 7 ring carbon atoms. In another
embodiment, a cycloalkenyl contains 5 or 6 ring atoms. Non-limiting examples
of
monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-
dienyl,
and the like. A cycloalkenyl group can be optionally substituted with one or
more
"ring system substituents" which may be the same or different, and are as
defined
herein below. A ring carbon atom of a cycloalkyl group may be functionalized
as a
carbonyl group. In one embodiment, a cycloalkenyl group is cyclopentenyl. In
another embodiment, a cycloalkenyl group is cyclohexenyl. The term "4 to 6-
membered cycloalkenyl" refers to a cycloalkenyl group having from 4 to 6 ring
carbon atoms. Unless otherwise indicated, a cycloalkenyl group is
unsubstituted.
The term "halo," as used herein, means ¨F, -Cl, -Br or -I.
The term "haloalkyl," as used herein, refers to an alkyl group as
defined above, wherein one or more of the alkyl group's hydrogen atoms has
been
replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6
carbon atoms. In another embodiment, a haloalkyl group is substituted with
from 1 to
3 F atoms. Non-limiting examples of haloalkyl groups include ¨CH2F, -CTF2, -
CF3, -
CH2C1 and -CC13. The term "C1-C6 haloalkyl" refers to a haloalkyl group having

from 1 to 6 carbon atoms.
The term "hydroxyalkyl," as used herein, refers to an alkyl group as
defined above, wherein one or more of the alkyl group's hydrogen atoms has
been
replaced with an ¨OH group. In one embodiment, a hydroxyalkyl group has from 1
to
6 carbon atoms. Non-limiting examples of hydroxyalkyl groups include ¨CH2OH, -

CH2CH2OH, -CH2CH2CH2OH and -CH2CH(OH)CH3. The term "C1-C6
hydroxyalkyl" refers to a hydroxyalkyl group having from 1 to 6 carbon atoms.
The term "heteroaryl," as used herein, refers to an aromatic monocyclic
or multicyclic ring system comprising about 5 to about 14 ring atoms, wherein
from 1
to 4 of the ring atoms is independently 0, N or S and the remaining ring atoms
are
carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In

another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring
atoms. In
another embodiment, a heteroaryl group is bicyclic and had 9 or 10 ring atoms.
A
heteroaryl group can be optionally substituted by one or more "ring system

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13
substituents" which may be the same or different, and are as defined herein
below. A
heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a
heteroaryl can be optionally oxidized to the corresponding N-oxide. The term
"heteroaryl" also encompasses a heteroaryl group, as defined above, which is
fused to
a benzene ring. Non-limiting examples of heteroaryls include pyridyl,
pyrazinyl,
furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones),
isoxazolyl,
isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl,
pyrrolyl, triazolyl,
1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,
oxindolyl,
imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl,
azaindolyl,
benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, benzimidazolyl,
thienopyridyl,
quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,
benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and all
isomeric forms
thereof. The term "heteroaryl" also refers to partially saturated heteroaryl
moieties
such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
In one
embodiment, a heteroaryl group is a 5 or 6-membered monocyclic heteroaryl. In
another embodiment, a heteroaryl group is a 6-membered monocyclic heteroaryl.
In
another embodiment, a heteroaryl group is a 5-membered monocyclic heteroaryl.
In
one embodiment, a heteroaryl group is a 9 or 10-membered monocyclic
heteroaryl. In
another embodiment, a heteroaryl group is a 9-membered monocyclic heteroaryl.
Unless otherwise indicated, a heteroaryl group is unsubstituted.
The term "heteroarylene," as used herein, refers to a bivalent group
derived from an heteroaryl group, as defined above, by removal of a hydrogen
atom '
from a ring carbon or ring heteroatom of a heteroaryl group. A heteroarylene
group
can be derived from a monocyclic or multicyclic ring system comprising about 5
to
about 14 ring atoms, wherein from 1 to 4 of the ring atoms are each
independently 0,
N or S and the remaining ring atoms are carbon atoms. A heteroarylene group
can be
optionally substituted by one or more "ring system substituents" which may be
the
same or different, and are as defined herein below. A heteroarylene group is
joined
via a ring carbon atom or by a nitrogen atom with an open valence, and any
nitrogen
atom of a heteroarylene can be optionally oxidized to the corresponding N-
oxide. The
term "heteroarylene" also encompasses a heteroarylene group, as defined above,

which is fused to a benzene ring. Non-limiting examples of heteroarylenes
include
pyridylene, pyrazinylene, furanylene, thienylene, pyrimidinylene, pyridonylene

(including those derived from N-substituted pyridonyls), isoxazolylene,

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isothiazolylene, oxazolylene, oxadiazolylene, thiazolylene, pyrazolylene,
thiophenylene, furazanylene, pyrrolylene, triazolylene, 1,2,4-thiadiazolylene,

pyrazinylene, pyridazinylene, quinoxalinylene, phthalazinylene, oxindolylene,
imidazo[1,2-a]pyridinylene, imidazo[2,1-b]thiazolylene, benzofurazanylene,
indolylene, azaindolylene, benzimidazolylene, benzothienylene, quinolinylene,
imidazolylene, benzimidazolylene, thienopyridylene, quinazolinylene,
thienopyrimidylene, pyrrolopyridylene, imidazopyridylene, isoquinolinylene,
benzoazaindolylene, 1,2,4-triazinylene, benzothiazolylene and the like, and
all
isomeric forms thereof. The term "heteroarylene" also refers to partially
saturated
heteroarylene moieties such as, for example, tetrahydroisoquinolylene,
tetrahydroquinolylene, and the like. A heteroarylene group is divalent and
either
available bond on a heteroarylene ring can connect to either group flanking
the
heteroarylene group. For example, the group "A-heteroarylene-B," wherein the
heteroarylene group is:
izz.,-- 0 _sis,
is understood to represent both:
N 1 N
C . B and
A A--"0---13
0 0 .
In one embodiment, a heteroarylene group is a monocyclic
heteroarylene group or a bicyclic heteroarylene group. In another embodiment,
a
heteroarylene group is a monocyclic heteroarylene group. In another
embodiment, a
heteroarylene group is a bicyclic heteroarylene group. In still another
embodiment, a
heteroarylene group has from about 5 to about 10 ring atoms. In another
embodiment,
a heteroarylene group is monocyclic and has 5 or 6 ring atoms. In another
embodiment, a heteroarylene group is bicyclic and has 9 or 10 ring atoms. In
another
embodiment, a heteroarylene group is a 5-membered monocyclic heteroarylene. In

another embodiment, a heteroarylene group is a 6-membered monocyclic
heteroarylene. In another embodiment, a bicyclic heteroarylene group comprises
a 5
or 6-membered monocyclic heteroarylene group fused to a benzene ring. Unless
otherwise indicated, a heteroarylene group is unsubstituted.

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The term "heterocycloalkyl," as used herein, refers to a non-aromatic
saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring
atoms,
wherein from 1 to 4 of the ring atoms are independently 0, S, N or Si, and the

remainder of the ring atoms are carbon atoms. A heterocycloalkyl group can be
joined via a ring carbon, ring silicon atom or ring nitrogen atom. In one
embodiment,
a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring
atoms.
In another embodiment, a heterocycloalkyl group is monocyclic has from about 4
to
about 7 ring atoms. In another embodiment, a heterocycloalkyl group is
bicyclic and
has from about 7 to about 11 ring atoms. In still another embodiment, a
heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one
embodiment,
a heterocycloalkyl group is monocyclic. In another embodiment, a
heterocycloalkyl
group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in
the
ring system. Any ¨NH group in a heterocycloalkyl ring may exist protected such
as,
for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such
protected
heterocycloalkyl groups are considered part of this invention. The term
"heterocycloalkyl" also encompasses a heterocycloalkyl group, as defined
above,
which is fused to an aryl (e.g., benzene) or heteroaryl ring. A
heterocycloalkyl group
can be optionally substituted by one or more "ring system substituents" which
may be
the same or different, and are as defined herein below. The nitrogen or sulfur
atom of
the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide,
S-oxide
or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings
include
oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-
lactam,
delta-lactone, silacyclopentane, silapyrrolidine and the like, and all isomers
thereof.
Non-limiting illustrative examples of a silyl-containing heterocycloalkyl
group
include:

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I I I
I
(1 .N,=\,
o_N 1
H
Si 3C\SiSi Si
\ F \
H3C
'
CH3 \-...__CH3 H3C/ \CH3 F
6-1
0-1
Si Si-0 0 0
\ \ Si
H3C H3C
F \
CH3 CH3
H3C/ "CH3 F
A ring carbon atom of a heterocycloalkyl group may be functionalized
as a carbonyl group. An illustrative example of such a heterocycloalkyl group
is:
H
Al
c --1
0 .
In one embodiment, a heterocycloalkyl group is a 5-membered
monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group
is a
6-membered monocyclic heterocycloalkyl. The term "3 to 6-membered monocyclic
cycloalkyl" refers to a monocyclic heterocycloalkyl group having from 3 to 6
ring
atoms. The term "4 to 6-membered monocyclic cycloalkyl" refers to a monocyclic

heterocycloalkyl group having from 4 to 6 ring atoms. The term "7 to 11-
membered
bicyclic heterocycloalkyl" refers to a bicyclic heterocycloalkyl group having
from 7
to 11 ring atoms. Unless otherwise indicated, an heterocycloalkyl group is
unsubstituted.
The term "heterocycloalkenyl," as used herein, refers to a
heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group
contains from 4 to 10 ring atoms, and at least one endocyclic carbon-carbon or

carbon-nitrogen double bond. A heterocycloalkenyl group can be joined via a
ring
carbon or ring nitrogen atom. In one embodiment, a heterocycloalkenyl group
has
from 4 to 6 ring atoms. In another embodiment, a heterocycloalkenyl group is
monocyclic and has 5 or 6 ring atoms. In another embodiment, a
heterocycloalkenyl
group is bicyclic. A heterocycloalkenyl group can optionally substituted by
one or
more ring system substituents, wherein "ring system substituent" is as defined
above.

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The nitrogen or sulfur atom of the heterocycloalkenyl can be optionally
oxidized to
the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of
heterocycloalkenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-
dihydropyridinyl,
1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-
tetrahydropyrimidinyl, 2-
pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl,
dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,

dihydrofuranyl, fluoro-substituted dihydrofuranyl, 7-
oxabicyclo[2.2.1]heptenyl,
dihydrothiophenyl, dihydrothiopyranyl, and the like and the like. A ring
carbon atom
of a heterocycloalkenyl group may be functionalized as a carbonyl group. In
one
embodiment, a heterocycloalkenyl group is a 5-membered heterocycloalkenyl. In
another embodiment, a heterocycloalkenyl group is a 6-membered
heterocycloalkenyl.
The term "4 to 6-membered heterocycloalkenyl" refers to a heterocycloalkenyl
group
having from 4 to 6 ring atoms. Unless otherwise indicated, a
heterocycloalkenyl
group is unsubstituted.
The term "ring system substituent," as used herein, refers to a
substituent group attached to an aromatic or non-aromatic ring system which,
for
example, replaces an available hydrogen on the ring system. Ring system
substituents
may be the same or different, each being independently selected from the group

consisting of alkyl, alkenyl, allcynyl, aryl, heteroaryl, -allcylene-aryl, -
arylene-alkyl, -
alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, -OH,
hydroxyalkyl, haloalkyl, -0-alkyl, -0-haloalkyl, -allcylene-O-alkyl, -0-aryl, -
0-
alkylene-aryl, acyl, -C(0)-aryl, halo, -NO2, -CN, -SF5, -C(0)0H, -C(0)0-alkyl,
-
C(0)0-aryl, -C(0)0-alkylene-aryl, -5(0)-alkyl, -S(0)2-alkyl, -5(0)-aryl, -
S(0)2-aryl,
-S(0)-heteroaryl, -S(0)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-
alkylene-aryl,
-S-alkylene-heteroaryl, -S(0)2-alkylene-aryl, -S(0)2-alkylene-heteroaryl, -
Si(alkyl)2, -
Si(aryl)2, -Si(heteroary1)2, -Si(alkyl)(ary1), -Si(alkyl)(cycloalkyl), -
Si(alkyl)(heteroary1), cycloalkyl, heterocycloalkyl, -0-C(0)-alkyl, -0-C(0)-
aryl, -0-
C(0)-cycloalkyl, -C(=N-CN)-NH2, -C(=N1-I)-NH2, -C(=NH)-NH(alkyl), -N(Y1)(Y2), -

alkylene-N(Yi)(Y2), -C(0)N(Y1)(Y2) and -S(0)2N(Y1)(Y2), wherein Y1 and Y2 can
be
the same or different and are independently selected from the group consisting
of
hydrogen, alkyl, aryl, cycloalkyl, and -allcylene-aryl. "Ring system
substituent" may
also mean a single moiety which simultaneously replaces two available
hydrogens on
two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of

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18
such moiety are methylenedioxy, ethylenedioxy, -C(CH3)2- and the like which
form
moieties such as, for example:
or"
* , ()0 and
The term "silylalkyl," as used herein, refers to an alkyl group as
defined above, wherein one or more of the alkyl group's hydrogen atoms has
been
replaced with a ¨Si(Rx)3 group, wherein each occurrence of It' is
independently C1-C6
alkyl, phenyl or a 3 to 6-membered cycloalkyl group. In one embodiment, a
silylalkyl
group has from 1 to 6 carbon atoms. In another embodiment, a silyl alkyl group

contains a ¨Si(CH3)3 moiety. Non-limiting examples of silylalkyl groups
include
¨CH2-Si(CH3)3 and ¨CH2CH2-Si(CH3)3.
The term "substituted" means that one or more hydrogens on the
designated atom is replaced with a selection from the indicated group,
provided that
the designated atom's normal valency under the existing circumstances is not
exceeded, and that the substitution results in a stable compound. Combinations
of
substituents and/or variables are permissible only if such combinations result
in stable
compounds. By "stable compound' or "stable structure" is meant a compound that
is
sufficiently robust to survive isolation to a useful degree of purity from a
reaction
mixture, and formulation into an efficacious therapeutic agent.
The term "in substantially purified form," as used herein, refers to the
physical state of a compound after the compound is isolated from a synthetic
process
(e.g., from a reaction mixture), a natural source, or a combination thereof.
The term
"in substantially purified form," also refers to the physical state of a
compound after
the compound is obtained from a purification process or processes described
herein or
well-known to the skilled artisan (e.g., chromatography, recrystallization and
the like),
in sufficient purity to be characterizable by standard analytical techniques
described
herein or well-known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with
unsatisfied valences in the text, schemes, examples and tables herein is
assumed to
have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this
means that the group is in modified form to preclude undesired side reactions
at the

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19
protected site when the compound is subjected to a reaction. Suitable
protecting
groups will be recognized by those with ordinary skill in the art as well as
by
reference to standard textbooks such as, for example, T. W. Greene et al,
Protective
Groups in Organic Synthesis (1991), Wiley, New York.
When any substituent or variable (e.g., alkyl, R6, Ra, etc.) occurs more
than one time in any constituent or in Formula (I), its definition on each
occurrence is
independent of its definition at every other occurrence, unless otherwise
indicated.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any
product which results, directly or indirectly, from combination of the
specified
ingredients in the specified amounts.
Prodrugs and solvates of the compounds of the invention are also
contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V.
Stella,
Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series,
and
in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed.,
American
Pharmaceutical Association and Pergamon Press. The term "prodrug" means a
compound (e.g., a drug precursor) that is transformed in vivo to provide a
Tetracyclic
Indole Derivative or a pharmaceutically acceptable salt or solvate of the
compound.
The transformation may occur by various mechanisms (e.g., by metabolic or
chemical
processes), such as, for example, through hydrolysis in blood.
For example, if a Tetracyclic Indole Derivative or a pharmaceutically
acceptable salt, hydrate or solvate of the compound contains a carboxylic acid

functional group, a prodrug can comprise an ester formed by the replacement of
the
hydrogen atom of the acid group with a group such as, for example,
(CI¨C8)alkyl,
(C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon
atoms,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-
(alkoxycarbonyloxy)ethyl having from 4 to 6 carbon atoms, 1-methy1-1-
(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-
(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-
(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-
crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(Ci-C2)alkylamino(C2-C3)alkyl

(such as f3-dimethylaminoethyl), carbamoy1-(Ci-C2)alkyl, N,N-di (CI-

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C2)alkylcarbamoy1-(Ci-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-
C3)alkyl, and the like.
Similarly, if a Tetracyclic Indole Derivative contains an alcohol
functional group, a prodrug can be formed by the replacement of the hydrogen
atom
of the alcohol group with a group such as, for example, (Ci-
C6)alkanoyloxymethyl, 1-
((C 1-C6)alkanoy loxy)ethyl, 1-methyl-1 -((Ci-C6)alkanoyloxy)ethyl, (C I -
C6)alkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-

C6)alkanoyl, a-amino(Ci-C4)alkyl, a-amino(Ci-C4)alkylene-aryl, arylacyl and a-
aminoacyl, or a-aminoacyl-a-aminoacyl, where each a-aminoacyl group is
independently selected from the naturally occurring L-amino acids, -P(0)(OH)2,
-
P(0)(0(Ci-C6)alky1)2 or glycosyl (the radical resulting from the removal of a
hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a Tetracyclic Indole Derivative incorporates an amine functional
group, a prodrug can be formed by the replacement of a hydrogen atom in the
amine
group with a group such as, for example, R-carbonyl-, RO-carbonyl-, NRR'-
carbonyl-
wherein R and R' are each independently (Ci-Cio)alkyl, (C3-C7) cycloalkyl,
benzyl, a
natural a-aminoacyl, -C(OH)C(0)0Y1 wherein Y1 is H, (Ci-C6)alkyl or benzyl, -
C(0Y2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (Ci-C6)alkyl; carboxy (Ci-
C6)alkyl;
amino(Ci-C4)alkyl or mono-N- or di-N,N-(Ci-C6)alkylaminoallcyl; -C(Y4)Y5
wherein
Y4 is H or methyl and Y5 is mono-N- or di-N,N-(Ci-C6)alkylamino morpholino;
piperidin-1-y1 or pyrrolidin-l-yl, and the like.
Pharmaceutically acceptable esters of the present compounds include
the following groups: (1) carboxylic acid esters obtained by esterification of
the
hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the
carboxylic acid portion of the ester grouping is selected from straight or
branched
chain alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, sec-butyl or n-
butyl),
alkoxyalkyl (e.g., methoxymethyl), arallcyl (e.g., benzyl), aryloxyalkyl (for
example,
phenoxymethyl), aryl (e.g., phenyl optionally substituted with, for example,
halogen,
Ci_4alkyl, -0-(Ci_4alkyl) or amino); (2) sulfonate esters, such as alkyl- or
aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (e.g., L-
valyl or
L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate
esters. The
phosphate esters may be further esterified by, for example, a C1_20 alcohol or
reactive
derivative thereof, or by a 2,3-di (C6_24)acyl glycerol.

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One or more compounds of the invention may exist in unsolvated as
well as solvated forms with pharmaceutically acceptable solvents such as
water,
ethanol, and the like, and it is intended that the invention embrace both
solvated and
unsolvated forms. "Solvate" means a physical association of a compound of this

invention with one or more solvent molecules. This physical association
involves
varying degrees of ionic and covalent bonding, including hydrogen bonding. In
certain instances the solvate will be capable of isolation, for example when
one or
more solvent molecules are incorporated in the crystal lattice of the
crystalline solid.
"Solvate" encompasses both solution-phase and isolatable solvates. Non-
limiting
examples of solvates include ethanolates, methanolates, and the like. A
"hydrate" is a
solvate wherein the solvent molecule is water.
One or more compounds of the invention may optionally be converted
to a solvate. Preparation of solvates is generally known. Thus, for example,
M. Caira
eta!, J. Pharmaceutical Sci., 93(3), 601-611(2004) describe the preparation of
the
solvates of the antifungal fluconazole in ethyl acetate as well as from water.
Similar
preparations of solvates, hemisolvate, hydrates and the like are described by
E. C. van
Tonder eta!, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L.
Bingham
eta!, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves

dissolving the inventive compound in desired amounts of the desired solvent
(organic
or water or mixtures thereof) at a higher than room temperature, and cooling
the
solution at a rate sufficient to form crystals which are then isolated by
standard
methods. Analytical techniques such as, for example IR spectroscopy, show the
presence of the solvent (or water) in the crystals as a solvate (or hydrate).
The Tetracyclic Indole Derivatives can form salts which are also
within the scope of this invention. Reference to a Tetracyclic Indole
Derivative
herein is understood to include reference to salts thereof, unless otherwise
indicated.
The term "salt(s)", as employed herein, denotes acidic salts formed with
inorganic
and/or organic acids, as well as basic salts formed with inorganic and/or
organic bases.
In addition, when a Tetracyclic Indole Derivative contains both a basic
moiety, such
as, but not limited to a pyridine or imidazole, and an acidic moiety, such as,
but not
limited to a carboxylic acid, zwitterions ("inner salts") may be formed and
are
included within the term "salt(s)" as used herein. In one embodiment, the salt
is a
pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable)
salt. In
another embodiment, the salt is other than a pharmaceutically acceptable salt.
Salts of

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the Compounds of Formula (I) may be formed, for example, by reacting a
Tetracyclic
Indole Derivative with an amount of acid or base, such as an equivalent
amount, in a
medium such as one in which the salt precipitates or in an aqueous medium
followed
by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates,
benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,
camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides,
lactates,
maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates,
phosphates,
propionates, salicylates, succinates, sulfates, tartarates, thiocyanates,
toluenesulfonates (also known as tosylates) and the like. Additionally, acids
which are
generally considered suitable for the formation of pharmaceutically useful
salts from
basic pharmaceutical compounds are discussed, for example, by P. Stahl et al,
Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and
Use.
(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977)
66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217;
Anderson
eta!, The Practice of Medicinal Chemistry (1996), Academic Press, New York;
and in
The Orange Book (Food & Drug Administration, Washington, D.C. on their
website).
These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such
as sodium, lithium, and potassium salts, alkaline earth metal salts such as
calcium and
magnesium salts, salts with organic bases (for example, organic amines) such
as
dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as
arginine, lysine and the like. Basic nitrogen-containing groups may be
quarternized
with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl
chlorides,
bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl
sulfates),
long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and
iodides),
aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically
acceptable salts within the scope of the invention and all acid and base salts
are
considered equivalent to the free forms of the corresponding compounds for
purposes
of the invention.
Diastereomeric mixtures can be separated into their individual
diastereomers on the basis of their physical chemical differences by methods
well-
known to those skilled in the art, such as, for example, by chromatography
and/or

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fractional crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with an
appropriate
optically active compound (e.g., chiral auxiliary such as a chiral alcohol or
Mosher's
acid chloride), separating the diastereomers and converting (e.g.,
hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers.
Sterochemically
pure compounds may also be prepared by using chiral starting materials or by
employing salt resolution techniques. Also, some of the Tetracyclic Indole
Derivatives may be atropisomers (e.g., substituted biaryls) and are considered
as part
of this invention. Enantiomers can also be directly separated using chiral
chromatographic techniques.
It is also possible that the Tetracyclic Indole Derivatives may exist in
different tautomeric forms, and all such forms are embraced within the scope
of the
invention. For example, all keto-enol and imine-enamine forms of the compounds
are
included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and
the like) of the present compounds (including those of the salts, solvates,
hydrates,
esters and prodrugs of the compounds as well as the salts, solvates and esters
of the
prodrugs), such as those which may exist due to asymmetric carbons on various
substituents, including enantiomeric forms (which may exist even in the
absence of
asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms,
are
contemplated within the scope of this invention. If a Tetracyclic Indole
Derivative
incorporates a double bond or a fused ring, both the cis- and trans-forms, as
well as
mixtures, are embraced within the scope of the invention.
Individual stereoisomers of the compounds of the invention may, for
example, be substantially free of other isomers, or may be admixed, for
example, as
racemates or with all other, or other selected, stereoisomers. The chiral
centers of the
present invention can have the S or R configuration as defined by the IUPAC
1974
Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug"
and the
like, is intended to apply equally to the salt, solvate, ester and prodrug of
enantiomers,
stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs
of the
inventive compounds.
In the Compounds of Formula (I), the atoms may exhibit their natural
isotopic abundances, or one or more of the atoms may be artificially enriched
in a
particular isotope having the same atomic number, but an atomic mass or mass

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24
number different from the atomic mass or mass number predominantly found in
nature. The present invention is meant to include all suitable isotopic
variations of the
compounds of generic Formula I. For example, different isotopic forms of
hydrogen
(H) include protium (1H) and deuterium (2H). Protium is the predominant
hydrogen
isotope found in nature. Enriching for deuterium may afford certain
therapeutic
advantages, such as increasing in vivo half-life or reducing dosage
requirements, or
may provide a compound useful as a standard for characterization of biological

samples. Isotopically-enriched Compounds of Formula (I) can be prepared
without
undue experimentation by conventional techniques well known to those skilled
in the
art or by processes analogous to those described in the Schemes and Examples
herein
using appropriate isotopically-enriched reagents and/or intermediates. In one
embodiment, a Compound of Formula (I) has one or more of its hydrogen atoms
replaced with deuterium.
Polymorphic forms of the Tetracyclic Indole Derivatives, and of the
salts, solvates, hydrates, esters and prodrugs of the Tetracyclic Indole
Derivatives, are
intended to be included in the present invention.
The following abbreviations are used below and have the following
meanings: Ac is acyl; AcC1 is acetyl chloride; AcOH or HOAc is acetic acid;
Amphos
is (4-(N,N)-dimethylaminopheny1)-di-tertbutylphosphine; Aq is aqueous; BF3-
0Et2 is
boron trifluoride etherate; BOC or Boc is tert-butyloxycarbonyl; Boc20 is Boc
anhydride; Boc-Pro-OH is Boc protected proline; L-Boc-Val-OH is Boc protected
L-
valine; BOP is Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium
hexafluorophosphate; n-BuLi is n-butyllithium; CBZ or Cbz is carbobenzoxy; DCM

is dichloromethane; DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; Dess-
Martin
reagent is ,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxo1-3(1H)-one; DIPEA is
diisopropylethylamine; DME is dimethoxyethane; DMF is /V,N-dimethylformamide;
dppf is diphenylphosphinoferrocene; DMSO is dimethylsulfoxide; EtMgBr is
ethylmagnesium bromide; Et0Ac is ethyl acetate; Et20 is diethyl ether; Et3N or
NEt3
is triethylamine; HATU is 0-(7-azabenzotriazol-1-y1)-N,N,N',N'-
tetramethyluronium
hexafluorophosphate; HPLC is high performance liquid chromatography; HRMS is
high resolution mass spectrometry; KOAc is potassium acetate; LCMS is liquid
chromatography/mass spectrometry; LiHMDS is lithium hexamethyldisilazide;
LRMS is low resolution mass spectrometry; Mel is iodomethane; Me0H is
methanol;
NBS is N-bromosuccinimide; NH40Ac is ammonium acetate; NMM is N-
L

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methylmorpholine; Pd/C is palladium on carbon; Pd(PPh3)4 is tetrakis
(triphenylphosphine)palladium(0); PdC12(dppf)2 is [1,1 -Bis(diphenylphosphino)

ferrocene]dichloro palladium(11); PdC12(dpp02-CH2C12 is [1,1 -
Bis(diphenylphosphino)ferrocene] dichloro palladium(II) complex with
dichloromethane; pinacol2B2 is bis(pinacolato)diboron; PPTS is pyridinium p-
toluene
sulfonate; RPLC is reverse-phase liquid chromatography; Select-F is 1-
Chloromethy1-
4-Fluoro-1, 4-Diazoniabicyclo[2.2.2]Octane Bis-(Tetrafluoroborate); SEM-C1 is
2-
(trimethylsilypethoxymethyl chloride; TBAF is tetrabutylammonium fluoride;
TBDMSC1 is tert-butyldimethylsilyl chloride; TFA is trifluoroacetic acid; Tf20
is
triflic anhydride; TI-IF is tetrahydrofuran; TLC is thin-layer chromatography;
and
TosC1 is p-toluenesulfonyl chloride.
The Compounds of Formula (I)
The present invention provides Tetracyclic Indole Derivatives of Formula (I):
Y-,..
A /Jw X
R15
'
N
H A'
V'
R1 W.
(I)
and pharmaceutically acceptable salts thereof, wherein A, A', G, U, V, V',
W, W',
X, X', Y and Y' are defined above for the Compounds of Formula (I).
In one embodiment, A and A' are each a 5-membered heterocycloallcyl
group.
In another embodiment, A and A' are each a 6-membered
heterocycloalkyl group.
In another embodiment, A and A' are each independently selected from:

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R4 R4 R4 R4 R4 R4
stõ,..tiji1,,,,,c121 ist,c141 , s.1 N e ,_N
, F , ..---(4..CH3 skN...J..
, , e
F F CH3
R4
R4
R4
Ay) if.....N4
Ay7R1
I----C) ). skcilb and
Si , Si ,' \--so , si,cH3
H3c CH3 H3C/ -CH3 \
'CH3 .
In still another embodiment, A and A' are each independently selected
from:
R4 R4 R4 R4 R4 R4
i
.11.1 R:11:7
skci:1) iss,..1..s1 stõ..14.1 1....01 .. is....eN and N
F , CH3 , \¨.p' , =Nt,
F F CH3 .
In another embodiment, A and A' are each independently selected from:
R4
R4 R4
Si and 1,..(_tt,\
pi, , ,si ,
H3
SrC
H3C CH3 H3C µCH3
"CH3 .
In another embodiment, A and A' are each independently:
R4 ..1.
V'
R13 R13
In another embodiment, A and A' are each independently:
R4µN 614
c...t
R13 R13
wherein each occurrence of R13 is independently H, CH3, or F.
In one embodiment, each occurrence of R4 is independently -C(0)-
[C(R7)2],iN(R6)C(0)0-R11.
In another embodiment, each occurrence of R4 is independently:

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Rb-01rNfiss
Ra , wherein Rb is H, alkyl, haloalkyl, 3 to 6-
membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and
Ra is
alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered
heterocycloalkyl, aryl or heteroaryl.
In another embodiment, each occurrence of R4 is independently:
HIA"
s
R13-0)1,N
0
Ra , wherein Ra is H, methyl, ethyl, propyl,
isopropyl,
t-butyl, cyclopropyl, -CH2CH2Si(CH3)3, -CH2CH2CF3, pyranyl, benzyl or phenyl,
and
Rb is methyl, ethyl or isopropyl.
In still another embodiment, each occurrence of R4 is independently ¨
C(0)CH(alkyl)-NHC(0)0alkyl.
In another embodiment, each occurrence of R4 is independently:
E4
H3c-cly NC ,,sc
(3
In one embodiment, A and A' are each independently selected from:
R4 Fr R4 R4 R4 R4
,
ti
1....6 bci_z=J sk( 141 s.,.....(4. be N
15...,Q
F F CH3
R4 R4
R4
1.,,c.1=_1) j((4) of,.eN Fit4
, ) skc_Ni.tµ and "12,
, ,1¨.) , . CH
H3d CH3 H3C -CH3
Ch13
and R4 is:
0
FH
Rb---OrA"
Ra , wherein Rb is H, alkyl, haloalkyl, 3 to 6-
membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and
Ra is
alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered
heterocycloalkyl, aryl or heteroaryl.
In another embodiment, A and A' are each independently selected from:

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R4 R4 R4Fr R4 R4
1
.5 ri
A N
ILO iss_l .1.114

F 5......4
, CH3
F F CH3
R4 R4 R4
1....(1,R4
At N /11:7R4,
and N
1 i(c 4)
s.----( sktit
Si 1-so , H3
Si 'C
NM
H3C CH3, H3C' µC H3 CH3
and R4 is:
0
Rt¨OTNHIA,
0
Ra , wherein Ra is H, methyl, ethyl, propyl,
isopropyl,
t-butyl, cyclopropyl, -CH2CH2Si(CH3)3, -CH2CH2CF3, pyranyl, benzyl or phenyl,
and
R1 is methyl, ethyl or isopropyl.
In another embodiment, A and A' are each independently selected from:
R4R4 R4 R4 R4 R4
A N
ILO 1,..õ( liz1 I, #....t14. .s.....4
isscri,b,
F CH3 ,
F F CH3
R4 R4 R4 R4
1....eN) 4-(4) and :trit2,1
\-si, , si ,
S)

, si-cH3
H3d -cH3 14 r= (-14
..3.,/ µ.... .3 Ntt
NC H3
and R4 is:
H
CH3 TNX)cs
0
In another embodiment, A and A' are each independently selected from:
R4 R4 R4 R4Fr R4
1 1
iss,..(3 ,it_ct_iz s:Lc_N_z_F ,
f-st41 -CH3 , 11 , bVA and Rri 7IN
'IN
F F CH3
and R4 is:
1-13?)yNEccis
2.
In yet another embodiment, A and A' are each:

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R4
R13 R13
, wherein each occurrence of R13 is independently H,
CH3, or F;
and R4 is
0
H3c- T ,jsz
0
In one embodiment, G is ¨C(R3)2-0-.
In another embodiment, G is _c(R14)=N-
In another embodiment, G is ¨C(R3)2¨C(R3)2- or _c(R14)=c(R14)_.
In still another embodiment, G is ¨C(R3)2¨C(R3)2- or
In one embodiment, G is ¨C(R3)2-0- and each occurrence of R3 is
independently selected from H, C1-C6 alkyl, 3 to 6-membered cycloalkyl, 4 to 6-

membered heterocycloalkyl, aryl and 5 or 6-membered monocyclic heteroaryl,
wherein said 5 or 6-membered monocyclic heteroaryl group and said phenyl
groups
can be optionally substituted with up to 2 groups, which can be the same or
different,
and are selected from halo, -CN, Ci-C6 alkyl, C1-C6 haloalkyl, -0-Ci-C6 alkyl,
¨(C1-
C6 alkylene)-0-Ci-C6 alkyl and -0-C1-C6 haloalkyl.
In another embodiment, G is ¨C(R3)2-0-, wherein one occurrence of
R3 is H, and the other occurrence of R3 is selected from C1-C6 alkyl,
cycloalkyl and
phenyl, wherein said phenyl group can be optionally substituted with up to 2
groups,
which can be the same or different, and are selected from halo, -CN, C1-C6
alkyl,
C6 haloalkyl, -0-Ci-C6 alkyl, ¨(C1-C6 alkylene)-0-Ci-C6 alkyl and -0-C1-C6
haloalkyl.
In one embodiment, G is ¨C(R3)2-0- and each occurrence of R3 is
independently selected from H, methyl, ethyl, isopropyl, cyclopropyl,
methylcyclopropyl, methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl
wherein
said phenyl, pyridyl and pyrimidinyl group can be optionally substituted with
up to 2
groups, which can be the same or different, and are selected from F, Cl, -CN,
CH3,
CF3, OCF3 and OCH2CH2OCH3.
In one embodiment, G is ¨CH(R3)-0-, wherein R3 is selected from C1-
C6 alkyl, phenyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered

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bicyclic heteroaryl, wherein said phenyl group, said 5 or 6-membered
monocyclic
heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be
optionally substituted with a C1-C6 alkyl group.
In another embodiment, G is ¨CH(R3)-0-, wherein R3 is selected from
methyl, phenyl, 5-methyl-thiophen-2-y1 and benzothiophen-2-yl.
In another embodiment, G is ¨C(R3)2-0-, wherein one occurrence of
R3 is H, and the other occurrence of R3 is selected from phenyl, methyl,
thiophenyl or
benzothiophenyl, wherein said benzothiophenyl can be optionally substituted
witha
C1-C6 alkyl, cycloalkyl and phenyl, wherein said phenyl group can be
optionally
substituted with up to 2 groups, which can be the same or different, and are
selected
from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -0-CI-C6 alkyl, ¨(C1-C6
alkylene)-0-
Ci-C6 alkyl and -0-C1-C6 haloalkyl.
In one embodiment, G is ¨C(R3)2-0- and each occurrence of R3 is
independently selected from H, methyl, ethyl, isopropyl, cyclopropyl, l'-
methylcyclopropyl, methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl
wherein
said phenyl, pyridyl and pyrimidinyl group can be optionally substituted with
up to 2
groups, which can be the same or different, and are selected from F, Cl, -CN,
CH3,
CF3, OCF3 and OCH2CH2OCH3.
In another embodiment, G is ¨C(R3)2-0-, wherein one occurrence of
R3 is H, and the other occurrence of R3 is selected from methyl, ethyl,
isopropyl,
cyclopropyl, l'-methylcyclopropyl, methylenecyclopropyl, phenyl, pyridyl, and
pyrimidyl wherein said phenyl, pyridyl and pyrimidinyl group can be optionally

substituted with up to 2 groups, which can be the same or different, and are
selected
from F, Cl, -CN, CH3, CF3, OCF3 and OCH2CH2OCH3.
In one embodiment, G is ¨C(R3)2-0-, wherein both R3 groups, together
with the common carbon atom to which they are attached, join to form a
carbonyl
group, a 3 to 6-membered spirocyclic cycloalkyl group or a 3 to 6-membered
spirocyclic heterocycloalkyl group.
In one embodiment, G is ¨C(R14)=N-, wherein R14 is selected from H,
C1-C6 alkyl, cycloalkyl and phenyl, wherein said phenyl group can be
optionally
substituted with up to 2 groups, which can be the same or different, and are
selected
from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -0-C1-C6 alkyl, ¨(C1-C6
alkylene)-0-
C1-C6 alkyl and -0-C1-C6 haloalkyl.

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In one embodiment, each occurrence of R3 is independently selected
from H, methyl, ethyl, isopropyl, cyclopropyl, l'-methylcyclopropyl,
methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl wherein said phenyl,
pyridyl
and pyrimidinyl group can be optionally substituted with up to 2 groups, which
can be
the same or different, and are selected from F, Cl, -CN, CH3, CF3, OCF3 and
OCH2CH2OCH3.
In another embodiment, two R3 groups on the same carbon atom,
together with the common carbon atom to which they are attached, join to form
a
carbonyl group, a 3 to 6-membered spirocyclic cycloalkyl group or a 3 to 6-
membered
spirocyclic heterocycloalkyl group.
In one embodiment, U is C(R2).
In another embodiment, U is CH.
In another embodiment, U is CF.
In one embodiment, V is C(R15).
In another embodiment, V is CH.
In another embodiment, V is CF.
In another embodiment, V is N.
In one embodiment, V' is C(R15).
In another embodiment, V' is CH.
In another embodiment, V' is CF.
In another embodiment, V' is N.
In still another embodiment, V and V' are each CH.
In one embodiment, W is C(RI5).
In another embodiment, W is CH.
In another embodiment, W is CF.
In another embodiment, W is N.
In one embodiment, W ' is C(R15).
In another embodiment, W 'is CH.
In another embodiment, W 'is CF.
In another embodiment, W ' is N.
In still another embodiment, W and W' are each CH.
In a further embodiment, V, V' W and W' are each CH.
In one embodiment, R1 is absent.
In another embodiment, R1 is F.

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In one embodiment, each occurrence of R3 is independently selected
from H, methyl, ethyl, isopropyl, cyclopropyl, l'-methylcyclopropyl,
methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl wherein said phenyl,
pyridyl
and pyrimidinyl group can be optionally substituted with up to 2 groups, which
can be
the same or different, and are selected from F, Cl, -CN, CH3, CF3, OCF3 and
OCH2CH2OCH3.
In another embodiment, two R3 groups on the same carbon atom,
together with the common carbon atom to which they are attached, join to form
a
carbonyl group, a 3 to 6-membered spirocyclic cycloallcyl group or a 3 to 6-
membered
spirocyclic heterocycloalkyl group.
In one embodiment, each occurrence of R1 is independently H or F.
In another embodiment, each occurrence of RI is H.
In one embodiment, the group:
R15
I i
'
R1 W V
has the structure:
R2 R15
________________________________ --N/S
V
In another embodiment, the group:
R15
R1 W V
has the structure:

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33
R15
AR2 R15 R15 -s-rrN
\ 41 \ 41
N
N
)\---0
)70
R3 R3 R3 R3 .
In another embodiment, the group:
R15
rw.....- )
Rik,k ¨
,,-----N --v)'
G
has the structure:
R2 R15 R15
-.5:5= R15N
A
\ II I \ =
N
N
)=----N
)=N
RU
R14
=
In still another embodiment, the group:
R15
R1 ¨
%,,,,
G
has the structure:
F
\ = i
N
\-0
R3 R3 .
In one embodiment, variables A, A', G, RI, U, V, V', W, W', X, X', Y
and Y' for the Compounds of Formula (I) are selected independently of each
other.
In another embodiment, the Compounds of Formula (I) are in
substantially purified form.

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In one embodiment, the Compounds of Formula (I) have the formula
(Ia):
Rlo
CI /N T R2 R15 Rio
________________________________________ V N
H
R1 G CO
(Ia)
and pharmaceutically acceptable salts thereof, wherein:
A and A' are each independently a 5-membered monocyclic
heterocycloalkyl, wherein said 5-membered monocyclic heterocycloalkyl group
can
be optionally and independently substituted on one or more ring carbon atoms
with
R13, such that any two R13 groups on the same ring, together with the carbon
atoms to
which they are attached, can join to form a fused, bridged or spirocyclic 3 to
6-
membered cycloalkyl group or a fused, bridged or spirocyclic 4 to 6-membered
heterocycloalkyl group, wherein said 5-membered monocyclic heterocycloalkyl
contains from 1 to 2 ring heteroatoms, each independently selected from N(W4)
and
Si(R16)2;
G is selected from ¨C(R3)2-, ¨C(R3)2-0-, ¨C(R14)=N-, ¨C(R3)2¨C(R3)2-
and _c (Ri4)=c (Ri4)_;
V and V' are each independently selected from N and C(R15);
R1 represents an optional ring substituent on the phenyl ring to which
R1 is attached, wherein said substituent is selected from C1-C6 alkyl and
halo;
each occurrence of R2 is independently selected from H, C1-C6 alkyl, 3
to 6 membered cycloalkyl, -0-(C1-C6 alkyl), C1-C6 haloalkyl ¨0-(C1-C6
haloalkyl);
halo, -OH, aryl, and heteroaryl
each occurrence of R3 is independently selected from H, C1-C6 alkyl, -
(C1-C6 alkylene)-0-(Ci-C6 alkyl), 3 to 6-membered cycloalkyl, C1-C6 haloalkyl,
aryl,
or 6-membered monocyclic heteroaryl and benzyl, wherein said aryl group, said
5
or 6-membered monocyclic heteroaryl group or the phenyl group of said benzyl
group can be optionally substituted with up to 3 groups, which can be the same
or
different, and are selected from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -0-
C1-C6
alkyl, ¨(C1-C6 alkylene)-0-Ci-C6 alkyl and -0-(C1-C6 haloalkyl);

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each occurrence of R4 is independently -C(0)-[C(R7)2]N(R6)C(0)0-
R11;
each occurrence of R6 is independently selected from H and C1-C6
alkyl;
each occurrence of R7 is independently selected from C1-C6 alkyl, C 1 -
C6 haloalkyl, 3 to 6-membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
aryl
and 5 or 6-membered monocyclic heteroaryl, wherein said 3 to 6-membered
cycloalkyl group, said 4 to 6-membered heterocycloalkyl group, said aryl group
and
said 5 or 6-membered monocyclic heteroaryl group can be optionally and
independently substituted with up to three R8 groups;
each occurrence of R8 is independently selected from H, Ci-C6 alkyl,
halo, -Ci-C6 haloalkyl, Ci-C6 hydroxyallcyl, -OH, -C(0)NH-(C1-C6 alkyl), -
C(0)N(C1-
C6 alky02, -0-(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alky1)2 and -
NHC(0)-
(Ci-C6 alkyl);
each occurrence of R1 is independently selected from H and halo;
each occurrence of R11 is independently C1-C6 alkyl;
each occurrence of R13 is independently selected from H and halo,
wherein two R13 groups, together with the carbon atom(s) to which they are
attached,
can optionally join to form a 3 to 6-membered cycloalkyl group or 4 to 6-
membered
heterocycloalkyl group;
each occurrence of R14 is independently selected from H, halo, C1-C6
alkyl, -(C1-C6 alkylene)-0-Ci-C6 alkyl, 3 to 6-membered cycloalkyl, C1-C6
haloalkyl,
aryl, 5 or 6-membered monocyclic heteroaryl and benzyl, wherein said aryl
group,
said 5 or 6-membered monocyclic heteroaryl group or the phenyl group of said
benzyl group can be optionally substituted with up to 3 groups, which can be
the same
or different, and are selected from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -
0-Ci-C6
alkyl, ¨(C1-C6 alkylene)-0-Ci-C6 alkyl and -0-C1-C6 haloalkyl;
each occurrence of R15 is independently selected from H and halo; and
each occurrence of R16 is independently selected from C1-C6 alkyl.
In one embodiment, for the Compounds of Formula (Ia), A and A' are
each a 5-membered monocyclic heteroaryl group.
In another embodiment, for the Compounds of Formula (Ia), A and A'
are each a 6-membered monocyclic heteroaryl group.

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In another embodiment, for the Compounds of Formula (Ia), A and A'
are each independently selected from:
R4 R4 R4 R4 R4 R4
1 1
1....6
F
F F
j R4 R4 R4 R4
R:LNI:7 R4sN , kc> , i,,(41 ,
\ , \ f? \--(c)H '
R4 R4 R4 R4 R4
, 3.---Qi
si,CH3 and
* . ,,,/ =,,,,
.3,.. .... õ, u r. Si '
- ..3..../ 't1-13 CH3
In still another embodiment, for the Compounds of Formula (Ia), A
and A' are each independently selected from:
R4ir R
I Fr 4 ir
skso_ ,
F
F F
R
R4 4
is, (.:, 31----(11
N and "-Si
*NI, H3c/ µcH3 .
In another embodiment, for the Compounds of Formula (Ia), A and A'
are each independently selected from:
R4 R4 R4
1,.....(1) R4
) and/
so . cH
Si- 3
H3d , CH3 u ,
I nror=
\CH3 NCH3 .
In one embodiment, for the Compounds of Formula (Ia), A and A' are
each:
R4
N
<
Z
R13' \R13
wherein each occurrence of Z is independently ¨Si(R13)2-, ¨C(R13)2- or ¨S-,

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PCT/CN2011/001638
and each occurrence of R13 is independently H, Me, F or two R13 groups
together with
Z, can combine to form a spirocyclic 3 to 6-membered cycloalkyl group or a
spirocyclic 3 to 6-membered silyl-containing heterocycloalkyl group.
In another embodiment, for the Compounds of Formula (Ia), A and A'
are each independently:
R4 t
=1\.)/"
R13 Ri3
In another embodiment, for the Compounds of Formula (Ia), A and A'
are each independently:
R4 t
R13 R13
wherein each occurrence of R13 is independently H, CH3, or F.
In one embodiment, for the Compounds of Formula (Ia), each
occurrence of R4 is independently -C(0)C(R7)2NHC(0)0-R1 1 or -
C(0)C(R7)2N(R6)2.
In another embodiment, for the Compounds of Formula (Ia), each
occurrence of R4 is independently -C(0)4C(R7)2]qN(R6)C(0)0-R11.
In another embodiment, for the Compounds of Formula (Ia), each
occurrence of R4 is independently ¨C(0)CH(alkyl)-NHC(0)0alkyl,
C(0)CH(cycloalkyl)-NHC(0)0alkyl, C(0)CH(heterocycloalkyl)-NHC(0)0alkyl,
C(0)CH(ary1)-NHC(0)0alkyl or C(0)CH(aryl)-N(alkyl)2.
In another embodiment, for the Compounds of Formula (Ia), each
occurrence of R4 is independently:
ROyNsJ
Ra , wherein Rb is H, alkyl, haloalkyl, 3 to 6-
membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and
Ra is
alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered
heterocycloalkyl, aryl or heteroaryl.

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In another embodiment, for the Compounds of Formula (Ia), each
occurrence of R4 is independently:
Rb¨OliNFIss
0
Ra , wherein Ra is H, methyl, ethyl, propyl, isopropyl,
t-butyl, cyclopropyl, -CH2CH2Si(CH3)3, -CH2CH2CF3, pyranyl, benzyl or phenyl,
and
Rb is methyl, ethyl or isopropyl.
In still another embodiment, for the Compounds of Formula (Ia), each
occurrence of R4 is independently ¨C(0)CH(alkyl)-NHC(0)0alkyl.
In another embodiment, for the Compounds of Formula (Ia), each
occurrence of R4 is independently:
H3c- 1( Ns-cF1
0
In one embodiment, for the Compounds of Formula (Ia), A and A' are
each independently selected from:
R4 R4 Fe R4 R4 Fe
F
F F
R4 R4 R4 R4
"lb R4sN 3(6 , (6 Ar 4)
I N
\ , \
OH
R4 R4 i R4 R4 R4
I N
, i t .....c_.tµ . arid
* Si ,
Li r/ =,...0
riv., ...i ..1 u r.
/Si '
- ..3%. µCH3 Sr.C1-13
Ci-13 b
and R4 is:
HI.s.s
RI¨OyNA
0
Ra , wherein le is H, alkyl, haloalkyl, 3 to 6-
membered cycloalkyl, 4 to 6-membered heterocycloalkyl, aryl or heteroaryl and
Ra is
alkyl, haloalkyl, silylalkyl, 3 to 6-membered cycloalkyl or 4 to 6-membered
heterocycloalkyl, aryl or heteroaryl.

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In another embodiment, for the Compounds of Formula (Ia), A and A'
are each independently selected from:
R4 R4 R4 R4 R4 R4
F
F F
R4 R4 R4 R4
15.17, R1N s(01 , > isscri_zi
OH
R4 R4 R4 R4 R4
N / ri
, --0 k(N)
lir
Li,/ µisi.,
HC vi il u r/Si '
" I .3so NC H3 41---c_rbi,CI-13 and
cii3 so
and R4 is:
R HIA/C)
I¨OisN
Ra , wherein Ra is H, methyl, ethyl, propyl, isopropyl,
t-butyl, cyclopropyl, -CH2CH2Si(CH3)3, -CH2CH2CF3, pyranyl, benzyl or phenyl,
and
R1 is methyl, ethyl or isopropyl.
In another embodiment, for the Compounds of Formula (Ia), A and A'
are each independently selected from:
R4 R4 R4 R4 R4 R4
1....C.) , Asc. lir/ . , it_s_c_h_?>1 , Iss.(Lz1 , Is.sc
F
F F
R4 R4 R4 R4
R:112R4sN , &a
N
---\()H '
R4 R4_N) R4 R4 R4
zI
i N isL,NN /N õN)
Le
- SrCH3
# H3c/ µcH3 ,si, and
'
H3c -CH3 cH3
and R4 is:
E 0
H3C'ipy ;C ,ssr
0

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In another embodiment, for the Compounds of Formula (Ia), A and A'
are each independently selected from:
R4 R4 R4 R4 R4
jb6I sktI4.1 F '
R4
R4
and
n3ta,
and R4 is:
0
CH3' y Ass
0
In yet another embodiment, for the Compounds of Formula (Ia), A and
A' are each:
R4
R13 R13
, wherein each occurrence of Ri3 is independently H,
CH3, or F;
and R4 is
H
H3c" yNx),
In one embodiment, for the Compounds of Formula (Ia), G is ¨C(R3)2-
0-.
In another embodiment, for the Compounds of Formula (Ia), G is ¨
C(R14)=N-
In another embodiment, for the Compounds of Formula (Ia), G is ¨
C(R3)2¨C(R3)2-, ¨C(R14)=C(R14)-.
In still another embodiment, for the Compounds of Formula (Ia), G is ¨
C(R3)2¨C(R3)2-, _c(R14)=c(R14)_..
In one embodiment, for the Compounds of Formula (Ia), G is ¨C(R3)2-
0- and each occurrence of R3 is independently selected from H, C1-C6 alkyl,
cycloalkyl and phenyl, wherein said phenyl group can be optionally substituted
with

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up to 2 groups, which can be the same or different, and are selected from
halo, -CN,
C1-C6 alkyl, C1-C6 haloalkyl, -0-C1-C6 alkyl, ¨(C1-C6 alkylene)-0-Ci-C6 alkyl
and -
0-C1-C6 haloalkyl.
In another embodiment, for the Compounds of Formula (Ia), G is ¨
C(R3)2-0-, wherein one occurrence of R3 is H, and the other occurrence of R3
is
selected from C1-C6 alkyl, cycloalkyl and phenyl, wherein said phenyl group
can be
optionally substituted with up to 2 groups, which can be the same or
different, and are
selected from halo, -CN, Ci-C6 alkyl, C1-C6 haloalkyl, -0-C1-C6 alkyl, ¨(C1-C6

alkylene)-0-Ci-C6 alkyl and -0-C1-C6 haloalkyl.
In one embodiment, for the Compounds of Formula (Ia), G is ¨C(R3)2-
0- and each occurrence of R3 is independently selected from H, methyl, ethyl,
isopropyl, cyclopropyl, l'-methylcyclopropyl, methylenecyclopropyl, phenyl,
pyridyl,
and pyrimidyl wherein said phenyl, pyridyl and pyrimidinyl group can be
optionally
substituted with up to 2 groups, which can be the same or different, and are
selected
from F, Cl, -CN, CH3, CF3, OCF3 and OCH2CH2OCH3.
In another embodiment, for the Compounds of Formula (Ia), G is ¨
C(R3)2-0-, wherein one occurrence of R3 is H, and the other occurrence of R3
is
selected from methyl, ethyl, isopropyl, cyclopropyl, l'-methylcyclopropyl,
methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl wherein said phenyl,
pyridyl
and pyrimidinyl group can be optionally substituted with up to 2 groups, which
can be
the same or different, and are selected from F, Cl, -CN, CH3, CF3, OCF3 and
OCH2CH2OCH3.
In one embodiment, for the Compounds of Formula (Ia), G is ¨
C(R14)=N-, wherein R14 is selected from H, C1-C6 alkyl, cycloalkyl and phenyl,

wherein said phenyl group can be optionally substituted with up to 2 groups,
which
can be the same or different, and are selected from halo, -CN, C1-C6 alkyl, C1-
C6
haloalkyl, -0-C1-C6 alkyl, ¨(C1-C6 alkylene)-0-C1-C6 alkyl and -0-C1-C6
haloalkyl.
In one embodiment, for the Compounds of Formula (Ia), U is C(R2).
In another embodiment, for the Compounds of Formula (Ia), U is CH.
In another embodiment, for the Compounds of Formula (Ia), U is CF.
In one embodiment, for the Compounds of Formula (Ia), V is C(R15).
In another embodiment, for the Compounds of Formula (la), V is CH.
In another embodiment, for the Compounds of Formula (Ia), V is N.
In one embodiment, for the Compounds of Formula (Ia), V' is C(R15).

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In another embodiment, for the Compounds of Formula (Ia), V' is CH.
In another embodiment, for the Compounds of Formula (Ia), V' is N.
In still another embodiment, for the Compounds of Formula (Ia), V
and V' are each CH.
In one embodiment, for the Compounds of Formula (Ia), Rl is absent.
In another embodiment, for the Compounds of Formula (Ia), RI is F.
In one embodiment, each occurrence of R3 is independently selected
from H, methyl, ethyl, isopropyl, cyclopropyl, l'-methylcyclopropyl,
methylenecyclopropyl, phenyl, pyridyl, and pyrimidyl wherein said phenyl,
pyridyl
and pyrimidinyl group can be optionally substituted with up to 2 groups, which
can be
the same or different, and are selected from F, Cl, -CN, CH3, CF3, OCF3 and
OCH2CH2OCH3.
In one embodiment, for the Compounds of Formula (Ia), each
occurrence of RI is independently H or F.
In another embodiment, for the Compounds of Formula (Ia), each
occurrence of RI is H.
In one embodiment, for the Compounds of Formula (Ia), the group:
R2 R15
_________________________________________ V'
R1
has the structure:
R15
R2 R15
R15
IN = 441
N
N )70
)\--0
R
R3 R3 3 R3
In another embodiment, for the Compounds of Formula (Ia), the group:
R2 R15
V_
cSSS
_________________________________________ V'
R1
has the structure:

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R15
R2 -s-rsN
IN IN =
N N
R14
In another embodiment, for the Compounds of Formula (Ia), the group:
R2 R15
V¨

V'
R1
has the structure:
-.PC(
N
)\-0
R3 R3
In one embodiment, variables A, A', G, RI, R2, RH), ¨15,
U, V and V'
for the Compounds of Formula (Ia) are selected independently of each other.
In another embodiment, the Compounds of Formula (Ia) are in
substantially purified form.
In one embodiment, the Compounds of Formula (I) have the formula
(Ib):
R4
,13b N R2 R4
R13a N N
/ 3b
R13a
\
N (s)
R13a
>0 R15 H
R13a
R3 R3
(Ib)
or a pharmaceutically acceptable salt thereof, wherein:
R2 is H or F;
each occurrence of R3 is independently selected from H, C1-C6 alkyl,
C1-C6 haloalkyl, 3 to 6 membered cycloalkyl, 4 to 6-membered heterocycloalkyl,
aryl,

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or 6-membered monocyclic heteroaryl, 9 or 10-membered bicyclic heteroaryl, -0-
(C1-C6 alkyl), Ci-C6 haloalkylene ¨0-(C1-C6 haloalkyl); -(C1-C6
alkylene)C(=0)NH-
alkyl, -(Ci-C6 alkylene)aryl, and -(Ci-C6 alkylene)heteroaryl, wherein said
aryl group,
said 5 or 6-membered monocyclic heteroaryl group, said 9 or 10-membered
bicyclic
heteroaryl group or the phenyl group of said benzyl group can be optionally
substituted with up to 3 groups, which can be the same or different, and are
selected
from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -0-C1-C6 alkyl, ¨(C1-C6
alkylene)-0-
C1-C6 alkyl and -0-(C1-C6 haloalkyl);
each occurrence of R4 is independently selected from ¨C(0)0-(Ci-C6
alkyl), ¨C(0)-CH(R7)N(R6)2 and ¨C(0)-CH(R7)C(0)0-R11;
each occurrence of R6 is independently H or C1-C6 alkyl;
each occurrence of R7 is independently selected from C1-C6 alkyl,
phenyl, 4 to 6-membered heterocycloalkyl and 3 to 6 membered cycloalkyl;
each occurrence of Ril is independently C1-C6 alkyl;
each occurrence of R13a is independently H, Me or F; or two R13a
groups that are attached to the same carbon atom, together with the common
carbon
atom to which they are attached, combine to form a spirocyclic 3 to 6 membered

cycloalkyl group;
each occurrence of R13b is independently H, or one or both R13b groups
and an R1 3a group that are attached to same ring, together with the ring
carbon atoms
to which they are attached, can combine to form a fused 3 to 6 membered
cycloalkyl
group; and
R15 represents up to 2 substituents, each independently selected from H,
halo, C1-C6 alkyl, C1-C6 haloalkyl, 3 to 6 membered cycloalkyl, 4 to 6-
membered
heterocycloalkyl, aryl, 5 or 6-membered monocyclic heteroaryl, benzyl, -0-(C1-
C6
alkyl), C1-C6 haloalkylene ¨0-(C1-C6 haloalkyl) -(Ci-C6allcylene)C(=0)NH-
alkyl, -
(C1-C6 alkylene)aryl, and -(C1-C6 allcylene)heteroaryl, wherein said aryl
group, said 5
or 6-membered monocyclic heteroaryl group or the phenyl group of said benzyl
group can be optionally substituted with up to 3 groups, which can be the same
or
different, and are selected from halo, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -0-
C1-C6
alkyl, ¨(C1-C6 allcylene)-0-CI-C6 alkyl and -0-(C1-C6 haloalkyl).
In one embodiment, for the Compounds of Formula (Ib), R2 is H.
In another embodiment, for the Compounds of Formula (Ih), R2 is F.

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In one embodiment, for the Compounds of Formula (Ib), one
occurrence of R3 is H and the other occurrence of R3 is selected from H,
methyl, ethyl,
isopropyl, cyclopropyl, I '-methylcyclopropyl, methylenecyclopropyl, phenyl,
pyridyl,
and pyrimidyl wherein said phenyl, pyridyl and pyrimidinyl group can be
optionally
substituted with up to 2 groups, which can be the same or different, and are
selected
from F, Cl, -CN, CH3, CF3, OCF3, OCH2CH2OCH3.
In another embodiment, for the Compounds of Formula (Ib), two R3
groups that are attached to the same carbon atom, together with the common
carbon
atom that they are attached to, join to form a carbonyl group, a 3 to 6-
membered
spirocyclic cycloalkyl group or a 3 to 6-membered spirocyclic heterocycloalkyl

group.
In one embodiment, for the Compounds of Formula (Ib), each
occurrence of R3 is C1-C6 alkyl.
In another embodiment, for the Compounds of Formula (Ib), one
occurrence of R3 is H.
In another embodiment, for the Compounds of Formula (Ib), one
occurrence of R3 is H and the other occurrence of R3 is methyl, phenyl, 5 or 6-

membered monocyclic heteroaryl or 9-membered bicyclic heteroaryl.
In still another embodiment, for the Compounds of Formula (Ib), one
occurrence of R3 is H and the other occurrence of R3 is phenyl, methyl,
w r, S 2 or
In one embodiment, for the Compounds of Formula (Ib), each
occurrence of R4 is ¨C(0)CH(le)NHC(0)0R11.
In another embodiment, for the Compounds of Formula (Ib), each
occurrence of R4 is ¨C(0)CH(le)NHC(0)0RI I and each occurrence of R1' is
methyl.
In another embodiment, for the Compounds of Formula (lb), each
occurrence of R4 is ¨C(0)CH(le)NHC(0)0R11; each occurrence of le is isopropyl,

benzyl, cyclopropyl or tetrahyropyranyl; and each occurrence of R" is methyl.

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In still another embodiment, for the Compounds of Formula (Ib), each
occurrence of R4 is ¨C(0)CH(R7)NHC(0)0R11; each occurrence of R7 is isopropyl
or
tetrahyropyranyl; and each occurrence of R11 is methyl.
In another embodiment, for the Compounds of Formula (Ib), each
occurrence of R4 is ¨C(0)CH(R7)NHC(0)0R11; each occurrence of R7 is isopropyl;

and each occurrence of R11 is methyl.
In yetanother embodiment, for the Compounds of Formula (Ib), each
occurrence of R4 is ¨C(0)CH(R7)NHC(0)0R11; each occurrence of R7 is
tetrahyropyranyl; and each occurrence of R" is methyl.
In one embodiment, for the Compounds of Formula (Ib), each
occurrence of R13a is independently H, or F.
In another embodiment, for the Compounds of Formula (Ib), two R13a
groups that are attached to the same carbon atom, together with the common
carbon
atom to which they are attached, combine to form a spirocyclic 3 to 6 membered

cycloalkyl group.
In another embodiment, for the Compounds of Formula (Ib), two R13a
groups that are attached to the same carbon atom, together with the common
carbon
atom to which they are attached, combine to form a spirocyclic cyclopropyl
group.
In one embodiment, for the Compounds of Formula (Ib), each
occurrence of R131 is H.
In another embodiment, for the Compounds of Formula (Ib), one or
both R13" groups and an R1 3a group that are attached to same ring, together
with the
ring carbon atoms to which they are attached, can combine to form a fused 3 to
6
membered cycloalkyl group.
In another embodiment, for the Compounds of Formula (Ib), one or
both R13b groups and an R1 3a group that are attached to same ring, together
with the
ring carbon atoms to which they are attached, can combine to form a fused 3 to
6
membered cyclopropyl group.
In one embodiment, for the Compounds of Formula (lb), each
occurrence of R15 is independently selected from H and F.
In another embodiment, for the Compounds of Formula (Ib), each
occurrence of R15 is H.
In one embodiment, for the Compounds of Formula (lb), each
occurrence of R2, R13 and R15 is independently selected from H and F.

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In another embodiment, for the Compounds of Formula (Tb), each
occurrence of R2, R13 and R15 is independently selected from H and F and one
occurrence of R3 is H.
In one embodiment, variables R2, R3, R13 and R15 for the Compounds
of Formula (Ib) are selected independently of each other.
In another embodiment, the Compounds of Formula (Ib) are in
substantially purified form.
In one embodiment, the Compounds of Formula (I) have the formula
(Ic):
0 RY
0
H3C0)(N (s)
H N IR' 0
R134Ns) R2 R15
N7 ci I N / N "1-,SN OCH3
R13 N N (s) _._R13
>-0 H
R3 R13
(Ic)
and pharmaceutically acceptable salts thereof, wherein:
RY is isopropyl or tetrahydropyranyl;
Rz is isopropyl or tetrahydropyranyl;
R2 is H or halo;
R3 is selected from 3 to 6-membered cycloalkyl or phenyl, wherein
said phenyl group can be optionally substituted with up to 2 groups, which can
be the
same or different, and are selected from halo, -CN, C1-C6 alkyl, C1-C6
haloallcyl, -0-
C1-C6 alkyl, ¨(C1-C6 allcylene)-0-Ci-C6 alkyl and -0-C1-C6 haloalkyland
each occurrence of R13 is independently selected from H and halo; and
each occurrence of R15 is independently selected from H and halo.
In one embodiment, for the compounds of formula (Ic), R3 is phenyl,
wherein said phenyl group can be optionally substituted with up to 2 groups,
which
can be the same or different, and are selected from F, Cl, -CN, CH3, CF3,
OCF3,
OCH2CH2OCH3.

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In another embodiment, for the compounds of formula (Ic), R3 is
cyclopropyl.
In another embodiment, for the compounds of formula (Ic), R2 and R15
are each independently H or F.
In another embodiment, for the compounds of formula (Ic), each
occurrence of R13 is independently H or F;
In one embodiment, for the compounds of formula (Ic), R3 is phenyl;
each occurrence of R13 is independently H or F; and R2 and R15 are each
independently H or F, wherein said phenyl group can be optionally substituted
with
up to 2 groups, which can be the same or different, and are selected from F,
Cl, -CN,
CH3, CF3, OCF3, OCH2CH2OCH3.
In another embodiment, for the compounds of formula (Ic), R3 is
cyclopropyl; each occurrence of R13 is independently H or F; and R2 and R15
are each
independently H or F.
In one embodiment, the Compounds of Formula (I) have the formula
(Id):
0
\ 0 0 0
)0/
0-4HN--c)
0/11
RwrN Er\ii
/
Rz
NLN \/ \N
)-0
R3
(Id)
or a pharmaceutically acceptable salt thereof,
wherein:
R3 is C1-C6 alkyl, aryl, 5 or 6-membered monocyclic heteroaryl or 9-
membered bicyclic heteroaryl;
Rw is H, or Rw and Rx, together with the ring carbon atoms to which
they are attached, combine to form a fused 3 to 6-membered cycloalkyl group;
Rx is H or F, or Rw and Rx, together with the ring carbon atoms to
which they are attached, combine to form a fused 3 to 6-membered cycloalkyl
group;

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49
RY is H, or RY and le, together with the ring carbon atoms to which
they are attached, combine to form a fused 3 to 6-membered cycloalkyl group;
and
R is H or F, or RY and re, together with the ring carbon atoms to
which they are attached, combine to form a fused 3 to 6-membered cycloalkyl
group.
In one embodiment, for the compounds of formula (Id), R3 is phenyl,
methyl,
H3C/-'s 2 or
In another embodiment, for the compounds of formula (Id), Ir and le,
together with the ring carbon atoms to which they are attached, combine to
form a
fused cyclopropyl group.
In another embodiment, for the compounds of formula (Id), RY and Rz,
together with the ring carbon atoms to which they are attached, combine to
form a
fused cyclopropyl group.
In still another embodiment, for the compounds of formula (Id), RY and
Rz, together with the ring carbon atoms to which they are attached, combine to
form a
fused cyclopropyl group and le' and Rx, together with the ring carbon atoms to
which
they are attached, combine to form a fused cyclopropyl group.
In another embodiment, for the compounds of formula (Id), IV% le,
and RY are each H and le is F.
In another embodiment, for the compounds of formula (Id), Ir and le,
together with the ring carbon atoms to which they are attached, combine to
form a
fused cyclopropyl group; RY is H and le is F.
In one embodiment, for the compounds of formula (Id), variables R30

,
Rx, RY, and le are selected independently of each other.
In another embodiment, the Compounds of Formula (Ic) are in
substantially purified form.
Other embodiments of the present invention include the following:

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(a) A pharmaceutical composition comprising an effective amount
of a Compound of Formula (I) or a pharmaceutically acceptable salt thereof,
and a
pharmaceutically acceptable carrier.
(b) The pharmaceutical composition of (a), further comprising a
second therapeutic agent selected from the group consisting of HCV antiviral
agents,
immunomodulators, and anti-infective agents.
(c) The pharmaceutical composition of (b), wherein the HCV
antiviral agent is an antiviral selected from the group consisting of HCV
protease
inhibitors and HCV NS5B polymerase inhibitors.
(d) A pharmaceutical combination that is (i) a Compound of
Formula (I) and (ii) a second therapeutic agent selected from the group
consisting of
HCV antiviral agents, immunomodulators, and anti-infective agents; wherein the

Compound of Formula (I) and the second therapeutic agent are each employed in
an
amount that renders the combination effective for inhibiting HCV replication,
or for
treating HCV infection and/or reducing the likelihood or severity of symptoms
of
HCV infection.
(e) The combination of (d), wherein the HCV antiviral agent is an
antiviral selected from the group consisting of HCV protease inhibitors and
HCV
NS5B polymerase inhibitors.
(0 A method of inhibiting HCV replication in a subject in need
thereof which comprises administering to the subject an effective amount of a
Compound of Formula (I).
(g) A method of treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection in a subject in need
thereof
which comprises administering to the subject an effective amount of a Compound
of
Formula (I).
(h) The method of (g), wherein the Compound of Formula (I) is
administered in combination with an effective amount of at least one second
therapeutic agent selected from the group consisting of HCV antiviral agents,
immunomodulators, and anti-infective agents.
(i) The method of (h), wherein the HCV antiviral agent is an
antiviral selected from the group consisting of HCV protease inhibitors and
HCV
NS5B polymerase inhibitors.

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(j) A method of inhibiting HCV replication in a subject in need
thereof which comprises administering to the subject the pharmaceutical
composition
of (a), (b) or (c) or the combination of (d) or (e).
(k) A method of treating HCV infection and/or reducing the
likelihood or severity of symptoms of HCV infection in a subject in need
thereof
which comprises administering to the subject the pharmaceutical composition of
(a),
(b) or (c) or the combination of (d) or (e).
The present invention also includes a compound of the present
invention for use (i) in, (ii) as a medicament for, or (iii) in the
preparation of a
medicament for: (a) medicine; (b) inhibiting HCV replication or (c) treating
HCV
infection and/or reducing the likelihood or severity of symptoms of HCV
infection.
In these uses, the compounds of the present invention can optionally be
employed in
combination with one or more second therapeutic agents selected from HCV
antiviral
agents, anti-infective agents, and immunomodulators.
The present invention also includes the use of a compound of the
present invention for (i) inhibiting HCV replication or (ii) treating HCV
infection
and/or reducing the likelihood or severity of symptoms of HCV infection.
Additional embodiments of the invention include the pharmaceutical
compositions, combinations and methods set forth in (a)-(k) above and the uses
set
forth in the preceding paragraph, wherein the compound of the present
invention
employed therein is a compound of one of the embodiments, aspects, classes,
sub-
classes, or features of the compounds described above. In all of these
embodiments,
the compound may optionally be used in the form of a pharmaceutically
acceptable
salt or hydrate as appropriate.
It is further to be understood that the embodiments of compositions
and methods provided as (a) through (k) above are understood to include all
embodiments of the compounds, including such embodiments as result from
combinations of embodiments.
The Compounds of Formula (I) may be referred to herein by chemical
structure and/or by chemical name. In the instance that both the structure and
the
name of a Compound of Formula (I) are provided and a discrepancy is found to
exist
between the chemical structure and the corresponding chemical name, it is
understood
that the chemical structure will predominate.

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Non-limiting examples of the Compounds of Formula (I) include (i)
compounds 1-1542, as set forth in Tables 1 and 2 in the Examples Section
below.
Methods For Makin2 the Compounds of Formula (I)
The Compounds of Formula (I) may be prepared from known or
readily prepared starting materials, following methods known to one skilled in
the art
of organic synthesis. Methods useful for making the Compounds of Formula (I)
are
set forth in the Examples below and generalized in Schemes 1-5 below.
Alternative
synthetic pathways and analogous structures will be apparent to those skilled
in the art
of organic synthesis.
Scheme 1 shows methods useful for making the Compounds of
formula G8, which correspond to the Compounds of Formula (I), wherein B is
phenyl
and the group ¨U-V-W- is ¨C(R2)=CH-N-.
Scheme 1
H HCI
3

7
r
R

1


G1 G2 G3
R'5
R2 R2 R15 R2 R15
Q I Q" Q I \-1-/ Cr ______________ =#
H R1 K.
G4 R1 G5 G6 G7
R2 R15
*
G8
Wherein Q and Q' are each independently halo, hydroxy, or a protected
hydroxy such as methoxy or benzyloxy; M, M', M" are each independently halo,
hydroxy, or a protected hydroxy, triflate, boronic acid or boronic ester; K
represents a
group that can form a bond to the indole nitrogen. One skilled in the art of
organic
synthesis will recognize that when G is single or multiatom bridge, K should
contain
all the atoms of the bridge and a reactive group capable of forming a bond to
nitrogen
of the indole. Examples of reactive groups capable of forming a bond to
nitrogen are

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well known to one skilled in the art of organic synthesis and non-limiting
examples
include an alkyl halide, vinyl halide, aldehyde group or a vicinal dihalide. Z
represents an appropriate aryl coupling partner which will be well known to
one
skilled in the art of organic chemistry. An example of aryl coupling partners
include
but are not limited to halide and triflate when the other partner is an
arylboron or
arylstannane derivative.
Tetracyclic Compounds of formula G8 can be prepared from suitably
substituted indole derivatives of formula G6. An indole derivative of formula
G6 is
cyclized to provide tetracyclic Compounds of formula G7. Indole derivatives of

formula G6 may be obtained commercially or prepared by using methods known to
those skilled in the art of organic synthesis. In an illustrative example, the
Compounds of formula G6 can be made via dehydration of a hydrazide of formula
G1
with a ketone of formula G2 to provide hydrazones of formula G3, which can
then be
cyclized in the presence of a strong acid such as PPA or a Lewis acid such as
aluminum chloride, to provide the hydroxyl-substituted indole Compounds of
formula
G4. A Compound of formula G4 can then be reacted with an aldehyde of formula
R3-
CHO to provide the cyclized Compounds of formula G8, wherein G is ¨CHR3-0-.
Compounds of formula G7 can be made, for example, via the arylation
of the 2-position of an indole of formula G5 with a coupling partner of
formula G6.
A Compound of formula G7 can then be cyclized by reacting Y and K' to provide
the
Compounds of formula G8. It will be obvious to one skilled in the art of
organic
synthesis that the Compounds of formulas G4 and G7 may undergo further
functional
group manipulations prior to cyclization as necessary in order to provide the
scope of
the Compounds of Formula (I).
Scheme 2 shows a method useful for making the Compounds of
formula G12, which correspond to the Compounds of Formula (I), wherein B is
phenyl; X and X' are each CH; Y and Y' are each N; and the group ¨U-V-W- is ¨
C(R2)=CH-N-.
Scheme 2

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R2 R15 PG
- I N
(N.....r__ 1
...-- G24 R2 G9 R15
/
)
G D'
G8
H N M 1-
R2 R15 R4
amide coupling I N
R1
'
G10 G11 G D
Wherein D and D' are each independently C(R13)2, N(R4), S, 0 or
Si(R16) 2; M and M' are each independently halo, triflate, boronic acid or
boronic ester;
PG is a protecting group, such as Boc or 4-methoxybenzyl; R4 is -C(0)R11, -
C(0)-
[C(R7)2]1N(R6)2, -C(0)-[C(R7)21q_Ri 1,
-C(0)4C(R7)2LN(R6)C(0)-R11, -
C(0)[C(R7)2]qN(R6)S02-R11, -C(0)-[C(R7)2]qN(R6)C(0)0-R11 or -C(0)-
[C(R7)2]qC(0)0-R11; and G, R1, R2 and R15 are defined above for the Compounds
of
Formula (I).
Scheme 3 shows a method useful for making the Compounds of
formula G16, which correspond to the Compounds of Formula (I), wherein B is
phenyl; X and X' are each CH; Y and Y' are each N; and the group ¨U-V-W- is -
N=CH-N-.
Scheme 3
R
R15 15
Q R1
SPI NH2
\ / Q
X R1 N NH2
H
K' K'
G12 G13 G14
II 1
t
R4
õ,µ N R15
R15
z- H
7---)--,---\N -.--
..._____ M & N\>_0_m,
RI N.-- R1 ..."11" N
\
G16 G15
Wherein Z and Z' are each independently C(R13)2, N(R4), S, 0 or
Si(R16) 2; M and M' are each independently halo, triflate, boronic acid or
boronic ester;
X is halo; R4 is -C(0)R11, -C(0)4C(R7)2]qN(R6)2, -C(0)1C(R7)2L-R11, -C(0)-

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[C(R7)2]qN(R6)C(0)-RI I, -C(0)[C(R7)2]qN(R6)S02-RII, -C(0)-
[C(R7)2]qN(R6)C(0)0-
Ril or -C(0)-[C(R7)2]qC(0)0-R"; K, Q and Q' are defined above in connection
with
Scheme 1; and G, R2 and R15 are defined above for the Compounds of Formula
(I).
A 2-amino aniline derivative of formula G12 can be reacted with an
acyl halide of formula G13 to provide the 2-substituted benzimidazole
Compounds of
formula G14. The Compounds of formula G14.can be cyclized and derivatized to
provide Compounds of formula G15, using at methods analogous to those
described
in Scheme 1 for the conversion of G6 to G8. A Compound of formula G15 can then

be carried forth to the Compounds of formula G16 using methods analogous to
those
described in Scheme 2.
Scheme 4 shows a method useful for making the Compounds of
formula G20, which correspond to the Compounds of Formula (I), wherein B is
pyridyl; X and X' are each CH; Y and Y' are each N; and the group ¨U-V-W- is ¨

C(R2)=CH-N-.
Scheme 4
R2
N
Q Q' R1 K N\NG
'
G17
G18 G19
R4
LJ
R2
N
H
R1
G20
Wherein Z and Z' are each independently C(R13)2, N(R4), S, 0 or
Si(R16)2; M and M' are each independently halo, triflate, boronic acid or
boronic ester;
R4 is -C(0)R11, -C(0)-[C(R7)2]qN(R6)2, -C(0)-[C(R7)2]q-Rii,
[C(R7)2LN(R6)C(0)-RI 1, -C(0)[C(R7)2]qN(R6)S02-R11 , -C(0)-[C(R7)2]qN(R6)C(0)0-

R11 or -C(0)-[C(R7)2]qC(0)0-R11; and G, RI and R2 are defined above for the
Compounds of Formula (I).
A pyridyl hydrazone of formula G17 can be converted to the
tetracyclic Compounds of formula G19 using methods analogous to those
described
in Scheme 1 for the conversion of G3 to G8. A Compound of formula G19 can then

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be carried forth to the Compounds of G20 using methods analogous to those
described in Scheme 2.
Scheme 5 shows methods useful for making the Compounds of
formula G24, which are useful intermediates for making the Compounds of
Formula
(I) wherein X and X' are each CH and Y and Y' are each N.
Scheme 5
PGPG 0 PG N
N
I
Z--' H N
Z¨ H Z¨ H
G21 G22 G24
%ee >70%
PG N X
N X
Z¨ H
G23
Wherein Z or Z' is C(R13)2, N(R4), S, 0 or Si(R16)2; X is halo or triflate;
and PG is a amino protecting group, such as Boc or 4-methoxybenzyl..
An appropriately functionalized aldehyde of formula G21 can be
reacted with glyoxal and ammonia to provide a substituted imidazole of formula
G22.
A Compound of formula G22 can subsequently be selectively mono-halogenated to
provide a mono-halogenated imidazole Compound of formula G24. Alternatively, a

Compound of formula G24 can subsequently be di-halogenated to provide a
Compound of formula G23, which is then selectively reduced to provide a mono-
halogenated imidazole Compound of formula G24.
In some of the Compounds of Formula (I) contemplated in Schemes 1-
5, amino acids (such as, but not limited to proline, 4-(R)-fluoroproline, 4-
(S)-
fluoroproline, 4,4-difluoroproline, 4,4-dimethylsilylproline, aza-
bicyclo[2.2.1]heptane
carboxylic acid, aza-bicyclo[2.2.2]octane carboxylic acid, (S)-2-piperidine
carboxylic
acid, valine, alanine, norvaline, etc.) are incorporated as part of the
structures.
Methods have been described in the organic chemistry literature as well as in
Banchard US 2009/0068140 (Published March 9th 2009) for the preparation of
such
amino acid-derived intermediates.
One skilled in the art of organic synthesis will recognize that the
synthesis of fused tetracyclic cores contained in Compounds of Formula (I) may

require protection of certain functional groups (i.e., derivatization for the
purpose of

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57
chemical compatibility with a particular reaction condition). Suitable
protecting
groups for the various functional groups of these Compounds and methods for
their
installation and removal are well known in the art of organic chemistry. A
summary
of many of these methods can be found in Greene et al., Protective Groups in
Organic Synthesis, Wiley-Interscience, New York, (1999).
One skilled in the art of organic synthesis will also recognize that one
route for the synthesis of the fused tetracyclic cores of the Compounds of
Formula (I)
may be more desirable depending on the choice of appendage substituents.
Additionally, one skilled in the art will recognize that in some cases the
order of
reactions may differ from that presented herein to avoid functional group
incompatibilities and thus adjust the synthetic route accordingly.
One skilled in the art of organic synthesis will recognize that the
synthesis of certain fused tetracyclic cores of the Compounds of Formula (I)
require
the construction of an amide bond. Methods useful for making such amide bonds,

include but are not limited to, the use of a reactive carboxy derivative
(e.g., an acid
halide, or ester at elevated temperatures) or the use of an acid with a
coupling reagent
(e.g., HOBt, EDCI, DCC, HATU, PyBrop) with an amine.
The preparation of multicyclic intermediates useful for making the
fused tetracyclic ring systems of the Compounds of Formula (I) have been
described
in the literature and in compendia such as "Comprehensive Heterocyclic
Chemistry"
editions I, II and III, published by Elsevier and edited by A.R. Katritzky &
R. JK
Taylor. Manipulation of the required substitution patterns have also been
described in
the available chemical literature as summarized in compendia such as
"Comprehensive Organic Chemistry" published by Elsevier and edited by DH R.
Barton and W. D. 011is; "Comprehensive Organic Functional Group
Transformations"
edited by edited by A.R. Katritzky & R. JK Taylor and "Comprehensive Organic
Transformation" published by Wily-CVH and edited by R. C. Larock.
The Compounds Formula (I) may contain one or more silicon atoms.
The Compounds contemplated in this invention in general can be prepared using
the
carba-analog methodology unless otherwise noted. A recent review of the
synthesis of
silicon containing Compounds can be found in "Silicon Chemistry: from Atom to
Extended Systems", Ed P. Jutzi & U. Schubet; ISBN 978-3-527-30647-3.
Preparation of silyl containing amino acids has been described. See Bolm et
al.,
Angew. Chem. Int Ed., 39:2289 (2000). Descriptions of improved cellular update

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58
( Giralt, J. Am. Chem. Soc., 128:8479 (2006)) and reduced metabolic processing
of
silyl containing Compounds have been described ( Johansson et al., Drug
Metabolism
& Disposition, 38:73 (2009)).
The starting materials used and the intermediates prepared using the
methods set forth in Schemes 1-5 may be isolated and purified if desired using

conventional techniques, including but not limited to filtration,
distillation,
crystallization, chromatography and alike. Such materials can be characterized
using
conventional means, including physical constants and spectral data.
Uses of the Tetracvclic Indole Derivatives
The Tetracyclic Indole Derivatives are useful in human and veterinary
medicine for treating or preventing a viral infection in a patient. In one
embodiment,
the Tetracyclic Indole Derivatives can be inhibitors of viral replication. In
another
embodiment, the Tetracyclic Indole Derivatives can be inhibitors of HCV
replication.
Accordingly, the Tetracyclic Indole Derivatives are useful for treating viral
infections,
such as HCV. In accordance with the invention, the Tetracyclic Indole
Derivatives
can be administered to a patient in need of treatment or prevention of a viral
infection.
Accordingly, in one embodiment, the invention provides methods for
treating a viral infection in a patient comprising administering to the
patient an
effective amount of at least one Tetracyclic Indole Derivative or a
pharmaceutically
acceptable salt thereof.
Treatment or Prevention of a Flaviviridae Virus
The Tetracyclic Indole Derivatives can be useful for treating or
preventing a viral infection caused by the Flaviviridae family of viruses.
Examples of Flaviviridae infections that can be treated or prevented
using the present methods include but are not limited to, dengue fever,
Japanese
encephalitis, Kyasanur Forest disease, Murray Valley encephalitis, St. Louis
encephalitis, Tick-borne encephalitis, West Nile encephalitis, yellow fever
and
Hepatitis C Virus (HCV) infection.
In one embodiment, the Flaviviridae infection being treated is hepatitis
C virus infection.
Treatment or Prevention of HCV Infection

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The Tetracyclic Indole Derivatives are useful in the inhibition of HCV
(e.g., HCV NS5A), the treatment of HCV infection and/or reduction of the
likelihood
or severity of symptoms of HCV infection and the inhibition of HCV viral
replication
and/or HCV viral production in a cell-based system. For example, the
Tetracyclic
Indole Derivatives are useful in treating infection by HCV after suspected
past
exposure to HCV by such means as blood transfusion, exchange of body fluids,
bites,
accidental needle stick, or exposure to patient blood during surgery or other
medical
procedures.
In one embodiment, the hepatitis C infection is acute hepatitis C. In
another embodiment, the hepatitis C infection is chronic hepatitis C.
Accordingly, in one embodiment, the invention provides methods for
treating HCV infection in a patient, the methods comprising administering to
the
patient an effective amount of at least one Tetracyclic Indole Derivative or a

pharmaceutically acceptable salt thereof. In a specific embodiment, the amount

administered is effective to treat or prevent infection by HCV in the patient.
In
another specific embodiment, the amount administered is effective to inhibit
HCV
viral replication and/or viral production in the patient.
The Tetracyclic Indole Derivatives are also useful in the preparation
and execution of screening assays for antiviral compounds. For example the
Tetracyclic Indole Derivatives are useful for identifying resistant HCV
replicon cell
lines harboring mutations within NS5A, which are excellent screening tools for
more
powerful antiviral compounds. Furthermore, the Tetracyclic Indole Derivatives
are
useful in establishing or determining the binding site of other antivirals to
the HCV
replicase.
The compositions and combinations of the present invention can be
useful for treating a patient suffering from infection related to any HCV
genotype.
HCV types and subtypes may differ in their antigenicity, level of viremia,
severity of
disease produced, and response to interferon therapy as described in Holland
et al.,
Pathology, 30(2):192-195 (1998). The nomenclature set forth in Simmonds etal.,
J
Gen Virol, 74(Pt11):2391-2399 (1993) is widely used and classifies isolates
into six
major genotypes, 1 through 6, with two or more related subtypes, e.g., la and
lb.
Additional genotypes 7-10 and 11 have been proposed, however the phylogenetic
basis on which this classification is based has been questioned, and thus
types 7, 8, 9
and 11 isolates have been reassigned as type 6, and type 10 isolates as type 3
(see

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Lamballerie et al., J Gen Virol, 78(Pt1):45-51 (1997)). The major genotypes
have
been defined as having sequence similarities of between 55 and 72% (mean
64.5%),
and subtypes within types as having 75%-86% similarity (mean 80%) when
sequenced in the NS-5 region (see Simmonds etal., J Gen Virol, 75(Pt 5):1053-
1061
(1994)).
Combination Therapy
In another embodiment, the present methods for treating or preventing
HCV infection can further comprise the administration of one or more
additional
therapeutic agents which are not Tetracyclic Indole Derivatives.
In one embodiment, the additional therapeutic agent is an antiviral
agent.
In another embodiment, the additional therapeutic agent is an
immunomodulatory agent, such as an immunosuppressive agent.
Accordingly, in one embodiment, the present invention provides
methods for treating a viral infection in a patient, the method comprising
administering to the patient: (i) at least one Tetracyclic Indole Derivative,
or a
pharmaceutically acceptable salt thereof, and (ii) at least one additional
therapeutic
agent that is other than a Tetracyclic Indole Derivative, wherein the amounts
administered are together effective to treat or prevent a viral infection.
When administering a combination therapy of the invention to a patient,
therapeutic agents in the combination, or a pharmaceutical composition or
compositions comprising therapeutic agents, may be administered in any order
such
as, for example, sequentially, concurrently, together, simultaneously and the
like. The
amounts of the various actives in such combination therapy may be different
amounts
(different dosage amounts) or same amounts (same dosage amounts). Thus, for
non-
limiting illustration purposes, a Tetracyclic Indole Derivative and an
additional
therapeutic agent may be present in fixed amounts (dosage amounts) in a single

dosage unit (e.g., a capsule, a tablet and the like).
In one embodiment, the at least one Tetracyclic Indole Derivative is
administered during a time when the additional therapeutic agent(s) exert
their
prophylactic or therapeutic effect, or vice versa.

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In another embodiment, the at least one Tetracyclic Indole Derivative
and the additional therapeutic agent(s) are administered in doses commonly
employed
when such agents are used as monotherapy for treating a viral infection.
In another embodiment, the at least one Tetracyclic Indole Derivative
and the additional therapeutic agent(s) are administered in doses lower than
the doses
commonly employed when such agents are used as monotherapy for treating a
viral
infection.
In still another embodiment, the at least one Tetracyclic Indole
Derivative and the additional therapeutic agent(s) act synergistically and are
administered in doses lower than the doses commonly employed when such agents
are
used as monotherapy for treating a viral infection.
In one embodiment, the at least one Tetracyclic Indole Derivative and
the additional therapeutic agent(s) are present in the same composition. In
one
embodiment, this composition is suitable for oral administration. In another
embodiment, this composition is suitable for intravenous administration. In
another
embodiment, this composition is suitable for subcutaneous administration. In
still
another embodiment, this composition is suitable for parenteral
administration.
Viral infections and virus-related disorders that can be treated or
prevented using the combination therapy methods of the present invention
include,
but are not limited to, those listed above.
In one embodiment, the viral infection is HCV infection.
The at least one Tetracyclic Indole Derivative and the additional
therapeutic agent(s) can act additively or synergistically. A synergistic
combination
may allow the use of lower dosages of one or more agents and/or less frequent
administration of one or more agents of a combination therapy. A lower dosage
or
less frequent administration of one or more agents may lower toxicity of
therapy
without reducing the efficacy of therapy.
In one embodiment, the administration of at least one Tetracyclic
Indole Derivative and the additional therapeutic agent(s) may inhibit the
resistance of
a viral infection to these agents.
Non-limiting examples of additional therapeutic agents useful in the
present compositions and methods include an interferon, an immunomodulator, a
viral
replication inhibitor, an antisense agent, a therapeutic vaccine, a viral
polymerase
inhibitor, a nucleoside inhibitor, a viral protease inhibitor, a viral
helicase inhibitor, a

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62
virion production inhibitor, a viral entry inhibitor, a viral assembly
inhibitor, an
antibody therapy (monoclonal or polyclonal), and any agent useful for treating
an
RNA-dependent polymerase-related disorder.
In one embodiment, the additional therapeutic agent is a viral protease
inhibitor.
In another embodiment, the additional therapeutic agent is a viral
replication inhibitor.
In another embodiment, the additional therapeutic agent is an HCV
NS3 protease inhibitor.
In still another embodiment, the additional therapeutic agent is an
HCV NS5B polymerase inhibitor.
In another embodiment, the additional therapeutic agent is a nucleoside
inhibitor.
In another embodiment, the additional therapeutic agent is an
interferon.
In yet another embodiment, the additional therapeutic agent is an HCV
replicase inhibitor.
In another embodiment, the additional therapeutic agent is an antisense
agent.
In another embodiment, the additional therapeutic agent is a
therapeutic vaccine.
In a further embodiment, the additional therapeutic agent is a virion
production inhibitor.
In another embodiment, the additional therapeutic agent is an antibody
therapy.
In another embodiment, the additional therapeutic agent is an HCV
NS2 inhibitor.
In still another embodiment, the additional therapeutic agent is an
HCV NS4A inhibitor.
In another embodiment, the additional therapeutic agent is an HCV
NS4B inhibitor.
In another embodiment, the additional therapeutic agent is an HCV
NS5A inhibitor

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In yet another embodiment, the additional therapeutic agent is an HCV
NS3 helicase inhibitor.
In another embodiment, the additional therapeutic agent is an HCV
IRES inhibitor.
In another embodiment, the additional therapeutic agent is an HCV p7
inhibitor.
In a further embodiment, the additional therapeutic agent is an HCV
entry inhibitor.
In another embodiment, the additional therapeutic agent is an HCV
assembly inhibitor.
In one embodiment, the additional therapeutic agents comprise a viral
protease inhibitor and a viral polymerase inhibitor.
In still another embodiment, the additional therapeutic agents comprise
a viral protease inhibitor and an immunomodulatory agent.
In yet another embodiment, the additional therapeutic agents comprise
a polymerase inhibitor and an immunomodulatory agent.
In another embodiment, the additional therapeutic agents comprise a
viral protease inhibitor and a nucleoside.
In another embodiment, the additional therapeutic agents comprise an
immunomodulatory agent and a nucleoside.
In one embodiment, the additional therapeutic agents comprise an
HCV protease inhibitor and an HCV polymerase inhibitor.
In another embodiment, the additional therapeutic agents comprise a
nucleoside and an HCV NS5A inhibitor.
In another embodiment, the additional therapeutic agents comprise a
viral protease inhibitor, an immunomodulatory agent and a nucleoside.
In a further embodiment, the additional therapeutic agents comprise a
viral protease inhibitor, a viral polymerase inhibitor and an immunomodulatory
agent.
In another embodiment, the additional therapeutic agent is ribavirin.
HCV polymerase inhibitors useful in the present compositions and
methods include, but are not limited to, VP-19744 (Wyeth/ViroPharma), PSI-7851

(Pharmasset), RG7128 (Roche/Pharmasset), PSI-938 (Pharmasset), PSI-7977
(Pharmasset), PF-868554/filibuvir (Pfizer), VCH-759 (ViroChem Pharma), HCV-796

(Wyeth/ViroPharma), IDX-184 (Idenix), IDX-375 (Idenix), NM-283

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(Idenix/Novartis), R-1626 (Roche), MK-0608 (Isis/Merck), INX-8014 (Inhibitex),

1NX-8018 (Inhibitex), INX-189 (Inhibitex), GS 9190 (Gilead), A-848837
(Abbott),
ABT-333 (Abbott), ABT-072 (Abbott), A-837093 (Abbott), BI-207127 (Boehringer-
Ingelheim), BILB-1941 (Boehringer-Ingelheim), MK-3281 (Merck), VCH222
(ViroChem), VCH916 (ViroChem), VCH716(ViroChem), GSK-71185 (Glaxo
SmithKline), ANA598 (Anadys), GSK-625433 (Glaxo SmithKline), XTL-2125 (XTL
Biopharmaceuticals), and those disclosed in Ni et al., Current Opinion in Drug

Discovery and Development, 7(4):446 (2004); Tan et al., Nature Reviews, 1:867
(2002); and Beaulieu et al., Current Opinion in Investigational Drugs, 5:838
(2004).
Other HCV polymerase inhibitors useful in the present compositions
and methods include, but are not limited to, those disclosed in International
Publication Nos. WO 08/082484, WO 08/082488, WO 08/083351, WO 08/136815,
WO 09/032116, WO 09/032123, WO 09/032124 and WO 09/032125.
Interferons useful in the present compositions and methods include, but
are not limited to, interferon alfa-2a, interferon alfa-2b, interferon alfacon-
1 and PEG-
interferon alpha conjugates. "PEG-interferon alpha conjugates" are interferon
alpha
molecules covalently attached to a PEG molecule. Illustrative PEG-interferon
alpha
conjugates include interferon alpha-2a (RoferonTm, Hoffman La-Roche, Nutley,
New
Jersey) in the form of pegylated interferon alpha-2a (e.g., as sold under the
trade name
PegasysTm), interferon alpha-2b (IntronTm, from Schering-Plough Corporation)
in the
form of pegylated interferon alpha-2b (e.g., as sold under the trade name PEG-
Intronlivi from Schering-Plough Corporation), interferon alpha-2b-XL (e.g., as
sold
under the trade name PEG-IntronTm), interferon alpha-2c (Berofor AlphaTm,
Boehringer Ingelheim, Ingelheim, Germany), PEG-interferon lambda (Bristol-
Myers
Squibb and ZymoGenetics), interferon alfa-2b alpha fusion polypeptides,
interferon
fused with the human blood protein albumin (AlbuferonTm, Human Genome
Sciences), Omega Interferon (Intarcia), Locteron controlled release interferon

(Biolex/OctoPlus), Biomed-510 (omega interferon), Peg-IL-29 (ZymoGenetics),
Locteron CR (Octoplus), IFN-a-2b-XL (Flamel Technologies), and consensus
interferon as defined by determination of a consensus sequence of naturally
occurring
interferon alphas (InfergenTm, Amgen, Thousand Oaks, California).
Antibody therapy agents useful in the present compositions and
methods include, but are not limited to, antibodies specific to IL-10 (such as
those
disclosed in US Patent Publication No. US2005/0101770, humanized 12G8, a

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humanized monoclonal antibody against human IL-10, plasmids containing the
nucleic acids encoding the humanized 12G8 light and heavy chains were
deposited
with the American Type Culture Collection (ATCC) as deposit numbers PTA-5923
and PTA-5922, respectively), and the like).
Examples of viral protease inhbitors useful in the present compositions
and methods include, but are not limited to, an HCV protease inhibitor.
HCV protease inhibitors useful in the present compositions and
methods include, but are not limited to, those disclosed in U.S. Patent Nos.
7,494,988,
7,485,625, 7,449,447, 7,442,695, 7,425,576, 7,342,041, 7,253,160, 7,244,721,
7,205,330, 7,192,957, 7,186,747, 7,173,057, 7,169,760, 7,012,066, 6,914,122,
6,911,428, 6,894,072, 6,846,802, 6,838,475, 6,800,434, 6,767,991, 5,017,380,
4,933,443, 4,812,561 and 4,634,697; U.S. Patent Publication Nos.
U520020068702,
U520020160962, US20050119168, US20050176648, US20050209164,
US20050249702 and US20070042968; and International Publication Nos. WO
03/006490, WO 03/087092, WO 04/092161 and WO 08/124148.
Additional HCV protease inhibitors useful in the present compositions
and methods include, but are not limited to, SCH503034 (Boceprevir, Schering-
Plough), SCH900518 (Schering-Plough), VX-950 (Telaprevir, Vertex), VX-500
(Vertex), VX-813 (Vertex), VBY-376 (Virobay), MK-7009 (Merck), MK-5172
(Merck), BI-201335 (Boehringer Ingelheim), TMC-435 (Medivir/Tibotec), ABT-450
(Abbott), TMC-435350 (Medivir), ITMN-191/R7227 (InterMune/Roche), EA-058
(Abbott/Enanta), EA-063 (Abbott/Enanta), GS-9132 (Gilead/Achillion), ACH-1095
(Gilead/Achillon), IDX-136 (Idenix), IDX-316 (Idenix), ITMN-8356 (InterMune),
ITMN-8347 (InterMune), ITMN-8096 (InterMune), ITMN-7587 (InterMune), BMS-
650032 (Bristol-Myers Squibb), VX-985 (Vertex) and PHX1766 (Phenomix).
Further examples of HCV protease inhbitors useful in the present
compositions and methods include, but are not limited to, those disclosed in
Landro et
al., Biochemistry, 36(31):9340-9348 (1997); Ingallinella etal., Biochemistry,
37(25):8906-8914 (1998); Llinas-Brunet etal., Bioorg Med Chem Lett, 8(13):1713-

1718 (1998); Martin etal., Biochemistry, 37(33):11459-11468 (1998); Dimasi
etal., J
Virol, 71(10):7461-7469 (1997); Martin etal., Protein Eng, 10(5):607-614
(1997);
Elzouki etal., J Hepat, 27(1):42-48 (1997); BioWorld Today, 9(217):4 (November
10,
1998); U.S. Patent Publication Nos. US2005/0249702 and US 2007/0274951; and

CA 02811662 2013-03-19
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66
International Publication Nos. WO 98/14181, WO 98/17679, WO 98/17679, WO
98/22496 and WO 99/07734 and WO 05/087731.
Further examples of HCV protease inhibitors useful in the present
compositions and methods include, but are not limited to, the following
compounds:
a
OCH3
N '
I
N
I
Q 0
Q. o= Ho\sõo
H H 0, õ0
HN 'V
1µ1)(N\N-S.7 .,õ,, 0 \
'0 H j I
0
y
'0 H j I.,, N ..,
0 0
0 /\
ati OCH3
N ' I
N 'WI
N
i' o y)
jN
H
H o 'o N
j.",'s (I
L "H
.s
j o
,,,,0 ( I
V
o
0 0
0 /\
OCH3
N*
I
<rN 0 isi_c0
Q o

H H 0,_.õ0 q
c(N1µ11-b7 Q.
Y H 0 0
.,
: HJO
b N Y i 0
--1,_ 0
0

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67
\/
H 0 y
\/
$1.1.,
0
H
C.3.1(NrNH2 0
H H 7 0 OyNH
>rNyNo
011H
'r
Ozfs
\/ \/
0 s--...
H 0
4---)e
....NjcNH2 Cfi g 0 NeFil
H H N " i II
FI H H 9.)1.H2
0 ,
y LI o
\./
.,õ
b
-40 +9.0 ,__,
S'
rl rµikA 0 T il H H N 11 E II
y 1 o il bNyN,0 0 r 0V
v \/
,.... ,....
0 H 0 H
+P H
+ g
-to H H 4-121 I II
81 N,A 0.<- 0 bNyN00.(r.7 0
y E 0
\/ \/
9 F0 H 9 l
0 H
H H 1 'YN1N ilyKrN
CO i II S(:) H H C-Iri
orbNyN,..A00; 0 N N,. 0 -/ 0
o =-N.

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68
CL
,CI
õciA
0 0
9 r
H H 0,1rH 1
(\111j=yi
0)..u,oN No 0 0 SO2EiHy0i0N=7
Y i f NyNo I
o

\/
\/
H >1.....rtalor
NrNH
0
0 II
o
-1,Nr ,--7
H H 1 V 0
\0_7 bN N, 0 Oy NH
y E o
o 011H
0\r:::
\/ \/
."..-% 7 .,, 7
0...y 1-NiJir NH fly EN11,5.1r NH
>40 0 i 0
)Lr0
OyN H
ON H
OsN H CINH
0.7.-,,sµ z
6/
\/v
wriAr_,
0-- 1,Nµ 0
b
y 6 0
0 v
and 'C) rj)ro EN1 0 110 v
Viral replication inhibitors useful in the present compositions and
methods include, but are not limited to, HCV replicase inhibitors, IRES
inhibitors,
NS4A inhibitors, NS3 helicase inhibitors, NS5A inhibitors, NS5B inhibitors,
ribavirin,
AZD-2836 (Astra Zeneca), BMS-790052 (Bristol-Myers Squibb, see Gao et al.,
Nature, 465:96-100 (2010)), viramidine, A-831 (Arrow Therapeutics); an
antisense
agent or a therapeutic vaccine.

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HCV NS4A inhibitors useful in the useful in the present compositions
and methods include, but are not limited to, those disclosed in U.S. Patent
Nos.
7,476,686 and 7,273,885; U.S. Patent Publication No. US20090022688; and
International Publication Nos. WO 2006/019831 and WO 2006/019832. Additional
HCV NS4A inhibitors useful in the useful in the present compositions and
methods
include, but are not limited to, AZD2836 (Astra Zeneca) and ACH-806 (Achillon
Pharmaceuticals, New Haven, CT).
HCV replicase inhibitors useful in the useful in the present
compositions and methods include, but are not limited to, those disclosed in
U.S.
Patent Publication No. US20090081636.
Therapeutic vaccines useful in the present compositions and methods
include, but are not limited to, IC41 (Intercell Novartis), CSL123
(Chiron/CSL), GI
5005 (Globeimmune), TG-4040 (Transgene), GNI-103 (GENimmune), Hepavaxx C
(ViRex Medical), ChronVac-C (Inovio/Tripep), PeviPROTM (Pevion Biotect),
HCV/MF59 (Chiron/Novartis) and Civacir (NABI).
Examples of further additional therapeutic agents that may be useful in
the present compositions and methods include, but are not limited to,
Ritonavir
(Abbott), TT033 (Benitec/Tacere Bio/Pfizer), Sirna-034 (Sirna Therapeutics),
GNI-
104 (GENimmune), GI-5005 (GlobeImmune), IDX-102 (Idenix), LevovirinTm (ICN
Pharmaceuticals, Costa Mesa, California); Humax (Genmab), ITX-2155
(Ithrex/Novartis), PRO 206 (Progenics), HepaCide-I (NanoVirocides), M1X3235
(Migenix), SCY-635 (Scynexis); KPE02003002 (Kemin Pharma), Lenocta (VioQuest
Pharmaceuticals), JET ¨ Interferon Enhancing Therapy (Transition
Therapeutics),
Zadaxin (SciClone Pharma), VP 50406Tm (Viropharma, Incorporated, Exton,
Pennsylvania); Taribavirin (Valeant Pharmaceuticals); Nitazoxanide (Romark);
Debio
025 (Debiopharm); GS-9450 (Gilead); PF-4878691 (Pfizer); ANA773 (Anadys);
SCV-07 (SciClone Pharmaceuticals); NIM-881 (Novartis); ISIS 14803Tm (ISIS
Pharmaceuticals, Carlsbad, California); HeptazymeTm (Ribozyme Pharmaceuticals,

Boulder, Colorado); ThymosinTm (SciClone Pharmaceuticals, San Mateo,
California);
MaxamineTm (Maxim Pharmaceuticals, San Diego, California); NKB-122 (JenKen
Bioscience Inc., North Carolina); Alinia (Romark Laboratories), INFORM-1 (a
combination of R7128 and ITMN-191); and mycophenolate mofetil (Hoffman-
LaRoche, Nutley, New Jersey).

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The doses and dosage regimen of the other agents used in the
combination therapies of the present invention for the treatment or prevention
of HCV
infection can be determined by the attending clinician, taking into
consideration the
approved doses and dosage regimen in the package insert; the age, sex and
general
health of the patient; and the type and severity of the viral infection or
related disease
or disorder. When administered in combination, the Tetracyclic Indole
Derivative(s)
and the other agent(s) can be administered simultaneously (i.e., in the same
composition or in separate compositions one right after the other) or
sequentially.
This particularly useful when the components of the combination are given on
different dosing schedules, e.g., one component is administered once daily and

another component is administered every six hours, or when the preferred
pharmaceutical compositions are different, e.g., one is a tablet and one is a
capsule. A
kit comprising the separate dosage forms is therefore advantageous.
Generally, a total daily dosage of the at least one Tetracyclic Indole
Derivative(s) alone, or when administered as combination therapy, can range
from
about 1 to about 2500 mg per day, although variations will necessarily occur
depending on the target of therapy, the patient and the route of
administration. In one
embodiment, the dosage is from about 10 to about 1000 mg/day, administered in
a
single dose or in 2-4 divided doses. In another embodiment, the dosage is from
about
1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
In still
another embodiment, the dosage is from about 1 to about 100 mg/day,
administered in
a single dose or in 2-4 divided doses. In yet another embodiment, the dosage
is from
about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided
doses. In
another embodiment, the dosage is from about 500 to about 1500 mg/day,
administered in a single dose or in 2-4 divided doses. In still another
embodiment, the
dosage is from about 500 to about 1000 mg/day, administered in a single dose
or in 2-
4 divided doses. In yet another embodiment, the dosage is from about 100 to
about
500 mg/day, administered in a single dose or in 2-4 divided doses.
In one embodiment, when the additional therapeutic agent is INTRON-
A interferon alpha 2b (commercially available from Schering-Plough Corp.),
this
agent is administered by subcutaneous injection at 3MIU(12 mcg)/0.5mL/TIW for
24
weeks or 48 weeks for first time treatment.
In another embodiment, when the additional therapeutic agent is PEG-
INTRON interferon alpha 2b pegylated (commercially available from Schering-

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Plough Corp.), this agent is administered by subcutaneous injection at 1.5
mcg/kg/week, within a range of 40 to 150 mcg/week, for at least 24 weeks.
In another embodiment, when the additional therapeutic agent is
ROFERON A interferon alpha 2a (commercially available from Hoffmann-La Roche),

this agent is administered by subcutaneous or intramuscular injection at
3MIU(11.1
mcg/mL)/TIW for at least 48 to 52 weeks, or alternatively 6MIU/TIW for 12
weeks
followed by 3MIU/TIW for 36 weeks.
In still another embodiment, when the additional therapeutic agent is
PEGASUS interferon alpha 2a pegylated (commercially available from Hoffmann-La

Roche), this agent is administered by subcutaneous injection at 180 mcg/lmL or
180
mcg/0.5mL, once a week for at least 24 weeks.
In yet another embodiment, when the additional therapeutic agent is
INFERGEN interferon alphacon-1 (commercially available from Amgen), this agent

is administered by subcutaneous injection at 9 mcg/TIW is 24 weeks for first
time
treatment and up to 15 mcg/TIW for 24 weeks for non-responsive or relapse
treatment.
In a further embodiment, when the additional therapeutic agent is
Ribavirin (commercially available as REBETOL ribavirin from Schering-Plough or

COPEGUS ribavirin from Hoffmann-La Roche), this agent is administered at a
daily
dosage of from about 600 to about 1400 mg/day for at least 24 weeks.
In one embodiment, one or more compounds of the present invention
are administered with one or more additional therapeutic agents selected from:
an
interferon, an immunomodulator, a viral replication inhibitor, an antisense
agent, a
therapeutic vaccine, a viral polymerase inhibitor, a nucleoside inhibitor, a
viral
protease inhibitor, a viral helicase inhibitor, a viral polymerase inhibitor a
virion
production inhibitor, a viral entry inhibitor, a viral assembly inhibitor, an
antibody
therapy (monoclonal or polyclonal), and any agent useful for treating an RNA-
dependent polymerase-related disorder.
In another embodiment, one or more compounds of the present
invention are administered with one or more additional therapeutic agents
selected
from an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV
replication
inhibitor, a nucleoside, an interferon, a pegylated interferon and ribavirin.
The
combination therapies can include any combination of these additional
therapeutic
agents.

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In another embodiment, one or more compounds of the present
invention are administered with one additional therapeutic agent selected from
an
HCV protease inhibitor, an interferon, a pegylated interferon and ribavirin.
In still another embodiment, one or more compounds of the present
invention are administered with two additional therapeutic agents selected
from an
HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an
interferon, a
pegylated interferon and ribavirin.
In another embodiment, one or more compounds of the present
invention are administered with an HCV protease inhibitor and ribavirin. In
another
specific embodiment, one or more compounds of the present invention are
administered with a pegylated interferon and ribavirin.
In another embodiment, one or more compounds of the present
invention are administered with three additional therapeutic agents selected
from an
HCV protease inhibitor, an HCV replication inhibitor, a nucleoside, an
interferon, a
pegylated interferon and ribavirin.
In one embodiment, one or more compounds of the present invention
are administered with one or more additional therapeutic agents selected from
an
HCV polymerase inhibitor, a viral protease inhibitor, an interferon, and a
viral
replication inhibitor. In another embodiment, one or more compounds of the
present
invention are administered with one or more additional therapeutic agents
selected
from an HCV polymerase inhibitor, a viral protease inhibitor, an interferon,
and a
viral replication inhibitor. In another embodiment, one or more compounds of
the
present invention are administered with one or more additional therapeutic
agents
selected from an HCV polymerase inhibitor, a viral protease inhibitor, an
interferon,
and ribavirin.
In one embodiment, one or more compounds of the present invention
are administered with one additional therapeutic agent selected from an HCV
polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral
replication
inhibitor. In another embodiment, one or more compounds of the present
invention
are administered with ribavirin.
In one embodiment, one or more compounds of the present invention
are administered with two additional therapeutic agents selected from an HCV
polymerase inhibitor, a viral protease inhibitor, an interferon, and a viral
replication
inhibitor.

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In another embodiment, one or more compounds of the present
invention are administered with ribavirin, interferon and another therapeutic
agent.
In another embodiment, one or more compounds of the present
invention are administered with ribavirin, interferon and another therapeutic
agent,
wherein the additional therapeutic agent is selected from an HCV polymerase
inhibitor, a viral protease inhibitor, and a viral replication inhibitor.
In still another embodiment, one or more compounds of the present
invention are administered with ribavirin, interferon and a viral protease
inhibitor.
In another embodiment, one or more compounds of the present
invention are administered with ribavirin, interferon and an HCV protease
inhibitor.
In another embodiment, one or more compounds of the present
invention are administered with ribavirin, interferon and boceprevir or
telaprevir.
In a further embodiment, one or more compounds of the present
invention are administered with ribavirin, interferon and an HCV polymerase
inhibitor.
In another embodiment, one or more compounds of the present
invention are administered with pegylated-interferon alpha and ribavirin.
In one embodiment, one or more compounds of the present invention
are administered with from one to three additional therapeutic agents, wherein
the
additional therapeutic agents are each independently selected from HCV
protease
inhibitors, HCV NS5A inhibitors and HCV NS5B polymerase inhibitors.
In one embodiment, one or more compounds of the present invention
are administered with MK-5172.
In another embodiment, one or more compounds of the present
invention are administered with MK-7009.
In another embodiment, one or more compounds of the present
invention are administered with boceprevir.
In still another embodiment, one or more compounds of the present
invention are administered with telaprevir.
In another embodiment, one or more compounds of the present
invention are administered with PSI-938.
In another embodiment, one or more compounds of the present
invention are administered with PSI-7977.

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In yet another embodiment, one or more compounds of the present
invention are administered with RG-7128.
In one embodiment, one or more compounds of the present invention
are administered with (i) a compound selected from PSI-7977, PSI-938 RG-7128;
and
(ii) a compound selected from boceprevir, telaprevir, MK-7009 and MK-5172.
In another embodiment, one or more compounds of the present
invention are administered with PSI-7977 and MK-5172.
Compositions and Administration
Due to their activity, the Tetracyclic Indole Derivatives are useful in
veterinary and human medicine. As described above, the Tetracyclic Indole
Derivatives are useful for treating or preventing HCV infection in a patient
in need
thereof.
When administered to a patient, the Tetracyclic Indole Derivatives can
be administered as a component of a composition that comprises a
pharmaceutically
acceptable carrier or vehicle. The present invention provides pharmaceutical
compositions comprising an effective amount of at least one Tetracyclic Indole

Derivative and a pharmaceutically acceptable carrier. In the pharmaceutical
compositions and methods of the present invention, the active ingredients will

typically be administered in admixture with suitable carrier materials
suitably selected
with respect to the intended form of administration, i.e., oral tablets,
capsules (either
solid-filled, semi-solid filled or liquid filled), powders for constitution,
oral gels,
elixirs, dispersible granules, syrups, suspensions, and the like, and
consistent with
conventional pharmaceutical practices. For example, for oral administration in
the
form of tablets or capsules, the active drug component may be combined with
any
oral non-toxic pharmaceutically acceptable inert carrier, such as lactose,
starch,
sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate,
talc,
mannitol, ethyl alcohol (liquid forms) and the like. Solid form preparations
include
powders, tablets, dispersible granules, capsules, cachets and suppositories.
Powders
and tablets may be comprised of from about 0.5 to about 95 percent inventive
composition. Tablets, powders, cachets and capsules can be used as solid
dosage
forms suitable for oral administration.
Moreover, when desired or needed, suitable binders, lubricants,
disintegrating agents and coloring agents may also be incorporated in the
mixture.

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Suitable binders include starch, gelatin, natural sugars, corn sweeteners,
natural and
synthetic gums such as acacia, sodium alginate, carboxymethylcellulose,
polyethylene
glycol and waxes. Among the lubricants there may be mentioned for use in these

dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride,
and the
like. Disintegrants include starch, methylcellulose, guar gum, and the like.
Sweetening and flavoring agents and preservatives may also be included where
appropriate.
Liquid form preparations include solutions, suspensions and emulsions
and may include water or water-propylene glycol solutions for parenteral
injection.
Liquid form preparations may also include solutions for intranasal
administration.
Aerosol preparations suitable for inhalation may include solutions and
solids in powder form, which may be in combination with a pharmaceutically
acceptable carrier, such as an inert compressed gas.
Also included are solid form preparations which are intended to be
converted, shortly before use, to liquid form preparations for either oral or
parenteral
administration. Such liquid forms include solutions, suspensions and
emulsions.
For preparing suppositories, a low melting wax such as a mixture of
fatty acid glycerides or cocoa butter is first melted, and the active
ingredient is
dispersed homogeneously therein as by stirring. The molten homogeneous mixture
is
then poured into convenient sized molds, allowed to cool and thereby solidify.
Additionally, the compositions of the present invention may be
formulated in sustained release form to provide the rate controlled release of
any one
or more of the components or active ingredients to optimize therapeutic
effects, i.e.,
antiviral activity and the like. Suitable dosage forms for sustained release
include
layered tablets containing layers of varying disintegration rates or
controlled release
polymeric matrices impregnated with the active components and shaped in tablet
form
or capsules containing such impregnated or encapsulated porous polymeric
matrices.
In one embodiment, the one or more Tetracyclic Indole Derivatives are
administered orally.
In another embodiment, the one or more Tetracyclic Indole Derivatives
are administered intravenously.
In another embodiment, the one or more Tetracyclic Indole Derivatives
are administered topically.

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In still another embodiment, the one or more Tetracyclic Indole
Derivatives are administered sublingually.
In one embodiment, a pharmaceutical preparation comprising at least
one Tetracyclic Indole Derivative is in unit dosage form. In such form, the
preparation is subdivided into unit doses containing effective amounts of the
active
components.
Compositions can be prepared according to conventional mixing,
granulating or coating methods, respectively, and the present compositions can

contain, in one embodiment, from about 0.1% to about 99% of the Tetracyclic
Indole
Derivative(s) by weight or volume. In various embodiments, the present
compositions can contain, in one embodiment, from about 1% to about 70% or
from
about 5% to about 60% of the Tetracyclic Indole Derivative(s) by weight or
volume.
The quantity of Tetracyclic Indole Derivative in a unit dose of
preparation may be varied or adjusted from about 1 mg to about 2500 mg. In
various
embodiments, the quantity is from about 10 mg to about 1000 mg, 1 mg to about
500
mg, 1 mg to about 100 mg, and 1 mg to about 100 mg.
For convenience, the total daily dosage may be divided and
administered in portions during the day if desired. In one embodiment, the
daily
dosage is administered in one portion. In another embodiment, the total daily
dosage
is administered in two divided doses over a 24 hour period. In another
embodiment,
the total daily dosage is administered in three divided doses over a 24 hour
period. In
still another embodiment, the total daily dosage is administered in four
divided doses
over a 24 hour period.
The amount and frequency of administration of the Tetracyclic Indole
Derivatives will be regulated according to the judgment of the attending
clinician
considering such factors as age, condition and size of the patient as well as
severity of
the symptoms being treated. Generally, a total daily dosage of the Tetracyclic
Indole
Derivatives range from about 0.1 to about 2000 mg per day, although variations
will
necessarily occur depending on the target of therapy, the patient and the
route of
administration. In one embodiment, the dosage is from about 1 to about 200
mg/day,
administered in a single dose or in 2-4 divided doses. In another embodiment,
the
dosage is from about 10 to about 2000 mg/day, administered in a single dose or
in 2-4
divided doses. In another embodiment, the dosage is from about 100 to about
2000
mg/day, administered in a single dose or in 2-4 divided doses. In still
another

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77
embodiment, the dosage is from about 500 to about 2000 mg/day, administered in
a
single dose or in 2-4 divided doses.
The compositions of the invention can further comprise one or more
additional therapeutic agents, selected from those listed above herein.
Accordingly, in
one embodiment, the present invention provides compositions comprising: (i) at
least
one Tetracyclic Indole Derivative or a pharmaceutically acceptable salt
thereof; (ii)
one or more additional therapeutic agents that are not a Tetracyclic Indole
Derivative;
and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the
composition are together effective to treat HCV infection.
In one embodiment, the present invention provides compositions
comprising a Compound of Formula (I) and a pharmaceutically acceptable
carrier.
In another embodiment, the present invention provides compositions
comprising a Compound of Formula (I), a pharmaceutically acceptable carrier,
and a
second therapeutic agent selected from the group consisting of HCV antiviral
agents,
immunomodulators, and anti-infective agents.
In another embodiment, the present invention provides compositions
comprising a Compound of Formula (I), a pharmaceutically acceptable carrier,
and
wto additional therapeutic agents, each of which are independently selected
from the
group consisting of HCV antiviral agents, immunomodulators, and anti-infective

agents.
Kits
In one aspect, the present invention provides a kit comprising a
therapeutically effective amount of at least one Tetracyclic Indole
Derivative, or a
pharmaceutically acceptable salt, solvate, ester or prodrug of said compound
and a
pharmaceutically acceptable carrier, vehicle or diluent.
In another aspect the present invention provides a kit comprising an
amount of at least one Tetracyclic Indole Derivative, or a pharmaceutically
acceptable
salt, solvate, ester or prodrug of said compound and an amount of at least one

additional therapeutic agent listed above, wherein the amounts of the two or
more
active ingredients result in a desired therapeutic effect. In one embodiment,
the one
or more Tetracyclic Indole Derivatives and the one or more additional
therapeutic
agents are provided in the same container. In one embodiment, the one or more

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Tetracyclic Indole Derivatives and the one or more additional therapeutic
agents are
provided in separate containers.

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79
EXAMPLES
General Methods
Solvents, reagents, and intermediates that are commercially available were
used as received. Reagents and intermediates that are not commercially
available were
prepared in the manner as described below. 1H NMR spectra when reported, were
obtained on either a Varian VNMR System 400 (400 MHz) or a Bruker Avance 500
(500
MHz) and resonances are reported as ppm downfield from Me4Si with number of
protons,
multiplicities, and coupling constants in Hertz indicated parenthetically.
Where LC/MS
data are presented, analyses was performed using an Agilent 6110A MSD or an
Applied
Biosystems API-100 mass spectrometer and Shimadzu SCL-10A LC column: Alltech
platinum C18 column, 3 micron, 33 mm x 7mrn ID; typical gradient flow: 0
minutes ¨
10% CH3CN, 5 minutes ¨95% CH3CN, 5-7 minutes ¨ 95% CH3CN, 7 minutes ¨ stop.
The retention time and observed parent ion are given. Chromatography was
performed
using partially automated systems manufactured by Gilson, ISCO or Biotage.
Unless
otherwise indicated, chromatography was performed using a gradient elution of
hexanes/ethyl acetate, from 100% hexanes to 100% ethyl acetate.
EXAMPLE 1
Preparation of Compound It-la
./'. 0
1 i
HO
1rNH2 ¨11 - Fl )rNA OMe
0 0 H
Int-la
To a solution of L-valine (10.0 g, 85.3 mmol) in 1M aqueous NaOH
solution (86 mL) at room temperature was added solid sodium carbonate (4.60 g,
43.4
mmol). The reaction mixture was cooled to 0 C (ice bath) and then methyl
chloroformate (7.20 inL, 93.6 mmol) was added dropwise over 20 minutes. The
reaction
mixture was then allowed to warm to room temperature, and allowed to stir at
room
temperature for an additional 4 hours. The reaction mixture was then diluted
with diethyl

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ether (100 mL), the resulting solution was cooled to at 0 C, and then
concentrated
hydrochloric acid (18 mL, 216 mmol) was added slowly. The reaction was
extracted
with Et0Ac (3 x 100 mL) and the combined organics were dried over MgSO4,
filtered
and concentrated in vacuo to provide Compound It-la (13.5 g, 90%), which was
used
without further purification.
The following intermediates can be prepared by the reaction of L-valine or
L- threonine with isopropyl chloroformate, 2-methoxyethyl chloroformate or
with 1-
methylcyclopropyl hydroxysuccinimide respectively as above.
0
0
I
HOIr"NA HO-
Olf A OCH3
0
0
It-lb Int-lc
0
0
HO1rNA0
HOlh: NAc>41
0
0
Int-id Int-le
EXAMPLE 2
Preparation of Intermediate Compound Int-2a
0
HO HO
(R) NH2 N10Me
0 0
Int-2a
To a solution of D-phenylglycine (10.0 g, 66.1 mmol) and NaOH (21.2 g,
265 mmol) in water (60 mL) at 0 C was added methyl chloroformate (10.2 mL,
133
mmol) dropwise over 20 minutes. The resulting mixture was allowed to stir at 0
C for 1
hour, then was acidified using concentrated hydrochloric acid (25 mL, 300
mmol). The
acidic solution was extracted with Et0Ac (3 x 100 mL) and the combined
organics were

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81
dried over MgSO4, filtered and concentrated in vacuo to provide Compound Int-
2a (12.6
g, 91%), which was used without further purification.
The following intermediates can be prepared by the reaction of glycine, L-
Alanine and 4-
F phenylglycine respectively with methyl chloroformate (Aldrich Inc.) using
the method
described above:
101
0 3 0 0
HO,IrNAcy HON.A A
N H yNAe
0 0 0
Int- 2b Int-2c Int-2d
EXAMPLE 3
Preparation of Intermediate Compound Int-3a
H = HO
NH2
0 0 I
Int-3a
A solution of D-phenylglycine (20.0 g, 132 mmol), 37% aqueous
formaldehyde (66 mL, 814 mmol) and 5 % Pd on carbon (8.0 g, mmol) in a mixture
of
methanol (80 mL) and 1 N HC1 (60 mL) was placed on a hydrogenation shaker and
shook
under an atmosphere of 35-40 psi hydrogen for 4 hours. The reaction was then
flushed
with nitrogen, filtered through a Celite pad and concentrated in vacuo to
provide
Compound Int-3a (29.7 g, quant.) as a white solid, which was used without
further
purification.
EXAMPLE 3A

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F F
Na+
-- N
.1
- 5-
0 + H3B.,...-
,i;
H____)0._
HO (13) HO (13)
NH2 N
0 o)
Int-3b Int-3c
To a solution of (R)-2-amino-2-(4-fluorophenyl)acetic acid (Int 3b) in
Me0H (20 mL) at 0 C was added sodium cyanoborohydride portionwise over ¨ 20
minutes. The resulting mixture was allowed to stir for 10 minutes and then
acetaldehyde
was added dropwise via syringe over ¨10 minutes. The resulting solution was
allowed to
stir for 1 hour at 0 C, and then allowed to warm to room temperature. After
12h, LC-MS
indicated disappearance of Int-3b, and the mixture was recooled to 0 C,
carefully
treated with water (3 mL) followed by addition of conc HCI over ¨40 minutes
(pH ¨2.0).
The cooling bath was removed and the mixture was allowed to stand for about 15
hours.
The precipitate was collected by filtration to provide Int-3c.
Intermediate It-3d can be prepared using the procedure above from R-
Phenyl glycine.
Na+
_.....-N
4 IP
-H3B
4. oil
'1/4H
(R) (R)
HO HO N
NH2
0 o)
Phenylglycine It-3d
EXAMPLE 4
Preparation of Intermediate Compound Int-4f

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P(0)(OCH3)2
H3C0yLN,CBz
0 (S,S-Me-BPE)-Rh)+BF4- ro
1. Pd/C, H2
LyJ
NH H3C I NrCBz
H3CO..A.
0
.NAN/ 0 H H2 (50 psi), Me0H H
0
Int-4a I I Int-41) Int-4c
1. CI(C0)0CH3 oLiOH
0
H3COIrNH2 H3C0y....NJ1/4OCH 3 1.4 I A
.. IrN 00H,
0 0
0
Int-4d Int-4e Int-4f
Step A ¨ Preparation of Compound Int-4b
To a solution of methyl 2-(benzyloxycarbonylamino)-2-
(dimethoxyphosphoryl) acetate (10.0 g, 30.2 mmol, made as decribed in Hamada
et al.,
Organic Letters; English, 20:4664-4667 (2009)) in THF (100 mL) at ¨20 C was
added
tetramethylguanidine (4.20 mL, 33.2 mmol). The reaction mixture was allowed to
stir at
¨20 C for 1 hour then dihydro-2H-pyran-4(3H)-one (4a) was added (3.1 mL, 33.2
mmol)
in THF (5 mL) and the reaction mixture was warmed to room temperature and
allowed to
stir for about 15 hours. Et0Ac (200 mL) was added and the organic mixture was
washed
with water (3 x 50 mL) and brine (50 mL). The organic layers were combined and
dried
with Na2SO4, filtered and concentrated in vacuo. The residue obtained was
purified
using flash chromatography on an ISCO 330 g Redi-Sep column using 0 35%
Et0Ac/hexanes as the eluent to provide Compound Int-4b as a white solid (615
mg,
45%). IHNMR (CDCI3) 7.40 7.30 (m, 5H), 6.00 (br s, 1H), 5.12 (s, 2H), 3.80
3.65 (m,
7H), 2.92 (m, 2H), 2.52 2.48 (m, 2H).
Step B ¨ Preparation of Compound Int-4c
To a solution of Int-4b (2.43 g, 7.96 mmol) in methanol (160 mL)
previously purged with N2 was added (¨)-1,2-Bis((2S,5S)-2,5-
dimethylphospholano)

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ethane (cyclooctadiene)rhodium(I) tetrafluoroborate (487 mg, 0.880 mmol) under
N2.
The mixture was shaken in a Parr shaker apparatus for 18 hours at 50 psi of
H2. After
evacuating the hydrogen, the suspension was filtered and the filtrate was
concentrated in
vacuo to provide Compound Int-4c as a white solid (1.30 g, 53%). 1H NMR
(CDC13) 8
7.40 7.30 (m, 5H), 5.32 (br s, 1H), 5.12 (s, 2H), 4.40 4.30 (m, 1H), 4.00 3.95
(m, 2H),
3.75 (s, 3H), 3.40 3.25 (m, 2H), 2.10 1.95 (m, 1H), 1.50 1.45 (m, 4H).
Step C - Preparation of Compound Int-4d
To a suspension of 50% palladium on carbon (10% wet, 200 mg) in
absolute ethanol (20 mL) under nitrogen was added Int-4c (1.06 g, 3.45 mmol).
With
stirring, the solution was placed in vacuo for 30 seconds and then was opened
to a
hydrogen gas balloon for 2 hours. After evacuating the hydrogen, the
suspension was
filtered through a Celite pad and the pad was washed with ethanol (2 x 20 mL).
The
filtrate was concentrated in vacuo to provide Compound Int-4d as a colorless
oil (585 mg,
98%). 1H NMR (CDC13) 8 4.06 3.96 (m, 2H), 3.73 (s, 31-1), 3.48 3.28 (m, 3H),
1.92
1.78(m, 1H), 1.61 1.47 (m, 6H).
Step D - Preparation of Compound Int-4e
To a solution of Compound Int-4d (585 mg, 3.37 mmol) and
triethylamine (0.710 mL, 5.09 mmol) in CH2C12 (6 mL) was added methyl
chloroformate
(0.290 mL, 3.76 mmol). The reaction was allowed to stir at room temperature
for about
15 hours, then water (15 mL) was added and the aqueous mixture was extracted
with
CH2C12 (3 x 20 mL). The combined organic extracts were dried over Na2SO4,
filtered
and concentrated in vacuo. The residue obtained was purified using flash
chromatography on an ISCO 24 g Redi-Sep column using 0 3% Me0H/CH2C12 as the
eluent to provide Compound Int-4e as a colorless oil (600 mg, 77%). 1H NMR
(CDC13)
8 5.27 5.18 (m, 1H), 4.38 4.28 (m, 1H), 4.06 3.96 (m, 2H), 3.75 (s, 3H), 3.69
(s, 3H),
3.39 3.30 (m, 2H), 2.09 1.94 (m, 1H), 1.59 1.48 (m, 4H).
Step E - Preparation of Compound Int-4f

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To a solution of Compound Int-4e (600 mg, 2.59 mmol) in THF (5 mL)
was added lithium hydroxide monohydrate (218 mg, 5.19 mmol) in water (5 mL).
The
reaction was allowed to stir at room temperature for 2 hours then was
concentrated in
vacuo to half of its original volume. The concentrated mixture was then
acidified with
6N HC1 and extracted with Et0Ac (7 x 50 mL). The combined organic extracts
were
dried over Na2SO4, filtered and concentrated in vacuo to provide Compound Int-
4f as an
off-white solid (485 mg, 86%). III NMR (CD30D) 8 4.09 4.07 (m, 1H), 3.96 3.92
(m,
2H), 3.65 (s, 3H), 3.40 3.34 (m, 2H), 2.10 1.99 (m, 1H), 1.56 1.47 (m, 411).
EXAMPLE 5
Preparation of Intermediate Compound Int-5f
P(0)(OCH3)2
H3C01(1.N.CBz yOC Y C E.30C
yoc
H N (S r ,,N r,isi
Y 1
rN,1 0 ,S-Me-BPE)-
) Pd/C, H2
c) , , 4
--0.- -OP-
NH H3C0 I N-C8zRill+BF -H300 1-13C0y;.NH2
0 1r. N.0Bz
H H2(50 psi), Me0H H
fil 1 0 0
Int-5a Int-5b Int-5c
yoe 11/4c pi,c
N. rnk ^
1. TFA
CI(C0)0CH3 C)- 0 2. AcCI 1),. 0 LiOH y 0
i -I I I I- H300,0A,N,NõOCH3 -IP' H300)...A _),...
H0 "3...A
H N OCH3 õ N OCH3
H
0 0 H 0
Int-5d Int-5e Int-5f
Step A ¨ Preparation of Compound Int-5a
To a solution of methyl 2-(benzyloxycarbonylamino)-2-
(dimethoxyphosphoryl) acetate (1.50g. 4.52 mmol) in THF (5 mL) at ¨20 C was
added
tetramethylguanidine (625 L, 4.98 mmol). The reaction mixture was allowed to
stir at ¨
20 C for 1 hour then tert-butyl 4-oxopiperidine-1-carboxylate was added (992
mg, 4.97
mmol) in THF (2 mL) and the reaction mixture was warmed to room temperature
and
allowed to stir for about 15 hours. Et0Ac (90 mL) was added and the organic
mixture
was washed with water (3 x 20 mL) and brine (25 mL). The combined organic
extracts

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86
were dried over Na2SO4, filtered and concentrated in vacuo. The residue
obtained was
purified using flash chromatography on an ISCO 40 g Redi-Sep column using 0
35%
Et0Ac/hexanes as the eluent to provide Compound Int-5a as a white semi-solid
(1.1 g,
61%). 1H NMR (CDC13) 6 7.40 7.30 (m, 5H), 6.02 (br s, 1H), 5.12 (s, 2H), 3.80
3.40 (m,
7H), 2.90 2.80 (m, 2H), 2.45 2.35 (m, 2H), 1.45 (s, 9H).
Step B - Preparation of Compound Int-5b
To a solution of Int-5a (1.30 g, 3.21 mmol) in methanol (90 mL)
previously purged with N2 was added (-)-1,2-Bis((2S,5S)-2,5-
dimethylphospholano)
ethane(cyclooctadiene)rhodium(I) tetrafluoroborate (197 mg, 0.354 mmol) under
N2.
The mixture was then shaken in a Parr shaker apparatus for 18 hours at 50 psi
of H2.
After evacuating the hydrogen, the suspension was filtered and the filtrate
was
concentrated in vacuo to provide Compound Int-5b as colorless oil (1.00 g,
77%). 1H
NMR (CDC13) 8 7.40 7.30 (m, 5H), 5.35 5.25 (m, 1H), 5.10 (s, 2H), 4.40 4.35
(m, 1H),
4.20 4.10 (m, 2H), 3.70 (s, 311), 2.70 2.55 (m, 2H), 2.00 1.90 (m, 1H), 1.65
1.40 (m,
11H), 1.30 1.20 (m, 2H).
Step C - Preparation of Compound Int-5c
To a solution of 50% palladium on carbon (10% wet, 250 mg) in absolute
ethanol (20 mL) under nitrogen was added Int-5b (1.00 g, 2.46 mmol). The
reaction was
evacuated, then put under an H2 atmosphere using a hydrogen-filled balloon and
allowed
to stir for 2 hours. The hydrogen was evacuated and the resulting suspension
was filtered
through a Celite pad and the pad washed with ethanol (2 x 20 mL). The filtrate
and
ethanol washings were combined and concentrated in vacuo to provide Compound
Int-5c
as a colorless oil (670 mg, quant.). 1H NMR (CDC13) 8 4.21 4.08 (m, 2H), 3.73
(s, 3H),
3.31 (d, J= 6.0 Hz, 1H), 2.75 2.57 (m, 2H), 1.84 1.70 (m, 1H), 1.68 1.56 (m,
1H), 1.45
(s, 911), 1.45 1.20 (m, 5H).
Step D - Preparation of Compound Int-5d
To a solution of Compound Int-5c (670 mg, 2.46 mmol) and triethylamine
(0.520 mL, 3.73 mmol) in CH2C12 (10 mL) was added methyl chloroformate (0.210
mL,

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2.72 mmol). The reaction mixture was allowed to stir at room temperature for
about 15
hours. Water (20 mL) was added and the aqueous mixture was extracted with
CH2C12 (2
x 15 mL). The combined organic extracts were dried over Na2SO4, filtered and
concentrated in vacuo. The residue obtained was purified using flash
chromatography on
an ISCO 24 g Redi-Sep column using 0 3% Me0H/CH2C12as the eluent to provide
Compound Int-5d as an off-white solid (515 mg, 63%). 1H NMR (CDC13) 8 5.26
5.17
(m, 1H), 4.38 4.30 (m, 1H), 4.20 4.07 (m, 2H), 3.75 (s, 3H), 3.68 (s, 311),
2.71 2.57 (m,
2H), 2.00 1.85 (m, 1H), 1.87 1.48 (m, 2H), 1.44 (s, 9H), 1.35 1.18 (m, 211).
Step E - Preparation of Compound It-Se
Compound Int-5d (300 mg, 0.908 mmol) was dissolved in a mixture of
TFA (2 mL) and CH2C12 (10 mL) and the solution was allowed to stir at room
temperature for 1 hour, then was concentrated in vacuo. To the resulting
residue was
added triethylamine (0.760 mL, 5.45 mmol) in CH2C12 (10 mL), then acetic
anhydride
(0.086 mL, 0.915 mmol). The reaction was allowed to stir at room temperature
for about
15 hours then concentrated in vacuo. The residue obtained was purified using
flash
chromatography on an ISCO 12 g Redi-Sep column using 0 4% Me0H/CH2C12 as the
eluent to provide Compound It-Se as colorless oil (247 mg, 99%). 1H NMR
(CDC13) 8
5.27 5.21 (m, 1H), 4.73 4.62 (m, 1H), 4.42 4.32 (m, 1H), 3.69 (s, 3H), 3.18
(s, 3H),
3.18 3.09 (m, 1H), 3.07 2.95 (m ,1H), 2.55 2.41 (m, 1H), 2.07 (s, 3H), 1.78
1.49 (m,
3H), 1.38 1.21 (m, 2H).
Step F - Preparation of Compound Int-5f
To a solution of Compound Int-5e (247 mg, 2.59 mmol) in THF (3 mL)
was added lithium hydroxide monohydrate (77 mg, 1.83 mmol) in water (3 mL).
The
reaction mixture was allowed to stir at room temperature for about 15 hours
then
concentrated in vacuo to 50% of its original volume. The concentrated solution
was then
acidified with 1N HC1 to pH 4 and extracted with Et0Ac (7 x 15 mL). The
combined
organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to
provide
Compound Int-5f as an off-white solid (106 mg, 45%). 1HNMR (CD30D) 8 5.52 5.43

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(m, 1H), 4.71 4.62 (m, 1H), 4.44 4.31 (m, 1H), 3.91 3.81 (M, 1H), 3.70 (s,
3H), 3.12
2.99 (m, 1H), 2.58 2.46 (m, 1H), 2.10 (m, 4H), 1.86 1.54 (m, 2H), 1.50 1.21
(m, 3H).
EXAMPLE 6
Preparation of Intermediate Compound Int-6f
OH
H2N Me
Et01(1OH Et0 2Et
0 1. 1\1 0
PPTS, benzene BF3=0Et2 "Me
reflux 0 TFA, ¨78 C
Int-6a Int-6b
Int-6c
exo : endo
9 : 1
i_b_4DEt
H2, Pd/C OEt Boc20
(s) 0
Et0Ac, Et0H N/H 0 sat. Na2CO3
THF, 0 C to rt µBoc
Int-6d
Int-6e
Li011=1120
H20, THF N
µBoc
Int-6f
Step A ¨ Preparation of Compound Int-6c
(s)
exo : endo
9 : 1
Int-6c
A stirred mixture of D-(+)-a-methylbenzyl amine Int-6a (50.0 g, 0.412
mol), ethyl glyoxylate (81.5 mL, 50% in toluene, 0.412 mol) and PPTS (0.50 g,
2.00
mmol) in benzene (600 mL) was heated to reflux in a Dean-Stark apparatus and
allowed
to remain at reflux until no further water (-8 mL) azeotroped from the
reaction (¨ 4
hours). The resulting mixture was concentrated in vacuo to provide Compound
Int-6b,

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which was used without further purification: 1H NMR (300 MHz, CDC13) 8 7.72
(s, 1H),
7.36 7.24 (m, 5H), 4.61 (q, J= 6.9 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.62 (d,
J= 6.6 Hz,
3H), 1.34 (t, J= 7.2 Hz, 3H).
To a stirred solution of crude Int-6b in methylene chloride (600 mL) at -
78 C were added the following in 10 minutesute intervals: TFA (31.0 mL, 0.416
mol),
boron trifluoride etherate (51.3 mL, 0.416 mol) and freshly distilled
cyclopentadiene
(32.7 g, 0.494 mol). After less than 2 minutes following the addition of
cyclopentadiene,
the reaction mixture formed a thick brown mass, which was allowed to stir for
6 hours at
-78 C. The reaction mixture was then allowed to warm to room temperature on
its own
and stir for an additional 15 hours. The resulting dark brown reaction mixture
was
quenched with sat. aq. Na2CO3 (- 900 mL) and allowed to stir for 30 minutes.
The
resultant suspension was filtered through a pad of Celite and the filtrate
was extracted
with methylene chloride (3 x 100 mL). The combined organic extracts were
washed with
sat. aq. NaCI (2 x 75 mL), dried over Na2SO4, filtered and concentrated in
vacuo. The
residue obtained was purified using flash column chromatography (silica; 8 x
18 cm,
10% to 25% ethyl acetate/hexanes as the eluent) to provide endo Int-6c (10.9
g, 9%) as a
brown oil: 1H NMR (300 MHz, CDC13) 8 7.34 7.19 (m, 5H), 6.00 5.95 (m, 1H),
4.18 (q,
J= 7.1 Hz, 3H), 3.47 (s, 1H), 3.03 (s, 1H), 2.97 (q, J= 6.5 Hz, 111), 2.41 (s,
1H), 1.86 (d,
J = 8.2 Hz, 11I), 1.26 (t, J = 6.6 Hz, 311), 1.17 (t, J= 6.6 Hz, 3H). Exo Int-
6c (84.3 g,
74%) was also collected as a brown oil: 1H NMR (300 MHz, CDC13) 8 7.34 7.19
(m,
5H), 6.36 6.33 (m, 1H), 6.22 6.18 (m, 1H), 4.37 (s, 1H), 3.87 (q, J= 6.8 Hz,
2H), 3.10
(q, J= 6.5 Hz, 1H), 2.96 (s, 114), 2.27 (s, 1H), 2.20 (d, J = 8.4 Hz, 1H),
1.48 (d, J= 6.5
Hz, 3H), 1.01 (d, J= 7.0 Hz, 3H), 1.00(m, 1H).
Step B- Representative Example for the Preparation of Compound Int-6d
A mixture of exo-Int-6c (15.8 g, 0.582 mol) and 10% Pd/C (4.07 g, 50%
wet) in a 1:2 mixture of Et0H/Et0Ac (150 mL) was shaken for 23 hours in a Parr

hydrogenation apparatus under an atmosphere of 112 (50 psi). The reaction
mixture was
then filtered through Celite and the filtrate was concentrated in vacuo. 1H
NMR
analysis of the residue (10.8 g) showed some aromatic resonances present.
Repetition of
the hydrogenation procedure using 10% Pd/C (2.0 g) provided Int-6d (10.0 g,
quant.) as

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a brown oil, which was used without further purification. 1H NMR (300 MHz,
CDC13)
4.18 (q, J = 7.2 Hz, 3H), 3.54 (s, 1H), 3.32 (s, 1H), 2.62 (s, 1H), 2.23 (s,
1H), 1.64 1.39
(m, 5H), 1.31 1.20 (m, 4H).
Step C - Preparation of Compound Int-6e
To a solution of Int-6d (36.6 g, 0.236 mol) and sat. aq. Na2CO3 (300 mL)
in THF (600 mL) at 0 C was added di-tert-butyl dicarbonate (59.0 g, 0.270
mol). The
resulting reaction was allowed to slowly warm to room temperature with
stirring over 6
hours, then was allowed to stir at room temperature for an additional 68
hours. The
reaction mixture was diluted with Et0Ac (250 mL) and water (250 mL) and the
aqueous
layer was extracted with Et0Ac (2 x 200 mL). The combined organic extracts
were
washed with sat. aq. NaC1 (2 x 75 mL), dried over Na2SO4, filtered and
concentrated in
vacuo. The residue obtained was purified using flash column chromatography
(silica; 16
x 10 cm) using 10 20% ethyl acetate/hexanes as the eluent to provide Compound
Int-6e
(49.0 g, 84%) as a pale yellow oil: 1H NMR (300 MHz, CDC13) 8 4.35 (s, 0.611),
4.22
4.10 (m, 2.4H), 3.81 (s, 0.45H), 3.71 (s, 0.55H), 2.66 (s, 1H), 1.96 1.90 (m,
1H), 1.76
1.50 (m, 3H), 1.55 1.45 (m, 5H), 1.39 (s, 511), 1.30 1.23 (m, 4H).
Step D- Preparation of Compound 2.2.1 Bicyclic Acid Intermediate Int-6f
To a stirred mixture of Int-6e (49.0 g, 0.182 mmol) in 1:1 THF/water (600
mL) was added LiOH=H20 (15.3 g, 0.364 mol). The reaction mixture was heated to

60 C and allowed to stir at this temperature for 47 hours. The reaction
mixture was then
cooled to room temperature, concentrated in vacuo, and the residue obtained
was diluted
with CH2C12 (200 mL) then acidified with 2N HC1to pH - 4. The acidic solution
was
extracted with CH2C12 (4 x 100 mL) and the combined organic extracts were
washed with
sat. aq. NaC1 (25 mL), dried over Na2SO4, filtered and concentrated in vacuo
to provide
Compound Int-6f, (1R, 3S, 45)-N-Boc-2-07abicyclo[2.2.1]heptane-3-carboxylic
acid
(41.2 g, 93%) as an off white solid, which was used without further
purification: 1H
NMR (400 MHz, DMSO-d6) 8 12.44 (s, 111), 4.13 (s, 0.56H), 4.06 (s, 0.47H),
3.61 (d, J =
4.0 Hz, 1H), 2.59 (s, 1H), 1.75 1.45 (m, 511), 1.39 (s, 411), 1.32 (s, 5H),
1.23 (t, J = 8.4
Hz, 1H); Optical Rotation: [a]D25 -169.0 (c = 1.1, CHC13).

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EXAMPLE 7
Preparation of Intermediate Compound Int-7h
0
Br
0)L IXr
N
Int-7h
Step A ¨ Preparation of Compound Int-7b
Bo c Bo
0
OxelylChloride
DMSO/NEt3 H
Int-7a Int-7b
A 2 L, 3-necked round bottomed flask equipped with an overhead stirrer
and a N2 inlet was charged with a solution of oxalyl chloride (130 mL, 0.26
mol) in
dichloromethane (250 mL). The solution was cooled to -78 C, and a solution of
DMSO
(20 mL, 0.28 mol) in dichloromethane (30 mL) was added dropwise. After 30
minutes, a
solution of (S)-N-Boc-prolinol, Int-7a (40 g, 0.20 mol) in dichloromethane
(200 mL) was
added dropwise. After 30 minutes, triethylamine (140 mL, 1.00 mol) was added
to the
solution, and the flask was transferred to an ice/water bath and allowed to
stir for another
30 minutes. The reaction mixture was diluted with dichloromethane (200 mL) and

washed successively with 1120, 1M HC1, saturated NaHCO3, and brine. The
organic
layer was dried over Na2SO4, filtered, and concentrated in vacuo to provide
crude (S)-2-
formyl-pyrrolidine-1-carboxylic acid tert-butyl ester, Int-7b (40 g) as oil,
which was
used without further purification.

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Step B ¨ Preparation of Compound Int-7c
0
Hy(ii >rOyO
NJ(0
H __________________________________
NH3, H20 z N
H
Int-7b Int-7c
To (S)-Boc-prolinal, Int-71) (crude, 80g, 0.4 mol) was added a solution of
ammonia in Me0H (prepared from 150 mL of 7 N ammonia/Me0H and 200 mL Me0H,
1.05 mol, 260 mol%). An exotherm was noted with the internal temperature
rising to ¨
30 C. The solution was allowed to stir for 0.5 hours at room temperature,
then glyoxal
(76 g, 0.52 mol, 130 mole%) was added over 5 minutes in portions, with the
internal
temperature rising to ¨ 60 C and then returning to room temperature after 1
hour. The
reaction was allowed to stir for an additional 15 hours and the reaction
mixture was
concentrated in vacuo. The resulting residue was diluted with dichloromethane
(1 L) and
water (0.5 L) were added and the organic phase was washed with water (0.25 L),
dried
over MgSO4, filtered and concentrated in vacuo. The residue obtained was
slurried with
warm ethyl acetate ( ¨ 100 mL) and Hexane (100 mL), then was cooled and
filtered. The
solid obtained was washed with 30%ethyl acetate/Hexane to provide Compound Int-
7c
(66.2g, 70% yield).
Step C ¨ Preparation of Compound list- 7d
)oNr
0
NBS '1 N(N......5=Br
N N
Int-7c Int-7d
N-Bromosuccinimide (838.4 mg, 4.71 mmol) was added in portions over
15 minutes to a cooled (ice/water) CH2C12 (20 mL) solution of imidazole Int-7c
(1.06 g,
4.50 mmol). The reaction mixture was allowed to stir for 75 minutes and
concentrated in

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vacuo to oil. The residue obtained was purified using silica-gel RPLC
(Acetonitrile/
water/ 0.1% TFA) to separate the mono bromide from its dibromo analog (over
bromination) and the starting material. The RPLC elute was neutralized with
excess
NI-13/Me0H, and the volatile component was removed in vacuo. The residue
obtained
was partitioned between CH2C12 and water, and the aqueous layer was extracted
with
water. The combined organic phase was dried (MgSO4), filtered, and
concentrated in
vacuo to provide Compound Int-7d as a white solid (374 mg). ill NMR (DMSO) 8:
12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, 1H; overlapped with
water signal),
2.25-1.73 (m, 4H), 1.39/1.17 (s, 3.8H + 5.2H).
Step D - Alternative Synthesis of Int-7d
Br
Boc N
NBS N,
(2-"*N Br
Int-7b Int-7e
To a suspension of Int-7b (140 g, 0.59 mol) in THF (2000 mL) was added
N-bromosuccinimide (200 g, 1.1 mol). The mixture was allowed to stir at room
temperature under N2 gas for about 15 hours. The solvent was then removed in
vacuo,
and the residue obtained was purified using silica-gel chromatography (ethyl
acetate
eluent) to provide 230 g of the desired dibromo Compound Int-7e. MS (ESI) rn/e

(M+H+): 396.
Br Br
ploc
Na2S03
N Br
Int-7e Int-7d
To a suspension of Int-7e (230 g, 0.58 mol) in Et0H/H20 (1:1 ratio, 3000
mL) was added Na2S03 (733 g, 5.8 mol). The resulting mixture was allowed to
stir at
mild reflux for about 15 hours. After cooling to room temperature, the mixture
was
extracted with dichloromethane twice and the combined organic layer was
concentrated

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in vacuo to a semi-solid. The residue obtained was purified using
chromatography on
silica gel to provide the desired Compound Int-7d. MS (ESI) m/e (M+H ): 317.
Step E ¨ Preparation of Compound Int-7f
SEM SEM
C-)¨<µ X
Br Br
Boc hoc
Int-7e Int-7f
Compound Int-7e (2.63 g, 5.0 mmol) was dissolved in TI-IF (30 mL) and
cooled to ¨ 78 C, n-BuLi (1M in hexane, 2.2 mL, 5.5 mmol) was added and the
reaction was allowed to stir for 20 minutes. N-fluorodibenzenesulfonamide (1.6
mL, 5.0
mmol) was added at -78 C and the reaction mixture was allowed to warm slowly
to
room temperature again. The reaction was quenched with aq. NRIC1then
partitioned
between water and ethyl acetate. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue obtained was purified using flash column
chromatography (Gradient Ethyl acetate:petroleum ether from 0-20% Ethyl
acetate) to
provide Compound Int-7f. (63 % yield). MS (ESI) m/z (M+H) : 464, 466. 19 F NMR
= -
151.8 ppm .
Step F¨ Preparation of Compound Int-7g
Br TFA Br
Boc 1
Int-7d Int-7g
Intermediate 7d (2.51 g, 7.94 mmol, 1.0 eq) was dissolved in 20 mL of
CH2C12and to the resulting solution was added trifluoroacetic acid (5 mL). The
reaction
mixture was allowed to stir for about 15 hours at room temperature under N2,
and the
reaction was diluted with hexanes (15 mL) and concentrated in vacuo to provide
a yellow
oil. CH2Cl2 and toluene were added and the solution was re-concentrated in
vacuo. This
step was repeated until excess TFA was removed, giving a solid which was dried
in
vacuo for 1 hour to provide 3.5 g of solid Int-7g. MS (ESI) m/z (M+H)+:217/
218.1.

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Step G ¨ Preparation of Compound Int-7h
Br 0
0
O AI=r Br
A HATU N
HO)rri OMe N
H
0
DMF/DIPEA N
It-la Int-7g Int-7h
Int-7g (3.01g, 6.78 mmol, 1.0 eq) and It-la (1.202 g, 6.86 mmol, 1.01 eq)
were added to a 250 mL round-bottomed flask equipped with a stir bar. DMF was
added,
and the flask was connected to a vacuum line. The flask was cycled between
vacuum and
N2 twice, then cooled in an ice-methanol bath for 10 minutes. HATU (2.75 g,
7.23 mmol,
1.07 eq) was added, followed by diisopropylethyl amine (2.80 mL). The reaction
mixture
was allowed to stir at -15 C for 20 minutes. Additional diisopropylethyl
amine (2.0 mL)
was added. The reaction mixture was allowed to stir for 40 minutes, then
quenched with
water (1.5 mL). The resulting solution was diluted with Et0Ac (100 mL) and
Et20 (100
mL), then washed with water (6 x 15 mL) and brine (2 x 25 mL). The organic
layer was
dried with MgSO4, filtered, and concentrated in vacuo yielding 2.23 g of a
clear oil. The
residue obtained was purified via chromatography using an 80 g Isco Gold Si02
cartridge
with a 0.5%-2.5% Me0H/ CH2C12 gradient as the mobile phase. The major peak was

collected to provide 1.28 g Int-7h as a white foam. This material was further
purified via
sgc on an 80 g Isco Gold Si02 cartridge using a 45%-65% gradient of (5%
methanol in
Et0Ac)/hexanes. Triethylamine 1% by volume was added to the Me0H/Et0Ac
solution.
The fractions were assayed via TLC using Hanessian's stain. (See Example 13
below for
more information on Hanessian's stain.) The major peak was collected as
product to
provide 1.18 g of Int-7h as a white foam. MS (ESI) m/z (M+H)+:373.1.
EXAMPLE 7B
Preparation of Intermediate Compound Int-7i

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0
O3j
r
NH j5¨Br )¨>¨çN-'\µ
0 NH H
HATU
0 Int-4f Int-7g Int-7h
N-Moc-(S)-tetrahydropyranyl glycine (Int-41) (252 mg, 1.160 mmol),
Int-7g (354 mg, 1.225 mmol), DMF (6 mL), and DIPEA (0.7 mL, 4.01 mmol) were
added to a 40 mL screw cap vial equipped with a stir bar. The reaction mixture
was
placed under a blanket of N2 and the vial was capped. The vial was cooled in
an ice-
methanol bath for 10 minutes. HATU (445 mg, 1.215 mmol) was added, and the
reaction
mixture was left stirring at -15 C. After 3 hours, the bath temp was 10 C.
The reaction
mixture was diluted with ethyl acetate and aqueous ammonium chloride. The
layers were
separated. The organic layer was washed with water and brine, gravity
filtered, dried
with MgSO4, and filtered again. The solvent was evaporated under reduced
pressure on
the rotovap to provide a clear oil-(458 mg). The crude product was purified
via flash
silica gel column chromatography on an Isco 24 g Si02 Gold cartridge, using a
Me0H(NH3)/CH2C12 gradient (0-5%) as the mobile phase to provide Int-7h as a
clear oil.
Weight = 246 mg Took 1H NMR and LC/MS. Obsd M+H = 415.1.
/¨

N-Aµ
¶Ie
H OH
HATU
Int-4g Int-10g Int-7i
N-Moc (S)-tetrahydropyranyl glycine Int-4f (236 mg, 1.086 mmol) and
Int-10g (333 mg, 1.085 mmol), DMF (5 mL), and DIPEA (0.6 mL, 3.44 mmol) were
added to a 40 mL screw cap vial equipped with a stir bar. The reaction mixture
was
placed under a blanket of N2 and the vial was capped. The vial was cooled in
an ice-
methanol bath for 15 minutes. HATU (418 mg, 1.141 mmol) was added, and the
reaction
mixture was left stirring at -15 C. After 3h, the bath temp was 10 C. The
reaction
mixture was diluted with ethyl acetate and water. The layers were separated.
The organic

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layer was washed with water and brine, gravity filtered, dried with MgSO4, and
filtered
again. The solvent was evaporated under reduced pressure on the rotovap to
provide a
clear oil. The crude product was dissolved in methanol and left standing at
room
temperature over the weekend.
The reaction mixture was concentrated in vacuo. The crude product was
purified via flash silica gel column chromatography on an Isco 40 g Si02 Gold
cartridge.
The column was initially eluted (mistakenly) with a 0%-50% Et0Ac/hexanes
gradient,
then flushed with 5% (Me0H/(1%NHD (Aq.)))/CH2C12.The fractions were combined
to
provide 0.50 g of impure product as a clear oil.
The impure product was purified via flash silica gel column
chromatography on an Isco 24 g Si02 Gold cartridge, using a 0%-5% Me0H/CH2C12
gradient as the mobile phase to provide Int-7i as a clear oil-(0.306g). When a
sample
was dissolved in deuterated methanol, a white solid formed in the flask. Took
IHNMR
and LC/MS. Obsd M+H = 433.1
EXAMPLE 8
Preparation of Intermediate Compound Int-8h
H3C
NBr
µ13oc
Int-8h
Step A ¨ Preparation of Compound Int-8b
0
N-0
EtMgBr
'N
Boc Boo
Int-8a Int-8b
A solution of Int-8a (11.0 g, 42.6 mmol) in THF (50 mL) was cooled to
0 C and to the cooled solution was added EtMgBr (82 mmol). After addition was

complete, the cooling bath was removed and the resulting reaction was allowed
to stir at
room temperature for 6 hours. 3 N HCI was then added and the reaction mixture
was

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extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were
washed
with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue
obtained
was purified using flash column chromatography on silica gel to provide
Compound Int-
8b (7.5 g, 50% yield).
Step B ¨ Preparation of Compound Int-8c
TFA
hoc
Int-8b Int-8c
Int-8b (7.5 g, 21.3 mmol) was dissolved in 100 mL of dichloromethane
and cooled to 0 C. TFA (100 mL) was added and the reaction was allowed to
stir to
room temperature over 2h. The solvent was removed and the residue obtained was

redissolved in Et0Ac then washed with saturated bicarbonate solution then
brine. The
extracts were dried over magnesium sulfate, filtered and concentrated in vacuo
to provide
Compound Int-8c as an oil, which was used without further purification.
Step C ¨ Preparation of Compound Int-8d
Trt
Int-8c Int-8d
To a solution of Compound Int-8c(4.2 g, 33 mmol) in THF (30 mL) was
added Et3N (4.1 g, 49 mmol) and then trityl chloride (8.7 g, 40 mmol). The
mixture was
allowed to stir at room temperature for 2 hours, then concentrated in vacuo.
The residue
obtained was purified using flash chromatography on silica gel to provide
Compound
Int-8d (8.7 g, 71% yield). MS (ESI) m/z (M+H) : 370.
Step D ¨ Preparation of Compound Int-8e

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"----= < ,0
LiHMDS ---- -S____
..---N NBS ---N Br
\ /
Trityl Trityl
Int-8d Int-8e
To a solution of Compound Int-8d (3.6 g, 10.0 mmol) in THF (30 mL)
was added LiHMDS (11.0 mmol) and then NBS (1.8 g, 10 mmol) at 0 C. The
mixture
was allowed to stir at room temperature for 2 hours and then 3 N HC1 was added
to the
mixture and the resulting solution was extracted with ethyl acetate (2 x 25
mL). The
combined organic extracts were concentrated in vacuo and the residue obtained
was
purified using chromatography to provide Compound Int-8e (1.98 g, 44% yield).
MS
(ESI) miz (M+H)+: 478, 480.
Step E- Preparation of Compound Int-8f
H3C
_.,-= ::,
hj
I H C N H
Trt 3 Trt
Int-8e Int-8f
To a solution of Compound Int-8e (3.6 g, 10.0 mmol) in THF (30 mL)
was added LiHMDS (11.0 mmol) and then NBS (1.8 g, 10 mmol). The mixture was
allowed to stir at room temperature for 2 hours and then 3 N HC1 was added to
the
mixture and extracted with ethyl acetate twice. The organic layer was
concentrated in
vacuo. The residue obtained was purified using chromatography to provide the
Int-8f
(1.98 g, 44% yield). MS (ESI) mh (M+H)+: 478, 480.
Step F - Preparation of Compound Int-8g

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H3C
H3C
hi NBS ---- --N
% H ----N N Trt H ._,.
or
Int-8f Int-8g
To a solution of Compound Int-8f (3.9 g, 10 mmol) in chloroform (30 mL)
was added NB S (1.76 g, 10 mmol) and the mixture was allowed to stir at room
temperature for 2 hours. The reaction mixture was then concentrated in vacuo
and the
residue obtained was purified using flash chromatography to provide Compound
Int-8g
(2.2 g, 47% yield).
Step G ¨ Preparation of Compound Int-8h
H3C H3C
---- .."-N
___k TFA
).-- ---- ----N
_k
--N N pi. Boc20 --N N
,
, H .... \ H Br
Trt Boc
Int-8g Int-8h
To a solution of Compound Int-8g (1.28 g, 2.7 mmol) in dichloromethane
(10 mL) was added TFA (10 mL) and the mixture was allowed to stir at room
temperature for 2 hours. Then the mixture was concentrated in vacuo and used
in the
next reaction directly. The residue obtained was dissolved in THF (20 mL) and
Et3N (5
mL) and to the resulting solution was added BOC anhydride (590 mg, 2.7 mmol).
The
mixture was allowed to stir at room temperature for 2 hours and concentrated
in vacuo.
The residue obtained was purified using chromatography to provide Compound Int-
8h
(600 mg, 67% yield). MS (ESI) m/z (M+H)+: 331.
EXAMPLE 9
Preparation of Intermediate Compound Int-9g

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Cbz
r,N N
Nit Br
SEM
Int-9g
Step A ¨ Preparation of Compound hit- 9b
Cbz Cbz
OH
Et3N vs) ¨N2
--N C.,
CH2N2 \
0
0
Int-9a Int-9b
To a solution of Compound Int-9a (50 g, 0.2 mol) in THF (500 mL) and
Et3N (20 mL) was added dropwise isopropyl chloroformate (25 g, 0.22 mol) at
ice water
bath. Then the resulting solution was allowed to warm to room temperature and
allowed
to stir for lh. Then a solution of CH2N2(0.22 mol) in ether was added slowly
until no N2
gas evolution was noted. Acetic acid (4 mL) was added and the reaction mixture
was
allowed to stir for 10 minutes. NaHCO3 solution was then added and the
reaction
mixture extracted three times with ethyl acetate. The organic layers were
combined, dried
over Na2SO4, and concentrated in vacuo to provide crude product. The crude
product was
then purified using column chromatography on silica gel (Pet Ether:
Ethyl.Acetate = 3:1)
to provide Compound Int-9b (38 g, 70% yield)
Step B ¨ Preparation of Compound Int-9c
Cbz Cbz
¨
HBr
2N
Int-9b Int-9c
To a solution of Int-9b (38 g, 0.14 mol) in HOAc (20 mL) was added
dropwise an aqueous HBr solution (11.2 g, 0.14 mol). After 10 minutes, the
mixture was

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poured into an aqueous NaHCO3 solution and extracted three times with ethyl
acetate.
The combined organic extracts were washed with brine, water, dried over Na2SO4
and
concentrated in vacuo to provide the product Int-9c (30 g, 68% yield).
Step C ¨ Preparation of Compound Int-9e
Cbz
Cbz
H2N,fNH K2CO3 NH
AcOH
Int-9c 9d Int-9e
To a solution of Int-9c (10 g, 32 mmol) and Compound 9d (8.4 g, 64
mmol) in DMF (70 mL) was added K2CO3 (18 g, 126 mmol). The mixture was allowed
to
stir at 100 C in a sealed tube for about 15 hours. The solvent was removed
and the
residue obtained was purified using column chromatography on silica gel
(dichloromethane: Me0H = 20:1) to provide the product Int-9e. (6 g, 59%
yield).
Step D ¨ Preparation of Compound Int-9f
Cbz Cbz
CN\JN SEMCI
N
SEM
Int-9e Int-9f
To a solution Int-9e (4 g, 14.7 mmol) in THF (40 mL) was added NaH
(6.6 g, 60 % content, 16.17 mmol) at 0 C. The mixture was allowed to stir at
room
temperature for 30 minutes. and then cooled to 0 C, and SEM-C1 (2.4 g, 14.7
mmol)
added dropwise. The resulting mixture was allowed to stir at 0 C for 2 hours.
The
solvent was removed in vacuo and the residue obtained was purified using
column
chromatography on silica gel (dichloromethane: Me0H =20:1) to provide the
product
Int-9f. (2 g, 34 % yield).
Step E ¨ Preparation of Compound Int-9g

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Cbz Cbz
r,N r,N
N
% NBS N%¨ Br
SEM SEM
Int-9f Int-9g
To a solution of Int-9f (2 g, 5 mmol) in THF (20 mL) was added dropwise
n-BuLi (2.5 mL, 6.3 mmol) at -78 C (bath) under N2 protection. The resulting
solution
was allowed to stir at this temperature for 30 minutes. Then a solution of NBS
(0.89 g, 5
mmol) in THF (10 mL) was added dropwise at -78 C. The mixture was allowed to
stir at
-78 C for 1 hour and then aqueous NRIC1 solution was added. The organic layer
was
separated and concentrated off to provide a crude residue, which was purified
using
column chromatography on silica gel (petroleum ether :EA=3:1 as the eluent) to
provide
Compound Int-9g (400 mg, 16.5% yield).
EXAMPLE 10
Preparation of Intermediate Compound Int-10f
Boc Boc Boc Im Boc
1 1 e---%= 1
HO2C.O1 step A HOH2C.O1 step B stepl\l C
H .
Int-10a Int-10b Int-10c Int-10d
Br Boc Boc
step D Br "--
_tr,µI lC)ki step E gr-TILI\J
N- ---4- N
H 1----/
H ,
-F F
Int-10e Int-10f
Step A ¨ Preparation of Compound Int-10b
(2S,4R)-1-(tert-butoxycarbony1)-4-fluoropyrrolidine-2-carboxylic acid
(Int-10a, 20 g, 85.75 mmol) was dissolved in anhydrous THF and cooled to 0 C.

BH3=THF (1M in THF, 171 mL, 171 mmol) was added via an addition funnel. The

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solution was gradually warmed up to room temperature and allowed to stir at
room
temperature for about 15 hours. Me0H was added until no bubbles came out. The
solution was concentrated in vacuo and the residue obtained was purified using
flash
column chromatography on silica gel (330g, 0% to 60% of Et0Ac in Hexane) to
provide
Compound Int-10b (15.1 g, 80.3%)
Step B ¨ Preparation of Compound Int-10c
To a dry 1000 mL round bottom flask was added oxalyl chloride (7.50 mL,
88.9 mmol) and dry dichloromethane (250 mL). After the solution was cooled to -
78 C,
DMSO (6.80 mL, 95.8 mmol) in dichloromethane (20 mL) was added dropwise. The
solution was allowed to stir at -78 C for 30 minutes. Int-10b (15.0 g, 68.4
mmol) in
dichloromethane (50 mL) was added via syringe. After the solution was allowed
to stir at
¨ 78 C for 30 minutes, TEA (38.1 mL, 273.6 mmol) was added. The solution was
allowed to stir at -78 C for 30 minutes and at 0 C for one hour. The
solution was
diluted with dichloromethane (300 mL) and washed with water, IN HCI, sat
NaHCO3,
and brine. It was dried over anhydrous Na2SO4, filtered and concentrated in
vacuo. The
residue obtained was dried in vacuo for 1 hour to provide Compound Int-10c
which was
used without further purification.
Step C ¨ Preparation of Compound Int-10d
To a 1000 mL round bottom flask was added Int-10c and NH3 (7N in
Me0H, 150 mL). Glyoxal (15 mL, 40% in water, 131 mmol) was added slowly. The
solution was allowed to stir at room temperature for about 15 hours.
Additional glyoxal
(5 mL, 44 mmol) was added and the reaction was allowed to stir at room
temperature for
another 24 hours. The solution was concentrated in vacuo and the residue
obtained was
purified using flash column chromatography on silica gel (240g, 0% to 5% of
Me0H in
dichloromethane, with 0.1% NH3-1-120) to provide Compound Int-10d (8.5 g,
48.7%
from 2)
Step D ¨ Preparation of Compound mitt-10e

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To a 100 mL round bottom flask was added Int-10d (8.5 g, 33.3 mmol)
and CH3CN (250 mL). More CH3CN was added to form a clear solution. NBS (11.3
g,
63.3 mmol) was added in one portion and the solution was allowed to stir at
room
temperature for about 15 hours. CH3CN was removed in vacuo and dichloromethane
(50
mL) was added with stirring. The solid was filtered and washed with
dichloromethane
twice. The filtrate was concentrated in vacuo to about 30 mL and filtered
again. The
filtrate was purified using flash column chromatography on silica gel (120g,
20% to 80%
of Et0Ac in Hexane) to provide Compound Int-10e (11.88 g, 86.4%).
Step E¨ Preparation of Compound It-10f
To a 1000 mL round bottom flask was added Int-10d (11.88 g, 28.76
mmol), sodium sulfite (Na2S03, 36.0 g, 288 mmol), Et0H (270 mL) and water (130
mL).
The solution was allowed to stir at reflux for about 15 hours. More Na2S03 (10
g, 79
mmol) was added and the solution was allowed to stir at reflux for another 24
hours.
After cooling down, the solid was filtered and washed with Et0Ac three times.
The
filtrate was concentrated in vacuo and the residue obtained was dissolved in a
mixture of
Et0Ac (300 mL) and water (200 mL). The organic layer was separated and washed
with
brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
residue
obtained was purified using flash column chromatography on silica gel (240g,
0% to 33%
of Et0Ac in Hexane) to provide Compound Int-10f (5.12 g, 53.3%).
EXAMPLE 11
Preparation of Intermediate Compound Int-lle
Br
Boc N
N
F
Int-11c
Step A ¨ Preparation of Compound It-Jib

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Boc 0 Boc
IN 4,0A NH3/ Me0H IµLos
H
Glyoxal/H20
F F F F
Int-ha Int-lib
The aldehyde Int-11a was prepared from the commercially available
alcohol using the method described in Example 10.
A flask was charged with aldehyde Int-ha (82g, 0.35 mol) and a 2.33 N
ammonia/Me0H solution was added with good stirring (600 mL, 4.0 eq., prepared
from
200m1 7N ammonia/Me0H diluted with 400 mL Me0H). The reaction was then heated
to 35 C and allowed to stir at this temperature for 2 hours, after which time
a solution of
40 wt% glyoxal in water (80 mL, 2.0 eq.) was added dropwise over about 15
minutes.
After stirring for an additional 2 hours, a solution of 7N ammonia/Me0H (100
mL, 2.0
eq.) was added and the reaction was allowed to stir at 35 C for 1 hour.
Additional
glyoxal (40 mL, 1.0 eq.) was then added dropwise over 5 minutes and the
resulting
reaction was allowed to stir at 35 C for 1 hour. The reaction mixture was
then allowed
to cool room temperature and stir for about 15 hours. Additional 7N
ammonia/Me0H
(50 mL, 1.0 eq.) was then added and the reaction reheated to 35 C and allowed
to stir at
this temperature for 1 hour. An additional amount of glyoxal (20 mL, 0.5 eq.)
was then
added and the resulting reaction was allowed to stir at 35 C for 1 hour, then
the reaction
mixture was cooled to room temperature and filtered. The filtrate was
concentrated in
vacuo and the residue obtained was diluted with dichloromethane and water (2
L, 1:1).
The organic layer was separated, washed with 1L of water, then brine and dried
(MgSO4),
filtered and concentrated in vacuo. The brown foam residue obtained was
further
purified using being passed through a short silica gel column to provide
Compound Int-
llb (60g, 62%).
Step B ¨ Preparation of Compound Int-11c

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Br
Boc Nr$ Boc N
c
NBS _ 11
FS\--
\F
Int-11b Int-11c
Int-11c was prepared from Int-llb using the method described in
Example 10.
Intermediate Compounds It-lid, Int-lie and Int-llf can be prepared
using the methods described in Example 10 and Example 11.
Br
Br Br
N
Boc N
Boc
H
H
CH3
It-lid It-he Int-11f
EXAMPLE 12
Preparation of Intermediate Compound Int-12i
Br
HN
Boc
Int-12i
Step A ¨ Preparation of Compound Int-12b
0 Boc 9
Bos
0 LHMDS 0
Mel
Int-12a Int-12b
To a solution of Compound Int-12a (60 g, 0.24 mol) in dry THF (1 L)
allowed to stir at -78 C was added lithium hexamethyldisilazide (82 g, 0.49
mol, 1 M in
TI-IF). After the reaction mixture had been allowed to stir at -78 C for 1
hour, the
iodomethane (66 g, 0.46 mol) dissolved in dry THF (100 mL) was added at -78 C
and the

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mixture was allowed to stir for 15 minutes at this temperature and 2 hours at
25 C. The
reaction mixture was quenched with saturated ammonium chloride solution and
extracted
with dichloromethane (3 x 300 mL). The combined organic phases were dried over

MgSO4, filtered, and concentrated in vacuo. The products were purified using
flash
column chromatography on silica gel to provide Compound Int-12b (18.3 g, 27%
yield).
IHNMR 8: 4.38-4.34 (m, 1 H), 4.08-4.05 (m, 2 H), 2.09-2.03 (m, 1 H), 1.77-1.73
(m, 1
H), 1.35 (s, 9 H), 1.12 (t, J= 8 Hz, 3 H), 1.06 (s, 6 H).
Step B ¨ Preparation of Compound Int-12c
0 0
Boc
J.L0 TFA LJL0
. 0
oç
Int-12b Int-12c
To a solution of Compound Int-12b (18.3 g, 60 mmol) in dichloromethane
(150 mL) was added TFA (15 mL) and the mixture allowed to stir at room
temperature for
30 minutes. The solvent was removed to provide Compound Int-12c (11.2 g, 100%
yield).
Step C ¨ Preparation of Compound Int-12d
0
NOH
0
Int-12c Int-12d
A suspension of LiAIH4 (16.2 g, 0.44 mol) and Compound Int-12c (11.2 g,
54.8 mmol) in THF (200 mL) was allowed to stir under reflux for 8 hours. After
successive addition of 17 mL of water, 17 mL of 10% aq NaOH, and 51 mL of
water, and
filtration, the filtrate was concentrated in vacuo to provide Compound Int-12d
(6.7 g,
94% yield).
Step D ¨ Preparation of Compound Int-12e

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Boo
N (Boc)20 N
Int-12d Int-12e
Compound Int-12D was dissolved in THF and Et3N, (Boc)20 were added.
The mixture was allowed to stir at room temperature for 2 hours and
concentrated in
vacuo. The residue obtained was purified using chromatography to provide
Compound
Int-12e (14 g, 100% yield).
Step E ¨ Preparation of Compound Int-12f
Boc, Boc,
Dess-mart N
Int-12e Int-12f
To a solution of Compound Int-12e (14g, 65.4 mmol) in dichloromethane
was added Dess-Martin reagent (41.6 g, 98.1 mol). After stirring at room
temperature for
about 15 hours, the solvent was removed and the residue obtained was purified
using flash
column chromatography on silica gel to provide Compound Int-12f (7 g, 47%
yield). 1H
NMR 5: 9.40 (s, 1 H), 4.05-4.03 (m, 1 H), 3.14-3.11 (m, 2 H), 1.83-1.79 (m, 1
H), 1.66-
1.63 (m, 1 H), 1.36 (s, 9 H), 1.02 (s, 6 H).
Step F ¨ Preparation of Compound Int-12g
Boci CD Boc, `10
NJ-NJ
0
Int-12f Int-12g
Glyoxal (1.75 mL of 40% in water) was added dropwise over 11 minutes
to a solution of NH4OH (26 mL) and Compound Int-12f (6.1 g, 28.8 mmol) in
methanol

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and allowed to stir at room temperature for 19 hours. The volatile component
was
removed in vacuo and the residue obtained was purified using a flash
chromatography on
silica gel to provide Compound Int-12g (3 g, 39% yield).
MS (ESI) m/z (M+H)+: 266.
Step G ¨ Preparation of Compound Int-12h
Br
HI=1"
Boc
NBS Boc L
FIN- N- ____
"Br
...... THF j
Int-12g Int-12h
A mixture of Compound Int-12g (2.2 g, 8.3 mmol), N-bromosuccinimide
(2.66 g, 14.9 mmol) in anhydrous THF (80 mL) was heated at reflux for about 15
hours.
After cooling to room temperature, the solids are removed by filtration and
the filtrate
was concentrated in vacuo and the residue obtained was purified using
chromatography
to provide Compound Int-12h (2.0 g, 57% yield). IfINMR (J000120117 H10170-003-
1
CDC13varian 400 MHz) 6: 11.03 (s, 1 H), 4.79 (t, J = 8 Hz, 1 H), 3.25 (t, .1=
12 Hz, 1 H),
2.96 (t, J= 12 Hz, 1 H), 2.58-2.53 (m, 1 H), 2.95-1.90 (m, 1 H), 1.34 (s, 9
H), 1.05 (s, 3
H), 0.99 (s, 3 H). MS (ES!) m/z (M+H) : 422.
Step H¨ Preparation of Compound Int-12i
Br Br
Boc

Br __,...
i`IN µ1=1,21N
Int-12h Int-12i
To a solution of Compound Int-12h (1.9 g, 4.5 mmol) in H20/Et0H (40
mL /20 mL) was added Na2S03 (5.6 g, 4.5 mmol) and the mixture was allowed to
stir at
room temperature for about 15 hours. The reaction mixture was concentrated in
vacuo and
the residue obtained was dissolved in ethyl acetate, washed with brine, dried
over MgSO4,
filtered, and concentrated in vacuo. The residue obtained was purified using

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chromatography on silica gel to provide Compound Int-12i (0.75 g, 48% yield).
1H NMR
8: 6.92 (s, 1 H), 4.71-4.67 (m, 1 H), 3.26-3.21 (m, 2 H), 2.01-1.96 (m, 1 H),
1.78-1.72 (m,
1 H), 1.13 (s, 9 H), 1.00 (s, 3 H).
EXAMPLE 12A
Preparation of Intermediate Compound Int-12o
0 t-Boc Step 1 Step 2 H t-
Boc Step 3 e = t-Boc t-Boc
HON.,
d\c
..r ..? _____________ 1::"(
Int-12j Int-12k Int-12I Int-12m
Br
t-Boc N t-Boc
Step 5 /1\(R)
Step 4
H (s) ____________________________________________
Int-12n Int-12o (R)
Step A
Acid Int-12j (22.7 g, 100 mmol) was dissolved in dry THF (400 ml) in a
1000 mL flask, and cooled with an ice-water bath. Borane tetrahydrofuran
complex (1.0
M in THF, 200 ml, 200 mmol) was added via an additional funnel dropwise over a
period
of 80 minutes. After 1 hour at 0 C the reaction was allowed to warm to room
temperature and stir for about 15 hours. Methanol was then added dropwise via
an
additional funnel (-100 ml) and then the reaction was then concentrated in
vacuo. The
residue was purified on a 300 g ISCO silica column/ Combi-Flash Rf system
using a
gradient of 0-70% ethyl acetate in hexanes to provide alcohol Int-12k as a
colorless oil
(18.2 g, 85%).
Step B
Oxalyl chloride (14.08 g, 111 mmol) was dissolved in methylene chloride
(340 ml) in a 1000 mL flask and cooled to -78 C under nitrogen atmosphere.
DMSO
(9.33 g, 119 mmol) was added slowly via syringe over a period of 10 minutes.
The
resulting solution was allowed to stir at -78 C for 45 minutes prior to the
slow addition
of the alcohol Int-12k (15.2 g, 85 mmol) in methylene chloride (50 ml) and
stirred at -

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78 C under nitrogen for 45 minutes before addition of triethylamine (34.5 g,
341 mmol).
After 40 minutes at -78 C, then reaction was warmed to 0 C and stirred at 0
C for an
additional 1 hour. After addition of 500 mL of methylene chloride, the organic
solution
was washed with water, 1N HC1 solution (300 ml), and water. The organic layer
was
dried over sodium sulfate, concentrated in vacuo to provide aldehyde Int-121
as a
colorless oil (18.14 g, ¨100%). This crude product was used for the next
reaction without
purification.
Step C
The aldehyde Int-121 (18.14 g, 86 mmol) was dissolved in methanol (37
ml) and the resulting solution was cooled with a RT water bath. A 7N ammonia
solution
in methanol (31.9 ml, 223 mmol) was then added dropwise via an additional
funnel over
a period of 15 minutes. The reaction mixture was allowed to stir at room
temperature for
20 minutes before a 40% aqueous solution of glyoxal (16.2 g, 112 mmol) was
added.
The reaction mixture was allowed to stir at room temperature for about 15
hours and then
concentrated in vacuo. The residue was purified using a 220 g ISCO silica
column/Combi-Flash Rf system (0-7% methanol in dichloromethane eluent) to
provide
Compound Int-12m as a slightly yellow solid (10.8 g, 51.5%).
Step D
Intermediate Int-12m (10.81 g, 43.4 mmol) was dissolved in THF (200 ml)
in a 250 mL flask and NBS (15.43 g, 87 mmol) was added slowly at room
temperature.
The resulting solution was allowed to stir at room temperature for 4.5 hours
and
concentrated to semi-solid. The residue was dissolved in ethyl acetate (300
ml), washed
with brine (3X100 ml), dried over sodium sulfate, and concentrated in vacuo.
The crude
material was purified using crystallization from dichloromethane to provide
Compound
Int-12n as a white solid (7.68 g, 43.5%). The mixture from mother liquid was
purified
using a 220 g ISCO silica column/Combi-Flash Rf system using 0-70% ethyl
acetate in
hexanes as the eluent to provide a second batch of Int-12n as a pale solid
(7.73g, 43.8).
Step E

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Intermediate Int-12n (14.4 g, 35.4 mmol) was dissolved in methanol (45
ml) and water (16 ml) and placed in a water bath. EDTA (10.34 g, 35.3 mmol)
followed
by 7N ammonia in methanol (20.21 ml, 141 mmol) were then added. Zinc powder
(2.314
g, 45.4 mmol) was then added and the resulting solution was allowed to stir at
room
temperature. After 6 hours the reaction was then concentrated and the residue
was
redissolved with ethyl acetate (100 ml), washed with water (2x50 ml), dried
over sodium
sulfate, and concentrated in vacuo. The crude product was purified on a 80 g
silica
column with a Combi-Flash RI system using a gradient of 0-70% ethyl acetate in
hexanes
to provide Int-12o as a white solid (7.56 g, 65%).
EXAMPLE 13
Preparation of Intermediate Compounds Int-13d and Int-13e
0 /
1) n-BuLifTHF 1) Column diast
__________________________________________________________ Boc
0 N 0 N soN^Ni 2) HCl/Me0H
Si' 3) DIPEA/Nal
Si
Int-13a r r , 3) Boc.20 /
Cl
Cl/ 80-90%
CI Si,C1 60%
Int-13b Int-13c Int-13c Int-13d
Step A ¨ Preparation of Compound Int ¨ 13c
A 5 L- 3 necked round bottomed flask, equipped with a mechanical stirrer,
temperature probe, addition funnel and N2 inlet, was charged with the
Schollkopf chiral
auxiliary-(Int-13a, 200 g, 1.09 mol, 1.0 eq), bis(chloromethyl) dimethylsilane
(Int-13b,
256 g, 1.63 mol, 1.5 eq), and THF (2 L, Aldrich anhydrous). The flask was
cooled in a
dry ice/ 2-propanol bath until the internal temperature reached -75 C. n-
Butyllithium
(Aldrich 2.5 M in hexanes , 478 mL, 1.19 mol, 1.09 eq) was added via a
dropping funnel
over 1 hour while maintaining the internal reaction temperature between -67 C
and -
76 C. The resulting orange-red solution was allowed to gradually warm to room

temperature for about 15 hours. The reaction mixture was then re-cooled to 0
C and
quenched with 500 mL of water. Diethyl ether (2L) was added and the layers
were

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separated. The aqueous layer was extracted with 1 L of diethyl ether. The
combined
organic extracts was washed with water and brine, dried with MgSO4, filtered,
and
concentrated in vacuo, giving 480 g of orange oil. This material was left in
vacuo for
about 15 hours to provide 420 g of oil. The crude product was split into two
batches and
purified via silica gel chromatography on a 1.6 kg flash column. The column
was eluted
with gradient of 0-4% Et20 in hexanes. The product fractions were concentrated
in
vacuo at a bath temperature at or below 40 C giving 190 grams of Int-13c-
(60%yield).
Step B ¨ Preparation of Compound Int-13d
A 5 L, 3-necked round bottomed flask equipped with a mechanical stirrer,
addition funnel, temperature probe, external water bath and N2 inlet was
charged with
Compound Int-13c (196 g, 0.643 mol, 1.0 eq) and methanol (1.5 L). Aqueous HC1
(500
mL of 10% by volume) was added at room temperature over 30 minutes, with a
mild
exotherm observed. The temperature increased to 37 C then dropped back down.
The
reaction mixture was allowed to stir at room temperature for 3 hours and was
monitored
by TLC and LC/MS. The reaction mixture was then concentrated in vacuo to an
oil.
Additional methanol (3 x 200 mL) was added and the reaction mixture was
concentrated
in vacuo again. The resulting crude product was dried under house vacuum for
about 15
hours. The crude product was then dissolved in CH2C12 (750 mL) and Et20 (1250
mL)
and sodium iodide (96.4 g, 0.643 mol, 1.0 eq) was added. Diisopropylethylamine
(336
mL, 1.929 mol, 3.0 eq) was added slowly over 25 minutes with stirring, causing
the
temperature to increase to 35 C then decrease to room temperature again. The
reaction
mixture was allowed to stir at room temperature for 2 hours, after which time
the MS of
an aliquot indicated consumption of the starting material. The reaction
mixture was
allowed to stir for an additional 2 hours and then Boc-anhydride (281 g, 1.286
mol, 2.0 eq)
was added. The reaction mixture was then allowed to stir at room temperature.
After two
days, the reaction mixture was diluted with Et0Ac (2 L) and water (1 L), and
he layers
were separated. The aqueous phase was extracted with 500 mL of Et0Ac. The
combined organic extracts were washed with water (500 mL) and brine (500 mL),
dried
with MgSO4, filtered, and concentrated in vacuo to a yellow oil (380 g). The
crude
product was split into two 180 g portions for convenience and each portion was
purified

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via flash silica gel chromatography. Column conditions for a 180 g portion of
crude
product are as follows. The 180 gram sample of crude product was loaded onto a
191 g
Si02 cartridge and purified on a 1.5 kg Si02 column. The column was eluted
using a 0%-
20% Et0Ac/hexanes gradient as the mobile phase to provide 52 grams of pure Int-
13d
and additional fractions of Int-13d that contained a small amount of a Boc-
valine
impurity. The impure fractions from the two columns were recombined and re-
purified.
After chromatography, Compound Int-13d was obtained as an oil which solidified
to a
white solid on standing (128 g, 65 % yield over the three steps.)
Step C ¨ Preparation of Compound Int-13e
0 BOC 0 BOC
LiOH
0 HO
Si¨

/
Int-13d Int-13e
A solution of Int-13d (8.5 g, 31.1 mmol) in methanol (100 mL) and 1.0 M
aqueous KOH solution (48 mL, 48 mmol) was allowed to stir at room temperature
for
about 15 hours. The reaction was then neutralized with 48 mL of 1.0 M aqueous
HC1
solution to pH ¨5, and partially concentrated in vacuo. The aqueous layer was
then
extracted twice with dichloromethane (2 x 100 mL). The combined organic
solutions
were concentrated in vacuo to provide Compound Int-13e as a gel (7.74 g, 96%).
Note: The above reactions were monitored by TLC using Hanessian's
stain. To prepare the visualization stain, combine 450 mL of H20, 25 g
ammonium
molybdate, 5 g of ceric sulfate, and 50 mL of conc. HC1 or conc. H2SO4.
EXAMPLE 14
Preparation of Intermediate Compound Int-14d

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HO)L0 Boc Boc 0 Boc
NN
t Step A HO/--C Step B
Int-13e Int-14a Int14b
ploc N Boc
Step C Step D
___________________________________________ Br
H Si, H
Int-14c Int-14d
Step A ¨ Preparation of Compound Int-14a
To a mixture of carboxylic acid Int-13e (20 g, 77 mmol) in THF (400 mL)
at 0 C was added 1M BH3 in THF ( 0.17 L) via addition funnel at 0 C. The
mixture
was allowed to warm to room temperature and stir for about 15 hours. The
reaction was
carefully quenched by addition of Me0H (¨ 75 mL) until bubbling ceased. The
reaction
mixture was concentrated in vacuo whereupon the residue obtained was
partitioned
between Et0Ac and H20. The layers were separated and the aqueous layer was
extracted
with Et0Ac (2x). The organic layers were combined, washed with brine, dried
(Na2SO4),
and concentrated in vacuo to provide Compound Int-14d (18 g, 99%) as a clear
oil,
which was used without further purification. MS (ESI) m/e (M+H+Na)+: 268.
Step B ¨ Preparation of Compound Int-14b
To a dry 2-necked flask equipped with a stir bar was added oxalyl chloride
(8.2 mL, 96 mmol) and CH2C12 (280 mL). The solution was cooled to -78 C
whereupon
a solution of DMSO (7.4 mL, 0.10 mol) in C112Cl2 (22 mL) was added and the
mixture
was allowed to stir for 30 minutes at -78 C. A solution of alcohol Int-14a
(18 g, 74
mmol) from Step A in CH2C12 (60 mL) was added dropwise via addition funnel
over 30
minutes. The resulting solution was allowed to stir for an additional 30
minutes at -78 C
whereupon Et3N (42 mL, 0.30 mol) was added dropwise. The mixture was allowed
to
stir for 30 minutes at -78 C, warmed to 0 C, and allowed to stir for an
additional 1.5
hours. The mixture was diluted with CH2C12 (400 mL) and was transferred to a
separatory funnel. The organic layer was washed with sat. aq NH4C1 (2 x 100
mL) and
brine (2 x 100 mL). The organic layer was dried (Na2SO4), filtered, and
concentrated in
vacuo to provide Compound Int-14b,18 g (99%) as a clear oil, which was used
without
further purification.

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Step C ¨ Preparation of Compound Int-14c
To a round bottom flask charged with aldehyde Int-14b (18 g, 74 mmol)
from Step B was added a 7N NH3 in Me0H solution (28 mL, 0.19 mol) in Me0H (37
mL)
at room temperature. The mixture was allowed to stir for 30 minutes at room
temperature
whereupon a solution of glyoxal (14 g, 96 mmol) was added over 5 minutes. The
resulting solution was allowed to stir for 12 hours at room temperature and
was
concentrated in vacuo. The residue obtained was purified using column
chromatography
using a gradient of 100% CH2C12to 97.5% CH2C12/2.5% Me0H to provide Compound
Int-14c, 9.9 g (48%) as yellow oil. MS (ESI) m/e (M+H)+: 282.
Step D ¨ Preparation of Compound Int-14d
To a solution of imidazole Int-14c (1.0 g, 3.6 mmol) from Step C in
CH2C12(5 mL) at 0 C, was added NBS (0.44 g, 2.5 mmol) in CH2C12 (10 mL)
dropwise
via addition funnel. The resulting mixture was allowed to stir for 90 minutes
at 0 C
whereupon the mixture was concentrated in vacuo. The crude residue obtained
was
partitioned between CHC13(10 mL) and water (3 mL) and the layers were
separated. The
organic layer was washed with water (3 x 3 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The residue obtained was purified using column
chromatography
(80g) using a gradient of 100% hexanes to 65% hexanes/35% Et0Ac to provide
Compound Int-14d, (0.35 g, 27%) as a white solid. MS (ESI) m/e (M+H)+:
360/362.
EXAMPLE 15
Preparation of Intermediate Compound Int-15c
0
¨It
HO Boc
N'
H 'H
/Si\
Int-15c
Step A -- Preparation of Compound Int-15a

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I
___________________________________ H
/Si\
Int-15a
To a solution of dichlorozirconocene (Cp2ZrC12) (4.2 g, 14.2 mmol) in 40
mL THF at -78 C was added n-BuLi (1.6 M in hexane, 18 mL, 28.4 mmol). The
resulting reaction was allowed to stir for 1 hour, then diphenyldiallylsilane
(2 g, 14.2
mmol) in 17 mL of THF was added at -78 C. The reaction was allowed to stir
for 1
hour at -78 C and for 18 hours at 25 C. Iodine (9 g, 35.5 mmol) in 20 mL THF
was
then added at -78 C and the mixture was allowed to stir for 1 hour. The
reaction was
quenched with 10% aqueous H2 SO4 and the organic phase was extracted by ether.
The
organic solution was washed with saturated aqueous NaHCO3 solution, brine
solution,
and dried (Na2SO4). After filtration, the filtrate was concentrated in vacuo
and the
residue obtained was purified using an ISCO 120 g column (hexane) to provide
Compound Int-15a, 2.75 g (49%). 1H NMR (CDCI3) 8 3.44 (dd, J = 2.2, 10.0 Hz,
2H),
3.33 (dd, J= 4.7, 10.0 Hz, 2H), 1.20 (m, 2H), 0.93 (dd, J = 5.9, 14.7 Hz,
211), 0.63 (dd, J
= 11.1, 14.2 Hz, 2H), 0.19 (s, 6H).
Step B ¨ Preparation of Compound Int-15b
Me0,1XNJ
OMe
Hf
Int-15b
To a solution of (2R)-(¨)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine
(0.61 g, 4.36 mmol) in THF (8 mL) was added n-BuLi (2.5 M in hexane, 1.8 mL,
4.58
mmol) at -78 C. After allowed to stir for 0.3 hours, Compound Int-15a (2.75
g, 6.98
mmol) in 2 mL of THF was added and the mixture was allowed to stir at the
temperature
for 4 hours. The reaction was quenched by saturated aqueous NH4C1 solution and
the

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organic layers were extracted with Et0Ac. The combined organic solution was
washed
with brine solution, dried (Na2SO4), and concentrated in vacuo. The residue
obtained
was purified using an ISCO 40 g column (gradient from 0% to 2.5% ether in
hexane) to
provide Compound Int-15b, 783 mg (44%). 1H NMR (CDC13) 6 4.05 (m, 1H), 3.96
(t, J
= 3.4 Hz, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.49 (dd, J = 2,8, 0.4 Hz, 1H),
3.26 (dd, J = 6,
9.4 Hz, 1H), 2.30 (m, 1H), 1.96(m, 1H), 1.60 (m, 2H), 1.37 1.17 (m, 3H), 1.08
(d, J =
6.9 Hz, 3H), 0.99 0.86 (m, 2H), 0.72 (d, J= 6.6 Hz, 3H), 0.49 (dd, J= 11.0,
14.4 Hz,
1H), 0.35 (dd, J= 11.0, 14.2 Hz, 1H), 0.16 (s, 6H).
Step C ¨ Preparation of Compound Int-15c
To a solution of Compound Int-15b (780 mg, 1.92 mmol) in Me0H (9
mL) was added 10% aqueous HCI (3 mL) at 0 C and the mixture was allowed to
stir at
25 C for 18 hours. The mixture was concentrated in vacuo and the residue
obtained
was reconcentrated in vacuo with Me0H twice. The resulting white foam was
dissolved
in ether (6 mL) and CH2C12 (9 mL), and diisopropylethylamine (1 mL, 5.7 mmol)
was
added. After allowed to stir at 25 C for 18 hours, di-t-butyl dicarbonate
(922 mg, 4.22
mmol) was added and the resulting mixture was allowed to stir at 25 C for 2
days. The
mixture was added to cold water and the organic layers were extracted with
Et0Ac. The
combined organic solution was washed with brine solution, dried (Na2SO4), and
concentrated in vacuo. Then the residue obtained was dissolved in Me0H (8 mL)
and
treated with aqueous 1 M KOH solution (3.3 mL, 3.3 mmol). After allowed to
stir at
0 C to 25 C, the reaction mixture was acidified with 10% aqueous HC1 and the
organic
layers were extracted with CH2C12. The combined organic solution was washed
with
brine solution, dried (Na2SO4), and concentrated in vacuo to provide Compound
Int-15c,
which was used without further purification.
EXAMPLE 16
Preparation of Intermediate Compound Int-16e

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OMe
CI CI
CI----s( step A ay... ) step B >--11-..,,\ /------1
0 ----- O Me0 ¨NCI--/SiN
Int-16a Int-16b Int-16c
Boc Boc
/ /
Me02C,r, 14) HO2C,r¨ N
step C step D
1-;si..,) ----- zsi...7
\____J \____/
Int-16d Int-16e
Step A ¨ Preparation of Compound Int-166
To a 1000 mL flame dried flask was added 1, 1-dichlorosilolane
(Int-16a, 28.09 g, 181.1 mmol), bromochloromethane (23.5 mL, 362.2 mmol), and
anhydrous THF (400 mL). The solution was cooled to -70 C, then n-BuLi (2.5M
in
hexane, 145 mL, 362 mmol) was added slowly over a period of 1 hour. The
resulting
reaction was allowed to stir at -70 to -60 C for 20 minutes, then was allowed
to warm to
room temperature over 1 hour. Saturated NH4C1 solution (200 mL) and Et20 (200
mL)
were then added and the organic layer was separated and the aqueous layer was
extracted
with Et20 (100 mL) twice. The organic layers were combined, washed with brine,
dried
over Na2SO4, filtered and concentrated in vacuo. The residue obtained was
purified
using 5i02 chromatography (240 g, eluted with hexane) to provide Compound Int-
16b
(17.2 g, 51.9%).
Step B ¨ Preparation of Compound Int-16c
To a 500 mL flame dried flask was added (R)-2-isopropyl-3, 6-
dimethoxy-2,5-dihydropyrazine (10.0 g, 54.3 mmol) and anhydrous THF (200 mL).
The
solution was cooled to -78 C. n-BuLi (2.5M in hexane, 24.0 mL, 59.7 mmol) was

added dropwise. After the solution was allowed to stir at -78 C for 30
minutes,
Compound Int-16b (in 5 mL anhydrous THF) was added dropwise. After the
solution
was allowed to stir at -78 C for 1 hour, it was allowed to warm up to room
temperature
in two hours. Water (100 mL) and Et20 (150 mL) were added. The organic layer
was

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separated and the aqueous layer was extracted with Et20 (100 mL) twice. The
organic
layers were combined, washed with brine, dried over Na2SO4, filtered and
concentrated
in vacuo. The residue obtained was purified using Si02 chromatography (40 g,
eluted
with Et20 in Hexane: 0% to 3%) to provide Compound Int-16c (10.43 g, 58.0%).
Step C ¨ Preparation of Compound Int-16d
To a 500 mL flask was added Compound Int-16c (11.5 g, 34.8 mmol)
and Me0H (80 mL). 10% HC1 (20 mL) was added. The solution was allowed to stir
at
room temperature for 5 hours and concentrated in vacuo. The residue obtained
was
dissolved in 20 mL Me0H and concentrated again to remove water and HC1. This
process was repeated three times. The residue obtained was dissolved in
dichloromethane (50 mL) and Et20 (70 mL). DIPEA (15.4 mL, 86.9 mmol) and NaI
(5.2
g, 34.75 mmol) were added. The solution was allowed to stir at room
temperature for
about 15 hours. Di-tert-butyl dicarbonate (18.9 g, 86.9 mmol) was added. The
solution
was allowed to stir at room temperature for 4 hours. Water (100 mL) and Et0Ac
(100
mL) were added. The organic layer was separated and the aqueous layer was
extracted
with Et0Ac (100 mL) twice. The organic layers were combined and washed with
brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue
obtained
was purified using Si02 chromatography (220g. Hexane/EtOAC: 0% to 20%) to
provide
Compound Int-16d (7.9 g, 75.9%).
Step D ¨ Preparation of Compound Int-16e
Compound Int-16d (7.9 g, 26.4 mmol) was dissolved in Me0H (100 mL)
and cooled to 0 C. KOH (1M in water, 39.6 mL, 39.6 mmol) was added. The
solution
was allowed to stir at 0 C for 2 hours, and then at room temperature for 3
hours. HC1 (2
N, 20 mL) was added, then additional HC1 was added slowly to adjust the
solution to pH
4. The acidified solution was concentrated in vacuo and to the residue
obtained was
added water (150 mL) and Et0Ac (200 mL). The organic layer was separated and
the
aqueous layer was extracted with Et0Ac (2 x 100 mL). The combined organic
extracts
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated in

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vacuo. The residue obtained was dried in vacuo for 48 hours to provide
Compound Int-
16e (7.45 g, 99%), which was used without further purification.
EXAMPLE 17
Preparation of Intermediate Compounds Int-17c and Int-17d
Step A ¨ Preparation of Compound It-17b
Br 0 OHBr 0 OAc
_...
F F
Int-17a Int-1713
To a 500 mL flask was added Int-17a (25.0 g, 130 mmol), dry
dichloromethane (250 mL) and DIPEA (25.37 g, 195 mmol). The solution was
cooled to
0 C and acetyl chloride (13.27g, 169 mmol, in 30 mL dry dichloromethane) was
added
dropwise. The resulting reaction was allowed to stir at 0 C for one hour and
then at
room temperature for about 15 hours. The solution was diluted with Et0Ac and
washed
with water. The organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated in vacuo. The residue obtained was purified using flash column
chromatography on silica gel (330g, 0% to 50% of Et0Ac in Hexane) to provide
Compound Int-17b (22.58 g, 74.5%)
Step B ¨ Preparation of Compound It-17c
Br0 OAc Br 0 OH
_,õ...
0
F F
Int-17b Int-17c
To a 500 mL flask was added Int-17b (21.45 g, 92.05 mmol) and dry
dichloromethane (200 mL). It was cooled to 0 C and aluminum trichloride
(A1C13, 36.82
g, 276.2 mmol) was added in portions. After the solution was allowed to stir
at 0 C for .
30 minutes, it was concentrated in vacuo. The semi-solid residue obtained was
heated at
140 C for three hours. After it was cooled to 80 C, water (10 mL) was added
dropwise.

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It was then cooled to 0 C and Et0Ac (300 mL) and water (200 mL) were added.
The
suspension was allowed to stir at 0 C until the entire solid dissolved. More
Et0Ac was
added and the organic layer was separated. The organic layer was washed with
water,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue
obtained
was purified using flash column chromatography on silica gel (330g, 0% to 10%
of
Et0Ac in Hexane)to provide Compound Int-17c (18.76 g, 87%).
Step C - Preparation of Compound It-17d
0
HO Br
It-17d
Compound Int-17d was prepared using the method described above for
the synthesis of Compound Int-17c and substituting 2-bromophenol for Compound
Int-
17a in Step A
EXAMPLE 18
Preparation of Intermediate Compound Int-18c
Br
H3CeBr
0
Int-18c
Step A ¨ Preparation of Compound Int-18b
0
H3C6-,,OH H3C6-11..
0 0
Int-18a Int-18b
To a stirred solution of (3-methyloxetan-3-yl)methanol (Int-18a,10.0 g,
97.9 mmol) in methylene chloride (400 mL) at 0 C, under inert atmosphere, was
added
silica gel (20 g). PCC (29.5 g, 137 mmol) was then added in portions over a 2
minutesute

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period. The solution was allowed to slowly warm to room temperature and
stirred for 6.5
hours. The reaction mixture was then filtered through a mixture of
Celite:silica gel (1:1,
400 g total) and the Celite:Silica gel was washed with methylene chloride (4
L). The
filtrate and washing were combined and concentrated in vacuo to provide 4.98 g
(51%) of
Int-18b as a clear solution (48.5 wt%) in methylene chloride. 1HNMR (CDC13 500

MHz): 9.94 (s, 1H), 4.89 4.83 (m, 2H), 4.52 4.46 (m, 211), 1.48 (s, 3H).
Step B ¨ Preparation of Compound Int-18c
0 Br
H3ceN ________________________________ H3CeBr
0 0
Int-18b Int-18c
To a stirred solution of triphenylphosphite (5.10 mL, 19.5 mmol) in
methylene chloride (9 mL) at 0 C, under inert atmosphere, was added bromine
(1.00
mL, 19.5 mmol) dropwise at 0 C. A solution of Compound Int-18b (1.00 g, 9.99
mmol) in methylene chloride (1 mL) was then added and the resulting reaction
was
allowed to stir for 40 minutes at 0 C. The reaction mixture was diluted with
hexanes
(10 mL) and the solution was passed through a plug of silica gel (4 g). The
solids were
washed with MTBE (20 mL). The filtrate and washing was combined and
concentrated
in vacuo to ¨10 mL and purified using flash column chromatography on silica
gel
(methylene chloride/pentane) to provide 1.06 g (44%) of Compound Int-18e as
clear
colorless oil. IFINMR (CDC13,500 MHz): 6 5.98 (s, 1H), 3.76 (d, J = 10.5 Hz,
2H),
3.65 (d, J = 10.5 Hz, 2H), 1.44 (s, 3H).
EXAMPLE 19
Preparation of Intermediate Compound Int-19e
Br* *
Br
HO
It-19e

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Step A ¨ Preparation of Compound Int-19a
0 H HCI
101 N,NH2 AcOH,Et0H
N,
N
HO Br Br Br HO Br
Int-17d Int-19a
A mixture of Int-17d (4.2 g, 20 mmol) and 4-bromophenyl hydrazine
hydrochloride (4.4 g, 20 mmol) in AcOH and Et0H (1:10, 100 mL) was heated to
reflux
and allowed to stir at this temperature for 6 hours. The reaction mixture was
cooled to
room temperature and concentrate in vacuo to provide Compound Int-19a as a
solid,
which was used without further purification (9.2 g). MS (ESI) m / e (M+H ):
383.
Step B ¨ Preparation of Compound Int-19b
Br
N.
[10 N 110 PPAIm. 1101 \ Br
Br HO Br HHO
Int-19a Int-19b
A mixture of Int-19a (9.2 g) in PPA was heated to 80 C and allowed to
stir at this temperature for 2 hours. After cooling to room temperature, the
reaction
mixture was poured into ice water. The resulting solution was extracted with
dichloromethane and the organic extract was washed with brine, dried over
Na2SO4,
filtered and concentrated in vacuo. The residue obtained was purified using
column
chromatography to provide Compound Int-19b (4.8 g). MS (ESI) m / e (M+H ):
368.
Step C ¨ Preparation of Compound Int-19c
Br___
select F
* Br
N\ *
Br
DMSO,CH3CN
HO HHO
Int-19b Int-19c

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To a solution of Int-19b (6 g, 16.3 mmol) in DMSO/CH3CN (1:1, 24 mL)
was added Select-F (5.8 g, 16.3 mmol) in portions. The reaction was allowed to
stir for 1
hour at room temperature, then the reaction mixture was concentrated in vacuo
and the
residue obtained was purified using HPLC to provide Compound Int-19c as a
solid (1.0
g). MS (ESI) m / e (M+H+): 386.
Step D ¨ Preparation of Compound Int-19d
0 F H H HCI F
______________________________________________ 11
1. + Br (101 N,NH2 AcOH,Et0H
= NN: 0
HO Br Br HO Br
Int-17c Int-19d
A suspension of Int-17c (51.6 g, 221 mmol, 1.0 eq) in 910 mL of absolute
ethanol and 100 mL of glacial acetic acid was heated to 40 C and 4-
chlorophenyl
hydrazine hydrochloride (41.66 g/232 mmo1/1.05 eq) was added in portions, with
stirring,
followed by 3 Angstrom molecular sieves (23 g) and additional acetic acid (350
mL).
The reaction mixture was placed under a N2 atmosphere, heated to 70 C and
allowed to
stir at this temperature for 4 hours. The reaction mixture was allowed to cool
to room
temperature and was allowed to stand for about 15 hours, without stirring,
under N2. The
reaction mixture was filtered, the filtrate was concentrated in vacuo and the
residue
obtained was taken up in toluene (230 mL) and absolute ethanol (100 mL). The
resulting
solution was then concentrated in vacuo. The residue obtained was diluted with
absolute
ethanol (400 mL) and the resulting solution was allowed to stand in a 54 C
water bath
for 45 minutes, then was allowed to cool to room temperature with stirring.
The
resulting precipitate was filtered and the collected solid was washed with 30
mL of
absolute ethanol and 75 mL of hexanes, then dried in vacuo to provide Compound
Int-
19d as an off white solid (50.2 grams (63%)). This material was used without
further
purification. MS (ESI) m / e (M+11 ): 357.0, 359Ø
Step E ¨ Preparation of Compound Int-19e

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Br
N, PPA Br
(10 N
1101 \
Br HO Br HHO
Int-19d Int-19e
Polyphosphoric acid (111.8 g) and xylenes (260 mL) were added to a 1
liter 3-necked flask. The flask was placed in a 100 C oil bath, connected to
a N2 inlet,
and equipped with a mechanical stirrer. The PPAJxylenes mixture was allowed to
stir for
30 minutes to bring the internal temperature up to 100 C. Compound Int-19d
was then
added in portions over 10 minutes. The reaction was placed under N2
atmosphere,
capped, stirred for 30 minutes at 100 C, and then stirred for 2.5 hours at
110 C. The
flask was lifted out of the oil bath and allowed to cool for 15 minutes. Ice
(750 mL) was
added in portions to the reaction mixture with stirring. After about 15
minutes, the
reaction mixture was suction filtered through fiberglass filter paper in a
Buchner funnel
and an orange solid was collected. The collected solid was dissolved in Et0Ac,
and the
resulting purple solution was washed with water and brine, then dried over
MgSO4,
filtered, and concentrated in vacuo. The residue obtained was purified using
flash
chromatography on a 345 g Si02 column using 5%-25% Et0Ac/hexanes gradient, to
provide Compound Int-19e (11.22 g) as a yellow solid (47%).
The following 2-aryl indole intermediates can be made using the method
described above and substituting the appropriate reactants:

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F F
Br
N \>-Br Br 0
\.
N Br Br 0
\ IP Br
N
H

HO H HO H HO
It-19i
It-19b
F F
Br Br Br *
I \ . CI CI \ lik CI
N 0 11 N
H H H
HO HO HO
F F
CI CI
\ CI *
\ lik Br
110 lik
N Br 10 \ 11
N Br
N
H H H
HO HO HO
Int-19g Int-19h Int-19j
F F
I 0
\
H \/>C1 I la \ I*
N CI la \*
N CI
HH
HO H HO HO
F F
Me0 Me0 Me0
. 140 \ __
N _
\ / CI la \ *
N N
CI =' = CI
H

HO H HO H HO
F F
Me0 Me0 Me0 0
_
I \ \ / OMe OMe \ 11 OMe
.----IsJ N N
H H H
HO HO HO
EXAMPLE 19a
Preparation of Intermediate Compound Int-19i

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Br to OHCI step C
step A Ci
0 -I' step B * NHN 4
......-..-..Ø- 60 NN 4 Br -VP-
HO Br H HO
Int-17d Int-19f Int-19g
CI F 4 CI F \ 4 step D
Br -00- 4 µ 4 Br
N
N
H HO e-0
Me
Int-19h Int-19i
Step A - Preparation of Compound Int-19f
To a solution of Int-17d (14.0 g, 65.1 mmol), (4-chlorophenyl)hydrazine
(23.3g, 130 mmol) in Et0H (400 mL) was added glacial acetic acid (40 mL). The
reaction was heated to 90 C and allowed to stir at this temperature for about
15 hours.
The reaction mixture was cooled to room temperature, filtered, and the
filtrate was
concentrated in vacuo and dried in vacuo for 15 minutes. The resulting residue
was
diluted with dichloromethane (600 mL) and the resulting suspension was allowed
to stir
at room temperature for 30 minutes. The solid was removed by filtration and
washed
with dichloromethane five times. The filtrate was concentrated in vacuo and
Me0H (100
mL) was added. The suspension was allowed to stir at room temperature for 15
minutes
and filtered. The solid was dried in vacuo for two hours to provide Compound
Int-19f
(17.9 g, 81.0%).
Step B ¨ Preparation of Compound Int-19g
To a 250 mL three-neck flask with a mechanic stirrer was added
polyphosphoric acid (PPA, 100g). PPA was heated to 110 C and Int-19f (10.3 g,
30.3
mmol) was added in small portions. The reaction mixture gradually became dark
green.
The reaction mixture was allowed to stir at 110 C for two hours. After
cooling down,
crushed ice was added slowly with stirring until the dark green color
disappeared. Water
was added and the suspension was transferred into a 1000 mL beak. The
suspension was
allowed to stir for 10 minutes and filtered. The solid was washed with water
(100 mL)

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three times and dried in vacuo at 60 C for about 15 hours to provide Compound
Int-19g
(9.72 g, 99.4%).
Step C ¨ Preparation of Compound Int-19h
To a 100 mL round bottom flask was added Int-19g (2.62 g, 8.12 mmol),
DMSO (15 mL), and MeCN (15 mL). The solution was cooled to 0 C and Select-F
(2.3
g, 6.5 mmol) was added in three portions. The reaction was allowed to stir at
0 C for 1.5
hours, then gradually warmed up to room temperature in one hour. The reaction
mixture
was then diluted with 20 mL Me0H and filtered. The filtrate was concentrated
in vacuo
to about 20 inL and purified using C18 chromatography (150g, 50% to 100% of
MeCN in
water, with 0.05% TFA) to provide Compound Int-19h (964 mg, 35%).
Step D ¨ Preparation of Compound Int-19i
A solution of Int-19h (2.05 g, 6.02 mmol), DMF (120 mL), Cs2CO3 (10.0
g, 31.0 mmol), and dibromoethane (5.2 mL, 60.2 mmol) was heated to 100 C and
allowed to stir at this temperature for about 15 hours. Additional
dibromoethane (4.0 ml,
46 mmol) and Cs2CO3 (3.0 g, 9.2 mmol) were added and the reaction was allowed
to stir
at 100 C for 8 hours. The reaction mixture was cooled to room temperature and
water
(200 mL) and Et0Ac (250 mL) were added. The organic layer was separated and
the
aqueous layer was extracted with Et0Ac (100 mL). The organic layers were
combined,
washed with water (2 x 100 mL) and brine, dried over anhydrous Na2SO4,
filtered and
concentrated in vacuo. The resulting residue was purified using flash column
chromatography on silica gel (0% to 50% of Et0Ac in Hexane) to provide
Compound
Int-19i (1.24 g, 56.2%).
EXAMPLE 20
Preparation of Compound 37

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Y(:)c
CI CIµj N - \ Boc
*\ AL Br step A 1101 N= i.L.r.:17 step B ill = /
N N " H N
Me
MeF
-Me
Int-19i Int-20a Int-20b
step C N
C-i"mkN\ LIN-1 step D 1-1
N
H N N P."(N N\ /N
Me H
Me
Int-20c Compound 37
Step A ¨ Preparation of Compound Int-20a
To a 40 mL vial was added Int-19i (329 mg, 0.898 mmol),
bis(pinacolato)diboron (228 mg, 0.898 mmol), Pd(dppf)2C12.dichloromethane (146
mg,
0.18 mmol), and KOAc (264 mg, 2.7 mmol). The vial was degassed, refilled with
N2,
and capped. Dioxane was added via a syringe and the solution was allowed to
stir at
90 C for 2 hours. (2S,4R)-tert-buty1-2-(5-bromo-1H-imidazol-2-y/)-4-
fluoropyrrolidine-
l-carboxylate praline (300 mg, 0.90 mmol), Pd(dppf)2C12.dichloromethane (83
mg, 0.1
mmol), and K2CO3 (1M, 3.3 mL, 3.3 mmol) were added and the reaction was
allowed to
stir at 90 C for 2 hours. The reaction mixture was cooled to room
temperature, diluted
with 5 ml. Et0Ac, and the aqueous layer was separated and extracted with 3 mL
Et0Ac.
The combined organic extracts were dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The residue obtained was purified using flash column
chromatography on silica gel (24 g, 15% to 70% of Et0Ac in Hexane) to provide
Compound Int-20a (387 mg, 79.7%).
Step B ¨ Preparation of Compound Int-20b
To a 40 mL vial was added Int-20a (182 mg, 0.336 mmol),
bis(pinacolato)diboron (89.7 mg, 0.353 mmol), Pd2(dba)3=CHC13 (35 mg, 0.034
mmol),
X-phos (32 mg, 0.067 mmol), and KOAc (98 mg, 1.0 mmol). The vial was degassed,

refilled with 1\12, and capped. Dioxane was added via a syringe and the
solution was
allowed to stir at 120 C for 2 hours. (S)-tert-buty1-2-(5-bromo-1H-imidazol-2-

yl)pyrrolidine-l-carboxylate (116.9 mg, 0.37 mmol), Pd(dppO2C12-
dichloromethane (28
mg, 0.034 mmol), and K2CO3 (1M, 1.0 mL, 1.0 mmol) were added. The reaction was

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allowed to stir at 80 C for about 15 hours, then was cooled to room
temperature. The
aqueous layer were separated and extracted with 5 mL Et0Ac. The organic
extracts were
combined and dried over Na2SO4, filtered and concentrated in vacuo. The
residue
obtained was purified using flash column chromatography on silica gel (43 g,
A:
dichloromethane; B: 10% Me0H in Et0Ac: A/B: 0% to 80%) to provide Compound Int-

20b (191 mg, 89.9%).
Step C ¨ Preparation of Compound Int-20c
To a 40 mL vial was added Int-20a (190 mg, 0.256 mmol), Me0H (2 mL),
and HC1 (4M in dioxane, 6 mL, 24 mmol). The solution was allowed to stir at
room
temperature for two hours, then was concentrated in vacuo and the residue
obtained was
dried in vacuo for 30 minutes to provide Compound Int-20c, which was used
without
further purification.
Step D ¨ Preparation of Compound 37
To a 40 mL vial was added Int-20c (¨ 0.256 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (90.0 mg, 0.512 mmol), HATU (214
mg,
0.56 mmol), and DMF (3 mL). The resulting solution was cooled to 0 C and
DIPEA
(0.32 ml, 1.79 mmol) was added. The reaction was allowed to stir at 0 C for 2
hours,
then was diluted with water (0.2 mL) and the resulting solution was purified
using a C18
column (43g, 10% to 60%, of CH3CN in water with 0.05% TFA) to provide Compound

37 (46 mg, 21.4% from Int-20b). MS 874.4 [M+H]
The following Compounds of the present invention were made using the
method described in Example 20.
Compound Structure MS
0
N 07).-N"'0' 864.3
61 H N
me,e.)""%1 *
H L./ [1'I+141+
113C

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---./ o
o)%1).cc' o---N)Lo/ 838.4
62 H h / N / H
i_12 ..e_N\ * N\ N
F H )-0 1-1- -V [M+H]
H3C
o y
Y---NC)
H F 0--- N)L0/ 856.3
63 , Ise '

1N / H
j.. -Ni W rsi W/ N-Ly
H .i.15
H [M+H]
)-0
H3C
O y --/ 0
YL--N(:)
F 0 ' NX0r
,c_ _i N 110 N * 1rycN NrH 856.4
64 H N p," \
F H )-0 H L---/ [M+Hr
H3C
O )o --.1 0
(:, )-..'No
H F 0,;=--- N)L0' 874.3
66 ,N eN \ ,., / t \.1 / H
)- 2 .." -11 IIIP N\ w N-L(14)
F
F H )--0 H L--/ [M+H] +
H3C
o y ,./ 0
YL-N'''"C) ' ).\-- 874.4
N
H F / N Or¨ri 0
67 P',I \
F-P¨(11 110 N 14 H -1-11:1)
F [M+H]+
H3C
o y ,/ .
C:,)L-N.c 0).".-N)L0/ 856.4
31 H\NI eN \ 41,. \ -, -m,
F-},- ". -N ir r4)_c\iw /N)...-01
F H FI [1\4+1-1]
H3C
O y ,/ 0
-0A---N---c
320,-;----
H Nxoz 856.4
N N / H
___;15I i(N\ N\ * iN IL _N
F H lir H.- 7.) [M+H]+
F
H3C
O y õ/ 0
-- F oA--tr o--o' 873.5
68 r 1,4 \ At Adv / N / H
"" N w N\ ,_7 / Fi NI:..5
F [1\41+
H3C 'F
O y -,./ 0
-0A---N-Li 891.4
07;---- eV
69 H ,N t.,J \ F A. / N
F-+-1 "(NJ = N\ w N \--L-C:5
, )--0 H UV11+
H3C F
0
H3C0-1(No
87 .c...i.:NN 1..--
i N 0,.....,- 0 900.5
F
H 1N *
N N H OCH,
>-0 H [M+Hr
Ph

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Hp) N(s) N HN / 900.5
92
"('N le,j_1 14\ II /H-Nlis) N4N(S)
[M+H]
(Fi9 0
@
H3C0
H = N 900.5
93
N z
F H=\ 0 [M+H]
H
H3C01:('N,
H N 900.5
94
F H \ 7 1:14 N 0c H3 [m+H]
EXAMPLE 21
Preparation of Intermediate Compound Int-21a
CI
CI
\ 411 Br Br
N\ ¨P-
?-0
H HO
Int-19h Int-21a
To a 20 mL microwave vial was added Int-19h (1.16 g, 3.41 mmol),
anhydrous toluene (15 mL), cyclopropane-carboxaldehyde (1.28 mL, 17.1 mmol),
and p-
toluenesulfonyl chloride (65 mg, 0.34 mmol). The vial was capped and sealed,
then
placed in a microwave reactor and heated to 170 C for three hours. The
reaction mixture
was cooled to room temperature and concentrated in vacuo. The residue obtained
was
dissolved in dichloromethane (40 mL) and filtered through a short pad of
Celite. The
filtrate was concentrated in vacuo and purified using flash column
chromatography on
silica gel (80 g, hexane) to provide Compound Int-21a (778 mg, 58.1%).
EXAMPLE 22
Preparation of Intermediate Compound Int-22c

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\ci
Br
Br
N
Int-22c
Step A ¨ Preparation of Compound Int-22a
CI
Br Br __ NCS Br
Br
I \
1:1 CH2Cl2¨
THE HO HO
Int-19b Int-22a
Int-19b (5.82 g, 0.016 mmol) was dissolved in dichloromethane (50 mL)
and THF (50 mL) and the mixture was allowed to stir at room temperature until
all
solids dissolved. The resulting solution was cooled in an ice-water bath for
30 minutes,
after which NCS (2.13 g, 0.016 mmol) was added to the stirred reaction mixture
in
portions over ¨10 minutes. The reaction mixture was allowed to stir at 0 C
for 30
minutes and then at room temperature for 2 hours. The reaction mixture was
concentrated in vacuo to provide a brown semi-solid, which was dissolved in
dichloromethane (-300 mL). The organic solution was washed sequentially with
water
(1 x ¨200 mL), 10% (w/v) aq. sodium thiosulfate (1 x ¨200 mL), and brine (1 x
¨200
mL), then dried over anhydrous magnesium sulfate, filtered, and concentrated
in vacuo.
The resulting solid residue was purified using column chromatography (330 g
Teledyne-Isco RediSep silica column, 0-30% Et0Ac/hexanes over 12 column
volumes at 200 mL/min) to provide 2.97 g of Int-22a (47% yield) as a brown
solid.
MS (ESI) m / e (M+H+): 400.
Step B ¨ Preparation of Compound Int-22b
Cl CI
Br >¨CHO Br
\ /10 Br _______________________________
p-TsCI, toluene N Br
HO microwave, 170 C
Int-22a <1 Int-22b

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In a 20-mL microwave tube, Int-22a (1.075 g, 2.68 mmol) was dissolved
in dry toluene (13 mL). Cyclopropanecarboxaldehyde (1.0 mL, 0.94 g, 13.4
mmol), p-
toluenesulfonyl chloride (51 mg, 0.27 mmol), and a magnetic stir bar were
added. The
tube was sealed and the reaction mixture was heated at 170 C (microwave) with
stirring
for 3 hours. The reaction mixture was cooled to room temperature, the tube
opened, and
further aliquots of each of cyclopropanecarboxaldehyde (1.0 mL, 0.94 g, 13.4
mmol) and
p-toluenesulfonyl chloride (51 mg, 0.27 mmol) were added. The tube was re-
sealed and
the reaction was again subjected to microwave heating at 170 C for 4 hours,
then cooled
to room temperature and concentrated in vacuo to provide a brown solid
residue. The
brown solid residue was adsorbed onto silica gel (19 g) using Et0Ac (-100 mL),

followed by evaporation of the solvent, and then loaded onto a 100 g Biotage
KP-Sil
SNAP cartridge. Elution with 100% hexanes over 13 column volumes at 85 mL/min
provided 600 mg of Int-22b (50% yield) as a light brown solid. MS (ESI) m / e
(M+H+):
452.
EXAMPLE 23
Preparation of Compound 23A
o
A (s)
Me0 N o
H N 0
r-N.s.s4 1
0 qiAOMe
H (s) :
iqi.
N N
0
*
23A
Step A ¨ Preparation of Compound Int-23a
Br Br
l"-- ________________ p_Br PhCHBr2 I \ ¨)¨Br
/
H K2CO3
HO 0
IF
Int-19b Int-23a

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A mixture of Compound Int-19b (1.1 g, 3 mmol),
(dibromomethyl)benzene (2.25 g, 9 mmol) and K2CO3 (1.2 g, 9 mmol) in 15 mL of
DMF
was heated to 100 C and allowed to stir at this temperature for 3 hours. The
reaction
mixture was cooled to room temperature, concentrated in vacuo and the residue
obtained
was dissolved with dichloromethane and water. The aqueous phase was extracted
with
dichloromethane. The combined organic extracts were washed with brine, dried
over
Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified
using
flash column chromatography on silica gel to provide Compound Int-23a (380 mg,
28 %)
as a white solid. 1H NMR (CDC13): 6 7.72 (bs, 1 H), 7.44 - 7.46 (d, J = 8.4
Hz, 1 H),
.7.21 - 7.28 (m, 3 H), 7.09 - 7.12 (m, 3 H), 7.04 (s, 1 H), 6.99 - 7.01 (bs,
J= 6.8 Hz, 2 H),
6.78 (s, 1 H), 6.63 - 6.65 (d, J= 8.4 Hz, 1 H). MS (ES!) m/e (M+H ): 456.
Step B - Preparation of Compound Int-23b
i=-",01µ3
Br
0 -
Pd(dppf)O12, I
N
KOAc " 0
0 0
Int-23a Int-23b
To a solution of Int-23a (456 mg, 1.0 mmol) in 1,4-dioxane was added bis
pinacol borate (2.2 mmol) , Pd(dpp0C12 (0.04 mmol) and KOAc (4 mmol). The
reaction
mixture was put under N2, heated to 110 C and allowed to stir at this
temperature for 3
hours. The reaction mixture was cooled to room temperature, concentrated in
vacuo, and
the residue obtained was purified using column chromatography on silica gel to
provide
Compound Int-23b (590 mg, 87 % yield). 1H NMR (CDC13): 8 8.13 (s, 1 H), 7.60
(d, J =
7.6 Hz, 1 H), 7.52 (d, J = 8.0 Hz, 111), 7.36 - 7.39 (m, 1 H), 7.14 -7.19 (m,
4 H), 6.93 -
6.95 (m, 3 H), 6.90 (s, 1 H), 1.26 - 1.29 (s, 24 H). MS (ESI) m / e (M+H+):
550.

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Step C ¨ Preparation of Compound Int-23c
k-9B
W Na2CO3 Bp Pd(dppf)C12
I ,
Boc=H N-11
0 0
Boc
Int-23b Int-23c
A suspension of Int-23b (550 mg, 1.0 mmol), tert-butyl 2-(2-bromo-1H-
imidazol-5-y1) pyrrolidine-l-carboxylate (2.4 mmol), Pd(dppf) C12 (200 mg),
Na2CO3 (3
mmol) and in THF/1120 (10:1, 33 mL) was allowed to stir at reflux for about 15
hours
under N2. The reaction mixture was cooled to room temperature and filtered,
and the
filtrate was washed with water (50 mL) and extracted with Et0Ac (100 mL). The
organic extract was washed with brine, dried over anhydrous sodium sulfate,
filtered and
concentrated in vacuo. The resulting residue was purified using column
chromatography
on silica gel to provide Compound Int-23c (160 mg). MS (ESI) m / e (M+H+):
768.
Step D ¨ Preparation of Compound Int-23d
N Fri \
Boo N HCI
N-11 =,, NH N , =
N
N-11
H
IP Boo'
Int-23c
Int-23d
Int-23c (0.10 g, 0.13 mmol) was added to HC1/CH3OH (5 mL, 3M) and
the resulting reaction was allowed to stir at room temperature for about 3
hours. The
reaction mixture was then concentrated in vacuo to provide Compound Int-23d,
which
was used without further purification. MS (ESI) m / e (M+H+): 568.

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Step E - Preparation of Compound 23A
N
C.)-4 Me01:0
\ ,N H Bop,DIEA 0
rikc51 H 1.1 / YITIA0Me
0
N rliZ/5
Int-23d Compound 23A
To a solution of Int-23d (56.8 mg, 0.10 mmol), (S)-2-
(methoxycarbonylamino)-3-methylbutanoic acid (35.0 mg, 0.20 mmol) and DIPEA
(0.8
mmol) in CH3CN (1 mL) was added BOP (98 mg, 0.22 mmol). The resulting reaction

was allowed to stir at room temperature and monitored using LC/MS. After LC/MS

showed the starting material to be consumed, the reaction mixture was
filtered, and the
filtrate was purified using HPLC to provide Compound A as a white solid. 11-
1NMR
(Me0D): 6 7.94 (s, 1 H), 7.85 (d, J= 8.0 Hz, 1 H), 7.74 (s, 1 H), 7.63 (s, 1
H), 7.48 (s, 1
H), 7.35 -7.37 (m, 2 H), 7.31 (s, 1 H), 7.17 - 7.18 (m, 4 H), 7.11 (s, 1 H),
6.96 - 6.98 (d, J
= 7.6 Hz, 2 H), 5.09 - 5.17 (m, 2 H), 4.13 (t, J = 8.0 Hz, 2 H), 3.99 (bs, 2
H), 3.78 (bs, 2
H), 3.56 (s, 6 H), 2.44 - 2.47 (m, 2 H), 1.92 - 2.19 (m, 8 H), 0.77 - 0.85 (m,
12 H). MS
(ESI) m / e (M+H+): 882.
The diastereomers were separated on a chiral SFC column:
Isomer A: 1HNMR (Me0D): 6 8.08 (s, 1H), 7.91 - 7.93 (m, 1 H), 7.72 (s, 1 H),
7.56 (s,
1 H), 7.24 - 7.43 (m, 7 H), 7.19 (s, 1 H), 7.03 - 7.05 (m, 2 H), 5.16 - 5.24
(m, 2 H), 3.81 -
4.21 (m, 6 H), 3.62 (s, 6 H), 2.52 - 2.54 (m, 2 H), 2.00 - 2.25 (m, 8 H), 0.84
- 0.91 (m, 12
H). MS (ESI) mlz (M+H) : 882.
Isomer B: 1H NMR (Me0D): 6 7.90 (s, 1 H), 7.81 - 7.83 (m, 1 H), 7.72 (s, 1 H),
7.62 (s,
1 H), 7.45 (s, 1 H), 7.14 - 7.33 (m, 6 H), 7.09 (s, 1 H), 6.93 - 6.95 (m, 2
H), 5.06 - 5.14
(m, 2 H), 3.71 -4.11 (m, 6 H), 3.52 (s, 6 H), 2.41 -2.44 (m, 2 H), 1.90 - 2.15
(m, 8 H),
0.74 - 0.86 (m, 12 H). MS (ESI) m/z (M+H)+: 882.

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The Compounds of the present invention depicted in the table below were
made using the method described in Example 23 and substituting the appropriate

dibromotoluene derivative in Step A
0 IrH3COAN0
* *
!sr...IN() H OCH3
Zo e
Y-X
Cpd W X Y Z MS
95 CH CH C(OCH3) CH 912
99 CH CH CF CH 900
916,
103 CH CH CC! CH
918
104 CH CH C(CF3) CH 950
108 CH N CH CH 883
109 N CH CH CH 883
110 CH CF CH CH 900
916,
117 CH CC! CH CH
918
121 CH CH N CH 883
125 CH CH C(OCF3) CH 966
126 CH CF CF CH 918
129 CH CH C(CH3) CH 896
916,
130 CC1 CH CH CH
918
133 CF CF CH CH 918
136 CH CH CCN CH 907

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143 CH CF CH CF 918
145 CH C(OCH3) CH CH 912
149 CF CH CH CH 900
150 CH C(CF3) CH CH ' 950
153 CF CH CH C(OCH3) 930
EXAMPLE 24
Preparation of Compound 16
o
µoANI)co
H
Nõ...-
H
(00 N\ ir /IN HR).....k.N1Z-
)---0 HN : N H 0
/
16
Step A ¨ Preparation of Compound Int-24b
o
A
GIN OMe B
Br Br
Nr r
* 0 ¨Ili-
)--0 )--. CI
Int-24a Int-24b
To a solution of Compound Int-24a(1.48 g, 3.76 mmol) in 11 mL THF at
-78 C was added n-BuLi (2.5 M in hexane, 1.66 mL, 4.14 mmol). The reaction
was
allowed to stir at -78 C for 30 minutes, then 2-chloro-N-methoxy-N-
methylacetamide(1.1 g, 7.52 mmol) in 2 mL of THF was added at -78 C. The
reaction
was allowed to stir for 1 hour at -78 C, then was quenched with saturated
aqueous
NH4C1. The resulting solution was extracted with Et0Ac and the organic extract
was
washed with brine solution, dried (Na2SO4), filtered and concentrated in
vacuo. The
resulting residue was purified using an ISCO 80 g column (hexane to 50% Et0Ac-
hexane,
gradient) to provide Compound Int-24b, 503 mg (35%). LRMS: (M+H)+= 390.

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Step B ¨ Preparation of Compound Int-24d
Br*0)0 LL.6 Br Boc
\ 0
)...N =
CPO
CI
Int-24b Int-6f Int-24c
To a solution of Compound Int-24b (97 mg, 0.25 mmol) and Int-6f (91
mg, 0.38 mmol) in DMF (2 rnL) was added Cs2CO3 (163 mg, 0.50 mmol). The
resulting
reaction was heated to 40 C, allowed to stir at this temperature for 1 hour,
then cooled to
25 C. The reaction mixture was poured into ice-water and the organic phase
was
extracted with Et0Ac. The organic extract was washed with brine, dried
(Na2SO4),
filtered and concentrated in vacuo. The residue obtained was purified using an
ISCO 24
g column (gradient from hexane to 40% Et0Ac in hexane) to provide Compound Int-
24c,
135 mg (91%).
Step C ¨ Preparation of Compound Int-24d
Br* Boc Br 0 * / NBoc
N Li 4
Int-24c Int-24d
To a solution of Compound Int-24c (135 mg, 0.23 mmol) in o-xylene (2
mL) was added ammonium acetate (107 mg, 1.38 mmol) and the resulting reaction
was
allowed to stir at 140 C for 3 hours. After being cooled to 25 C, the
reaction mixture
was added to aqueous NaHCO3 solution and the organic layer were extracted with
Et0Ac.
The combined organic solutions was washed with brine, dried (Na2SO4), filtered
and
concentrated in vacuo. The residue obtained was purified using an ISCO 24 g
column
(gradient from hexane to 50% Et0Ac in hexane) to provide Compound Int-24d, 84
mg
(64%). LRMS: (M+H)+ = 575
Step D ¨ Preparation of Compound Int-24g

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Br __Q49
* \ * r,,13
N N
¨110- N; iF N 0E 1 1
Int-24e
Int-24f
Boc
641)
Boc
H N Br * H
N
Int-7d Int-
24g
To a solution of Compound Int-24d (81 mg, 0.14 mmol), bis-
pinacolatodiborane (53 mg, 0.21 mmol), PdC12(dpp02 CH2C12 complex (11.5 mg,
0.014
mmol) in 1,4-dioxane (2 mL) was added potassium acetate (41 mg, 0.42 mmol).
The
reaction was degassed and allowed to stir at 100 C for 2 hours. After being
cooled to
25 C, the reaction mixture was diluted with Et0Ac and filtered through a
Celite pad.
The filtrate was concentrated in vacuo to provide Compound Int-24f, which was
combined with Int-7d (66 mg, 0.21 mmol), and PdC12(dpp02 CH2C12 complex (11.5
mg,
0.014 mmol) and dissolved in 1,4-dioxane (2 mL). The resulting solution was
treated
with aqueous 2 M Na2CO3 solution (0.21 mL, 0.42 mmol) and the reaction mixture
was
degassed and allowed to stir at 100 C for 2 hours. After being cooled to 25
C, the
reaction mixture was diluted with Et0Ac and filtered through a Celite pad. The
filtrate
was concentrated in vacuo and the residue obtained was purified using an ISCO
24 g
column (gradient from 0% to 100% Et0Ac in hexane) to provide Compound Int-24g
(40
mg, 39%). LRMS: (M+H)+ = 732.
Step E ¨ Preparation of Compound Int-24h
Boc H
64 H
Of....q
HN N
\ H Boc
N = r!1N
* \ it I H H
Njya
)-0
Int-24g Int-24h

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To a 0 C solution of Compound Int-24g (40 mg, 0.054 mmol) in
dichloromethane (2 mL) was added TFA (0.4 mL). The reaction was allowed to
stir at
0 C for 0.5 hours and then was warmed to 25 C and allowed to stir for 2
additional
hours. The reaction mixture was concentrated in vacuo and the residue obtained
was
dissolved in Me0H (2 mL) followed by addition of 4N HC1 in dioxane (0.3 mL).
The
solution was concentrated in vacuo to provide Compound Int-24h as its HC1 salt
(40 mg),
which was used without further purification. LRMS: (M+H) = 532.
Step F¨ Preparation of Compound 16
0
H
\CrI(NO
" N
H
N + N
H * H H 0
N%.===:µ
)-0 N HO,C7 NHCO,Me .r'N 110
N rsj-kel
Int-24h It-la 16
To a -30 C solution of Compound Int-24h (41 mg, 0.068 mmol),
Compound It-la (36 mg, 0.20 mmol), and diisopropylethylamine (83 L, 0.48
mmol) in
DMF (1.5 mL) was added HATU (103 mg, 0.27mmol). The mixture was allowed to
stir
at -30 C to 0 C for 1 hour and for an additional 2 hours at 0 C. The
reaction was then
quenched by addition of cold water and the resulting mixture was purified
using Gilson
HPLC (CH3CN¨H20, 0.1% TFA) to provide Compound 16. Compound 16 was
dissolved in Me0H (10 mL) and treated with 4N HC1 in dioxane (0.3 mL) followed
by
concentration in vacuo to provide the HC1 salt of Compound 16 as a ¨1:1
mixture of
diastereomers, 16 mg (28%).
The diastereomers were separated by chiral HPLC using Chiral OD (Lux
Cellulose-1) Semi-prep column (20% Et0H-hexane, 0.1% DEA) to provide Compound
16A (retention time: 44 minutes), 6 mg, and Compound 37B (retention time : 66
minutes),
3 mg.
EXAMPLE 25
Preparation of Compound 17

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o
\OA
N-0
H
N RN
)--- o HN F-= N ri 0
/
17
Step A ¨ Preparation of Compound Int-25a
0 H yoc
Br
I \ lip 0 HO)¨: 11701 Br ,
1 \ lee 0 0 liTci
1 ,
N N
-.--14
)---0 CI
Int-24b Int-25a
Compound Int-25a was prepared from Compound Int-24b using the
method described in Example 24, Step B (100%).
Step B ¨ Preparation of Compound Int-25b
Br Boc Br ,
I \ 41104 0 OH 1 , \
)\_..:..N _ / N
-."----N ' N 11P I H tik)c
HN¨c4,
Int-25a Int-25b
Compound Int-25b was prepared from Compound Int-25a using the
method described in Example 24, Step C yield (45%). LRMS (M+H)+ = 589.
Step C ¨ Preparation of Compound Int-25d

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Br
ip
/N
HN ti jBoc ip
/ p ii Boc
N I
2-0 2-0 HN . N
Int-25b Int-25c
Boc
r;i H N
Boc Ci T\J 1
._A H r,J,Br
+ j' i - H io \ ip
N /NI
N HN
H )---0
Int-7d Int-25d
Compound Int-25d was prepared from Compound Int-25b using the
method described in Example 24, Step D yield (44%). LRMS: (M+H)+ = 746.
Step D ¨ Preparation of Compound Int-25e
Boc H
N H N
/ N
/ N 40 \ .
N I H Boc H
N HN 1 ti El
2-0 HN - N 2-0
Int-25d Int-25e
Compound Int-25e was prepared from Compound Int-25d using the
method described in Example 24, Step Eyield (100%).
Step E ¨ Preparation of Compound 17
0
H
OA 1 ...,,, \CANO
.
H * \It H02C.A.NHCO2Me
N / HN. j111:6-1N _p.m..
)--. H
)-6 H II N il 0
i
Int-25e It-la Cmpd 17
Compound 17 (HC1 salt) was prepared from Compound Int-25e using the
method described in Example 24, Step F yield (50%).
The diastereomers were separated by chiral HPLC using Chiral Lux C-2
Semi-prep column (50% Et0H-hexane, 0.1% DEA) to provide Compound 17A
(retention
time: 45 minutes) and Compound 17B (retention time: 59 minutes).

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EXAMPLE 26
Preparation of Compound 23
\
0-41;1 0
1.1 fa /5eic
N H
)-=
23
Step A ¨ Preparation of Compound Int-26a
0 Boc
HO E74
Br Br
N 0 0 IZ S
ip 0
F F
N
o CI N F
Int-24b Int-26a
Compound Int-26a was prepared from Compound Int-24b using the
method described in Example 24, step B (87%).
Step B ¨ Preparation of Compound Int-26b
Br Br
I ip 0 c4ciql, N= NH B c
OF N HN-kq
Int-26a Int-26b
Compound Int-26b was prepared from Compound Int-26a using the
method described in Example 24, step C (72%). LRMS (M+H) = 585.
Step C ¨ Preparation of Compound Int-26d

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Br
HNk
N Boc / N
N // Boc
HN--\f_Nj
Int-26b 4-F Int-26c
F ¨
Boc
H N
Boc
H N Br
+<if H N = Pc'e
HN - N
Int-7d
Int-26d
To a solution of Compound Int-26b (243 mg, 0.42 mmol), bis-pinacolato
diborane (127 mg, 0.50 mmol), PdC12(dpp02 CH2C12 complex (34 mg, 0.042 mmol)
in
1,4-dioxane (3 mL) was added potassium acetate (83 mg, 0.84 mmol). The mixture
was
degassed and allowed to stir at 100 C for 2 hours. After being cooled to 25
C, Int-7d
(265 mg, 0.84 mmol), PdC12(dpp02 CH2C12 complex (34 mg, 0.042 mmol), and K2CO3

(1N aqueous solution, 1.2 mL, 1.2 mmol) were added. The mixture was degassed
and
allowed to stir at 90 C for 18 hours. After being cooled to 25 C, the
mixture was
diluted with Et0Ac and filtered through a Celite pad. The filtrate was
concentrated in
vacuo and the residue obtained was purified using Prep TLC (5% Me0H in CH2C12)
to
provide Int-26d, 146 mg (47%). LRMS: (M+H)+ = 742.
Step D ¨ Preparation of Compound Int-26e
Boc
H N JHN
DL¨clD"N
H 140
H io
N 11, I H H
)--0
Int-26d F Int-26e
Compound Int-26e was prepared from Int-26d using the method
described in Example 24, step E (100%). LRMS: (M+H)+= 542.6.
Step E ¨ Preparation of Compound 23

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04Ei N
HO2el.NHCO,Me N,()
. El * \ it ,14,4 H
-,.. r-rsk. 1
i p _ 0
N)---N) ...1(
F N N"/=%.4 H f
,
F
Int-26e It-la 23 F
Compound 23 (HC1 salt) was prepared from Compound Int-26e using the
method described in Example 24, step F (53%).
The diastereomers were separated by chiral HPLC using Chiral Lux C-2
Semi-prep column (50% Et0H-hexane, 0.1% DEA) to provide Compound 23A
(retention
time: 16 minutes) and Compound 23B (retention time: 27 minutes).
EXAMPLE 27
Preparation of Compound 26
\criz
04N 1 %.,....-
o I lic)
N *\ co, , IN
N \MI
)-0 N'ccN, H ?
H i
Si¨

\
26
Step A ¨ Preparation of Compound Int-27a
Br 0 H Irc Br 0 0 B S
* N * 0
+ HO)L0 ¨1111.- AN1
N
)---0 CI Si--
\ )-0 Sc...
Int-24b Int-13e Int-27a
Compound Int-27a was prepared from Compound Int-24b using the
method described in Example 24, step B (85%).
Step B ¨ Preparation of Compound Int-27b
Br 0 B 0 Br *
/ N Boc
ill \ It 0 0)1,...,4cl,, .....õ...
\ * ..,*.14)
N 1.,
Si N N
Si¨

\
Int-27a Int-27b

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Compound Int-27b was prepared from Compound Int-27a using the
method described in Example 24, step C (75%). LRMS (M+H) = 593.
Step C ¨ Preparation of Compound Int-27d
Br r
N
d
_..._ r to , . , IN H pc
I1P
)-0 H.- r..1'1)
Si¨ N'kt.N)
H
)-0
\ /
Int-27b sic-
Int-27c
Pc
cy4NH NI
13oc
H N Br N Boc
+ C5/¨(i )1 # ¨30 / ..- H * \ * ' I H i
N IrltN)
N H
H

Int-7d 1
Int-27d
Compound Int-27d was prepared from Compound Int-27b using the
method described in Example 24, step D (40%). LRMS (M+H)+ = 750.
Step D ¨ Preparation of Compound Int-27e
H
poc N
1
H * \
*

, iN ,N
pc
N E
N'I
ccNI
Si¨

Si¨ \
I Int-27e
Int-27d
Compound Int-27e was prepared from Compound Int-27d using the
method described in Example 24, step E (100%). LRMS: (M+H)+= 550.
Step E ¨ Preparation of Compound 26

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0
Crjt N
4
H H 0--ci
0
reccH N .1.===="%
H \ N
H
St- esti) H
S
Int-27e Cmpd 26
Compound 26 (HC1 salt) was prepared from Compound Int-27e using the
method described in Example 24, step F (50%).
The diastereomers were separated by chiral HPLC using a Chiral Lux C-2
Semi-prep column (35% Et0H-hexane, 0.1% DEA) to provide Compound 26A
(retention
time: 38 minutes) and Compound 26B (retention time:50 minutes).
EXAMPLE 28
Preparation of Compound 240
);c,o
0 N\/ 0
rN, _1\1 -eV-
= .N1\15/
H - N
r-N
H3C
Cmpd 240
Step A ¨ Preparation of Compound Int-28c
CI
0
,
B(OH)2 Br 0 [101 \ 41 CI
boo NO2
Bo c 02N
Int-28a Int-28b Int-28c
A solution of Int-28a (13.2 g, 46mM), Int-28b (9.0g, 38 mM), Pd(PPh3)4
(4.4 g, 3.8 mM), K2CO3(13.1g, 95 mmol) in 28 mL H20 and 140 mL DME was purged
with nitrogen. The reaction was allowed to stir at refluxed for 3 hours.
Another portion
of boronic acid (0.5 equiv.), Pd(PPh3)4(0.01 eq) were added and the reaction
was allowed
to stir at reflux for an additional 4 hours. The reaction mixture was diluted
with Et0Ac
and filtered through a small Celite plug. The filtrate was concentrated in
vacuo and the

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residue obtained was purified using flash LC ( 0%-10% Et0Ac/Hexane) to provide

Compound Int-28c (14.5 g). MS (ESI) m / e (M+Na+): 425.
Step B ¨ Preparation of Compound Int-28d
0 401 \ is CI 2, ZTnFA, NH4CI 0 0 \ SCI
N N
B
j..1 2 oc NO2 NH
Int-28c Int-28d
To a suspension of Compound Int-28c (2 g, 5 mM) in CH2C12 (8 mL),
TFA (4 mL) was added dropwise and the reaction was allowed to stir at room
temperature for 14 hours. The reaction mixture was concentrated in vacuo and
the
resulting residue was suspended in a solvent mixture of THF (25 mL), ethanol
(6 mL)
and water (2.5 mL). Zn dust (3.25 g, 50 mmol) and NH4CI (1.3 g, 25 mmol) were
added
and the reaction was allowed to stir at reflux for 1 hour. The reaction
mixture was diluted
with Et0Ac and filtered through a small Celite plug. The filtrate was washed
with water
and brine, dried over MgSO4, filtered and concentrated in vacuo to provide
Compound
Int-28d (1.9 g). MS (ESI) m / e (M+H ): 273.
Step C ¨ Preparation of Compound Int-28e
1. SelectF F
2. Ac20
0
3. HCI 00 \
li
H ______________________________________________ t N
H2N
Int-28d Int-28e
To a suspension of Int-28d (1 g, 3.6 mM) in DMSO (5 mL)/ Acetonitrile
(5 mL) was added Select-F (1.53 g, 4.3 mmol). The reaction was allowed to stir
for 30
minutes, then was diluted with Et0Ac and washed with water and brine, and the
organic
phase was dried over MgSO4, filtered and concentrated in vacuo. The residue
obtained
was suspended in acetic anhydride (4 mL) and allowed to stir at room
temperature for 2
hours. The reaction mixture was then diluted with Et0Ac and washed with NaHCO3

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solution and water. The organic phase was dried over MgSO4, filtered and
concentrated
in vacuo and the residue obtained was suspended in Et0Ac (10 mL). To the
resulting
suspension was added 4M HC1 in dioxane (4 mL) and the reaction was allowed to
stir at
room temperature for 2 hours. The reaction mixture was filtered and the
collected solid
was washed with hexane, then recrystallized from ethanol to provide Compound
Int-28e
(200 mg). MS (EST) m / e (M+H ): 315.
Step D ¨ Preparation of Compound Int-28f
1. BBr3 0
2. Tf20
0
\ 3. Diboron \
N = N
)N )N
Int-28e Int-28f
To a 0 C suspension of Int-28e (200 mg, 0.63 mM) in CH2C12 (5 mL)
was added 1M solution of BBr3 in CH2C12 (5 mL) at 0 C. The reaction was
allowed to
stir at 0 C for 1.5 hours, then an additional 5 mL of 1M solution of BBr3 in
C112C12 was
added and the reaction was heated to 40 C and allowed to stir at this
temperature for 5
hours. The reaction mixture was then diluted with Et0Ac (200 mL) and the
resulting
solution was washed with NaHCO3 solution and NaOH solution. The organic layer
was
then washed with water and brine, dried over MgSO4, filtered and concentrated
in vacuo
to provide a residue which was subsequently suspended in CH2C12 (5 mL) cooled
at 0 C.
To this solution was added Et3N (0.6 mL) and Tf20 (0.5 mL) and the resulting
reaction
was allowed to stir at 0 C for 1.5 hours. The reaction was then diluted with
dichloromethane and quenched with 10 % citric acid. The organic layer was
washed with
water and brine, dried over MgSO4, filtered and concentrated in vacuo. The
residue
obtained was suspended in dioxane (8 mL) and to the resulting solution was
added bis-
pinacolatodiborane (265 mg), PdC12(dPPO2 CH2C12 complex (26 mg) and potassium
acetate (206 mg). The mixture was degassed, purged with nitrogen and allowed
to stir at
100 C for 1.6 hours. The reaction mixture was cooled to 25 C, diluted with
Et0Ac and
filtered through a Celite pad. The filtrate was concentrated in vacuo and the
residue

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obtained was purified using flash LC (0-100 % Et0Ac-Hex) to provide Compound
Int-
28f (100 mg).
Step E ¨ Preparation of Compound 240
A4- 0 0
9 F F
H r NN tIN µ ,d.. µ / is_ , NI H 0 [10 \NI \it CI
LYNNN- \I./ N-14-02
TN H r-N H ;;.
F
Int-28f 240
Compound 240 was prepared from Compound Int-28f using the method
described in Example 20.
EXAMPLE 29
Preparation of Intermediate Compound Int-29a
vA0)v, 0
0
7¨

r----- ----C1 __________________ __.N ¨CI
----N \)
H H2N 2. NCI <-7----"N
Int-28d Int-29a
To a suspension of Compound Int-28d (0.51 g, 1.87 mmol) in CH2C12 (3
mL) was added cyclopropyl anhydride (2 mL). The resulting reaction was allowed
to stir
at room temperature for 2 hours, then a solution of 4M HC1 in dioxane ( 3 mL)
was added
and the reaction was allowed to stir at room temperature for 2 hours. The
reaction
mixture was then filtered and the collected solid was washed with hexane and
dried in
vacuo to provide Compound Int-29a (590 mg). MS (ESI) m / e (M+H+): 323.
EXAMPLE 30

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0 OH
N.+ + NH3CH Step 1 ,-. N-N `111'1"
AI CI
CI (10
CI
OH H
Int-30a Int-30b Int-30c
Br
*
CI CI
CI Step 3 r. * ci Step 4 CI
Step 2 10 \ CI
11 N
H HO
Int-30d Int-30e Int-30f
Step A
Commercially available phenol Int-30a (125.g, 73.3 mmol), hydrazine
Int-30b (13.1 g, 73.3 mmol) and methanol (200 mg) were charged to a 500 mL
flask. To
the suspension was added potassium acetate (14.5 g, 148 mmol) and the
resulting
reaction mixture was allowed to stir at reflux. After 3 hours, the reaction
was cooled, and
the solid collected by filtration, washed with methanol (50 ml) and water
(2x50 ml), and
dried in vacuo to provide hydrazone Int-30c as a slightly orange solid (18.5
g, 50%).
Step B
Int-30c (18.5 g, 62.7 mmol) and polyphosphoric acid (50 g) were added to
a 250 mL flask equipped with mechanical stirrer. The mixture was allowed to
stir at
120 C for 30 minutes and cooled to room temperature. To the mixture were
added ice
and water. The solid was collected by filtration, washed with water (2x100 ml)
and then
dissolved in ethyl acetate (200 ml), and washed with water (2x200 ml) again.
The
solution was then dried over sodium sulfate, and concentrated in vacuo to
provide Indole
Int-30d as a solid (17 g, 98%).
Step C
Indole Int-30d (18.3 g, 65.8 mmol), cesium carbonate powder (356.6 g,
117 mmol), and DMSO (100 ml) were charged into a 500 mL flask. To the
resulting
suspension was added diiodomethane (134.4 g, 36 mmol) via a syringe. The
reaction
mixture was allowed to stir at room temperature for about 15 hours, treated
with water

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(300 ml) and filtered. The solid was purified using a 120 g silica
column/Combi-Flash Rf
system using a gradient of 0-20% ethyl acetate in hexanes to provide Int-30e
as a white
solid (8.5 g, 45%).
Step D
Int-30e (2.4 g, 8.27 mmol), NBS (1.47 g, 8.27 mmol), and THF (50 ml)
were added to a 100 rnL flask and stirred at room temperature. After 5h the
reaction was
concentrated in vacuo to a semi-solid and the residue was treated with water
(100 ml),
stirred at room temperature for about 15 hours, and filtered. The filter cake
was washed
with water (3X20 ml) and dried to provide indole Int-30f as a pale solid (2.7
g, 88%).
EXAMPLE 31
Preparation of Compound 1525 & Compound 1541
ck
0
BrI/
*
CI o NA0'
ci *
CI + \ step Br*
*11 CI --UN H
I I Nk__0
Int-30f Int-31a Int-31b Int-7h
* 0
\40
Step 2 "---0 N 1/
H OtY 0
* 4-Arl
N N
¨ H
0
Compound 1525
io ck
)0, )4
Step 3
N
H OtY 0
N H
\-0
Compound 1541
Step A

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To a 35 mL microwave reaction tube were added Int-30f (500 mg, 1.36
mmol), bis(triphenylphosphine)palladium (II) dichloride (95 mg, 0.135 mmol),
copper
iodide (258 mg, 1.355 mmol), and DMF (10 mL). The resulting suspension was
degassed and heated to 100 C, and then Int-31a was then added in portions via
a syringe.
The resulting mixture was allowed to stir at 100 C for additional 6 hours
under nitrogen.
After cooling, the solution was diluted with 10 mL of ethyl acetate, filtered,
and
concentrated in vacuo. The residue was purified using a 40 g silica
column/Combi-Flask
Rf system (0-15% ethyl acetate in hexanes eluent) to provide Int-31b as a wax
(370 mg,
65%).
Step B
Int-31b (120 mg, 0.286 mmol), bis(pinacolato)diboron (152 mg, 0.6
mmol), potassium acetate (280 mg, 2.86 mmol), Pd2(dba)3-CHC13(59.1 mg, 0.057
mmol),
X-PHOS (54.4 mg, 0.114 mmol), and dioxane (4 ml) were added to a 35 mL
microwave
reaction tube. The sealed mixture was degassed and stirred at 110 C under
nitrogen
atmosphere for 8 hours then cooled to room temperature. To this mixture were
added
bromide Int-7h (246 mg, 0.658 mmol), PdC12(dppf)-CH2C12 (46.7 mg, 0.0057
mmol), 1.5
M aqueous solution of sodium carbonate (1.9 ml, 2.9 mmol). The resulting
mixture was
degassed and stirred at 95 C under nitrogen atmosphere for 6 hours, cooled to
room
temperature, concentrated, purified using Gilson reverse phase chromatography
(10-80%
acetonitrile in water with 0.1% TFA eluent) to provide Compound 1525 as a wax
(68 mg,
20%). LC/MS anal. calcd. for: C52H53N908 935.4; Found: 937.1 (M+H) .
Step C
Compound 1525 (16 mg, 0.014 mmol) and 10% palladium on activated
carbon (5 mg, 4.7 iiM) were added to 8 mL of methanol in a 250 mL pressure
vessel and
the reaction was shaken at room temperature under 35 psi hydrogen atmosphere
using
PARR hydrogenation apparatus for 6 hours. The reaction mixture was filtered
through
celite, concentrated in vacuo to provide Compound 1541 as a solid (15 mg,
93%).
LC/MS anal. calcd. for: C521461N908 939.4; Found: 939.7 (M+H) .

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EXAMPLE 32
Preparation of Compound 752
4 10
*
N N HO ..",..
N
C--1¨cl I0 C C-.)-- 1
- N
H 4 \
H 4 \ * /,
14--- ON H Int-3d
N H N \IV rl() 1(7"
Int-32a Cmpd 752
A round bottom flask was charged with Int-32a (89 mg, 0.14 mmol), (R)-
2-(diethylamino)-2-phenylacetic acid hydrochloride (66 mg, 0.32 mmol), HATU
(58 mg,
0.153 mmol) and 2 mL DMF provided 50 mg (34%) of the title Compound 752 using
the
capping procedure as in Step D of Compound 752. LC-MS (M+H) = 946.8.
EXAMPLE 33
Preparation of Compound 1359
CI CI .46.
I NI\ RI
* Br + Byr
CS2CO3 4i' Br
I.)....
H H.
Int-19g Int-33a I
Chiral #
Resolution CkdE4 310 IircHN)13r fsj
CI
CI CI
41 N * Br + 1001µ * :r -)0.- MIN
rt-
Int-7d
Enantiomer A Enantiomer B Int-33b
Int-33a Int-33a"
r,HQ-Br
p(s)
ci ¨-.9. F IR) VocH µ
INis c Cr - 4 1 \ * r/4:44613 oc je.` 0 1 \
-i..-
41V, NH
te'..
FIR) .L)/
Int-33c Int-33d Int-33e
H
H H 0 0
f....)4r , 1 ' N-LOCH C0'112,r0
H rH a ' H S) Fits µ 0
1
F (R) N 0 0 * / N H
011)' 0 1\ ito / NH CkyJsOCH,
it Wit) -.... N-440 H
F (R) "'=
Int-33f Compound 1359

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Step A
Cs2CO3 (48.5g, 150 mmol)and dibromoethane (28g, 150mmol) was added
to a stirred, solution of Int-19g (9.6g, 30mmol) in DMSO (100 mL) and the
mixture was
allowed to stir at 90 C for for about 15 hours. The mixture was cooled,
diluted with
water (-200 mL). and extracted with Et0Ac (3 x 100mL). The combined organic
extracts and a Et0Ac washing was washed with brine (1 x 80 mL), dried over
Na2SO4.
The dried layer was evaporated, the solid residue solid was triturated with
methylene
chloride, filtered to provide first crop of Int-33a as off white solid
(4.33g). The filtrate
was purified using column chromatography on silica gel 330g column, eluting
with
Hex/Et0Ac (0 to 10% then 20%) to provide the 2nd crop of Int-33a as a off
white solid
(2.5g) yield 62.3%.
Step B
Int-33a (6.4g) was resolved on SFC (Chiral AD, 30% Me0H/AcCN (2:1)
in CO2, to provide Int-33a' (-3g) and Int-33a" (-2.8g).
Step C
Int-33a" (0.51 g, 1.463 mmol), bis(pinacolato)diboron 0.446 g, 1.755
mmol), KOAc(0.431 g, 4.40 mmol) and PdC12(dppf)2 (0.107 g, 0.146 mmol) were
added
into a microwave tube. After the flask was flashed with N2, dioxane (5 mL) was
added.
The mixture was allowed to stir at 95 C for 4 hours. The crude Int-33b was
used in the
next step without purification
Step D
Int-7d (0.51 g, 1.61 mmol), PdC12(dppf)2 (0.107 g, 0.146 mmol) and
K2CO3 (1 N aq., 5 ml) were added to the reaction mixture of above mentioned
Int-33b .
The tube was sealed and degassed and heated to 100 C for about 15 hours.
After
cooling, Et0Ac (30mL) was added and it was extracted with Brine (30 mL). The
organic
layer was separated and dried and concentrated in vacuo. The crude material
was
purified on a ISCO column (40 g) and eluted with Hex:Et0Ac 0% to 70% to
provide the
Int-33c (350 mg, 45%).

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Step E
Int-33c (160mg, 0.317 mmol), Pd2(dba)3, (44mg, 0.048 mmol), X-phos
(45.3mg, 0.095 mmol), KOAc (93mg, 0.950 mmol), bis(pinacolato)diboron (88 mg,
0.349 mmol) and dioxane (3 mL) are added into a 25 mL sealed tube. After the
tube was
degassed in vacuo followed by flashing with N2 for three times. The mixture
was
allowed to stir at 120 C for for about 15 hours. LC-MS indicated that the
reaction was
complete, the crude product Int-33d was used in the next step without further
purification.
Step F
Int-33d (131 mg, 0.392mmo1), PdC12(dppf)2, (26 mg, 0.036mmol) and
1M K2CO3 (-3 mL) were added to the above mentioned mixture of Int-7e. The
mixture
was allowed to stir at 90 C for 4 hours. After cooling down, the aqueous
layer was
separated and extracted with 10 mL Et0Ac. The organic layers were combined and
dried
over anhydrous Na2SO4. The solution was filtered and concentrated in vacuo.
The
product was purified using Si02 chromatography (24 g, solvent A: DCM; solvent
B:0-
50%) to provide Int-33e as desired product (95 mg, 37%).
Step G
' Int-33e (95 mg) was allowed to stir in dioxane (10 mL). HC1 (4N in
dioxane, 3 mL) was added and it was allowed to stir at room temperature for
1.5 hr. The
solvent was removed and the Int-33f was isolated without further purification
(95 mg,
100%).
Step H
Int-33f (50 mg, 0.075 mmol) was dissolved in DMF (1.5 mL) and cooled
to 0 C. HATU(68.2 mg, 0.179 mmol) Compound 10A (34.1 mg, 0.157 mmol were
added followed by addition of Hunig's base (0.062 mL, 0.45 mmol). The reaction
was
allowed to stir at 0 C for 45 minutes. Water was added to quench the reaction.
The
mixture purified using RP_HPLC (AcCN/H20,0-80%) to provide title Compound 1359

11 45 mg (52.4%).

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EXAMPLE 34
Preparation of Compound 851
0
0
0
CI
1 Cs'
HO-10¨Ct. -CV0 = .. V
I*1
=
40* 0
0 \al*
=
= 111, =
[S,R,R] DM F(10m1) = 0
40C/4hrs
Int-34a Int-12j Int-34b
cY.c)t- = TFA
C
NH40Ac
2. HATU o >
0
Xylene=
120C/4hrs H 1:110 'NH0
\ \FIrC7)
Clt:E9NA H=OC NH HCI
Int-34c H H =
HCI
Compound 851
Step A
A mixture of Int-34a (0.3G,0.773 mmol), cesium carbonate (0.755g,
2.318mmol) and 1R,3S,5R)-2-(tert-butoxycarbony1)-2-azabicyclo[3.1.0]hexane-3-
carboxylic acid (0.386g, 1.7mmol) in DMF(10m1) were combined in a microwave
tube
and heated at 40 C. After 4 hrs. TLC indicated complete reaction. The
reaction was
diluted with Et0Ac (30m1) washed with water (3x20m1), brine(lx20m1), dried
(Na2SO4),
filtered and concentrated under reduced pressure to provide Int-34b as red
oil. Int-34b
was used in the next step with out additional purification.
Step B
Int-34b (0.59g, 0.766mmo1), ammonium acetate (1.182g, 15.33mmol) and
xylenes (15m1) were charged in a microwave tube and heated at 120 C (oil
bath) for 4
hrs. (Note: This reaction should be carried out in a fume-hood with shield
protection).
The reaction was cooled and then diluted with Et0Ac (25m1) and water (25m1).
The
organic layer were washed with water (2x20m1), brine (1x20m1), dried (Na2SO4),
filtered
and concentrated to provide crude Int-34c which was purified on a ISCO
chromatography system using 5%Me0H/ CH2C12 .The relevant fraction were
collected

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and concentrated to provide Int-34c as an orange solid,
Step C
Standard capping procedure was used as for the Compound 851 from Int-
34c as above (41%).
EXAMPLE 35
Preparation of Intermediate Compound Int-35e
CI le
___________________ )¨Br
Br
H HO
Int-19g Int-35a
Step A
The indole phenol Int-19-g (10.0 g, 31.0 mmol), cesium carbonate (40.g,
123 mmol), and DMSO (77 ml) were added to a 500 mL round bottomed pressure
flask
equipped with a stir bar. 1, 1-Dichloropropane (10.09 g, 89 mmol) was added to
the
reaction mixture, N2 was blown over the reaction mixture, and the flask was
capped. The
flask was placed in a 90 C oil bath which was then heated to 110 C. After
¨16 hours at
110 C, the reaction mixture was allowed to cool to room temperature.
Additional 1,1-
dichloropropane was added (4 g, 35 mmol), the reaction mixture was blanketed
with N2
and reheated to 110 C. After 4.5 hours, the reaction was cooled to room
temperature,
and poured into 300 mL of water. Et0Ac was added (500 mL) and the layers were
separated. The aq. layer was extracted with additional Et0Ac. The combined
organic
layer was washed with water and brine, gravity filtered and dried over MgSO4.
The
mixture was filtered and the solvent concentrated under reduced pressure to
provide
11.62 g of a tan solid. The crude product Int-35a was dissolved in CH2C12 ,
Silica gel
was added (62 g) and the mixture was concentrated in vacua. The silica gel
containing
the crude product was dry loaded on a silica gel column (262 g) that had been
packed
with hexanes. The column was eluted with an Et0Ac/hexanes gradient (0%-1.5%).
The

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first major peak was collected as product to provide Int-35a as an off white
solid (3.11 g).
LC/MS. Obsd. M+H = 361.8.
Step B
P tel
_. (3-43
= HCC
c_6.:CH=ci CI
B
M.11: Pd
__________________________ e-Br K+
=HC, - p¨L 2¨o
cCH= =
B-13 \
=P
Int-35a 7-0 0-7 Int-35b
Int-35a (1.59 g, 4.38 mmol), PdC12(dppf) (0.493 g, 0.674 mmol),
Bis(pinacolato)diboron (1.08 g, 4.26 mmol), and potassium acetate (1.49 g,
15.18 mmol)
were added to a 20 mL microwave vial equipped with a stir bar. The vial was
cycled
between vacuum and nitrogen five times. Dioxane (16 ml) was added via syringe,
and
the vial was cycled between vacuum and nitrogen three more times. The vial was
placed
in a preheated reaction block and the reaction mixture was left stirring at 85
C. After 2.5
hours, the reaction mixture was allowed to cool to room temperature. The
reaction
mixture was diluted with ethyl acetate and water and the layers separated. The
organic
layer was washed with water and brine, filtered through a pad of Celite, dried
with
MgSO4, and filtered again. The solvent was evaporated under reduced pressure
to
provide Int-35b as a yellow oil. The crude product was further purified via
silica gel
column chromatography on an 80 g Isco Gold Si02 cartridge, using a Me0H/CH2C12

gradient (0%-5%) as the mobile phase to provide Int-35b (1.29 g) as an off
white foam.
LC/MS. Obsd M+H = 410.11.
Step C

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IP I.
pdi CI (00 ___________________________ tft K2CO3r,
*Ha., ,CH=
C= ?-0
1.1 P opi
I Int-35b Int-10f
o
a I* \ N
.31,01 Fliek
N W N
(-0
r.
Int-35c
Int-35b (0.66 g, 1.611 mmol), Int-10f (0.658 g, 1.682 mmol) and
PdC12(dppf) (0.120 g, 0.164 mmol) were added to 100 rnL round bottomed flask
equipped with a stir bar. The flask was capped with a septum, connected to a
vacuum
line via needle and tubing and cycled between vacuum and nitrogen five times.
Dioxane
(8 ml) was added via syringe, and the flask was cycled between vacuum and
nitrogen
three more times. Aqueous 2.0 M potassium carbonate (2.8 ml, 5.60 mmol) was
added
and the flask was cycled between vacuum and nitrogen five times and the flask
was
heated at 85 C in a heating block. After 16.5 hours, the reaction mixture was
allowed to
cool to room temperature, diluted with ethyl acetate and water and the layers
were
separated. The organic layer was washed with water and brine, gravity
filtered, dried with
MgSO4, and filtered again. The solvent was evaporated under reduced pressure
to
provide Int-35c (1.16 g) as a brown foam. The crude product was purified
further via
flash silica gel column chromatography on an ISCO 80 g Si02 Gold cartridge,
using a
Me0H/CH2C12 (0%-5%) gradient as the mobile phase. The major peak was isolated
as
product to provide Int-35c (0.41 g) as a tan foam.
LC/MS- Obsd M+H = 594.2.
Step D
CI is 0
.---
Pd2(dba)3CHCI3/ X-Phos cr-B N
N
KOAc B-13
7¨d s
r>¨I
I Int-35c nt-35d

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X-Phos (0.116 g, 0.243 mmol), Pd2(dba)3chloroform adduct (0.110 g,
0.106 mmol), Bis-(pinacolato)diboron (0.175 g, 0.689 mmol), and potassium
acetate
(0.254 g, 2.59 mmol) were added to a 5 mL microwave tube equipped with a stir
bar.
The tube was capped and connected to a vacuum line via needle and tubing. The
tube
was cycled between vacuum and nitrogen five times. Dioxane (0.3 mL) was added
via
syringe and the tube was cycled between vacuum and nitrogen five times. After
five
minutes, a solution of Int-35c (0.44 g, 0.741 mmol) in 2.2 mL of dioxane was
added via
syringe. The tube was cycled between vacuum and nitrogen five more times and
the tube
was placed in a heating block at 120 C. After 4h the reaction mixture was
allowed to
cool to room temperature and was used in the next step without further
purification.
Step E
õo o.
N-%
N....Arc-Br (0) H \ ifif,1N.A N N
PdC12dppf/ K2CO3
_________________________________________________________ )11.
?-0H
6 Dioxane/ water
Int-7d
I Int-35c
,o
0
H
2¨=
I Int-35d
PdC12(dppf) (81 mg, 0.111 mmol) and Int-7d (246 mg, 0.777 mmol) were
added to a 5 mL microwave tube equipped with a stir bar. The tube was capped
and
connected to a vacuum line via needle and tubing. The tube was cycled between
vacuum
and nitrogen five times. The crude Int-35c was added via syringe to the tube
containing
the Suzuki reaction. The tube was cycled between vacuum and nitrogen three
times. Aq.
2.0 M potassium carbonate (1.480 ml, 2.96 mmol) was added via syringe. The
tube was
cycled between vacuum and nitrogen three more times. The tube was placed in an
85 C
heating block and left stirring for about 15 hours. After ¨16h, the reaction
was cooled
and the aq layer was removed via pipette. The remaining organic layer was
diluted with
1.5 mL of DMF and 0.3 mL of water. The resulting material was passed through a

micron syringe filter while injecting it directly onto an ISCO Gold C-18
cartridge. The
cartridge had been conditioned with 15% acetonitrile in water. TFA (0.1%) was
added to

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each component of the mobile phase. The column was eluted with an
acetonitrile/water
gradient (15%-90% with and isocratic hold at 45% acetonitrile while the main
peak
eluted. Int-35d was obtained as an off white solid (262 mg). LC/MS Obsd M+H =
795.3.
Step F
>.( \--
- r N\ = /N PLOjT1N-(0_- H \ 0
=
/-0
Int-35 I Int-35e
Int-35d (257 mg, 0.323 mmol) and Methanol (15 ml) were added to a
round bottomed flask equipped with a stir bar. HC1 in Dioxane (4.0 M) (5 ml,
20.00
mmol) was added, and the reaction mixture stirred at room temperature. After ¨
45
minutes the reaction mixture was concentrated in vacuo. Int-35e was obtained
as a
colored solid (Int-5060. LC/MS. Obsd M+H = 695.3. The product was used in the
subsequent reactions without further purification.
EXAMPLE 36
Preparation of Compounds 814, 1450, and 1451
0 0
io
o o 0 Yt0 */ 0
H \ CY'N)11.0' '0AIY? ' 0 )IN 0.4.ANK
cy, Lc) Int-4f H OH H. NO\ * yi H
H N N H N
ro
0 . 0
1?:0^=''
Int-35e 0 .0 I 814
Op%
Amino acid Int-4f (44.6 mg, 0.205 mmol) and a solution containing Int-
35e (57 mg, 0.082 mmol), acetonitrile (410 I), THF (410 p.1), and DIPEA (71.6
1, 0.410
mmol) were added to a 1 dram vial equipped with a stir bar. Propylphosphonic
anhydride
(aka T3P) (164 1, 0.246 mmol) was added, and the reaction mixture was allowed
to stir
at room temperature. After 4 hours, the reaction mixture was diluted with
Et0Ac and
water and the layers were separated. The organic layer was washed with water
and brine,
dried with MgSO4, filtered, and concentrated to a brown oil. The aqueous layer
was then
basified with 2.0 M potassium carbonate and extracted with Et0Ac and CH2C12.
The

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combined organic layer was filtered, dried with MgSO4, filtered again, and
concentrated
to dryness. The crude product was purified via silica gel column
chromatography on an
ISCO 4 g Si02 cartridge, using a Me0H/ CH2Cl2 gradient as the mobile phase to
provide
an off white solid Compound 814 LC/MS. Obsd. M+H = 894.3.
o oLO . 0
_ ,
_,,,I-N N.....A 0 \=, N
,,,,./C?
0 (40 --,-- ..., H u: 14 . NATL)
F11,1 0--
0
'OA N Ni " N )\¨;- ..1:k) Chiral HPLC j-
14 0 H
H N....---N 0 , 4, ,
= ._...; H r 1450
/-0
I 814 Hlj
( --\o
oLO

N. + o
H Li
1 1451
Compound 814 (isomer mixture at ethyl position) was separated on a
Chiralcel OD column using 30% ethanol in hexanes as the mobile phase. Diethyl
amine
(0.1% by volume) was added to each component of the mobile phase. Two peaks
were
isolated that contained a molecular ion at 894.4 in the LC/MS. LC/MS. Obsd.
M+H =
895Ø Peak A = Compound 1450; Peak B = Compound 1451.
EXAMPLE 37
c, io 0 r0,
\
a .
*
..--._
N `ow 0 K2CO3 \ INLOH.:A0¨
¨e-Nli N...:AN Br
....õ,i" H
PdC12(dppf) N
?-0 H
Int-35b F Int-7i I Int-37a P
Int-35b (113 mg, 0.276 mmol), Int-7b (103 mg, 0.238 mmol), and
PdC12(dppf) (26 mg, 0.036 mmol) were added to a 2 inL microwave vial equipped
with a
stir bar. Using the procedure for Example 35, Step C provided 129 mg of Int-
37a as a
clear oil. LC/MS. Obsd M+H = 636.1

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0
r r
o 0\
io 9 o\
7c,'B
j_ N-k KOAc IN)
\
7'0 0 ?--0 H Pd2(dba)3/ X-Phos 411Ir ?_N 011,
-4(0
a
I Int-37a F I Int-37b
X-Phos (30 mg, 0.063 mmol), Pd2(dba)3 (31 mg, 0.034 mmol),
Bis(pinacolato)-diboron (47mg, 0.185 mmol), and potassium acetate (65 mg,
0.662 mmol)
were added to a 2 mL microwave vial equipped with a stir bar. The vial was
capped and
connected to a vacuum line via needle and tubing. The vial was cycled between
vacuum
and nitrogen five times. A solution of Int-37a (125 mg, 0.197 mmol) in dioxane
(800 I)
was added via syringe, and the vial was cycled between house vacuum and
nitrogen five
times. The vial was placed in a preheated reaction block and the reaction
mixture was
left stirring at 120 C, for 3.5 hours. The reaction mixture was allowed to
cool to room
temperature and left stirring for about 15 hours at room temperature. The
crude reaction
mixture, which contains intermediate compound Int-37b, was used without
further
purification.
EXAMPLE 38
Preparation of Compound 1453
cs14 N
R4c) B *6 N 9
NH)4 0
y
0)1... Ns=ABr H (WP
trkrY cr-
H ¨. iHN3i3HHAcr... K2CO3
Pda2(dPPO F
Int-71 I Int-3713 *Cmpd 1453
The microwave vial containing the Int-37b crude reaction mixture was
charged with Int-7i (0.063 g, 0.145 mmol) and PdC12(dppf) (17 mg, 0.023 mmol).
The
vial was recapped, and connected to a vacuum line via syringe needle and
tubing. Using
the procedure for Example 35, step C provided Compound 1453 as a tan solid-(43
mg).
LC/MS. Obsd. M+H = 936.4.
EXAMPLE 39
Preparation of Compound 1452

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0
(0 _.
oczi ,0
0 . . _7 ,---=<_4) N µ c--/
0' dilibB \
N (:)\)-\' s K CO )1-NH IL . 0õ 0
)NH N= go ii= =/ i.,OHN---',0- 2 3 .- 0
O ri
-0 N
H 2-N 0 H PdClicIPPf)
2-0 H
Int-71 I 1453 'F 1 1452
Int-7i (0.070 g, 0.169 mmol) and PdC12(dppf) (0.024 g, 0.033 mmol) were
added to a 2 mL microwave tube equipped with a stir bar. The vial was capped
and
connected to a vacuum line via needle and tubing. The vial was cycled between
vacuum
and nitrogen five times. A solution of compound 1453 (0.135 g, 0.185 mmol) in
dioxane
(0.9 mL) was added via syringe into the reaction vial. Using the procedure for
Example
35, step C provided Compound 1452 as a tan solid-(49 mg). LC/MS. Obsd. M+H =
936.4.
EXAMPLE 40
Preparation of Compound 751
t
¨1¨
ckro D,13-13,0--._/
N
cl.. I
Br \ *
Br Step A 0"0--7 a **-
)10
Illir N
J-0
then (:)C)--(--- N
...)-0 WI*01
H
It-10a
NI__01 Int-40a
j_
Br" NH
(3
Int-7d (
...) 0
H
c....NNN I H )1,0 n - I t 2b
0,....."-N
0 H
Step B H 4\ * /1\61
----I... N N Step C
Int-40b
0
0
0
A NYr0
r
H c.N)_< I
His!"-%0
Oyol
H la \ *
N I
;Jr) 0
J-0
Cmpd 751
Step A
Using the method described in Example 35, step B, Int-10a (0.34 g, 0.83
mmol) was converted to Int-40a (0.24 g, 40% yield) as a brown solid. LC/MS Obs

M+H = 720.4.

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Step B
Using the method described in Example 35, step F, Int-40a (78 mg, 0.11
mmol) was converted to Int-40b 72 mg (99%) as a dihydrochloride salt. LC/MS
Obs
M+H = 521.2.
Step C
Using the method described in Example 36, step A, Int-40b (72 mg, 0.11
mmol) was treated with Int-2b (49 mg, 0.23 mmol) to provide Compound 751 (80
mg,
75% yield) as the dihydrochloride salt. LC/MS Obs M+H = 918.5.
EXAMPLE 41
Preparation of Compound 1491
t=
HH = Step A Step B =
Int-22a Int-41a D. Int-4113 *
t j c*ol< --CkpC) H
Br-kr1...
i ,tµIN I Ca . 1 I
C.." 411
N L,
H H 40 ir 1,1.g.5 7
--31.- H4
_0...
H = EIN-iyiH
=
Step C Step D
Int-41c Int-41d .4HCI
0 .0ilsZ
H r
0
1-,1" = 1 I
. HI` Neb H li
Step E
Cmpd 1491
Step A
In a 20-mL Biotage microwave tube, cyclopropylacetaldehyde (2.0 g, 24
mmol) was dissolved in toluene (10 mL) to provide a milky mixture. Int-22a
(1.78 g,
4.43 mmol) was added and the resulting red-brown suspension was allowed to
stir at
room temperature for 10 minutes. p-Toluenesulfonyl chloride (85 mg, 0.443
mmol) and

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toluene (2 mL) were added and the tube was flushed with nitrogen. The sealed
reaction
was heated and stirred under microwave conditions (Biotage Initiator 8,
reaction
temperature = 170 C; total heating time = 12 h), after which the reaction
mixture was
allowed to cool to room temperature. The reaction mixture was concentrated
under
reduced pressure (bath temperature ¨50-60 C) and then coevaporated with Et0Ac
(2 x
100 mL) to provide a dark-brown semi-solid as crude product. The crude product
was
adsorbed onto 6.0 g silica gel and purified using flash silica gel
chromatography (ISCO ;
200 g RediSep Gold silica gel column; Eluent of 0-30% Et0Ac/hexanes gradient
@ 150
inUmin) to provide Int-41a as a light orange-yellow solid (710 mg, 34% yield).
Step B
In a 125-mL round-bottom flask, Int-41a (0.707 g, 1.51 mmol),
bis(pinacolato)-diboron (0.806 g, 3.18 mmol), (dppf)PdC12=CH2C12 (111 mg,
0.151 mmol)
and KOAc (445 mg, 4.54 mmol) were admixed. A magnetic stir bar was added, the
flask
was sealed and alternately evacuated and refilled with nitrogen (5x). Dry
dioxane (7.5
mL) was added and the flask was immersed in a preheated 90 C oil bath. After
1.5 hours
the reaction mixture was allowed to cool to room temperature, diluted with
Et0Ac (-100
mL) and washed with brine (-50 mL). The organic layer was dried over anhydrous

MgSO4, filtered, and concentrated under reduced pressure (water bath
temperature ¨50-
60 C) to provide a dark brown semi-solid as crude product. The crude product
was
purified using flash silica gel chromatography (ISCO ; 120 g RediSep Gold
silica gel
column; Eluent 0-70% Et0Ac/hexanes gradient @ 85 mL/min) to provide Int-41b as
a
beige solid (630 mg, 74% yield).
Step C
In a 125-mL round-bottom flask, Int-41b (618 mg, 1.10 mmol), bromo-
imidazole Int-7d (731 mg, 2.31 mmol), (dppf)PdC12=CH2C12 (81 mg, 0.110 mmol)
were
admixed. A magnetic stir bar was added and the flask was sealed with a rubber
septum.
The flask was alternately evacuated and refilled with nitrogen (5x). Dioxane
(11 mL)
was added and the reaction mixture was allowed to stir at room temperature for
5 minutes
after which aqueous potassium carbonate solution (5.5 mL, 1 M aqueous, 5.5
mmol) was

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added. The reaction mixture was allowed to stir at 90 C for 18 hours. The
reaction
mixture was allowed to cool to room temperature and was diluted with Et0Ac (-
100 mL).
The resulting solution was poured into a separatory funnel containing Et0Ac (-
50 mL)
and water (-50 mL). The organic layer was washed with brine (-50 mL). The
organic
layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced

pressure to provide an orange-brown as crude product. The crude product was
purified
using flash silica gel chromatography (ISCO ; 80 g RediSep Gold silica gel
column; 0-
100% Et0Ac-hexanes gradient @ 60 mL/min). Product-containing fractions were
collected, concentrated, and re-purified using reverse-phase chromatography
(Gilson ;
Phenomenex Gemini 150 x 21.20 mm x 5 gm column; Eluent of 10-70% MeCN/water
(+0.1% TFA) gradient over 20 minutes) to provide Int-41c as a beige solid (467
mg,
54% yield).
Step D
In a 50-mL round-bottom flask, Int-41c (411 mg, 0.527 mmol) was
dissolved in methanol (5.0 mL) and hydrogen chloride solution (1.5 mL, 4 M in
dioxane,
(1.8 g, 6 mmol) was added. The reaction mixture was allowed to stir at room
temperature
for 24 hours. The reaction mixture was concentrated under reduced pressure to
provide
Int-41d as a beige (396 mg, quantitative yield).
Step E
Int-4f (85 mg, 0.392 mmol), was weighed into a pre-tarred vial and
transferred to a 50-mL round-bottom flask containing Int-41d (142 mg, 0.196
mmol)
with the aid of dry DMF (4 x 500 L). Diisopropylamine (200 4, 148 mg, 1.15
mmol)
was added by syringe. The mixture was allowed to stir at room temperature for
¨1
minutes, during which time all solids dissolved. The flask was cooled in an
ice-water
bath for ¨10 minutes. Solid HATU (157 mg, 0.412 mmol) was added in one portion
at
0 C but gradually allowed to warm to room temperature as the cooling bath
expired.
After 24 hrs methanol (2 mL), water (0.2 inL) and potassium carbonate (135 mg,
0.980
mmol) were added sequentially. The reaction mixture was extracted with Et0Ac
(2 x 50
mL), the combined extracts were washed with brine (-50 mL), and dried over
anhydrous

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MgSO4. After filtration, the organic layer was concentrated under reduced
pressure to
provide a light brown solid as the crude product. Further purification by
reverse-phase
chromatography (Gilson ; Phenomenex Gemini 150 x 21.20 mm x 5 gm column; 10-
70% MeCN/water (+0.1% TFA) gradient over 15 minutes) provided Compound 1491 as

a beige solid (164 mg, 86% yield).
EXAMPLE 42
Preparation of Compound 1490
It-1 a y,0
C0 .4(.1 a Htr Ti 1;1
/t4 Irsjy)1 OH HAo c:" H CI \ jrZ'
Int-41d .4HCI 1490
In a 50-mL round-bottom flask, Int-41d (196 mg, 0.270 mmol) and It-la
(95 mg, 0.540 mmol) were admixed. A magnetic stir bar was added and the solids
were
dissolved in dry DMF (2.7 mL). Diisopropylethylamine (283 gL, 209 mg, 1.62
mmol)
was added, the reaction mixture cooled to 0 C (ice-water bath) and then
stirred for 15
minutes. Solid HATU (216 mg, 0.567 mmol) was added in one portion and the
reaction
mixture was allowed to stir at 0 C for 24 hours. Methanol (2 mL), water (0.2
mL) and
potassium carbonate (187 mg, 1.35 mmol) were added and the reaction was
allowed to
stir at room temperature for 18 hours. Water (20 mL) was added and the
reaction mixture
was extracted with Et0Ac (2 x 50 mL). The combined organic extracts were
washed
with brine (-50 mL), dried over anhydrous MgSO4, filtered, and concentrated
under
reduced pressure to provide a light brown solid as crude product. The crude
product was
purified directly by reverse-phase chromatography (Gilson ; Phenomenex Gemini
150 x
21.20 mm x 5 gm column; 10-70% MeCN/water (+0.1% TFA) gradient over 15 minutes

to provide Compound 1490 as a beige solid (151 mg, 63% yield).
EXAMPLE 43
Preparation of Compound 1499

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`C))0 jiXfo
(3'
H 1;1
CI 0 H (It
0
14 N\ /Nlil\c1) 1E1
N N
=
1490 1499
In a 5-mL Biotage microwave tube, Compound 1490 (128 mg, 0.143
mmol), bis(pinacolato)diboron (73 mg, 0.286 mmol), Pd2(dba)3=CHC13 (15 mg,
0.014
mmol) and X-Phos (14 mg, 0.029 mmol) were admixed. A magnetic stir bar was
added
and the tube was alternately evacuated and back-filled with nitrogen (5x). Dry
dioxane
(1.0 mL) was added and the reaction mixture immersed into a preheated 120 C
oil bath.
After 2 hours the reaction mixture was diluted with Et0Ac (-50 mL) and washed
with
brine (-25 mL). The organic layer was dried over anhydrous MgSO4, filtered,
and
concentrated under reduced pressure to provide an orange-red as crude product.
The
crude product was purified using reverse-phase chromatography (Gilson ;
Phenomenex
Gemini 150 x 21.20 mm x 5 pm column; 10-70% MeCN/water (+0.1% TFA) gradient
over 15 minutes) to provide Compound 1499 as a beige solid (75 mg, 61% yield).
EXAMPLE 44
Preparation of Compound 1500
OiN (3j)(N
CI
H NN 0 H N
0
II
N 40 A tAl tit z r \
N rt-t)
1491 1500
Using the method described in Example 43, Compound 1491 was
transformed to Compound 1500 and the crude product was purified directly by
reverse-
phase chromatography (Gilson ; Phenomenex Gemini 150 x 21.20 mm x 5 pm
column;
10-70% MeCN/water (+0.1% TFA) gradient over 15 minutes) to provide Compound
1500 as a beige solid (89 mg, 64% yield).

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EXAMPLE 45
Preparation of Int-45a and Int-45b
Br Br lo
Br r"
\ # Br Chiral SFC
killr N
\ * Br \ * Br
+ N
1111111.111 N _______________ .
0 0 ---0
* Int-23a lik Int-45a 0 Int-45b
Chiral SFC separation (Chiral AD, 30% Me0H/AcCN (2:1) in CO2) of
Int-23a yielded Compounds Int-45a and Int-45b.
EXAMPLE 46
Preparation of Compound 728
4-
-i--->-(...Z N
N_<, 1
1 qA0
Br is
\ * Br Step A ¨N-0 0 \
/
)111.
N
0 0,(7) __ "("--- N N
H
0
then
# Int-45a l ts411_0N it Int-46a
Br'NH
Int-2a
0
H
04N 1 H 2 i
N /
Step B 4 \ a¨ > / IN H cY'N 0
H
H 0
__]... ___________________________________ I.-
N =

0\W HNj\C)
Step Cint-a
. Int-46b
0
0
\OAN..o
H
53¨

LN)4 1
0 HN-4
,.. 1,,,olli
N N N
H
0
0
itCompound 728
Step A
To a 250 mL round bottomed flask with a stir bar under N2 was added
dibromoindole Int-45a (3 g, 6.6 mmol) followed by bis(pinacolato)diboron (3.7
g, 14.5

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mmol), KOAc (1.9 g, 20 mmol), and PdCl2 OPPO-CH2C12 (1.6 g, 2.0 mmol). Dioxane

(-45 mL) was added to the mixture which was degassed six times under house
vacuum
filling with 1\12 after each evacuation. The reaction flask was affixed with a
reflux
condenser and the mixture was heated to 90 C. After 5 hours the mixture was
deemed to
be complete by LC-MS, and the crude bisboronate used as is.
To a cooled flask containing the crude bisboronate above was added
bromo imidazole Int-4f (4.6 g, 14.5 mmol), PdC12dppfC112C12 (1.6 g, 1.98
mmol), and 1
M K2CO3 (-20 mL). The flask was flushed with N2, capped, and heated to 95 C.
After
12 hours at 95 C and the mixture was cooled to room temperature and the
mixture
diluted with Et0Ac (100 mL) and water (20 mL). The layers were separated and
the
aqueous layer was extracted with Et0Ac (3 x 75 mL). The organic layers were
combined
and were washed with brine (1 x 50 mL), dried (Na2SO4), filtered, and
concentrated
under reduced pressure. The crude material was purified using RS ISCO Gold 220
gm
column using a gradient of 100% CH2C12 to 92/8 % CH2C12/Me0H to provide 2.0
(39%)
of Int-46a as a brown solid.
LC-MS M+H = 769.2.
Step B
To a solution of Int-46a (0.11 g, 0.14 mmol) in CH2C12 (1.5 mL) under N2
was added excess TFA (1 mL) and the resultant mixture stirred at room
temperature for 2
hours. The reaction was concentrated in vacuo and then taken up in ¨ 2-3 mL
4.0 M HC1
in dioxane and concentrated to dryness to yield Int-46b (75 mg, 99% yield) as
the HC1
salt.
LC-MS M+= 568.2.
Step C
To a solution of Int-46b (75 mg, 0.13 mmol) in 1.5 mL DMF (1.5 mL) at -
15 C was added (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yOacetic
acid
Int-4f (60 mg, 0.28 mmol) and HATU (0.105 g, 0.277 mmol). The mixture was
allowed
to stir for ¨ 15 minutes whereupon DIPEA (0.17 mL, 0.925 mmol) was added. The
mixture was allowed to stir at - 15 C for 90 minutes whereupon H20 (3 mL) and
Et0Ac

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(15 mL) were added. The organic layer was washed with H20 (3 X 3 mL), brine (3
x 3
mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The
crude
material was purified using reverse-phase HPLC (Gilson) using a C18 column
with a
gradient: 0% ACN to 90% ACN/10% water (both with 0.1% TFA) to provide 120 mg
(87%) of the title Compound 728 as a light yellow dihydrochloride salt after
treatment
with HC1. LC-MS (M+H) = 966.6.
EXAMPLE 47
Preparation of Compound 538
¨I¨

µ o o r 0õr0
= e
Br
N Br Step A ToeB-Bs_l_
\
. LN¶: 1
--I---
H 0 \ 41 / N0
N Nr-L01
Othen
Int-45b
cN
i $
0 Int-47a
Br .....) "' NH
(0,1
Int-2a
C) 0
I A,
H
1=1
(___>_ 1
N HOõ,-,..N 0
B H Int-4f
Step B / N
N
- 4 \ ''I H
N Nk-r.:12 0
Step C
--0 H
$
0 Int-47b
0
H 0¨

(1)4 1
0 HN-i
-AA
N wi N N
$ 0
0 538
Step A
Using the procedure for the preparation of Int-46a, Int-45b (2.5 g, 5.5
mmol) was converted to 2.5 g (56%) of Int-47a as a brown solid. LC-MS M+H
768.4.
Step B

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Using the procedure for the preparation of Int-46b, Int-47a (0.10 g, 0.14
mmol) was converted to 98 mg (99%) of Int-47b as the hydrochloride salt. LC-MS

(M+H) = 568.3.
Step C
Using the method described in Example 46, step C, Int-47b (98 mg, 0.14
mmol) was treated with (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-
yl)acetic acid Int-4f (65 mg, 0.30 mmol) to provide 39 mg (26%) of Compound
538 as
the dihydrochloride salt after HC1 treatment. LC-MS M+H 966.4.
EXAMPLE 48
Preparation of Compound 725
N HO ---/NO
0 1,,
/ Int-2c r_NN I
H TRW N\ N-rcol Step A HN
N\
d-O
d¨O
Int-47b 725
Step A
Following the procedure for Example 46, Step C, treatment of Int-47b (75
mg, 0.13 mmol) with (R)-2-(diethylamino)-2-phenylacetic acid hydrochloride Int-
2c (68
mg, 0.28 mmol) provided 0.12 g (83%) of the title Compound 725. LC-MS (M+H) =
946.8.
EXAMPLE 49
40 \ Br 40 \ , \ =
Br Chiral SFC Br 40
0 0 N\_0` __ '
* Int-49
II I
Int-49a nt-49b
Chiral SFC separation (Chiral AD, 30% Me0H/AcCN (2:1) in CO2) of
Int-49 yielded Compounds Int-49a and Int-49b.

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Optical rotation: Int-49b [alpha]D 23 -362.4
EXAMPLE 50
Preparation of Compound 758
\ i
CI
¨
,B-Er a id. Step B
io N\ * Br Step A 7-0 )3 ,
\ * / '1 c'/---
¨`)
0
0 0
rir-1.
lit Int-49a then 0./C)--(--
Int-50a
.)Br) ._ Int-2a
NH
\.=''' --V--0õ0*
0 1 13,-B,
HO
CI
)L /
ci e=-=N 0 4 \ . /
. \ j
* / pi H 8 "
Int-la N N Step D
H
N Ny./21) Step C o
0 H
* 2 0 ID"(
41 Int-50b Int-50c
BrANrV_O
NH
Int-2a
)0y0 N
1. HCI
(5_11 1 ----
- E1 4 * / N 0 0
\ I r fiN
N 0¨ 2.00 W-4\0 -- 0
0
H
H0.1).--NAØ" Int-4f
H
# Int-50d o
Step E
0
o
i:)AN 0
H 4 i
N 0
0 A
0 Nj(f1) H
N
H
* 758
Step A
Using the procedure for the preparation of Int-46a, Int-49a (1.0g, 2.4
mmol) was converted to 0.73 g (49%) of Int-50a as a brown solid. LC-MS M+H
567.2.
Step B
To a round bottom flask charged with Int-50a (0.25 g, 0.44 mmol) and a
stir bar was added Me0H (1 mL) to provide a yellow, heterogeneous mixture. 4 N
HC1

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.
in dioxane (-1 mL) was added dropwise and the resulting solution was allowed
to stir for
2.5 hours at room temperature. The mixture was concentrated under reduced
pressure to
provide an orange solid. The solid was triturated with Et20 (4 x 4 mL),
concentrated
under reduced pressure, and placed under high vacuum to provide Int-50b (206
mg ,99%)
of a light yellow solid. LC-MS M+H = 467.2. This material was taken without
any
further characterization or purification.
Step C
To a solution of Int-50b (0.24 g, 0.44 mmol) in DMF (2.5 mL) at -10 'V
(ice/acetone) was added (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid Int-
2d
(85 mg, 0.49 mmol), HATU (0.18 g, 0.49 mmol), followed by dropwise addition of

DIPEA (0.23 mL, 1.3 mmol) to provide an orange, homogenous solution. The
resulting
solution was allowed to stir for 1 hour at -10 C whereupon the reaction
mixture was
diluted with water (1.5 mL) and Et0Ac (4 mL) and the layers were separated.
The
aqueous layer was extracted with Et0Ac (3 x 4 mL) and the organic layers were
combined. The organic layer was washed with brine (1 x 3 mL), dried (Na2SO4),
filtered,
and concentrated under reduced pressure. The resulting orange/brown semisolid
was
placed under high vacuum to provide a yellow semisolid. The crude material was
taken
up in CH2C12 (2 mL) and was loaded onto a 40 g silica gold column. A gradient
of 100%
CH2C12 to 85% CH2C12/15% Me0H was run over roughly 35 minutes. The major
fraction that was collected was concentrated under reduced pressure to provide
0.27 g
(95%) of Int-50c an off-white solid. LC-MS (M+H) = 624.2.
Step D
To a 20 mL pressure tube with a stir bar was added Int-50c (0.30 g, 0.48
mmol) in dioxane (4 mL). Bis(pinacolato)diboron (0.13 g, 0.53 mmol), KOAc
(0.14 g,
1.4 mmol), and Pd2(dba)3.CHC13 (75 mg, 0.07 mmol), and X-phos (69 mg, 0.14
mmol)
were added to the tube to provide a heterogeneous mixture. The reaction
mixture was
degassed under house vacuum and filled with N2 five times. The tube was
capped, the
reaction was heated to 120 C. After 4 hours LC-MS (M+H 716.2) in dicated that
the
reaction was complete. To the cooled pressure tube containing the crude
boronate was

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added bromo imidazole Int-2a (0.18 g, 0.58 mmol), PdC12c1ppf-CH2C12 (79 mg,
0.096
mmol), and 1 M K2CO3 (1.4 mL). The tube was flushed with N2, capped, and
heated to
95 C for 12 hours. The reaction was then cooled to room temperature, diluted
with
Et0Ac (100 mL) and water (20 mL). The layers were separated and the aqueous
layer
was extracted with Et0Ac (3 x 75 mL). The organic layers were combined and
were
washed with brine (1 x 50 mL). dried (Na2SO4), filtered, and concentrated
under reduced
pressure. The crude material was purified using RS ISCO Gold 40 gm column
using a
gradient of 100% CH2C12 to 90/10 % CH2C12/Me0H to provide 0.16 (37%) of Int-
50d as
a brown solid. LC-MS (M+H) = 825.4.
Step E
Using the procedure for the preparation of Int-3b, Int-50d (71 mg, 0.086
mmol) was converted to 71 mg (99%) of the free diamine as the hydrochloride
salt. LC-
MS (M+H) = 726.2.
Using the procedure in example 45, step C, The diamine intermediate Int-
50d' (71 mg, 0.086 mmol) was treated with (S)-2-(methoxycarbonylamino)-2-
(tetrahydro-2H-pyran-4-ypacetic acid Int-4f (20 mg, 0.094 mmol) to provide 70
mg
(82%) of Compound 758 as the dihydrochloride salt after HCI treatment. LC-MS
(M+H)
= 966.4.
Preparation of Compound 734
icrioc9r0
09
to
Br Steps A-E; Ex. 7
c.....NH,N
N
ri 00 \
Int-49b 0
Compound 734
Using the methods described in Example 7, Steps A-E, compound Int-49b
was converted into Compound 734. LC-MS (M+H) = 925.3.

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EXAMPLE 51
Preparation of Compound 760
., I 40
pot
CI
0 Step A = =
0

Il * I I
N N ______________________ .
s it S Int-50a then I--0/
0-1.1 Int-51a
rst..-_oi
Int-7b
Br NH
r,,CI
''01Xe
_ 0
Step B H O4
HO,),N)Lcf" Int-4f
1 i
- sii 41 \ri * ini e I-yr1) 8 "
Int-51b H
Step C
1 Y.,...r0
0 N
0
H N N
Cjisi 1 N A ,
N
760
Step A
Using the method described in Example 50, Int-50a (0.40 g, 0.71 mmol)
was treated with Int-7b (0.32 g, 0.85 mmol) after initial boronate formation
to provide
0.27 g (44%) of Int-51a as an off-white solid. LC-MS (M+H) = 825.2.
Step B
Using the method described in Example 5o, Int-51a (86 mg, 0.10 mmol)
was converted to 86 mg (99%) of Int-51b as the hydrochloride salt. LC-MS (M+H)
=
725.4.
Step C
Using the procedure in example 50, Int-51b (86 mg, 0.10 mmol) was
treated with (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic
acid Int-

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4f (25 mg, 0.12 mmol) to provide 65 mg (62%) of Compound 760 as the
dihydrochloride
salt after HC1 treatment. LC-MS (M+H) = 924.5.
Preparation of Compound 731
(2,1NY'-`) 0 0
CI 4 \N
H¨r N
N
* Br Steps A-C; Example 8 C-1-4 1 NjLe
____________________________ I.-
N
* 0 H
Int-49b
* Cmpd 731
In an analogous procedure, Int-50a was converted into Compound 731.
LC-MS (M+H) = 924.5.
EXAMPLE 52
Preparation of Compound 762
---0 N
H N, _71 i I
/1 ,1
_ 0
H N HO r )L 1 t 1
Mr N ril-j\C) ---K-"N 0 n - e
OInt-51b
e 8 "
Step A
j) )(C)
0 N1
--...,...,0 0
H N N - )L
. 0
H
H
d.c. NN
762
'Using the method described in Example 50, Int-51b (86 mg, 0.10 mmol)
was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid Int-
le (22
mg, 0.12 mmol) to provide 70 mg (69%) of Compound 762 as the dihydrochloride
salt
after HC1 treatment. LC-MS (M+H) = 899.4.
EXAMPLE 53
Preparation of Compound 732

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o
, A Yto
I.
a
4 \ 1*
N Br
Steps A-C; Example 50 0 N
H N
(Ny4N I
.
1111.. N
* 0 H
Int-49b * 732
In an analogous procedure to Example 50 using (R)-2-(diethylamino)-2-
phenylacetic acid hydrochloride Int-2c, and Int-49b was converted into
Compound 732.
LC-MS (M+H) = 914.4.
EXAMPLE 54
Preparation of Compound 1178 & compound 1179
Boc
F F N N
ci ic..._--, I F
N Boc
N +
0 lik Br step A CI 0 N . iNNL.,,c step B F - N so N #
/N3.....cN,
" 14:1--Br
t
S-J N -F o H L'i
0 +Int-10f cf=-0 H L-1-F
F
Int-54a Int-10f Int-54b Int-54c
H
N N '09-.N0n, , Y 0
step C .1...õ.:-- I F
i N W N H step D H N " \ F.4k H
z N ,,,,..-Nx0.
NiLrN,
N
0,1-0 H -F F H 60 H 1...../.
F
Int-54d Int-54e
0 y 0 y
.F -0-N-io 0
ONO -`/ n, 0 - . -= H + F 0 - A ,
step E H___," ,N \ at / N r¨N 0 11 ,N2 \ a., # / wN 0
F H _ H-0 F H
(3* =F F
1178 (Isomer A) 1179 (Isomer B)
Step A
Int-54a (prepared from Int-19i, 800 mg, 1.87 mmol), bis(pinacolato)diboron
(474
mg, 1.87 mmol), PdC12 (dppf) 2 (273 mg, 0.37 mmol), and KOAc (549 mg, 5.6
mmol) were added
into a 100 mL flask. After the flask was flashed with N2, dry dioxane (18 mL)
was added and the
reaction was allowed to stir at 90 C for 2 hours. After cooling down, Int-10f
(624 mg, 1.87 mmol),
PdC12 (dppf)2 (136 mg, 0.19 mmol) and 1M K2CO3 solution (1M, 5.6 mL, 5.6 mmol)
were added.
The mixture was allowed to stir at 90 C for 4 hours and allowed to cool to
room temperature . The
aqueous layer was separated and extracted with 10 mL Et0Ac. The organic layers
were combined

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185
and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The
product was purified
using silica-gel chromatography (80 g, Eluent:Et0Ac in Hexane: 0% to 80%) to
provide Int-54b
(791 mg, 70.3%).
Step B
Int-54b (791 mg, 1.31 mmol), bis(pinacolato)diboron (333 mg, 1.31 mmol),
Pd2(dba)3 (120 mg, 0.13 mmol), dicyclohexyl(2',4',6'-triisopropylbipheny1-2-
yl)phosphine (125 mg,
0.262) and KOAc (386 mg, 3.93 mmol) were added into a 100 mL flask. After the
flask was
flashed with N2' dioxane (13 mL) was added. The mixture was allowed to stir at
110 C for 2
hours. After cooling down, Compound Int-10f (438 mg, 1.31 mmol), PdC12 (dppf)2
(96 mg, 0.13
mmol) and 1M K2CO3 solution (1M, 3.9 mL, 3.9 mmol) were added. The mixture was
allowed to
stir at 90 C for an additional 4 hours and allowed to cool to room
temperature. The aqueous layer
was separated and extracted thrice with 10 mL Et0Ac. The combined organic
extracts, dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. The product was purified
using silica-gel
chromatography (40 g, Eluent: EtOAC (10% Me0H) in CH2C12: 0% to 80% to provide
Int-54c
(364 mg, 33.8%).
Step C
Int-54c was charged in a 50 mL flask, Me0H (0.5 mL) was added and the reaction

was allowed to stir at room temperature for 1 minutes. HC1 (4M in dioxane, 6.6
mL, 26.4 mmol)
was then added and the solution was allowed to stir at room temperature. After
1 hr the solution
was concentrated and the residue was dried in vacuo to provide Int-54d (364
mg, 100%) which
were used in the next step without further purification.
Step D
Int-54d (364 mg, 0.443 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic
acid (155 mg. 0.886 mmol), HATU (337 mg, 0.886 mmol), and DMF (4.5 mL) were
added into a
40 mL flask. The reaction mixture was cooled to 0 C and DIPEA (0.55 mL, 3.1
mmol) was
added. After 1 hour, water (0.7 mL) and TFA (0.7 mL) were added at 0 C. The
solution was then
stirred at room temperature for an additional 30 minutes, before concentration
to an oil.. The

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solution was purified using CI8 column (80 g, CH3CN/water 10% to 70%, with
0.05% TFA) to
provide Int-54e (312 mg, 60.5%).
Step E
Int-54e was resolved by Chiral SFC (Chiracel AS-H, 20x250 mm, Eluent:
40% Me0H (0.2% DEA)/CO2, 50 mL/min) to provide isomer A (Compound 1178, 1st
peak, 110 mg, 35.2%) and B (Compound 1179, 2nd peak, 108 mg, 34.6%).
The following Compounds were prepared as described above
'OYLX F _ / N Y--31)-()/ single
1463 H (1.11 N\ 10 \N \ / ile-I3
H 60
F isomer
I 0 mixture
H N N AO'
--V C'-- -14 ,1,'N
0 . 1--i.F
isomers
-40-
,0,
'-0-3---N9-r L.) 0 mixture
1 N
1507 4,,,,` * a * /,),O of two
F 4--0 il
'F
isomers
----/,<._
(,),,t,.,,,r0 0
0
F or NAO.' single
1508 L....T.7.11\ õ IN 1).___,,,,, H
4-0 H µ--/ isomer
--e(p__
EXAMPLE 55
Preparation of Compound 1353

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/
0 ---7---
40 \ it BrB-B
Step A (5 so¨v- CI
N 4. 0 0 \ / ry
N 'W =N N
H
111/ then
1 0
Int-5a ,ii: __ oN 111 Int-55a
Br NH
Int-7d
tO, /0 I )c0,(0
N
Step B 0'B-B,0-7 rN I 0
__________________________ =- ,11---- N a \ ii ,szov
o,0+ -w' N N N iN
then 1 0 H
N
Br Int-55b
NH .1-
I
Int-14d
H --,,--
- 0
ri N - .ILI
r I HO,
Tr N CY nt-la
-
Step C ... -sr N di \ . / II ti 0 H
.11*-11PPF N II-1y') Step D
d-o
Int-55c
o
H N N 0
-si-- N 0
ri-o--
N N)Nr_Ni
H
0
11 Compound 1353
Step A
Using the method described in Example 50 step A, Int-5a (1.0 g, 2.4
mmol) was converted to the boronate and was treated with Int-7d (0.92 g, 2.9
mmol) to
provide 0.92 g (67%) of Int-55a as a brown solid. LC-MS (M+H) = 566.7.
Step B
Using the method described in Example 50, Int-55a (0.70 g, 0.1.2 mmol)
was converted to the intermediate boronate followed by treatment with Int-7d
(0.53 g,
1.5 mmol) to provide 0.25 g (25%) of Int-55b. LC-MS (M+H) = 811.6.
Step C

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Using the method described in Example 50, Int-55b (0.25 g, 0.31 mmol)
was converted to 0.23 g (99%) of Int-55c as the hydrochloride salt. LC-MS
(M+H) =
611.8.
Step D Preparation of Compound 1353
Using the procedure Example 50 step E, Int-55c (23 mg, 0.31 mmol) was
treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid It-la (0.11 g,
0.65
mmol) to provide 0.19 g (66%) of Compound 1353 as the dihydrochloride salt. LC-
MS
(M+H) = 926.2.
EXAMPLE 56
Preparation of Intermediate Compound Int-56b
OMe
0 411 Br 4110
OMe
Br
Int-56a Int-56b
A 500-mL round-bottom flask was charged with triphenyl phosphite (31
mL, 37 g, 120 mmol), dichloromethane (250 mL) and cooled for 15 minutes in a
dry ice-
acetone bath that was maintained at -50 to -60 C. Bromine (6.2 mL, 19 g, 120
mmol)
was added dropwise over 15 minutes through an addition funnel. Triethylamine
(19 mL,
13 g, 132 mmol) and 3,5-dimethoxybenzaldehyde (Int-56a; 10.0 g, 60.2 mmol)
were
added sequentially. The reaction mixture was allowed to stir at -60 C for 1
hour. The
cold bath was removed and the reaction mixture was allowed to stir for a
further 18 hours
as the temperature was allowed to reach RT. The reaction mixture was
concentrated by
rotary evaporation under reduced pressure (water bath temperature ¨50-60 C)
to provide
a dark brown, viscous liquid as crude product. The crude product was taken up
in Et0Ac
(-100 mL) and filtered. The filtrate was concentrated under reduced pressure
(water bath
temperature ¨50-60 C) to provide a dark brown, crude Int-56b as a viscous
liquid. Int-
56b was loaded directly onto a pre-equilibrated 330 g RediSept Gold silica gel
column

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and purified using flash chromatography (Isco*; Eluent: 0-5% Et0Ac/hexanes
gradient,
to 5-70% Et0Ac/ hexane to provide Int-56b as a white solid (12.8 g, 68%
yield).
In the same manner, the following 1,1-dibromo intermediates were
prepared from the corresponding aldehydes.
F I. 0 110
Br OP 10
Br Br
Br Br lit
CI OMe 0 0 Br 411) 0
1
Br Br
Int-56c Int-56d Int-56e Int-56f
0 F
Br Si Br el
0 OMe
Br Br
Int-56g Int-56h
EXAMPLE 57
Preparation of Compound 1286

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CI CI
CI CI r-, N BOC
CI
Br ¨ * \ 11) Br ¨
Br gr-< µ...I1j1
N N N
N
H HO Step A H HO Step B = + H
Int-57b Int-7d
Int-19g Int-57a
crs-
CI
CIN BOC
\ * iN`)...T.:.) + ITN BOC
* N
Br--N`)....õ61
¨
Step C 0 H H -3' Step D
*
Int-12o
Int-57c
0--
BOC N H
AIAJ N rei \ tek , yi30C L¨I iNii 10 \ et
i N Y
H N µmf ¨ N N
6-1
0 N N H Step E o H
* Int-57d* Int-57e
0-=
0-
it Cfo
Step F
N
_ H N(,
N 4NA.C<
%
N)y) H
'N 0
HO H 0 H
Int-1 e *
1286
0-
Step A
Int-19g (10.0 g, 31 mmol), NCS (4.14 g, 31 mmol), dichloromethane (300
ml), and THF (300 ml) were added to a 1 L flask and the resulting mixture was
allowed
to stir at 0 C for 1 hour and then at room temperature for 2 hours. The
reaction mixture
was then concentrated to a semi-solid and the residue was suspended in
dichloromethane
(150 ml) and filtered. The solid was washed with dichloromethane (2x15 ml) and
dried
to provide Int-57a as a solid (6.4 g, 58%).
Step B
Int-57a (1.0 g, 2.8 mmol), 3-methoxybenzaldehyde (0.572 g, 0.58 mmol),
p-toluenesulfonic acid (0.0053 g, 0.28 mmol), and o-xylene (10 ml) were added
to a 35
mL pressure vessel. The resulting mixture was allowed to stir at 170 C for
about 15
hours under protection of a shield, cooled to room temperature, and purified
on a 80 g

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silica column/ Combi-Flash Rf system (Eluent: 0-5% ethyl acetate in hexanes
eluent) to
provide Int-57b as a gel (0.2 g, 15%).
Step C
Int-57b (200 mg, 0.421 mmol), bis(pinacolato)diboron (118 mg, 0.421
mmol), potassium acetate (207 mg, 2.1 mmol), PdC12(dppf)-CH2C12(34.4 mg, 0.042

mmol), and dioxane (5 ml) were added to a 35 mL microwave reaction tube. The
sealed
tube was degassed and stirred at 95 C under nitrogen atmosphere for 4 hours
then cooled
to room temperature. To this mixture were added bromide Int-7d (160 mg, 0.505
mmol),
PdC12(dPPO-CH2C12 (34.4 mg, 0.042 mmol), 1.5 M aqueous solution of sodium
carbonate (1.4 ml, 2.1 mmol). The resulting mixture was degassed and stirred
at 95 C
under nitrogen atmosphere for 6 hours, cooled to room temperature,
concentrated,
purified using a 12 g silica column on Combi-Flash Rf system (0-60% ethyl
acetate in
hexanes eluent) to provide Int-57c as a wax (114 mg, 43%).
Step D
Int-57c (65 mg, 0.103 mmol), bis(pinacolato)diboron ( 57.5 mg, 0.226
mmol), potassium acetate (101 mg, 1.03 mmol), Pd2(dba)3-CHC13(21.3 mg, 0.02
mmol),
X-PHOS (19.6 mg, 0.04 mmol), and dioxane (3 ml) were added to a 35 mL
microwave
reaction tube. The sealed mixture was degassed and stirred at 110 C under
nitrogen
atmosphere for 8 hours then cooled to room temperature. To this mixture were
added
bromide 27 (85 mg, 0.258 mmol), PdC12(dppp-CH2C12 (16.8 mg, 0.02 mmol), 1.5 M
aqueous solution of sodium carbonate (0.7 ml, 1.05 mmol). The resulting
mixture was
degassed and stirred at 95 C under nitrogen atmosphere for 6 hours, cooled to
room
temperature, concentrated, purified using a 4 g silica column / Combi-Flash Rf
system (0-
100% ethyl acetate in hexanes eluent) to provide Int-57d as a solid (39 mg,
47%).
Step E
Int-57d (39 mg, 0.048 mmol), TFA (1 ml) and dichloromethane (1 ml)
were added to a 25 mL flask and stirred at room temperature for 4 hours and
concentrated
in vacuo. The residue was dissolved in methanol (2 ml), treated with 0.1 mL of
4.0 M

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HC1 (0.4 mmol) solution in dioxane and concentrated again in vacuo to provide
Int-57e
as a white solid. This crude product was used for the next reaction without
purification.
Step F
Diamine Int-57e , Valine-MOC acid It-la (14.3 mg, 0.081 mmol), and
DMF (1 ml) were added to a 50 mL flask and cooled to 0 C. To this cooled
solution was
added HATU (30 mg, 0.08 mmol) and the reaction was allowed to stir at 0 C
over a
period of 1 hour, quenched with water (3 drops). The reaction mixture was
purified using
reverse phase chromatography (0-90% acetonitrile in water with 0.1% TFA
eluent) to
provide Compound 1286 as a wax (13 mg, 31%). LC/MS anal. calcd. for: C51
H57N908
923.4; Found: 924.5 (M+H)+.
EXAMPLE 58
Preparation of Compound 1198 & Compound 1199
0 y 0 y
-ekt\r`IP
o o
H N N

CI " H N N 0r-N 0
)4
Ls.¨(. I
F 1'1 iN..x_OctrEiNm - H iN=X¨rNI H
4-0 H 4-0 H L-1,F
0- 0-
1198 1199
Compound 1198 (20 mg, 0.020 mmol), trimethylboroxine (7.67 mg, 0.061 mmol),
Pd2(dba)3 (3.73 mg, 4.07 mop, and dicyclohexyl(2',4',6'-triisopropylbipheny1-
2-
yl)phosphine (3.88 mg, 8.14 mop are added into a 50 mL flask. After the flask
was
flashed with N2, 1,4-Dioxane (204 I) and K2CO3 (61.1 I, 0.061 mmol) was
added. The
mixture was allowed to stir at 110 C for 16 hours. After cooling down, the
aqueous
layer was separated and extracted with 5 mL Et0Ac. The organic layers were
combined
and dried over anhydrous Na2SO4. The solution was filtered and concentrated in
vacuo.
The solution was concentrated and purified using Si02 chromatography (24 g,
Me0H
(Eluent: 10% concentrated Me0H/NH3-1120) in CH2C12, 0% to 80%) to provide
Compound 1199 (15 mg, 77%).

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The following compound was made using the method described in the Example
above:
o y
-/ 0 mixture
H N N
N /;1\l'O'
S-'---( /6
1199 F N1 H H of two
H -F
isomers
0-
EXAMPLE 59
Preparation of Compound 1014

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Br
Br Br _____
CI
0 Br B,
Int-56c Br
N \ =
' N
Step A 6-0 Step B
H HO
Int-19b Int-59a
a
. ...0y0
N N
o- girb \ u__ 1 o
WI N 1, 13 ..1,-0
40 \ . /NYA5
Int-59b c
C5 -
step C N
i--0
In1-59:
CI
CI
- I N N
==>¨ 1 N '()
HN 40\µ 41
___________ - N --.-
Step D 0 H Step E
e
Int-59d
s
H
N N
-=>--- \ / N H
N 40 \ = N(tsil
N
H
0
Int-59e . Step F
.41-ICI
S
/ /
Me02C. Xr.0
N
H
N N
-=>¨ \ N (:)N
- ,CO2Me
N 5\ . / H
N HN Li
0
.
/
S Cmpd 1014
7
Step A
In a 250-mL round-bottom flask, Int-19b (2.006 g, 5.47 mmol) was
dissolved in DMSO (22 mL). Neat dibromide Int-56c (1.710 g, 6.01 mmol) was
added,
followed by solid cesium carbonate (5.34 g, 16.4 mmol). The reaction mixture
was
immersed into a preheated 90 C oil bath and stirred for 18 hours, then
allowed to cool to
room temperature, and poured into water (-100 mL), whereupon a tan solid
precipitated.
The aqueous mixture was extracted with Et0Ac (2 x 100 mL). The combined
organic
phases were washed with brine (-50 mL), then dried over anhydrous MgSO4,
filtered,

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and concentrated in vacuo to provide a tan-brown solid as crude product. The
crude
product was purified using flash silica gel chromatography (Isco ; 220 g
RediSep Gold
silica gel column; Eluent: 0-30% Et0Ac/hexanes gradient to provide Int-59a as
a pale
yellow solid (683 mg, 26% yield).
Step B
In a 20-mL Biotage microwave tube was charged with stir basr was
added Int-59a (670 mg, 1.37 mmol), bis(pinacolato)diboron (695 mg, 2.74 mmol),

(dppf)PdC12=CH2C12 (68 mg, 0.083 mmol) and potassium acetate (403 mg, 4.11
mmol).
The tube was alternately evacuated and back-filled with nitrogen 5 times.
Dioxane (14
mL) was added and the tube was immersed into a preheated 90 C oil bath. After
1.5
hours, then reaction was allowed to cool to room temperature, diluted with
Et0Ac (-20
mL) and filtered through a Celite pad. The pad was rinsed with Et0Ac (-50 mL)
and
the combined filtrate were washed with brine (-25 mL), dried over anhydrous
MgSO4,
filtered, and concentrated under reduced pressure to provide an light brown
solid as
crude product. The crude product was purified using flash silica gel
chromatography
(Isco ; 40 g RediSep Gold silica gel column; Eluent 0-50% Et0Ac/hexanes
gradient) to
provide Int-59b as a beige solid (705 mg, 88% yield).
Step C
A 20-mL Biotage microwave tube was charged with a stir bar, Int-59b
(700 mg, 1.20 mmol), bromoimidazole Int-7d (834 mg, 2.64 mmol), and
(dppf)PdC12=CH2C12 (49 mg, 0.060 mmol). The tube was alternately evacuated and

refilled with nitrogen (5x). Dioxane (8 mL) was added and the reaction mixture
was
allowed to stir at room temperature for 5 minutes. Aqueous potassium carbonate
solution
(6 mL, 1 M aqueous, 6 mmol) was then added and the reaction was immersed into
a
preheated 90 C oil bath. After 18 hours the reaction was allowed to cool to
room
temperature and was diluted with Et0Ac (-50 mL), filtered through a
polyethylene filter
frit and the filtrate was washed with brine (-25 mL). The organic layer was
dried over
anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide
an
orange-brown solid as crude product. The crude product was purified using
flash silica

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gel chromatography (Isco ; 120 g RediSep Gold silica gel column; Eluent 0-10%

Me0H/CH2C12 gradient) to provide Int-59c as a beige solid (719 mg, 75% yield).
Step D
A 5-mL Biotage microwave tube was charged with a stir bar, Int-59c
(130 mg, 0.162 mmol), (dba)3Pd2=CHC13 (25 mg, 0.024 mmol) and X-Phos (23 mg,
0.049 mmol). The tube was sealed and alternately evacuated and back-filled
with
nitrogen (5x). 5-methylthieny1-2-boronate (36 mg, 0.16 mmol), dissolved in
dioxane (1.6
mL), and potassium carbonate (0.8 mL, 1 M aqueous; 0.8 mmol) were added by
syringe.
The tube was immersed in preheated 120 C oil bath and stirred for 4 hours.
The reaction
mixture was then cooled, diluted with Et0Ac (-50 mL), filtered, and washed
with brine
(-25 mL). The organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to provide the crude product as a golden
yellow
solid. Further purification by reverse-phase chromatography (Gilson ;
Phenomenex
Gemini 150 x 21.20 mm x 5 gm column; 10-70% MeCN/water (+0.1% TFA) gradient
over 20 minutes) to provide Int-59d as a beige solid (26 mg, 19% yield).
Step E
In a 50-mL round-bottom flask Int-59d (20 mg, 0.03 mmol) was dissolved
in methanol (500 gL) and HC1 solution (60 gL, 4 M in dioxane, 0.240 mmol) was
added.
The clear, pale yellow tinged solution was allowed to stir at room temperature
for 24
hours. The reaction mixture was concentrated in vacuo to provide Int-59e a
beige solid
(15.6 mg, 83% yield).
Step F
In a 50-mL round-bottom flask, Int-59e (16 mg, 0.019 mmol) and It-la
(7 mg, 0.040 mmol) were dissolved in DMF (200 gL). Diisopropylethylamine (20
fiL, 15
mg, 0.118 mmol) was added and the reaction mixture was cooled in an ice-water
bath for
15 minutes. Solid HATU (15 mg, 0.039 mmol) was added slowly and the reaction
allowed to warm slowly to room temperature. After 3 hours the reaction was
purified
directly by reverse-phase chromatography (Gilson ; Phenomenex Gemini 150 x
21.20

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mm x 5 gm column; 10-70% MeCN/water (+0.1% TFA) gradient over minutes) to
provide Compound 1014 as a beige solid (12 mg, 62% yield).
EXAMPLE 60
Preparation of Compound 1005
->r =>
oyo (0....r0
N N N N
1,-?¨N I
0
H 140) \ \ ip oyoi<
N N N
0
Step A
0 *
CI Int-59c \OA Int-60a
N N Int-1a C.) N N
¨
EN 40 N\ 11). ti
H
OH
0
Step B
Step C
*
.4HCI Compound 1005
Int-60b
Step A
A 5-mL Biotage microwave tube equipped with a magnetic stir bar was
added, Int-59c (254 mg, 0.317 mmol), phenylboronic acid (77 mg, 0.634 mmol),
Pd2(dba)3=CHC13 (66 mg, 0.063 mmol) and X-Phos (61 mg, 0.127 mmol). The tube
was
sealed and alternately evacuated and back-filled with nitrogen (5x). Dioxane
(3 mL) and
potassium carbonate (0.78 mL, 1 M aqueous; 0.78 mmol) were added and the
reaction
immersed in a preheated 110 C oil bat. After 22 hours the reaction was
allowed to cool,
diluted with Et0Ac (-30 mL), and washed sequentially with water (-20 mL) and
brine
(-20 mL). The organic layer was dried over anhydrous MgSO4, filtered, and
concentrated in vacuo to provide the crude product as a light brown solid. The
crude
product was purified using flash silica gel chromatography (Isco ; 40 g
RediSep Gold
silica gel column; Eluent 0-10% Me0H/CH2C12 gradient) to provide Int-60a (134
mg,
50% yield) as a pale yellow-orange solid.
Step B

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In a 125-mL round-bottom flask, Int-60a (100 mg, 0.118 mmol) was
dissolved in methanol (1.2 mL). Hydrogen chloride solution (0.300 mL, 4 M in
dioxane,
1.2 mmol) was added and the reaction mixture was allowed to stir at room
temperature.
After 17 hours the reaction mixture was concentrated under reduced pressure to
provide a
golden-brown solid, which was dried in a vacuum oven (house vacuum, ¨60 C)
for 20
hours to provide Int-60b as a golden brown solid (99 mg, quantitative yield).
Step C
To a 50-mL flask equipped with a stir bar was added Int-60b (39 mg,
0.047 mmol) and It-la (17 mg, 0.094 mmol) , and dry DMF (472 gL).
Diisopropylethylamine (41 L, 31 mg, 0.236 mmol) was added and the reaction
mixture
was cooled to 0 C in an ice-water bath. After ¨15 minutes, solid HATU (40 mg,
0.104
mmol) was added and the reaction mixture stirred at 0 C, After 2 hours the
reaction was
quenched by addition of water (20 mL), whereupon a beige solid precipitated.
The solid
was collected by vacuum filtration and washed further with water (-50 mL). The
solid
was dissolved in Et0Ac (-100 mL) and the resulting solution was washed with
brine
(-25 mL). The organic layer was collected, dried over MgSO4, filtered, and
concentrated
under reduced pressure to provide a beige crude product. Further purification
by reverse
phase C18 chromatography (Gilson , Phenomenex Gemini C18 5 gm 150 x 21.20 mm
column, Eluent:10-70% MeCN/water + 0.1% TFA over 20 minutes @20 mL/min}
afford Compound 1005 as a beige solid (28.4 mg, 63% yield).
EXAMPLE 61
Preparation of Compounds 1166, 1171 & 1173

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Boc N ,
Boc N N, _.t, \ , N Boc
/
F H N Step A r H N
0 H '-'µF Step 6
c30 H -----µF
ifk
CI 4,
Int-61a Int-61b
4,
H N ,
Li- -N 0 \ * iN) '0)LN m 0
l
F H N 0 -11 ,
0 H --4F Step C H N .. \ ik \ * / LO7-111
Int-61c
. . Compound 1166
41
0y 0 y
C:1A--N---1 0 5,)
31:2
__;.------[4, * N
Step D F -0 H + F H 0 H
4/
11
lik Compound 1171 = Compound 1173
= *
Step A
Compound Int-61a (150 mg, 0.179 mmol, prepared by a similar route as
in example 59), biphenyl-4-ylboronic acid (35.4 mg, 0.179 mmol), Pd2(dba)3
(18.5 mg,
0.018 mmol), and dicyclohexyl(2',4',6'-triisopropylbipheny1-2-yl)phosphine (17
mg,
0.036 mmol) were added into a 40 mL flask. The flask was put in vacuo and
filled with
N2* This process was repeated once. Dioxane (1.8 mL) and K2CO3 (1M, 0.9 mL,
0.9
mmol) were added, and the sealed flask was allowed to stir at 110 C. After 3
hours the
reaction was cooled, the aqueous layer was separated and extracted with 3 mL
Et0Ac.
The organic layers were combined and dried over anhydrous Na2SO4, filtered and

concentrated to provide crude product. Further purification by Silica-gel
chromatography
(Eluent: EtOAC (10% Me0H) in CH2C12: 0% to 80%) gave Compound Int-61a (137 mg,

80%).

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Steps B to D were carried out using the methods described in Example 50.
The following compound was made using the method described in the Example
above:
0
0
is FH N /NI r 11 0
0 H single
1172
41k isomer
EXAMPLE 62
Preparation of Compound 1528

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F CI
CI r& , . Br + * * Br
` Br * ¨ N
N 0 0
H HO Br I Step A
F fito
Int-19g Int-56h Int-62a
0-
Br-41N BOC
-rK1\_ CI N BOC 01...Y p
N * \ . i 6 . Br-4N ''N-4C,-,
H 1--45. N N y-1 H s-c-
Int-12o 0 H .õ1:
H Int-7b
-----.- F 40
Int-62b
Step B 0¨ Step C
yi Zo ill
s'0 N
Fl ,N1n1 H N,.....r
"M) / lc. :).30C N H
H N µw N N ¨ c--1 11 110
N\ * 11\1=µ,3
0 H H
"1". Step D o ..1,
F ito
Int-62c F 41* Int-62d
o¨ o--
o
o,,Nicr --oAN\4 NI
OH H H ,N,4"-'1. OlY jt
* \ Alt
Int-1a H N \WI N N
0 H
...?
Step E F ile
Cmpd 1528
o¨

Step A
To a 250 mL flask were added Int-19g (5.0 g, 15.5 mmol), dibromide Int-
56h (5.8 g, 80% purity, 15.5 mmol), cesium carbonate (25.3 g, 77 mmol), and
acetonitrile
(50 ml) and the resulting suspension was allowed to stir at 60 C for about 15
hours.
Ethyl acetate (200 ml) was then added, and the organic layer was washed with
water
(2x150 ml), dried over sodium sulfate, and concentrated in vacuo. The residue
was
purified on a 120 g silica column/ Combi-Flash Rf system(Eluent: 0-10% ethyl
acetate in
hexanes) to provide Int-62a as a white solid (3.7 g, 52%).
Step B

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Intermediate Int-62a (500 mg, 1.09 mmol), bis(pinacolato)diboron ( 304
mg, 1.2 mmol), potassium acetate (535 mg, 5.45 mmol), PdCb(dppD-CH2C11 (89 mg,

0.109 mmol), and dioxane (8 ml) were added to a 35 mL microwave reaction tube.
The
sealed mixture was degassed and stirred at 95 C under nitrogen atmosphere for
4 hours
and then cooled to room temperature. To this mixture were added bromide Int-
12o (429
mg, 1.31 mmol), PdC12(dppf)-CH2C12 (89 mg, 0.109 mmol), 1.5 M aqueous solution
of
sodium carbonate (3.6 ml, 5.4 mmol). The resulting mixture was degassed and
stirred at
95 C under nitrogen atmosphere for 6 hours, cooled to room temperature,
concentrated,
to provide crude product. Further purification was accomplished on by a 40 g
pre-packed
silica gel column/ Combi-Flash Rf system (Eluent: 0-90% ethyl acetate in
hexanes) to
provide Int-62b as a wax (530 mg, 78%).
Step C
Int-62b (130 mg, 0.207 mmol), bis(pinacolato)diboron ( 58 mg, 0.23
mmol), potassium acetate (102 mg, 1.04 mmol), Pd2(dba)3-CHC13 (21.5 mg, 0.02
mmol),
X-PHOS (19.8 mg, 0.04 mmol), and dioxane (2 ml) were added to a 35 mL
microwave
reaction tube. The sealed mixture was degassed and stirred at 110 C under
nitrogen
atmosphere for 8 hours then cooled to room temperature. To this mixture were
added
bromide Int-7b (78 mg, 0.21 mmol), PdC12(dppf)-CH2C12 (14.2 mg, 0.02 mmol),
1.5 M
aqueous solution of sodium carbonate (0.6 ml, 0.9 mmol). The resulting mixture
was
degassed and stirred at 95 C under nitrogen atmosphere for 6 hours, cooled to
room
temperature, concentrated to provide crude product. Further purification on a
4 g silica
gel pre-packed column/ Combi-Flash Rf system (Eluent: 0-100% ethyl acetate in
hexanes)
provided Int-62c as a solid (105 mg, 68%).
Step D
Int-62c (98 mg, 0.11 mmol), TFA (1 ml) and dichloromethane (1 ml)
were added to a 25 mL flask. The resulting solution was allowed to stir at
room
temperature for 4 hours and concentrated in vacuo. The residue was dissolved
in
methanol (2 ml), treated with 0.1 mL of 4.0 M HC1 (0.4 mmol) solution in
dioxane and
concentrated again in vacuo to provide Int-62d as a solid (99 mg, 100%).

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Step E
Int-62d (30 mg, 0.034 mmol), acid It-la (6.5 mg, 0.04 mmol), and DMF
(1 ml) were added to a 25 mL flask and the resulting solution was cooled to 0
C. To this
cooled solution was added HATU (13 mg, 0.034 mmol) and the reaction was
allowed to
stir at 0 C, After lh , water (3 drops) was added and the reaction directly
purified using
reverse phase chromatography (10-80% acetonitrile in water with 0.1% TFA
eluent ) to
provide Compound 1528 as a white solid (5 mg, 13%). LC/MS anal. calcd. for:
C51f156FN908 941.4; Found: 942.5 (M+H)+.
EXAMPLE 63
Preparation of Compound 1496
i
. a h
Br 111,
F
Br 4 Br Int-56c H= Br Step; Br eith \ p J-q
. it. IV Br --="' Cr B 4
iltiP N N
H Step A = 0
F ft. 0\ F * \
Int-19b
Int-63a Int-63b
j--N o-ol< tc:roH
Br¨c9......01
L... -- I N Cil (>111 41 µrsi ito ir,iLON H
__________ = H H
Step C = Step D o
F * Ck E it C1/4
.4HCI
Int-63c Int-63d
ro o
,o)kr,Y,fo
0 .
y0 H
0r' NA0,. C:r14 I 0..1 Nike
H lil * \ N
* itslo
i
Step E . H
F * 0µ, 1496
Step A
Into a 250-mL round-bottom flask equipped with a stir bar,
dibromoindole Int-19b (4.41 g, 12.02 mmol), Int-56c (4.47 g, 14.4 mmol) were
added

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and dissolved in dry DMSO (50 mL). Solid cesium carbonate (20 g, 61 mmol) was
added. The reaction mixture was allowed to stir at 100 C for 14 hours. Water
(-150 mL)
was added to the reaction mixture, whereupon a beige solid precipitated. The
suspension
was extracted with Et0Ac (3 x 250 mL). Combined extracts were washed with
brine
(-250 mL). The organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to provide the crude product as a light
orange-brown
solid. The crude product was adsorbed onto silica gel (10.0 g), and then
further purified
using flash silica gel chromatography (Isco ; 330 g RediSep Gold silica gel
column;
Eluent: 0-10% Et0Ac/hexanes gradient) to provide Int-63a as a light brown
solid (2.77 g,
46% yield).
Step B
A 125-mL round-bottom flask equipped with a stir bar was charged with
Int-63a (1.46 g, 2.90 mmol), bis(pinacolato)diboron (1.55 g, 6.09 mmol),
(dppf)PdC12=C1-12C12 (106 mg, 0.145 mmol) and KOAc (854 mg, 8.71 mmol). The
reaction was sealed and alternately evacuated and refilled with nitrogen (5x).
Dry
dioxane (19 mL) was added and the flask was immersed in a preheated 90 C oil
bath.
After 1 hour the reaction mixture was allowed to cool to room temperature,
diluted with
Et0Ac (100 mL), filtered through a polyethylene fit and washed with brine (-50
mL).
The organic layer was dried over anhydrous MgSO4, filtered, and concentrated
to provide
the crude product as a dark-brown semi-solid. The crude product was purified
using
flash silica gel chromatography (Isco ; 220 g RediSep Gold silica gel column;
Eluent:
0-30% Et0Ac/hexanes gradient) to provide Int-63b (1.09 g, 63% yield).
Step C
A 125-mL round-bottom flask equipped with a stir bar was charged with
Int-63b (707 mg, 1.184 mmol), bromoimidazole Int-7d (786 mg, 2.49 mmol),
(dppf)PdC12=CH2C12 (87 mg, 0.118 mmol). The flask was alternately evacuated
and
refilled with nitrogen (5x). Dioxane (12 mL) was added and the reaction
mixture was
allowed to stir at room temperature for 5 minutes. Aqueous potassium carbonate
solution
(6 mL, 1 M aqueous, 6 mmol) was then added. The reaction mixture was allowed
to stir

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at 90 C for 2.5 hours, cooled to room temperature and was diluted with Et0Ac
(-50 mL).
The resulting solution was poured into a separatory funnel containing Et0Ac (-
50 mL)
and water (-50 mL). The organic layer was washed with brine (-50 mL). The
organic
layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced

pressure to provide the crude product as an orange-brown solid. The crude
product was
further purified using flash silica gel chromatography (Isco ; 120 g RediSep
Gold silica
gel column; Eluent : 0-100% {10% Me0H/Et0Ac}¨hexanes gradient) to provide Int-
63c a light brown solid (644 mg, 67% yield).
Step D
In a 50-mL round-bottom flask, Int-63c (633 mg, 0.776 mmol) was
dissolved in methanol (8.0 mL) and hydrogen chloride solution (2.0 mL, 4 M in
dioxane,
(2.4 g, 8 mmol) was added. The reaction mixture was allowed to stir at room
temperature
for 24 hours. The reaction mixture was concentrated under reduced pressure to
provide
Int-63d as a beige solid (572 mg, 97% yield).
Step E
Int-4f (57 mg, 0.263 mmol) was dissolved in dry DMF (1.3 mL). The
resulting solution was added to a 50-mL round-bottom flask containing solid
Int-63d
(100 mg, 0.131 mmol). /VN-Diisopropylethylamine (140 gL, 104 mg, 0.802 mmol)
was
added and the mixture agitated by sonication until no more solid adhered to
the walls of
the flask. The reaction mixture was allowed to stir at 0 C (ice-water bath)
for ¨15
minutes. Solid HATU (110 mg, 0.289 mmol) was added and the reaction mixture
was
allowed to stir at 0 C. After 1.5 hours the reaction was diluted with
methanol (1 mL),
and water (-0.1 mL) and solid potassium carbonate (36 mg, 0.263 mmol) were
added
sequentially. After 24 hours the reaction mixture was partitioned between
Et0Ac (-100
mL) and brine (-25 mL). The aqueous layer was extracted with a second portion
of
Et0Ac (-25 mL). The combined extracts were washed with brine (-25 mL), dried
over
anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide
crude
product as a light brown solid.. The crude product was purified directly by
reverse-phase
chromatography (Gilson ; Phenomenex Gemini 150 x 21.20 mm x 5 gm column;
Eluent:

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0-70% MeCN/water (+0.1% TFA) gradient over 15 minutes) to provide the targeted

product Compound 1496 as a white solid (84 mg, 63% yield).
EXAMPLE 64
Preparation of Compounds 1002, 1024, & 1025
OMe
Br 40
0
OMe >%9
Br \ 11
N Br Br Int-56g Br 0 \ 4I Br __ 0-13 di \ .
µ111PIP N \WI --* .14`111r N 0
H HO Step A0 Step B o
Int-19b \
o Int-64a = . Int-64b
i
o- N o-
il
N 0y0,<- ,j 0 0 N 1 Ai
Br¨r Int-7d ar / NO, Step D I - N
4. WI * 1H.4y;
N N
H 0
'''' N H
Step C
J o . .4HCI
/
Int-64c o-
Int-64d
o / ----\o-
oy1,11A0,
'ojcLnXf 0
OH Int-1a H N N 0 - A ..-
y..-'N L
N0

0
Step E W >¨N / z ,N H
Compounds 1024
" 4N\ 0411 "- -\--1
H and 1025
\
o
o- 1002
Step A
A 250-mL round-bottom flask was charged with Int-19b (3 g, 8.2 mmol)
and DMSO (35 mL). The 1,1-dibromide Int-56g (2.5 g, 8.1 mmol) and cesium
carbonate
(8.0 g, 25 mmol) were added and the mixture was heated with stirring at 90 C
for 18
hours. The reaction mixture was poured into water (-300 mL) and extracted with
Et0Ac
(3 x 250 mL). Combined extracts were washed with brine (-250 mL). The organic
layer
was dried over anhydrous MgSO4, filtered, and concentrated under reduced
pressure to
provide the crude product as a brown oil. The crude product was adsorbed onto
8.5 g
silica gel and further purified using flash silica gel chromatography (Iscot;
300 g
RediSep Gold silica gel column; Eluent: 0-50% Et0Ac/hexanes gradient) to
provide
Int-64a (751 mg, 18% yield).

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Step B
In a 20-mL Biotage microwave tube, Int-64a (276 mg, 0.535 mmol),
bis(pinacolato)diboron (220 mg, 0.866 mmol), (dppf)PdC12-CH2Cl2 (34 mg, 0.042
mmol)
and KOAc (122 mg, 1.24 mmol) were added. The tube was sealed and alternately
evacuated and refilled with nitrogen (5x). Dry dioxane (3.5 mL) was added and
the
reaction mixture was allowed to stir until homogeneity was achieved (< 1
minutes). The
tube was immersed in a preheated 90 C oil bath and stirred for 45 minutes.
The reaction mixture was cooled, diluted with Et0Ac (-10 mL) and filtered
through a
Celitet pad with washing (Et0Ac). The combined filtrates were washed with
brine (-25
mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced
pressure to
provide the crude product as an orange-brown solid. Further purification by
flash silica
gel chromatography (Isco ; 40 g RediSepe Gold silica gel column; Eluent: 0-30%

Et0Ac/hexanes gradient) to provide Int-64b as an off-white solid (127 mg, 39%
yield).
Step C
In a 20-mL Biotage microwave tube, Int-64b (122 mg, 0.200 mmol),
bromoimidazole Int-7d (133 mg, 0.420 mmol), and (dppf)PdC12=CH2C12 (16 mg,
0.020
mmol) were mixed. The tube was sealed and alternately evacuated and back-
filled with
nitrogen (5x). Dioxane (2 mL) and potassium carbonate (0.60 mL, 1 M aqueous;
0.60
mmol) were added and the reaction immersed in a preheated 90 C oil bath.
After 17
hours the reaction mixture was allowed to cool, diluted with Et0Ac (-100 mL)
and was
washed with brine (-50 mL). The organic layer was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to provide a light brown
solid. The
crude product was purified using flash silica gel chromatography (Isco ; 24 g
RediSep
Gold silica gel column; Eluent: 0-60% Me0H/CH2C12 gradient) to provide It-Me
as a
beige solid (111 mg, 67% yield).
Step D
In a 50-mL round-bottom flask, Int-64d (101 mg, 0.122 mmol) was
dissolved in methanol (2.0 mL) and HCI solution (300 lit, 4 M in dioxane, 1.2
mmol)
was added. The pale yellow solution was allowed to stir at room temperature
for 23

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208
hours, then concentrated under reduced pressure to provide Intermediate 900D
(100 mg,
¨100% yield) as a pale yellow powder..
Step E
A 50-mL flask was charged with Int-64d (55 mg, 0.072 mmol) and Jut-la
(25 mg, 0.143 mmol) and dissolved in dry DMF (716 W. Diisopropylethylamine
(61
pt, 46 mg, 0.358 mmol) was added and the reaction mixture was cooled to 0 C
in an
ice-water bath. After ¨15 minutes, solid HATU (57 mg, 0.150 mmol) was added.
After
3 hours at 0 C the reaction was quenched by addition of water (20 mL),
whereupon a
beige solid precipitated. The solid was collected by vacuum filtration and
washed again
with water (-50 mL). The solid was dissolved in Et0Ac (-100 mL) and the
resulting
solution was washed with brine (-25 mL). The organic layer was collected,
dried over
MgSO4, filtered, and concentrated under reduced pressure to provide the crude
product.
Further purification by reverse phase C18 chromatography (Gilson , Phenomenex
Gemini C18 5 p.m 150 x 21.20 mm column, Eluent: 10-70% MeCN/water + 0.1% TFA)
provided Compound 1002 as a beige solid (26 mg, 39% yield).
Step F: Isomer separation by HPLC.
Compound 1002 (48.8 mg) was dissolved in abs. Et0H (1.0 mL) and the
solution was filtered through a Whatman Puradisc 13 mm syringe filter. The
sample was
injected onto a Phenomenex Lux Cellulose-2 (5 Jim, 150 x 21.20 mm) semi-
preparative
column; detection wavelength = 350 nm. Elution with 50% Et0H/hexane @ 10
mL/min
provided the first peak (eluted between t = 0.5 minutes and t = 35 minutes)
which was
collected and concentrated to provide Compound 1024 (15 mg) as an off-white
solid.
The eluent solvent polarity was increased to 60% Et0H/hexane at t = 120
minutes while
maintaining a flow rate of 10 mL. The second component, (between t = 125
minutes and
t = 185 minutes), was collected and concentrated to provide Compound 1025 (15
mg) as
an off-white solid.
EXAMPLE 65
Preparation of Compound 1019

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OMe
Br 40
OMe
CI\ p-B, W Br
C4I
Int-56g 0 N\ . Br 01 dh \ Atik W 80
N --..- N O---
H HO Step A -o Step B _-(:)
Int-19g `0--i Int-65a 0--- Int-65b
/
\o- - \O-
Y 1
Br-n-NKN_LcN3 CI CI
H Int-7d 0 N\ it ':q5,-- 4 \ II /:3 y:51
NH ---"- H
0
Step C Step D
Int-65c , vg, Int-65d
/
0-
.2HCI
- \O
\/ 1õ,...-
0 - =-..õ---
. 0
0 - A
N k-98
(31-111 IMC)ra Ci 40 \ 11 'N)1-15/Nr:)1 'I
N H ¨.
._-_ -0 .__ -0 H
Step E Step F
\ \
o---, Int-65e o---. Int-65f
No- \o-
.---.0
0,(:),, / NO
Br-/L) I ' ....c,,__N ,
N Oy;-..N.J1Ø, ...CHN
F
H N
Int-10f F H 41111 \ . /N)L_Ol H F
H 011 N\ 40,
N
H H
Step G Step H ___ -0
.3HCI
\
0--- Int-65g \
0-µ j Int-65h
No- - No-
`-7 0 011XrC)
H /N
0y,1)Lo,
N 0,),tiiA0
F'*.''
÷ Int-1a FIN 5\ 0, /N,IL.,(t jkl
N
Step I__-, -0 H
\
0-'' Compound 1019
\O-
Step A
In a 250-mL round-bottom flask, the 2-(hydroxyphenyl)indole Int-19g
(3.03 g, 9.4 mmol) and gem-dibromide Int-56g (8.7 g, 28 mmol) were mixed and
dissolved in dry DMSO (94 mL). Solid cesium carbonate (21 g, 66 mmol) and a
magnetic stir bar were added. The reaction mixture was allowed to stir at 100
C for 21
hours. Water (-500 mL) was added to the reaction mixture, whereupon a beige
solid
precipitated. The suspension was extracted with Et0Ac (3 x 250 mL) and the
combined
extracts were washed with brine (-250 nit). The organic layer was dried over
anhydrous
Mg504, filtered, and concentrated under reduced pressure to provide the crude
product as

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a dark orange-brown solid. The crude product was adsorbed onto silica gel (10
g), and
then purified using flash silica gel chromatography (Isco ; 120 g RediSep
Gold silica
gel column; Eluent 0-50% Et0Ac/hexanes gradient) to provide Int-65a as a light
brown
solid (1.80 g, 41% yield).
Step B
In a 125-mL round-bottom flask, Int.-65a (2.644 g, 6.18 mmol),
bis(pinacolato)diboron (1.57 g, 6.18 mmol), (dppf)PdC12=CH2C12 (138 mg, 0.168
mmol)
and KOAc (1.65 g, 16.85 mmol) were mixed. The reaction was alternately
evacuated and
refilled with nitrogen (5x) followed by dry dioxane (38 mL). The flask was
immersed in
a preheated 90 C oil bath and the reaction mixture, was allowed to stir at 90
C for 2
hours. The reaction mixture was allowed to cool to room temperature, diluted
with
Et0Ac (-300 mL) and washed with brine (-200 mL). The organic layer was dried
over
anhydrous MgSO4, filtered, and concentrated in vacuo to provide a dark yellow
solid,
which was purified using flash silica gel chromatography (Isco ; 120 g RediSep
Gold
silica gel column; Eluent: 0-50% Et0Ac/hexanes gradient) to provide Int-65b as
yellow
solid (1.99 g, 68% yield).
Step C
In a 125-mL round-bottom flask, the boronate Int-65b (1.14 g, 2.21
mmol), bromoimidazole Int-7d (750 mg, 2.37 mmol), (dppf)PdC12=CH2C12 (90 mg,
0.110
mmol) were mixed. The flask was alternately evacuated and refilled with
nitrogen (5x)
and dry dioxane (15 mL) was added. The reaction mixture was allowed to stir at
room
temperature for 5 minutes and then aqueous potassium carbonate solution (11
mL, 1 M
aqueous, 11 mmol) was added. The flask was immersed into a preheated 90 C oil
bath
and stirred at 90 C for 3 hours. The reaction mixture was allowed to cool to
room
temperature, diluted with Et0Ac (-100 mL) and the resulting solution was
filtered and
washed with brine (-50 mL). The organic layer was dried over anhydrous MgSO4,
filtered, and concentrated ration under reduced pressure to provide an orange-
brown solid.
The crude product was purified using flash silica gel chromatography (Isco ;
220 g

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RediSep Gold silica gel column; Eluent: 0-100% Et0Ac/hexanes) to provide Int-
65c as
a golden yellow solid (1.06 g, 76% yield).
Step D
In a 150-mL round-bottom flask, substrate Int-65c (754 mg, 1.202 mmol)
was dissolved in methanol (12 mL) and HC1 solution (3 mL, 4 M in dioxane, 12
mmol)
was added. The clear, pale yellow solution was allowed to stir at room
temperature for
18 hours. The reaction mixture was concentrated by rotary evaporation under
reduced
pressure to provide Intermediate Int-65d as a pale yellow solid (728 mg,
quantitative
yield).
Step E
In a 50-mL round-bottom flask, Int-65d (719 mg, 1.20 mmol) and It-la
(231 mg, 1.318 mmol) were dissolved in dry DMF (12 mL). Diisopropylethylamine
(1.0
mL, 774 mg, 5.99 mmol) was added and the he reaction mixture cooled to 0 C
(ice-
water bath). After 15 minutes., solid HATU (684 mg, 1.80 mmol) was added in
one
portion. The reaction mixture was allowed to stir at 0 C for 1 hour. Water (-
20 mL)
was added and the precipitated solid was collected by vacuum filtration. The
collected
solid was washed with water (-5 mL) and air-dried. The crude product was
subsequently
purified using flash silica gel chromatography (Isco ; 40 g RediSep Gold
silica gel
column; Eluent: 0-10% Me0H/CH2C12 gradient). All product-containing fractions
were
collected, concentrated, and re-purified using flash silica gel chromatography
(Isco ; 80 g
RediSep Gold silica gel column; Eluent: 0-3.5% Me0H/CH2C12 gradient) to
provide
Int-65e (286 mg, 35% yield).
Step F
In a 50-mL round-bottom flask, Int-65e (285 mg, 0.417 mmol),
bis(pinacolato)diboron (127 mg, 0.500 mmol), Pd2(dba)3=CHC13 (43 mg, 0.042
mmol),
X-Phos (40 mg, 0.083 mmol) and KOAc (123 mg, 1.25 mmol) were mixed. The flask
was alternately evacuated and refilled with nitrogen (5x). Dioxane (3 mL) was
added and
the reaction was allowed to stir at 120 C for 1.5 hours. The reaction mixture
was

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allowed to cool slowly to room temperature for 12 hours. The reaction mixture
was
diluted with Et0Ac (-100 mL) and washed with brine (-50 mL). The organic layer
was
dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure
to
provide an orange solid as crude product. The crude product was purified using
flash
silica gel chromatography (Isco ; 40 g RediSep Gold silica gel column;
Eluent: 0-9%
Me0H/CH2C12 gradient) to provide Int-65f as an orange-yellow foamy solid (253
mg,
78% yield).
Step G
In a 5-mL Biotage microwave tube, Int-65f (123 mg, 0.159 mmol),
bromoimidazole It-10f (64 mg, 0.190 mmol), OPPOPdC12=CH2C12 (13 mg, 0.016
mmol)
were mixed. The tube was alternately evacuated and refilled with nitrogen
(5x), dry
dioxane (1.5 mL) was added and the reaction mixture stirred at room
temperature for 5
minutes. Aqueous potassium carbonate solution (0.800 mL, 1 M aqueous, 0.8
mmol) was
then added. The tube was immersed into a preheated 90 C oil bath and the
reaction was
allowed to stir for 16 hours. The reaction mixture was allowed to cool to room
temperature, diluted with Et0Ac (-50 mL), and filtered through a polyethylene
filter frit.
The filtrate was washed with brine (-25 mL), dried over anhydrous MgSO4,
filtered,
and concentrated under reduced pressure to provide a light brown solid. The
crude
product was purified using flash silica gel chromatography (Isco ; 24 g
RediSep Gold
silica gel column; Eluent: 0-9% Me0H/CH2C12 gradient) to provide Int-65g as a
beige
solid (92 mg, 64% yield).
Step H:
In a 50-mL round-bottom flask, the Int-65g (73 mg, 0.081 mmol) was
dissolved in methanol (0.8 mL) and hydrogen chloride solution (200 L, 4 M in
dioxane,
(240 mg, 0.800 mmol) was added. The reaction mixture was allowed to stir at
room
temperature for 18 hours. The reaction mixture was concentrated under reduced
pressure
to provide Int-65h as a beige solid (77 mg, quantitative yield).
Step I.

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In a 50-mL round-bottom flask, Int-65h (73 mg, 0.080 mmol) and It-la
(17 mg, 0.096 mmol) were mixed and dry DMF (1 mL) was added.
Diisopropylethylamine (70 gL, 53 mg, 0.412 mmol) was added and the reaction
cooled to
0 C (ice-water bath). After 15 minutes. solid HATU (46 mg, 0.120 mmol) was
added in
one portion. The reaction mixture was allowed to stir at 0 C for 1 hour.
Water (-20 mL)
was added and the precipitated solid was collected by vacuum filtration. The
collected
solid was washed with water (-5 mL), air-dried briefly, dissolved in DMF (-1
mL) and
purified using reverse-phase C18 chromatography (Gilson , Phenomenex Gemini
C18 5
gm 150 x 21.20 mm column, Eluent: 10-70% MeCN/water + 0.1% TFA) to provide
Compound 1019 (21 mg, 28% yield) as a beige solid.
EXAMPLE 66
Preparation of Compound 1033
OMe
F
Br . i%9
OMe F F
Br 40 Br Br Br
\ 11 Int-56g . 40 , .
Br B
0-
[I
N 0-\---
HO Step A o Step B
Int-19c `o = Int-66a \
o-- i Int-66b
o- ---o-
Int-7d C1-41[,,, a C\¨<'IN \ -- ,6 ci F F
Br _ 1- , N s--- / N H
H N\ 11 Njlyyj i ' H 40 \ = }4N15
N
H 0
Step C 0
Step D
\o . Int-66c \ C Int-66d
44HCI
0- 0--
0 Me02C. Xr.0
/µ1)(e H ,N N
It-la OH H L-->-- \ F ,= CO2Me
HN 40 \ *
N
Step E o H
\o ft
1033
0-
Step A
In a 200-mL pear-shaped flask was charged with Int-19c (1.64 g, 4.26
mmol), Int-56g (2.64 g, 8.52 mmol), DMSO (17 mL) and stirred until
homogeneous.

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Solid cesium carbonate (10 g, 66 mmol) was added, the flask fitted with a
condenser and
then immersed into a preheated 100 C oil bath. After 18 hours the reaction
mixture was
poured into water (-400 mL) and Extracted with Et0Ac (2 x 150 mL, 1 x 300 mL).
The
aqueous layer was diluted with brine (-200 mL) and was extracted with Et0Ac (-
150
mL). The combined organic phases were washed with brine (-100 mL), dried over
anhydrous Mg504, filtered, and concentrated under reduced pressure to provide
an
orange-red semi-solid. The crude product was adsorbed onto silica gel (10.0 g)
and was
purified using flash silica gel chromatography (Isco ; 220 g RediSep Gold
silica gel
column; Eluent: 0-40% Et0Ac/hexanes gradient) to provide Int-66a (1.09 g, 48%
yield)
as a beige solid.
Step B
In a 125-mL round-bottom flask, Int-66a (1.03 mg, 1.93 mmol),
bis(pinacolato)diboron (1.08 g, 4.25 mmol), (dppf)PdC12=CH2C12 (158 mg, 0.193
mmol)
and KOAc (569 mg, 5.80 mmol) were mixed. The tube was sealed and alternately
evacuated and refilled with nitrogen (5x) and dry dioxane (13 mL) was added.
The flask
was immersed in a preheated 90 C oil bath and the reaction mixture was
allowed to stir
for 1 hour. The reaction mixture was allowed to cool to room temperature,
diluted with
Et0Ac (100 mL), filtered and washed with brine (-50 mL). The organic layer was
dried
over anhydrous MgSO4, filtered, and concentrated to provide a light brown
solid. The
crude product was purified using flash silica gel chromatography (Isco ; 120 g
RediSep
Gold silica gel column; Eluent: 0-40% Et0Ac/hexanes gradient) to provide Int-
66b as a
dark beige (1.00 g, 83% yield).
Step C
A 125-mL round-bottom flask was charged with intermediate Int-66b
(992 mg, 1.58 mmol), bromoimidazole Int-7d (1100 mg, 3.48 mmol), and
(dppf)PdC12 CH2C12 (129 mg, 0.158 mmol). The flask was sealed and alternately
evacuated and refilled with nitrogen (5x). Dioxane (11 mL) was added and the
reaction
mixture was allowed to stir at room temperature for 5 minutes. Aqueous
potassium
carbonate solution (5 mL, 1 M aqueous, 5 mmol) was added and the flask
immersed into

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a preheated 90 C oil bath. After 22 hours the reaction was allowed to cool to
room
temperature, diluted with Et0Ac (-100 mL) and the resulting solution washed
with brine
(-50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure to provide a light brown solid. The crude
product
was purified using flash silica gel chromatography (Isco ; 80 g RediSep Gold
silica gel
column; Eluent: 0-6% Me0H/CH2C12 gradient) to provide Int-66c as an orange-
yellow
solid (867 mg, 65% yield).
Step D
In a 100-mL round-bottom flask, Int-66c (690 mg, 0.816 mmol) was
dissolved in methanol (8 mL) and hydrogen chloride solution (2 mL, 4 M in
dioxane, (2.4
g, 8 mmol) was added. The reaction mixture was allowed to stir at room
temperature for
12 hours. The reaction mixture was concentrated under reduced pressure to
provide Int-
66d as a beige solid (648 mg, quantitative yield).
Step E
In a 50-mL round-bottom flask was charged with Int-66d (200 mg, 0.253
mmol) and It-la (97 mg, 0.556 mmol) and dry DMF (2.5 mL).
Diisopropylethylamine
(265 pL, 196 mg, 1.5 mmol) was added and the reaction cooled to 0 C (ice-
water bath).
After 15 minutes. solid HATU (240 mg, 0.632 mmol) was added in one portion.
The
reaction mixture was allowed to stir at 0 C for 10 hours. Water (20 mL) was
added to
quench the reaction. The cream-colored suspension was extracted with Et0Ac (2
x 50
mL) and the combined extracts were washed with brine (-25 mL). The organic
layer was
dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure
to
provide a light yellow-brown solid. The crude product was purified using
reverse-phase
chromatography (Gilson ; Phenomenex Gemini 150 x 21.20 mm x 5 m column;
Eluent: 10-70% MeCN/water (+0.1% TFA) gradient) to provide Compound 1033 as a
beige solid (79 mg, 33% yield).
EXAMPLE 67
Preparation of Compound 1038

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216
-B
Br¨cd
0 N\= /
Int-7dN I
H N\ 1111 N H
0 0
Step A
\o \o
Int-65f Int-67a
0¨ 0-
0 ..}-,N,CO2Me
lel * NJ
I N H
Step B
\o .3HCI
0 0_ Int-67b
Ojt 0
Me02C.N 0
OH H
Int-4f cNN
0,,N,CO2Me
Step C
11 = / I H
0
*
1038
0¨

Step A
In a 250-mL round-bottom flask was charged with Int-65f (1.51 g, 1.95
mmol), bromoimidazole Int-7d (739 mg, 2.34 mmol), (dppf)PdC12=CH2C12 (143 mg,
0.195 mmol). The flask was alternately evacuated and refilled with nitrogen
(5x) and dry
dioxane (19 mL) was added. After 5 minutes. aqueous potassium carbonate
solution (10
mL, 1 M aqueous, 10 mmol) was added and the reaction immersed into a preheated
90 C
oil bath. After 10 hours, the reaction was allowed to cool to room temperature
and was
diluted with Et0Ac (-100 mL) and water (-50 mL). The organic layer was washed
with
brine (-50 mL), dried over anhydrous MgSO4, filtered, and concentrated by
rotary
evaporation under reduced pressure to provide an orange-brown solid. The crude
product
was purified using flash silica gel chromatography (Isco ; 220 g RediSep Gold
silica gel
column; Eluent: 0-100% Et0Ac/hexanes gradient) to provide Int-67a as a golden
yellow
solid (1.23 g, 71% yield).
Step B

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In a 50-mL round-bottom flask, Int-67a (1.222 g, 1.381 mmol) was
dissolved in methanol (14 mL) and hydrogen chloride solution (3.5 mL, 4 M in
dioxane,
(4.20 g, 14 mmol) was added. The reaction mixture was allowed to stir at room
temperature for 9 hours, and then concentrated under reduced pressure to
provide Int-67b
as a beige solid (1.222 g, 99% yield).
Step C
A 50-mL round-bottom flask was charged with Int-67b (155 mg, 0.73
mmol), Int-4f (45 mg, 0.208 mmol) and the solids were dissolved in a solution
of
diisopropylethylamine (151 pit, 112 mg, 0.867 mmol) in dry DMF (1.7 mL). The
reaction mixture was cooled to 0 C (ice-water bath) and stirred for 15
minutes. Solid
HATU (99 mg, 0.260 mmol) was added in one portion. The reaction mixture was
allowed to stir at 0 C for 2 hours. Methanol (1 mL) and TFA (56 AL) were
added
sequentially at room temperature and the reaction mixture was allowed to stir
at room
temperature for an additional 2 hours. Water (20 mL) and aqueous sodium
bicarbonate
solution (-10 mL) were added, and the aqueous phase was extracted with Et0Ac
(2 x
¨50 mL). The combined organic phase was washed with brine (-25 mL), dried over

anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide
a light
brown solid. The crude product was purified directly by reverse-phase
chromatography
(Gilson ; Phenomenex Gemini 150 x 21.20 mm x 5 p.m column; Run 1: Eluent: 10-
70%
MeCN/water (+0.1% TFA) gradient; Run 2: 10-60% MeCN/water (+0.1% TFA)
gradient) to provide Compound 1038 as a beige solid (80 mg, 47% yield).
EXAMPLE 68
Preparation of Compound 1048
0
Int-4f
N N HN
N N
- 0
0, A
- 0
T N 0
OH H H \
HN--COH __________________________________________________ H
0 0
\c> .41-1C1 0
0- 0-
Int-64d 1048

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A 50-mL round-bottom flask was charged with Int-64d (167 mg, 0.216
mmol), Int-4f (103 mg, 0.475 mmol) and the solids were dissolved in dry DMF (2
mL).
Diisopropylethylamine (226 gL, (167 mg, 1.30 mmol) was then added to the
reaction at
0 C (ice-water bath) and stirred for 15 minutes. Solid HATU (204 mg, 0.537
mmol) was
then added in one portion and the reaction was allowed to stir at 0 C for 1
hour.
Methanol (1 mL) and trifluoroacetic acid (200 gL) were added and the reaction
was
allowed to stir at room temperature for 30 minutes. Water (20 mL) was added to
quench
the reaction. The reaction mixture was extracted with Et0Ac (2 x 50 mL), the
combined
organic phase was washed with brine (-50 mL), dried over anhydrous MgSO4,
filtered,
and concentrated under reduced pressure to provide a light orange-yellow
solid. The
crude product was purified directly by reverse-phase chromatography (Gilson ;
Phenomenex Gemini 150 x 21.20 mm x 5 gm column; Eluent: 10-60% MeCN/water
(+0.1% TFA)) to provide the Compound 1048 as a beige solid (135 mg, 61% yield)
EXAMPLE 69
Preparation of Compound 1488
0
>%9
4
0
N 11111 B,- f Int-10f rF1 / N
0
0
\o 0
Step A Step B
= \o
o¨ Int-64b
¨ Int-69a
Int-4f
0 Yr
vri r-
r;1 0
F ->¨( H
N
N F H is *
0
N /r4
OH
HN--CON ___________________________
0
Step C
4HCI \O =
Int-69b 0¨ 1488
Step A
A 20-mL Biotage microwave vial was charged with Int-64b (392 mg,
0.643 mmol), bromoimidazole Int-10f (451 mg, 1.35 mmol), and
(dppf)PdC12=CH2C12

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(47 mg, 0.064 mmol). The flask was alternately evacuated and refilled with
nitrogen (5x)
and dry dioxane (6.5 mL) was added and stirred vigorously. After 5 minutes
aqueous
potassium carbonate solution (3 mL, 1 M aqueous, 3 mmol) was added and the
reaction
immersed into a preheated 90 C oil bath. After 18 hours the reaction was
allowed to
cool to room temperature, and diluted with Et0Ac (-100 mL) and water was
added. The
reaction was extracted thrice with Et0Ac (-50 mL), and the combined organic
phase was
washed with brine (-50 mL). The organic phase was dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure to provide an orange-brown
solid. The
crude product was purified using flash silica gel chromatography (Isce; 40 g
RediSep
Gold silica gel column; Eluent: 0-100% Et0Ac/hexanes gradient) to provide Int-
69a as a
golden yellow solid (409 mg, 74% yield). '
Step B
In a 50-mL round-bottom flask, the Int-69a (375 mg, 0.434 mmol) was
dissolved in methanol (4.5 mL) and a hydrogen chloride solution (1.0 mL, 4 M
in
dioxane, (1.2 g, 4 mmol) was added. The reaction mixture was allowed to stir
at room
temperature for 24 hours. The reaction mixture was concentrated under reduced
pressure
to provide Int-69b as a beige solid (344 mg, 98% yield).
Step C
Int-4f (99 mg, 0.454 mmol) was weighed into a pre-tarred vial and
transferred using DMF solvent (4 x 500 L) to a 50-mL round-bottom flask
containing
Int-69b (167 mg, 0.206 mmol)). Diisopropylethylamine (220 pt, 163 mg, 1.26
mmol)
was added by syringe. The mixture was allowed to stir at room temperature for
¨1
minutes, during which time all solids dissolved. The flask was cooled in an
ice-water
bath for ¨15 minutes and solid HATU (196 mg, 0.516 mmol) was added in one
portion.
After 1.5 hours at 0 C, Methanol (1 mL) and TFA (190 tiL) were added
sequentially and
the reaction mixture was allowed to stir for an additional 2 hours. Water (-20
mL) was
added and the reaction mixture was extracted with Et0Ac (2 x ¨50 mL). The
combined
organic phases was washed with brine (-50 mL), dried over anhydrous MgSO4,
filtered,
and concentrated under reduced pressure to provide a light orange solid. The
crude

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product was purified directly by reverse-phase chromatography (Gilson ;
Phenomenex
Gemini 150 x 21.20 mm x 5 gm column; Eluent: 0-60% MeCN/water (+0.1% TFA)
gradient over 15 minutes. Major components that eluted were Compound 1488 and
a
TFA adduct of same. The total yield of the final product was 146 mg, 67%
yield.
EXAMPLE 70:
Preparation of Compound 1492
110
H N0
N N 0 N N
L,\-4
/N
OH C +ICI
H ________________ 40 , rsr--
N
isr-Lt.t)1 N--1\oN
0
0
\O \O
4HCI 4HCI
0- Int-64d ¨ 1492
A 50-mL round-bottom flask was charged with Int-64d (183 mg, 0.237
mmol) and (R)-N,N-diethylphenylglycine hydrochloride (127 mg, 0.520 mmol) and
the
solids were dissolved in dry DMF (2.5 mL). Diisopropylethylamine (400 gL, 296
mg,
2.29 mmol) was added, the reaction cooled to 0 C (ice-water bath) and stirred
for 15
minutes. Solid HATU (225 mg, 0.591 mmol) was added in one portion. After 1
hour
methanol (1 mL) and trifluoroacetic acid (365 L) were added and the reaction
was
allowed to stir at room temperature for 30 minutes. The reaction was quenched
with
water (20 mL) and the product was extracted into Et0Ac (2 x 50 mL). The
combined
organic phase were washed with brine (-50 mL), dried over anhydrous MgSO4,
filtered,
and concentrated under reduced pressure to provide a light orange-yellow
solid. The
crude product was purified directly by reverse-phase chromatography (Gilson ;
Phenomenex Gemini 150 x 21.20 mm x 5 gm column; Eluent:10-60% MeCN/water
(+0.1% TFA) gradient over 15 minutes) to provide fractions containing Compound
1492
and a TFA adduct of same. Retreatment of the TFA-adduct fractions with
methanol as
above, provided additional amounts of the desired Compound. Total yield of
Compound
1492 was 201 mg, 74% yield.

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EXAMPLE 71
Preparation of Compound 1044
O
, 0
r.
0 ts1 'N¨t4 N
S'= N N
N 0- 0, +ICI
H N\ N H
11,
0 0 H
.3HCI
0¨ 0¨

Int-67b 1044
A 50-mL round-bottom flask was charged with Int-67b (123 mg, 0.138
mmol) and (R)-/V,N-diethylphenylglycine hydrochloride (40 mg, 0.165 mmol) and
the
solids were dissolved in a solution of diisopropylethylamine (240 gL, 178 mg,
1.375
mmol) in dry DMF (1.4 mL). The reaction mixture was cooled to 0 C (ice-water
bath)
and stirred for 15 minutes. Solid HATU (78 mg, 0.206 mmol) was added in one
portion.
After 1 hour the reaction mixture was concentrated under reduced pressure to
provide
brown, viscous oil, which was purified using reverse-phase chromatography
(Gilson ;
Phenomenex Gemini 150 x 21.20 mm x 5 gm C-18 column; Run 1: 450 gL injection;

10-70% MeCN/water (+0.1% TFA) gradient over 15 minutes. Run 2: 600 gL
injection;
10-60% MeCN/water (+0.1% TFA) gradient over 20 minutes) to provide Compound
1044 as a beige solid (88 mg, 66% yield).
EXAMPLE 72
Preparation of Compound 1039
Me02 re:0 N
\_<H /NN e 'ar
CO M ,CO2Me
N 11:11-
H ,e, N\ HO2C
H
0
0
"c)= .3HCI Step A
o¨ Int-67b 0¨ 1039
A 50-mL round-bottom flask was charged with Inter Int-67b (104 mg,
0.116 mmol), Int-le (27 mg, 0.140 mmol) and a solution of
diisopropylethylamine (102

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pit, 75 mg, 0.581 mmol) in dry DMF (1 mL). The reaction mixture was cooled to
0 C
(ice-water bath) and stirred for 15 minutes. Solid HATU (66 mg, 0.174 mmol)
was
added in one portion and the reaction mixture was allowed to stir for 2 hours
and allowed
to warm to room temperature. Methanol (1 mL) and TFA (56 IAL) were added
sequentially at room temperature and the reaction was allowed to stir at room
temperature
for 2 hours. Water (20 mL) followed by aqueous sodium bicarbonate solution (-
10 mL)
were then added. The reaction was extracted with Et0Ac (2 x ¨50 mL) and the
combined extracts were washed with brine (-25 mL). The organic phase was dried
over
anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide
a light
brown solid. The crude product was purified directly by reverse-phase
chromatography
(Gilson ; Phenomenex Gemini 150 x 21.20 mm x 5 jim column; Run 1: 10-70%
MeCN/water (+0.1% TFA) gradient over 20 minutes. Run 2: 10-60% MeCN/water
(+0.1% TFA) gradient over 20 minutes) to provide Compound 1039 as a beige
solid (65
mg, 82% yield).
EXAMPLE 73
Preparation of Compounds 959, 950, & 951

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Cpii
Boc H
CI CI-
c, Br (14/fs)
CI N 0
CI 0 1 \ 11 Sr rµB-135,): ci F E,0--,
Int Br-
10f 1 \ 4I
N N
-----. ?_,
___________________________________ .. N
cl)-0 0----
I-1 HO \ f S
Int-22a 40 Int-73a Int-73b
so2c1
1) .,oµB-13:::)
CI .0 ,0'' BocHN \
CI 0
1 , li
s/1)N el , . , NH to, HCVDioxane
_
0 2) rcHio
-Br F CR) 0
t
(R)
`.
s..5S -
Int-73c
F)(iTq' Int-10f Int-73d -F
3IN (s) ----
H HN \ HN \ o
s
H3COIN (s) H0co H F,j,lils
H 9s) N el N\ fl /N_F:4,71-gjti OCH3
N N OH
Int-1a
`c-
F (R) 0
, (R) --(:-. N, S
Int-73e 959
ci
chiral 'separation
Compound 950
and
Compound 951
Step A
Int-22a (1g, 2.8 mmol), 2-methyl thiophenecarboxaldehyde (1.06g, 8.4
mmol) and p-tosyl chloride were dissolved in toluene (10 mL) and stirred in a
pressure
tube at 150 C for 6 hr. After cooling, the crude material was purified using
an ISCO
silica gel column (pre-packed, 80 g) eluted with Et0Ac : Hex (0% to 5%) to
yield Int-
73a (500 mg, 38%).
Step B
Int-73a (0.5 g, 1.08 mmol), bis(pinacolato)diboron (0.3 g, 1.2 mmol),
KOAc (316 mg, 3.2 mmol) and PdC12(dppf)2 (88 mg g, 0.11 mmol) were added into
a
microwave tube. After the flask was flashed with N2, and dioxane (3 mL) was
added.
The mixture was allowed to stir at 110 C for 1 hour. The crude reaction
containing Int-
73b was used without further purification.

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Step C
To the reaction flask charged with Int-73b was added Int-10f (430 mg,
1.3 mmol), PdC12(dppf)2 (88 mg, 0.11 mmol) and K2CO3 (1 N aq., 3.23 m1). The
tube
was sealed, degassed and stirred at 90 C for about 15 hours. After cooling,
Et0Ac
(100mL) was added , the layers separated and the organic phase washed with
brine (100
mL). The organic phase dried and concentrated to provide a semi-solid. The
crude
product was purified on a ISCO column (pre-packed silica gel, 40 g) and eluted
with
Hex:Et0Ac 0% to 70% gradient to provide product Int-73c 650 mg (94%).
Step D
Int-73c (640 mg, 1.0 mmol), bis(pinacolato)diboron (508 mg, 2 mmol),
Pd2dba3 (155 mg, 0.15 mmol), X-Phos (143 mg, 0.3 mmol) and KOAc (491 mg, 5
mmol)
were added to a 20 mL microwave tube. The tube was sealed, degassed and the
reaction
was allowed to stir at 117 C for 8 hr. To this reaction mixture was added Int-
10f (259
mg, 0.78 mmol), PdC12(dppf)2 (106 mg, 0.13 mmol) and K2CO3 (1 N aq., 1.9 ml)
The
tube was sealed and degassed and heated to 100 C for an additional 24 hr.
After cooling,
Et0Ac (100mL) was added, the layers separated, and the organic phase washed
with
Brine (100 mL). The organic phase was dried and concentrated to provide a
solid. The
crude material was purified on an ISCO column (pre-packed silica gel, 24 g)
and eluted
with DCM: DCM/Me0H/NH3.Me0H (90:10:1) 0% to 80% to provide the product Int-
73d 130 mg (24%).
Step E
Int-73d (145 mg, 0.18 mmol) was dissolved in dioxane (2 mL) and HC1
(4N in dioxane, 0.9 mL) was added at room temperature. After 1.5 hours, the
reaction
was concentrated in vacuo in vacuo. The product Int-73e was isolated without
further
purification (123 mg, 100%).
Step F

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Int-73e (123 mg, 0.18 mmol) was dissolved in DMF (5 mL) and cooled to
0 C. HATU(154 mg, 0.41 mmol), It-la (71.1 mg, 0.41 mmol ) were added followed

by addition of Hunig's base (0.19 mL, 1.06 mmol). After 1.5 hours at 0 C,
water was
added to quench the reaction. The mixture was diluted with Et0Ac and extracted
with
NaClaq. The organic pahse was dried and concentrated to affors a solid.
Further
purification with by silica- gel chromatography (pre-packed column, 23 g)
eluted with
DCM and EtOAC/Me0H/NH3.H20 (90:10:1) 0% to 80% to gave Compound 959 103 mg
(62%).
Compounds 950 & 951
The diastereomers of Compound 959 (103 mg) were separated by chiral
SFC separation on a AS-H column (50% Me0H (0.2% DEA)/CO2, 50 ml/min, 100 bar),

to provide isomer A Compound 950 (27 mg, 35%) and isomer B Compound 951 (28
mg).
EXAMPLE 74
Preparation of Compound 1464
zi
s rcHQ¨sr
_
Br j-33 O F pl Ints)
CI 10
a, \ if, Br 0 H N\ * q (Ft)
Br -f
01 \ * Br -...,, N
.....,...)--0
N /....)--0
,
H HO Cs2CO3 0 0--.
4B-Lr----A
Int-19b Int-74a Ø, ,A-0 % .. Int-74b
ci CI
4A
BocHN
1 separation H H
. N Ai, alb. \
/ NH
NH Boc Int-74c' & int-7d" is) " ill=i p 1 =
*
pis) N VI N\ * /N__ s 4 p
F(R) e... 2 Deprotection F (RI _ N 0
1"4
t (R) k
--.. s ... s Int-74d
Int-74c a
CI
.13c liN 0
n'i F rr HN , Nr 0
p p
FI,C0 1:if \ f0H \ SI N\ * /,...t,el.NH "<si`7
[sekOCH,
H N µµt
/ NH 7 A CH 0 3
(R)
L4R) F
'... S a.
970 P
CI

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Step A
2-Chloro-5-dichloromethylthiophene prepared from 2-chlorothiophene-
aldehyde (5 g, 13.62 mmol) and Cs2CO3 (19.97 g, 61.3 mmol) was charged in a
flask and
dissolved in DMSO (50 mL). Int-19b (5.49 g, 27.2 mmol) was added and the
reaction
was heated to 100 C. After 1 hour, the reaction was filtered and the
filtrated was
extracted with NaC1 aq. The organic phase was dried and concentrated in vacuo
to a
semi-solid. The crude material was purified using flash column chromatography
on silica
gel (220 g column) eluted with Et0Ac in Hex 0% to 5% to provide Int-74a
(1.35g, 20%).
Step B
Int-74a (1.53 g, 3.09 mmol), dipinacolatoborane (1.8 g, 7.1 mmol),
KOAc( 1.52 g, 15.44 mmol) and PdC12(dpp02 (0.504 g, 0.62 mmol) were charged
into a
microwave tube. After the flask was flashed with N2, dioxane (20 mL) was
added. The
mixture was allowed to stir at 95 C for 4 hours. The crude reaction was
diluted with
Et0Ac (100 mL) and it was extracted with NaC1 aq. The organic phase was dried
and
concentrated in vacuo. The crude material was purified using flash column
chromatography on silica gel with Et0Ac in Hex (0% to 20%) eluent to provide
Int-74b
(990 mg, 54%).
Step C
Int-74b (990 mg, 1.68 mmol), Int-10f (1.35 g, 4.03 mmol), PdC12(dpp02
(0.274 g, 0.342 mmol) and K2CO3 (1 N aq., 8.4 ml) were added to a 20 mL
microwave
tube. The tube was sealed, degassed with nitrogen and stirred at 100 C for
about 15
hours. After cooling, Et0Ac (100mL) was added and the reaction was extracted
with
brine (100 mL). The organic phase was separated, dried and concentrated in
vacuo. The
crude material was purified on a ISCO silica-gel column (40 g) and with
Et0Ac/Hex (0%
to 70%) eluent to provide product Int-74c 500 mg (33%).
Int-74c (504 mg) was subjected to SFC chiral separation on OD-H column (IPA
(0.05%
DEA)/CO2) to provide isomers Int-74c' and Int-74c" (176 mg, 35%).

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Step D
Int-74c" ((176 mg) was dissolved in dioxane (10 mL) and HC1 (4N in
dioxane, 0.53 mL) was added and stirred at room temperature. After 1.5 hr. the
solvent
was removed in vacuo. Int-74d was isolated without further purification (167
mg, 100%).
Step E
Int-74d (diastereomer B, 167 mg, 0.21 mmol) was dissolved in DMF (3
mL) and cooled to 0 C. HATU(169 mg, 0.44 mmol), Int-10f (74.1 mg, 0.423 mmol
were added followed by addition of Hunig's base (0.22 mL, 1.27 rru-nol) and
the reaction
was allowed to stir at 0 C. After 1.5 hours, water was added and the reaction
diluted with
Et0Ac and extracted with NaClaq. The organic phase was dried and concentrated
in
vacuo to provide a solid.. Purification by silica gel chromatography (23 g)
with DCM
and EtOAC/Me0H/NH3 (90:10:1 - 0% to 100%) eluent provided the title Compound
970
(140 mg, 69.1%).
Compound 1464 (diastereomer B).
Compound 970 (60 mg, 0.063 mmol), cyclopropylboronic acid (81 mg,
0.94 mmol), Pd2dba3 (6.5 mg, 6.26 p.mol), X-Phos (5.97 mg, 0.013 mmol) and
K2CO3 (1
N aq., 188 pl) were added to a 20 mL microwave tube. The tube was sealed and
degassed with nitrogen. The reaction was allowed to stir at 110 C for 5 hr.
The crude
material was purified on silica gel using DCM to Et0Ac/Me0H/NH3.H20 (100:10:1-
0%
to 90%) eluent to provide Compound 1464 (40 mg, 62%).
EXAMPLE 75
Preparation of Compound 1459

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Pd(dppf)C12.CH2Cl2
B ¨ti,
*
Cs2CO3/CH3CN Br * \ ^ * \ * , : Dioxane IV µ Br 55C /15hrs
,
Bispinacolodiboron
)- Pd(dppf)C12.CH2C12
H H. CI k. KOAC/Dioxane tziN
1 N-Boc-proline-
Int-19b imidazolebromide
...;
Int-75b Int-75c (It-id)
Int-76a
0
CNH(s,
1. TFA, Neat, DC to r.t H ...N ...,
-.N IL * ,p
it \.'-
H .... \
N...rON. 2.4M HCI in Dioxane IP N\ 11) CC"

5HCI
\8- --
.-
A--. Int-75d Int-75e
1. HATU, N,N-diisopropyl,ethyl
amine / DMF /-15C /1.5h 0
0 0
,47
7N-11.0/
Coq-trko--
0 0
Int-4a ,,yNyL oc., ...N ... P
H
le \ NH
3HCI
2. 2MHCI in Ether(XS)
ccs
1459
Step A
To a solution of 4-Methyl-2-thiazole-2-carboxaldehyde (2.0g, 15.73mmol)
in CH2C12 (40 mL) at -200C, added pyridine(0.254m1, 3.15mmol) followed by
addition
of PC15(6.55g, 31.5mmol) . The mixture was allowed to stir at -20 C for 30
minutes.
NaHCO3 (13.2g, 10eq.) was added as solid to the reaction mixture. After
stirring for
additional 30 minutes the reaction was filtered through celite and washed with
2 X 25 mL
CH2C12. The filtrate was concentrated under reduced pressure to provide the
crude. It
was re-dissolved in CH2C12 and filtered through a pad of silica-gel. Filtrate
on
concentration and drying gave Int-75a as brown oil. (32%)
Step B
The dibromo indole (Int-19b, 0.5g, 1.362mmol), 2-(dichloromethyl)-4-
methylthiazole(Int-75a, 0.496g, 2.72mmol) and Cesium carbonate (0.976g,
3.00mmol)
were combined in acetonitrile (10m1) in a 50mL round bottomed flask equipped
with
condenser and heated at 55 C for 15 hrs. TLC analysis showed consumption of
starting

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material. The reaction was diluted with Et0Ac, washed with water(3X20m1),
brine
(1x20m1), dried(Na2SO4), filtered and concentrated under reduced pressure to
provide
brown semi-solid crude. It was allowed to stir with ether and filtered to
provide Int-75b
as yellow solid. The filterate was concentrated and purified using ISCO silica-
gel column.
The combined yield of 4 was 0.32g (49%).
Step C
Intermediate Int-75b (0.095g, 0.2mmol), bis(pinacolato)diboron ( 0.106g,
0.419mmol), potassium acetate( 0.117g, 1.197mmol) and PdC12(dppf).CH2C12
(0.065g,
0.08mmol) and Dioxane (2.0m1) were combined in a microwave tube and sealed and

purged with nitrogen (3 x). The reaction was heated at 90 C for 2hrs. TLC
showed
complete reaction. The reaction mixture containing Int-75c was used without
additional
workup.
Step D
To the above reaction mixture (Intermediate Int-75c (0.114g, 0.2mmol)
in the microwave tube, was added N-Bocproline imidazole bromide(Int-7d,
0.139g,
0.44mmol), PdC12(dppf).CH2C12 (0.033g, 0.04mmol) and Potassium carbonate
( 1.199ml of 1M aqueous solution, 1.199mmol) . Sealed and purged with nitrogen
(3 x).
The reaction was heated at 90 C for 4hrs. Reaction was worked up by diluting
with
Et0Ac (25m1) and water (20m1). The resulting mixture was vigorously stirred
for 10
minutes and then filtered through Celite. Filtrate was partitioned. The
organics were
washed with water (3x15m1) and brine(lx15m1), dried(Na2SO4), filtered and
concentrated
in vacuo. The resulting crude was purified using preparatory silica gel column

chromatography, using 5%Me0H/CH2C12 to provide desired product Int-75d ( 79%).
Step E
Trifluoroacetic acid (0.25m1, 3.24mmol) was added to Intermediate Int-
75d at C. The mixture was allowed to warm room temperature and stirred for
additional
1 hour. The solvent was removed under reduced pressure. The product was
treated with

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0.36m1 of 4MHC1 in dioxane (1.44mmol). After 10 minutes of stirring, excess
acid and
solvent removed and the product Int-75e was dried for about 15 hours.
Preparation of Compound 1459
To a solution of Intermediate Int-75e (0.035g, 0.045mmol) in DMF
(1.4m1) was added (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-y1)
acetic
acid (0.022g, 0.1mmol), HATU(0.038g, 0.1mmol). The reaction was cooled to -15
C and
Hunig's base (0.051m1, 0.363nunol) was added drop-wise. The resulting mixture
was
allowed to stir for 1.5 hrs at -15 C. The reaction was quenched with water
(20m1). The
product was extracted with EtOAC (3x20m1). The organics were washed with water

(3x20m1), brine (1x20m1), dried (Na2SO4), filtered and concentrated under
reduced
pressure to provide crude which was purified using Gilson reverse phase
chromatography using gradient elution of 0% to90% CH3CN with 0.1%TFA and water

with 0.1% TFA. The desired fractions were collected and concentrated under
reduced
pressure and then treated with 0.3ml of 2MHC1 in ether. The solvent was
removed and
the sample was dried for about 15 hours to provide Compound 1459 as an orange
brown
solid. (32%).
EXAMPLE 76
Preparation of Intermediate Compound Int-76d

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CI
Boc
CHO ag;I IP \ un li Br \ Br CI 0 BrNc N, , ....IN
int-19g ' '`-' N
H N
,s 0 N
H '''F
____),..
Int-10f
8
Step A Step B _s _0.....
Step C
Int-76a 1101 Int-76b
Boc
N 40
,.._6 Boo
N N
CI \ , -J I \ r- \__4 1 / * IN poc L. N
*
0 H
0 H
¨ s Step D
F ¨ :.
* Int-76c * s
Int-76d
Step A ¨ Preparation of Int-76a
To a cooled mixture of thionyl chloride (20 ml, 274 mmol) and DMF (0.7
ml) at 0 C, benzothiophene 2-carboxaldehyde (4.7 g, 29.0 mmol) was added in 3

portionas, and stirred at 0 C for 30 minutes and then a;lowed to warm for
about 15 hours.
The mixture was poured into ice and aqueous 1N sodium hydrogen carbonate and
then
extracted with Et0Ac. The combined organic solution was washed with brine and
dried
(Na2SO4) and concentrated in vacuo to provide Int-76a (6.1 g, 28.1 mmol, 97 %
yield).
Step B ¨ Preparation of Compound Int-76b
Int-19g (4.5 g, 13.95 mmol), Int-76a (6.06 g, 27.9 mmol) , and cesium
carbonate (18.18 g, 55.8 mmol) in DMSO (22 ml) was allowed to stir at 80 C
for 2 hours.
The mixture was then added to cold water and the resulting solid was filtered
off and
washed with water to provide a 1.55 g of a solid. The filtrate was
concentrated and the
residue was allowed to stir with 1:1 Me0H-MC to provide crude solid material
which
was further purified using silica-gel Chromatography (Pre-packed Biotage
column, 80g
solid loading, Eluent: 1000% Hex to 15% Et0Ac/Hex) to provide the desired
product
Int-76b (650 mg, Yield 33.8%).
Step C ¨ Preparation of Int-76c

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232
A mixture of Int76b(0.418 g, 0.90 mmol), bis(pinacolato)diboron (0.25 g,
0.99 mmol), KOAc (0.176 g, 1.80 mmol), and Pd(dppf)C12 (0.066 g, 0.09 mmol) in
1,4-
Dioxane (3 ml) was degassed (by N2 flush) and heated to 100 C. After 4h, the
reaction
was cooled to room temperature, and Int-10f (329 mg, 0.99 mmol), Pd(dppf)C12
(66 mg,
0.09 mmol) and 1N K2CO3 (1.8 ml, 1.8 mmol) were added. The mixture was
degassed
and heated at 100 C for 2 hours. The mixture was cooled to room temperature,
diluted
in Et0Ac, and filtered through celite pad. The filtrate was concentrated in
vacuo and the
residue was purified on an ISCO 80 g gold column (Eluent: CH2C12-5%Me0H/
CH2C12)
to provide Int-76c (503 mg, 0.785 mmol, 88 % yield) as a pale yellow solid.
LC/MS (M+H) = 641.2.
Step D ¨ Preparation of Int-76d
A mixture of Int-76c (0.292 g, 0.455 mmol), bis(pinacolato)diboron
(0.127 g, 0.50 mmol), KOAc (0.089 g, 0.91 mmol), X-Phos (0.043 g, 0.091 mmol),
and
Pd2dba3 (0.047 g, 0.046 mmol) in 1,4-Dioxane (3.5 ml) was degassed (by N2
flush) and
heated to 100 C. After 18 hours, the reaction was cooled to room temperature,
the crude
mixture was treated with Int-7d (160 mg, 0.51 mmol), Pd(dppf)C12 (34 mg, 0.046
mmol)
and 1N K2CO3 (0.92 ml, 0.92 mmol). The mixture was degassed and stirred at 100
C for
6 hours, cooled to room temperature, diluted in Et0Ac, and filtered through
celite pad.
The filtrate was concentrated in vacuo and the residue was purified on an ISCO
40 g gold
column (Eluent: Hex-Et0Ac 100:1 to 85:15 gradient) to provide Int-76d (225 mg,
58 %
yield) as a pale yellow solid. LC/MS (M+H) = 842.3.
EXAMPLE 77
Preparation of Compounds 792, 422 & 423

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Boc
NI N H
N N
1
- ,11 io o* /NI jccBiN oc
N N /NjiNcElf)11N
H H
0
¨ s 7- Step A ¨ =
HCI salt =F
-F s
40 Int-76d
40 Int-77a
r(:)
0
C') 0
.: .
Ho2c , 1 A 0 0
, , A
00
Y
0 e
Int-4a =N H N N SFC
0
Step B r- )..... i
L.... \ / ryN DI ::: 1 --.- Diastereomers
1:1 =* ,
Compound 422
Compound 423
N N N H i
0 H
¨ -
S
1110 792
Step A
Trifluoroacetic acid (1 ml, 12.98 mmol) was added to a stirred, cooled
0 C solution of Int-76d (0.171 g, 0.203 mmol) in CH2C12 (3 m1). After 5
minutes the
reaction was allowed to warm to room temperature and stir an additional 90
minutes..
The mixture was concentrated in vacuo and the residue was dissolved in Me0H
followed
by treatment with 2N HC1 in ether. The methanol solution was then concentrated
to
dryness providing Int-77a (0.145 g, 0.203 mmol, 100 % yield) which was used
without
further purification.
LC/MS (M+H) = 642.3.
Step B
A round flask was charged with Int-77a (145 mg, 0.203 mmol), DMF (1.5
ml) and Int-4a (88 mg, 0.406 mmol) and cooled to -15 C. To the reaction
mixture were
added N,N-diisopropylethylamine (0.248 ml, 1.42 mmol) and HATU (154 mg, 0.406
mmol). After 10 minutes and the reaction was allowed to warm to 0 C. After 3
hours,
the reaction was quenched by 0.5 mL of water and the mixture was filtered and
purified

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on a Gilson HPLC (Eluent: Acetonitrile/Water + 0.1% TFA) to provide Compound
792
(106 mg, 41 % yield) as a diastereomeric mixture (-1:1).
The diastereomers of Compound 792 were separated by SFC to provide
pure diastereomers Compound 422 and Compound 423.
LC/MS (M+H) = 1041.4. SFC separation condition:
Instrument: Thar 80 SFC ; Column: Chiral Cel OJ, 20pm ,Daicel Chemical
Industries,
Ltd 250x30mmI.D. Mobile phase: A: Supercritical CO2, B:ETOH(contained 0.2%
DEA) , A:B =45:55 at 80m1/min; Column Temp: 38 C
EXAMPLE 78
Preparation of Intermediate Compound Int-78a
Boc
BrN......N `1,1 Pc/c
N "
L
CI -(.D.,
F,i--i N
/
H 1101 \ * IN Boc
'W N N-N Int-10f
H
0 0
Step A
¨ I. ¨ =:.
S Int-76c -F id S Int-78a
..
Int-78a (248 mg, 0.288 mmol, 62 % yield) was prepared from Int-76c
(343 mg, 0.47 mmol) using the method described in Example 50..
LC/MS (M+H) = 860.3.
EXAMPLE 79
Preparation of Compounds 791, 703 & 704

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Boc
r:1 N
N
H Step A
xLs5_4 \ / Boc \ / Tc6
NJNO N N
0 =
Int-78a HCI salt ¨ Int-79a
S
rTh0
y 0
.
..20 A 0 ,
SFC
Int-4fH Diastereomers
Step B
yLs5_41N 703 and 704
0 io 0 /rirolNoIN
0
¨ s
40 791
Step A
Compound Int-79a (211 mg, 0.29 mmol, 100% crude yield).was prepared
from Int-78a (248 mg, 0.29 mmol) following the method described in Example 77
Step
A LC/MS (M+H) = 660.3.
Step B
Compound 791 (112 mg, 0.087 mmol, 44% yield) was prepared from Int-
79a (147 mg, 0.20 mmol) using the method described in Example 77, Step B SFC
separation provided the pure diastereomers Compound 703 and Compound 704 LC/MS

(M+H) = 1058.2.
SFC Separation condition: (Thar 80 SFC , Chiral Pak AS, 20 m, Daicel Chemical
Industries, Ltd 250x30mmI.D.
Mobile phase: A: Supercritical CO2. B:ETOH(contained 0.2% DEA) , A:B =60:40at
80m1/min
EXAMPLE 80
Preparation of Compound 789

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\c'jc()No
11 N
C-N 1

/Y
, 0 C"..-' W0 H'.
H ir N\ 111 Ni)1HO2
h i-% -----. H /
0 0
Step A
¨ ¨ -'
S S
40 Int-77a . 789
Compound 789 (106 mg, 0.084 mmol, 41% yield) was prepared from Int-
77a (145 mg, 0.203 mmol) using It-la using the method described in Example 77,
Step
B LC/MS (M+H) = 1041.4.
EXAMPLE 81
Preparation of Intermediate Compound Int-81d
CI
Br io \ ip
Br
N CI
H Br
HO
N
N NInt-22a Br
Co . Step A Co = Step B 0
Br CHO
Int-81a Int-81b * Int-81c
¨N 0
\_.../
Boc Boc
N\
Br / ii N
- FN
H * \ *
N / IN Boc
H N''
Int-10f 0 HN
Step C * .
'F
-
n I t 81d
\,.... j
Step A
n-BuLi (5.79 ml, 14.47 mmol) was added to a stirred, cooled -78 C
solution of 7-bromo-4-methyl-3,4-dihydro-2H-1,4-benzoxazine (Int-81a, 3 g,
13.15
mmol) in THF (24 m1). After stirring lh at -78 C for 1 hour., DMF (2.037 ml,
26.3

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mmol) was added dropwise and the mixture allowed to warm slowly over 2 hours
to
room temperature. The reaction was quenched with aqueous ammonium chloride,
and
the product extracted into ethyl acetate. The organic phase was washed with
brine, dried
(Na2SO4), filtered and under reduced pressure to provide Int-81b (2.32 g,
13.09 mmol,
100 % yield) as a green solid.
Step B
A 0.2-0.5 mL microwave tube was charged with Int-22a (1g, 2.491 mmol),
Int-81b (1.12 g, 6.32 mmol), p-TsC1 (0.142 g, 0.747 mmol) and Toluene (8 m1).
The
reaction was heated in the microwave reactor at 170 C for 6 hours. The
mixture was
cooled, concentrated in vacuo and the residue was purified on an ISCO 24 g
gold column
(Eluent: 100% Hex to 50% EA/Hex gradient) to provide Int-81c (190 mg, 0.339
mmol,
13.61 % yield).
Step C
A mixture of Int-81c (350 mg, 0.624 mmol), bis(pinacolato)diboron (349
mg, 1.373 mmol), KOAc (245 mg, 2.497 mmol), and Pd(dppf)C12 (45.7 mg, 0.062
mmol)
in 1,4-Dioxane (5 ml) was degassed (by N2 flush) and heated to 100 C. After
18h, the
reaction wascooled to room temperature, the mixture was treated with Int-10f
(438 mg,
1.310 mmol), IN K2CO3 (2.5 ml, 2.5 mmol) and Pd(dppf)C12 (45.7 mg, 0.062
mmol).
The mixture was degassed and heated to 100 C for 18 hours. The mixture was
cooled,
diluted in Et0Ac and filtered through celite pad, and the filtrate was
concentrated in
vacuo to provide a solid. The crude product was purified using flash column
chromatography on silica gel on (ISCO 40g gold, Eluent:Hex-Et0Ac 100:0 to
85:15) to
provide Int-81d (233 mg, 0.256 mmol, 41.1 % yield) as a pale yellow solid.
LC/MS
(M+H) = 909.4.
EXAMPLE 82
Preparation of Compound 793

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Boc H
rj N
Cl fiL_Ni H NN i
Cl
f,N 1
F - H * \ *
N / p Boc
N"....51 F H * \ * / N
N Njc61
:. Step A :.
..
li Int-82a F
lit Int-81d .P HCI salt
¨N 0 ¨N 0
\--/ \-..-/
0 o
HO2Ci.NA0 iDj(N0
H H
Int-la iciL.N H NN 1
Cl
.-----
__.._.____...
0 - 0
F H 11 01 N\ 41)
r,i
0 /
* 1
F
793
--N
\.....i)
Step A
Compound Int-82a was prepared from Int-81d (100 mg, 0.11 mmol)
using the method described in Example 77, Step A (86 mg, 0.11 mmol, 100%
yield). LC/
MS (M+H) = 709.3.
Step B
Compound 793 was prepared from Int-82a (86 mg, 0.11 mmol) using the
method described in Example 77, Step B (63 mg, 0.050 mmol, 46% yield). LC/
MS (M+H) = 1024.4.
EXAMPLE 83
Preparation of Compound 794
o\.._
H
\ --k
0 140 \OA
H N'O
NHN H
\-----
0 = 0 fLIN 1 a 0
F H (101 N\ ip /Njiti Nnii-ko F f:j

N\ * /N-kbl - Nj(0
H / H
, -0 Step A cir
'k :.
F
793 794
--2-Co ----N 0

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A mixture of X-Phos (4.27 mg, 8.95 mol), Compound 793 (56 mg, 0.045
mmol), Pd2dba3 (4.63 mg, 4.47 mop, KOAc (10.98 mg, 0.112 mmol) and
bis(pinacolato)diboron (17.04 mg, 0.067 mmol) in 1,4-Dioxane (1 ml) was
degassed and
heated to 100 C for about 15 hours. The mixture was the then cooled to room
temperature, filtered and the crude reaction mixture purified on a Gilson HPLC
(Eluent:
Acetonitrile/Water + 0.1% TFA) to provide Compound 794 (30.5 mg, 0.025 mmol,
56%
yield). LC/MS (M+H) = 989.5.
EXAMPLE 84
Preparation of Compounds 1051, 1061 & 1062
ci ci 4-9 CI
Br
* \ *
N HHO Br ---- - Br
Step A 4 \N * Br ¨.-
Step B a B
0
.-B \ * 's k
"4"1--111V N 0
O f0
Int-22a Int- 84
84a Int-b
J c
...).-
0\ro
N N..),..0\ro
N N CI
F N Br f..)¨<1 1 0
H 0
Int-10f F 4\ * 1 K6 )C
N N _..
Step C J H O Step D
F
Int-84c
Me02C, ---rf
F0
H N
>--
N N CI 0 1 a /si
. - r-N N
OMe F)...) I CI
. * HO)r ['ir)
H
N 0 H 4 \N * iNily.):
N Oy.....w.0O2Me
H
'III N N Int.la
H
'-F
,A--0 H
JO Step E
..-..F
.4HCI
Int-84d 1051
Me02C,r)Cr.0
H'...õ..."
N N A: Compound 1061
N 0.y,..N...0O2Me _..
Step F Ff rhl 4 \ * 1 3y.) H Step G B: Compound 1062
N N
H
JO .
.F
Int-84e
Step A
A 20-mL microwave tube was charged with Int-22a (1.0 g, 2.5 mmol), 3-
phenylpropanal (3.3 mL, 3.3 g, 25 mmol) and p-toluenesulfonyl chloride (48 mg,
0.25

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mmol) and toluene (8 mL). The reaction mixture was heated and stirred at 170
C in a
microwave for 12 hours. The reaction mixture was concentrated in vacuo in
vacuo, and
the residue adsorbed onto silica gel. Purification by by silica gel
chromatography
(Eluent:0-15% Et0Ac/hexanes) provided Int-84a as a yellow oil (901 mg, 70%
yield)
Step B
A 20-mL microwave tube was charged with Int-84a (901 mg, 1.74 mmol),
bis(pinacolato)diboron (1.1 g, 4.4 mmol), (dppf)PdC12=CH2C12 (142 mg, 0.17
mmol) and
KOAc (512 mg, 5.22 mmol). Dioxane (10 mL) was added, and the sealed reaction
degassed with dry nitrogen. The reaction was allowed to stir at 90 C for 2
hours, then
allowed to cool to room temperature, and diluted with Et0Ac (100 mL). The
organic
phase was washed sequentially with water (10 mL) and brine (10 mL). The
organic
phase was dried over MgSO4, filtered, and concentrated in vacuo to provide a
solid. The
crude product was purified using flash column chromatography on silica gel
(Eluent: 0-
20% Et0Ac/hexanes) to provide Int-84b (1.3 g).
Step C
A 20-mL microwave tube was charged with Int-84b (572 mg, 0.93 mmol),
Int-10f (687 mg, 2.05 mmol), and (dppf)PdC12=C1-12C12 (38 mg, 0.047 mmol). The
tube
was sealed, dioxane (8 mL) was added, degassed with nitrogen, and aqueous
potassium
carbonate (6 mL, 1 M, 6 mmol) added. The reaction mixture was heated at 90 C
for 16
hours, cooled to room temperature and diluted with Et0Ac (100 mL). The aqueous
layer
was extracted with Et0Ac (2 x 20 mL), and the combined organic extracts were
washed
with brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The
crude
product was purified using flash column chromatography on silica gel (Eluent:
Et0Ac
(containing 10% Me0H): hexanes of 10:90 to 90:10) to provide Int-84c (580 mg,
72%
yield).
Step D
A 125-mL round-bottom flask was charged with Int-84c (411 mg, 0.47
mmol) and methanol (9 mL). HC1 (9.4 mL, 2 M in diethyl ether, 19 mmol) was
added

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and the reaction mixture was allowed to stir for about 15 hours at room
temperature. The
reaction mixture was concentrated in vacuo to provide Int-84d (384 mg,
quantitative
yield).
Step E
In a 125-mL round-bottom flask, Int-84d (382 mg, 0.52 mmol) and It-la
(228 mg, 1.3 mmol) were dissolved in DMF (7.5 mL) and diisopropylethylamine
(0.63
mL, 0.47 g, 3.6 mmol) was added. The reaction mixture was cooled to 0 C and
was
allowed to stir for 15 minutes. HATU (395 mg, 1.04 mmol) was added and the
reaction
mixture was allowed to stir at 0 C for 30 minutes, and then at room
temperature for 2.5
hours. The reaction mixture was poured into water (30 mL). The precipitate was

collected by filtration, then dissolved in methylene chloride (200 mL), dried
over MgSO4,
filtered, and concentrated in vacuo. The resulting crude product was purified
using
reverse-phase C18 chromatography (Gilson, 0-90% CH3CN (+ 0.1% TFA)¨water (+
0.1% TFA) over 15 minutes) to provide Compound 1051 as a yellow foam (199 mg,
39%
yield).
Step F
Compound 1051 (247 mg, 0.251 mmol) was dissolved in methanol (13
mL) and palladium (268 mg, 10 wt% on carbon, containing 50 wt% water) was
added.
The reaction mixture was hydrogenated for 71 hours, at which point LC/MS
analysis
showed a 4:1 mixture of desired product and starting mixture. The
hydrogenation was
continued for a further 92 hours. The reaction mixture was filtered and the
catalyst was
rinsd with methanol (-100 mL). The filtrate was concentrated, adsorbed onto
silica gel
(15 mL), then purified using flash column chromatography on silica gel (0-10%
Me0H
(+1% NH4OH)/CH2C12) to provide Int-85e (164 mg, 69% yield).
Step G
The isomers of Int-85e were separated by I-IPLC. Int-85e (164 mg) was
dissolved in abs. Et0H (6.0 mL) and the solution was filtered. The sample was
divided
into four equal portions, each of which was injected onto a Phenomenex Lux
Cellulose-2

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(5 gm, 150 x 21.20 mm) semi-preparative column; detection wavelength = 350 nm.

Initial elution with 25% Et0H/hexane @ 10 mL/min for 159 minutes gave Compound

1061 (tR = 83 minutes; 62 mg). The solvent polarity was increased to 35%
Et0H/hexane,
and further elution at 10 mL/min gave Compound 1062 (tR = 163 minutes; 72 mg).
EXAMPLE 85
Preparation of Compounds 1049, 1054, 1059 & 1060
C.
a B
Int-7d N N N I * ci 0
,0
\ * sc, c ..NNN 1 N 1--0µ....õ
' 41 \N iNiLt)
Q." N
_..
O Br JO H
H .
It-Mb Step A Int-85a Step B
J
Me02C, Xr0
H N
1 H
N HO)kome
HN 411 N lik N C)IN'C 2Nie
\N * / N
NA-61 IHnt-1a H
\N * iffkr...31
n .4HCIH
, .--
t-85b ---F Step C i-0
1049
J ( H
Me02C,rXr0
HN.,,.... .-
Cl.,..,.<3,1 I A: Compound 1059
N 0.,,kN..0O2Ivie _..
Step D 11 4 \ * /N361 H Step E B: Compound 1060
N
¨0
H
1054
c
Step A
In a 20-mL microwave tube, Int-84b (229 mg, 0.37 mmol), Int-7d (261
mg, 0.82 mmol), and (dppf)PdC12=CH2C12 (15 mg, 0.019 mmol) were combined. The
tube was sealed, evacuated, and placed under nitrogen atmosphere. Dioxane (4
mL) and
aqueous potassium carbonate (3 mL, 1 M, 3 mmol) was added. The reaction
mixture was
allowed to stir for about 15 hours at 90 C, then allowed to cool to room
temperature.
The reaction mixture was diluted with Et0Ac (50 mL). The aqueous layer was
extracted
with Et0Ac (2 x 10 mL). The combined organic extracts were washed with brine
(20
mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was
purified

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using flash column chromatography on silica gel (0-100% Et0Ac(containing 10%
Me0H)¨hexanes) to provide Int-85a (212 mg, 69% yield).
Step B
In a 125-mL round-bottom flask, Int-85a (456 mg, 0.55 mmol) was
dissolved in methanol (11 mL). HC1 (5.5 mL, 2 M in diethyl ether, 11 mmol) was
added
and the reaction mixture was allowed to stir for about 15 hours at room
temperature. The
reaction mixture was concentrated in vacuo to provide Int-85b (425 mg,
quantitative
yield).
Step C
In a 125-mL round-bottom flask, Int-85b (439 mg, 0.62 mmol) and It-la
(274 mg, 1.56 mmol) were dissolved in DMF (8 mL) and diisopropylethylamine
(0.76
mL, 0.56 g, 4.3 mmol) was added. The reaction mixture was cooled to 0 C and
was
allowed to stir for 15 minutes. HATU (475 mg, 1.24 mmol) was added and the
reaction
mixture was allowed to stir at 0 C for 30 minutes, and then at room
temperature for 2
hours. The reaction mixture was poured into water (30 mL). The precipitate was

collected by filtration, then dissolved in Et0Ac (200 mL), dried over MgSO4,
filtered,
and concentrated in vacuo. The resulting crude product was purified using
reverse-phase
C18 chromatography (Gilson, 0-90% CH3CN (+ 0.1% TFA)¨water (+ 0.1% TFA) over
15 minutes) to provide Compound 1049 as a yellow foam (362 mg, 62% yield).
Step D
Compound 1049 (362 mg, 0.383 mmol) was dissolved in methanol (20
mL) and palladium (163 mg, 10 wt% on carbon, containing 50 wt% water) was
added.
The reaction mixture was hydrogenated for 71 hours, at which point LCMS
analysis
showed only a trace amount of remaining starting material. The reaction
mixture was
filtered and the catalyst was rinsed with methanol (-100 tnL). The filtrate
was
concentrated, adsorbed onto silica gel (15 mL), then purified using flash
column
chromatography on silica gel (0-10% Me0H (+1% NH4OH)/CH2C12) to provide
Compound 1054 (231 mg, 66% yield).

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Step E
The isomers comprising Compound 1054 were separated by HPLC.
Compound 1054 (222 mg) was dissolved in abs. Et0H (6.0 mL) and the solution
was
filtered. The sample was divided into two equal portions, each of which was
injected
onto a Phenomenex Lux Cellulose-2 (5 gm, 150 x 21.20 mm) semi-preparative
column;
detection wavelength = 350 nm. Elution with 45% Et0H/hexane (+ 0.1%
diethylamine)
@ 10 mL/min gave Fraction A: Compound 1059 (tR = 32 minutes, 91 mg) and
Fraction B:
Compound 1060 (tR = 97 minutes, 68 mg).
EXAMPLE 86
Preparation of Compound 1100

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CI a CI
CI am is
\ * Br ____.. CI \ *
Br -.- CI
4 \
mil' N Step A N Step B N
H HO 0 0
Int-22a Int-86a Int-86b
Mel * Mel *
0
MeCANXfo
H \/
N N1 CI
CICO N - õ 02Me
N Br \ * 1 jyjr H
H 11141F N ,
Int-7h H
_____________ - 0 N
Step D
Step C
Int-86c
M- = Ilk
Boc
c..N.,N ),
1.-C t)
-B N 0.y.0O2Me 1.1 Sr
0 gib
ihrk01 H Int-7d
H
0
Int-86d Step E
Mel *
CNBoc N H ....".!'
,'>--- I z--.- N)-- N
Cs I ,...õ,,
HN An \ AIL_ 1 N oy-..,N,co2me . [sil \ * / il N
02.,CO2Me
'
gill 11 N W NAV) H N N
H
0 H _______,_ 0
-3HCI
Step F
Int-86f
Me0 * Int-86e Mel *
k
Me02C-N,c0
H *****
N N
HO2C 'H 0-- C.,)-- 1
Int-le rl -1 4 \
_____________ - N
H
Step G 0
Compound 1100
Mel *
Step A
A 20-mL microwave tube was charged with Int-22a (1.0 g, 2.8 mmol), 3-
(3'-methoxyphenyl)propanal (2.3 g, 14 mmol), p-toluenesulfonyl chloride (53
mg, 0.280
mmol) and dissolved in toluene (9 rnL). The tube was sealed and heated in a
microwave
with stirring at 170 C. After 12 hours the reaction was concentrated
partially in vacuo,

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and the residue was adsorbed onto silica gel (20 mL). The crude product was
purified
using flash column chromatography on silica gel (Eluent: 0-10% Et0Ac: hexanes)
to
provide Int-86a (1.39 g, 99% yield)
Step B
A20-mL microwave tube was charged with, Int-86a (1.39 g, 2.76 mmol),
bis(pinacolato)diboron (772 mg, 3.04 mmol), (dppf)PdC12=CH2C12 (202 mg, 0.276
mmol)
and KOAc (813 mg, 8.29 mmol). The tube was sealed, evacuated, and placed under

nitrogen atmosphere. Dioxane (11 mL) was added, the reaction was allowed to
stir at
90 C for 2 hours, and then allowed to cool to room temperature. Et0Ac (40 mL)
and
water ( 40 tnL) were added. The aqueous layer was extracted with Et0Ac (2 x 40
mL).
Combined organic layers were washed with brine (40 mL), dried over MgSO4,
filtered,
and concentrated in vacuo. The crude product was purified using flash column
chromatography on silica gel (Eluent 0-30% Et0Ac/hexanes) to provide Int-86b
(1.07 g,
70% yield).
Step C
A 20-mL microwave tube was charged with Int-86b (500 mg, 0.91 mmol),
Int-7h (373 mg, 0.999 mmol), and (dppf)PdC12=CH2C12 (67 mg, 0.091 mmol). The
tube
was sealed, evacuated, and placed under nitrogen atmosphere. Dioxane (9 mL)
and
aqueous potassium carbonate (2.7 mL, 1 M, 2.7 mmol) was added and the reaction
was
allowed to stir for about 15 hours at 80 C. After cooling to room
temperature, Et0Ac
(50 mL) and water (50 mL) were added. and the layers separated. The aqueous
layer was
extracted with Et0Ac (2 x 10 mL), and the combined organic extracts were
washed with
brine (20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The
crude product
was purified using flash column chromatography on silica gel (Eluent: 0-100%
Et0Ac/hexanes) to provide Int-86c (385 mg, 59% yield).
Step D
In a 20-mL microwave tube, Int-86c (380 mg, 0.530 mmol),
bis(pinacolato)diboron (336 mg, 1.3 mmol), (dba)3Pd2=CHC13 (55 mg, 0.053
mmol), X-

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Phos (51 mg, 0.106 mmol) and KOAc (156 mg, 1.61 mmol) were combined. The tube
was sealed, evacuated, and placed under nitrogen atmosphere. Dioxane (5.3 mL)
was
added and the reaction was allowed to stir at 120 C for 1 hour, then allowed
to cool to
room temperature. The reaction mixture was diluted with Et0Ac (20 mL) and
washed
sequentially with water (5 mL) and brine (5 mL). The organic layer was dried
over
MgSO4, filtered, and concentrated in vacuo. The crude product was purified
using flash
column chromatography on silica gel (Eluent: 0-100% Et0Ac/hexanes) to provide
Int-
86d (382 mg, 93% yield).
Step E
In a 20-mL microwave tube, Int-86d (302 mg, 0.391 mmol), Int-7d (124
mg, 0.391 mmol), and (dppf)PdC12=CH2C12 (32 mg, 0.039 mmol) were combined. The

tube was sealed, evacuated, and placed under nitrogen atmosphere. Dioxane (8
mL) and
aqueous potassium carbonate (1.2 mL, 1 M, 1.2 mmol) was added. The reaction
was
allowed to stir for about 15 hours at 80 C, then allowed to cool to room
temperature.
The reaction mixture was diluted with Et0Ac (200 mL). The aqueous layer was
extracted with Et0Ac (2 x 10 mL). The combined organic extracts were washed
with
brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The
crude product
was purified using flash column chromatography on silica gel (Eluent: 0-100%
Et0Ac
(containing 10% Me0H)¨hexanes) to provide Int-86e (78 mg, 22% yield).
Step F
A 125-mL round-bottom flask was charged with Int-86e (81 mg, 0.092
mmol) and methanol (2 mL). HC1 (0.84 mL, 2 M in diethyl ether, 1.7 mmol) was
added
and the reaction was allowed to stir for about 15 hours at room temperature.
The reaction
mixture was concentrated in vacuo to provide Int-86f (109 mg, quantitative
yield).
Step G
A 25-mL round-bottom flask was charged with Int-le (53 mg, 0.067
mmol), Int-86f (15.5 mg, 0.081 mmol) and DMF (1 mL). Diisopropylethylamine (82
uL,
61 mg, 0.472 mmol) was added to the solution. The reaction mixture was cooled
to 0 C,

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stirred for 15 minutes and HATU (395 mg, 1.04 mmol) was added. The reaction
mixture
was allowed to stir at 0 C for 30 minutes, and then at room temperature for 2
hours.
Additional diisopropylethylamine (20 uL, 2 eq) was added and the reaction was
allowed
to proceed for an additional 1 hour. The reaction mixture was diluted with
Et0Ac (30
mL) and poured into water (30 mL). The aqueous layer was extracted with Et0Ac
(2 x
mL). The combined organic phase were dried over MgSO4, filtered, and
concentrated
in vacuo. The resulting crude product was purified using reverse-phase C18
chromatography (Gilson, 0-90% CH3CN (+ 0.1% TFA)¨water (+ 0.1% TFA) over 15
minutes) to provide Compound 1100 as a yellow solid (31 mg, 48% yield).
EXAMPLE 87
Preparation of Compound 1099
0
0
Me02C,N 0
HO2C N cr"
1N N OliN
.1)-- N 0,y,N,CO2Me Int-4f N 0.y.N.0O2Me
N \
N *
- \N * IN 3 1)
Step H
0 0
.3HCI
Int-86f (4" "99
Me0 meo
A 25-mL round-bottom flask was charged with Int-86f (53 mg, 0.067
mmol), Int-4f (18 mg, 0.081 mmol), DMF (1 mL) and diisopropylethylamine (82
uL, 61
mg, 0.47 mmol). The reaction mixture was cooled to 0 C and was allowed to
stir for 15
minutes. HATU (26 mg, 0.067 mmol) was added and the reaction mixture was
allowed
to stir at 0 C for 30 minutes, and then at allowed to warm to room
temperature over 2
hours. Additional Int-4f (8.8 mg, 0.6 eq), HATU (5 mg, 0.2 eq) and
diisopropylethylamine (20 uL, 2 eq) were added and the reaction was allowed to
proceed
for an additional 1 hour. The reaction was diluted with Et0Ac (30 mL) and
poured into
water (30 mL). The aqueous layer was extracted with Et0Ac (2 x 10 mL) and the
combined organic phase were dried over MgSO4, filtered, and concentrated in
vacuo.
The crude product was purified using reverse-phase C18 chromatography (Gilson,
0-90%
CH3CN (+ 0.1% TFA)¨water (+ 0.1% TFA) over 15 minutes) to provide Compound
1099 as a yellow solid (28 mg, 43% yield).

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EXAMPLE 88
Preparation of Compounds 1502 and 1505
0
C)-1(NO
N H N
r Y-4 N H N
Si N so , , N
\ H = I H It-la
,
N N H 0 N N N H 0
¨0
793=Compounds
1502 and 1505
Compound 793 (prepared as above in example 57 from Int-14d and Int-19j) (38
mg, 0.039 mmol) and It-la (7.5 mg, 0.04 mmol) using the method described in
Example 57, step E to provide Isomeric Compounds 1502 and 1505 (19 mg, 46%
yield).
EXAMPLE 89
Cell-Based HCV Replicon Assay
To measure cell-based anti-HCV activity of selected Compounds of the
present invention, replicon cells were seeded at 5000 cells/well in 96-well
collagen I-
coated Nunc plates in the presence of the test Compound. Various
concentrations of test
Compound, typically in 10 serial 2-fold dilutions, were added to the assay
mixture, with
the starting concentration ranging from 250 ptM to 1 M. The final
concentration of
DMSO was 0.5%, fetal bovine serum was 5%, in the assay media. Cells were
harvested
on day 3 by the addition of lx cell lysis buffer (Ambion cat #8721). The
replicon RNA
level was measured using real time PCR (Taqman assay). The amplicon was
located in
5B. The PCR primers were: 5B.2F, ATGGACAGGCGCCCTGA (SEQ ID NO. 1);
5B.2R, TTGATGGGCAGCTTGGTTTC (SEQ ID NO. 2); the probe sequence was
FAM-labeled CACGCCATGCGCTGCGG (SEQ ID NO. 3). GAPDH RNA was used as
endogenous control and was amplified in the same reaction as NS5B (multiplex
PCR)
using primers and VIC-labeled probe recommended by the manufacturer (PE
Applied
Biosystem). The real-time RT-PCR reactions were run on ABI PRISM 7900HT
Sequence
Detection System using the following program: 48 C for 30 minutes, 95 C for 10
minutes,
40 cycles of 95 C for 15 sec, 60 C for 1 minutes. The ACT values (CT5B-
CTGAppx) were

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plotted against the concentration of test Compound and fitted to the sigmoid
dose-
response model using XLfit4 (MDL). EC50 was defined as the concentration of
inhibitor
necessary to achieve ACT=1 over the projected baseline; EC90 the concentration

necessary to achieve CT=3.2 over the baseline. Alternatively, to quantitate
the absolute
amount of replicon RNA, a standard curve was established by including serially
diluted
T7 transcripts of replicon RNA in the Taqman assay. All Taqman reagents were
from PE
Applied Biosystems. Such an assay procedure was described in detail in e.g.
Malcolm et
al., Antimicrobial Agents and Chemotherapy 50: 1013-1020 (2006).
HCV replicon assay EC90data was calculated for selected Compounds of
the present invention using this method and is provided in the table
immediately below
and in Table 2 in Example 89.
Compound la WT lb WT la Y93H 2a WT 3a WT
No. (nM) (nM) (nM) (nM) (nM)
31 0.004 0.003 15 0.05 1.2
32 0.002 0.002 3 0.007 0.3
61 0.036 0.011 14.6 0.27 2.7
62 0.011 0.006 8.4 0.12 3
63 0.005 0.003 1.8 0.045 2.7
64 0.013 0.008 6.2 0.083 4.8
66 0.006 0.004 27 0.06 2.7
67 0.005 0.008 29 0.1 2.5
68 0.002 0.002 0.02 0.21 1.0
69 0.001 0.001 0.6 0.11 1.8
75 0.005 0.006 28.937 0.006 0.465
76 0.010 0.005 68.123 0.018 5.367
79 0.004 0.004 28.273 0.010 1.357
84 0.012 0.007 6.086 NA 1.239
86 0.004 0.004 1.619 0.298 0.402
87 0.007 0.006 13 0.22 1.7

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88 0.004 0.002 13.648 0.133 0.727
89 0.014 0.022 77.94 0.682 3.921
90 0.012 0.004 2.840 NA 2.301
91 0.003 0.004 0.401 0.306 0.354
92 0.011 0.007 6 0.46 1.2
93 0.026 0.009 14.7 0.36 3
94 0.003 0.004 0.06 0.3 0.35
95 0.02 0.01 100 0.11 0.98
99 0.004 0.007 39 0.022 0.17
103 0.015 0.016 38 0.032 0.16
104 0.005 0.003 14 0.023 0.09
108 0.014 0.015 68 0.13 5.4
109 0.015 0.016 139 0.13 0.4
110 0.006 0.006 68 0.02 0.25
117 0.004 0.003 44 0.063 0.08
121 0.027 0.021 256 0.15 3.5
125 0.020 0.016 18 0.04 0.14
126 0.003 0.005 20 0.066 >10
129 0.016 0.009 80 0.047 0.65
130 0.03 0.006 211 0.3 5.8
133 0.002 0.002 32 0.15 0.58
136 0.006 0.006 78 0.07 0.31
143 0.020 0.013 26 0.23 0.31
145 0.004 0.005 8 0.007 0.1
149 0.004 0.004 29 0.04 0.4
150 0.001 0.003 7 0.11 0.21
153 0.003 0.003 12 0.008 0.074

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EXAMPLE 90
Additional Compounds of the Invention
Additional illustrative compounds of the present invention are set forth
. below in Table 2. The Replicon data provided for selected compounds depicted
in Table
2 was generated using the method described in Example 89.

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Table 1
Compound
Structure MS
No.
N,.....4, F
1 H3c4-- ti * * ' N rj.riZOCH, 880
11,C .
113C C.,
õ,001X,0
2"F4Irs¶ c't-(-a 897
F F
11,001,
4 ' ' 1.1 ' = & ''VCe ..,
3 912
.,..
4 C-s 4 ''CCC.P-e'::rcrrk `''' 820
¶,colXr0 F F , ,.._
Qtr-C-k
\_,, 861
. h_õ.
6 = " CrVtn-P-e" q't'a 806
7 = ".47-4,?-Cct-p-V-IL 877
õ,c.J.
8 t. \__:_k:
825
825
, 0
.,0,01X.r. \_._
" cir9)cck>--p-0%)--cji 825
?1")c N ;ri'SY:r1Z 882.5
l'IN- Y
.
12 .-It.,7)-00-24-1,d1-c7.2_ F 874.5
(M+1)
13 " e4----1. . 4 iN N C'`.....cri('
883
'1'--- " - )--0 .-ki!)"
1 Xr.
N
14 II N ,
C-' .1 40 \ \-/ iNctj'eCC., 883
")--0 . >
P' \

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9 y _r '
F
H200 1. 21(..
15 0 Q. 950
/1.1Jc17r1(ocs
/ 11N
16
, .
^ /---' 6, 847.5
I
)-,
.
17 .tcN
0
...0
,,c-- ' sc-
r¨ 861.5
Cc .,,
/
.., iii \ i k \ A
.,_. =
18 p',H,'''-'a
o= ls 1., 847.5
")--.
19P-1CeN
= --" L. 847.5
.,.
pl ',,
-,,___ )c
-.< ' 6., 856.5
'-.
,.
,,,e01:30:,.% 0
21 c . H,0-0-xN
860.5
.().,-N
)-
N,C
22 860.5

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,,,C- -ce'6
õ'c'c,
0,
,e
pio c,,,
,c¨i.eN .
23 ¶,c ,, - )Lo
0-(-- 6õ 856.5
$
'-.
1%C
0 H,C
.
24 p-Q--,
, xo
.,/--" ,o, 856.5
,
._õ
II,C
H3c,0y0 Cl,
0
NY\ Di, j't ,,, Cl, 25 CrO fi,C r
0..'''N--"" \ ,cm,
N 864.5
)7"-N
, . L
N,C
N,c-oy. cH,
,:z..õ4õ,3
26 (....( 0
>/--N H3cpr
X
864.5
0
itor,i'LL7'
)_.
õ,,C
N,c-oyo
CH,
27
1_cõ
)C,N. , 2--0,cm,
864.5
0 .
0
._.
H,C

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,col(r.
28S' -'r?-00)-2-e,- -T.1 ,1-Y(3 892.2
õ
29N N j
i'-'-'11X5-94:1 AC., 892.2
F
0 -
A 7
? VI-Nr? / N ?.4-1Z0
30 NA
, ,N---)..__c1)--ci_i____.5 H 1
F ---0
0 F ?
31 N .7---- \ hr=- (h F--F---/ NA i \
F )._.0 ?
32 , H N ..)---- \ te \,.,
,N,_11-Cr,_3)--0.,...c5 H T NA
0 \
0--i'vrc0 ,...--
33 NA
)---0
F
Fico
N..."
N NA
34 ,,õ N F )---- \ N--Z,
'(N ' ' '. t=I'LLN_ H 1
H NI H
F F
0
--k
7 11.--0 0 Y ?
NA
F H N H
y--0
0
0-I(
/ rX,0
36 NA
.30014jr
11 ,,___Z , \ --
37 ,5-' " 0 r, # i--(õde 856
)-0 H " II 0C1.1,
F
113COINXe
. ,,......-- F
38 0 --
,--' H .1.. IP /1-,-',a 892
F '
,ifj1 Xfo
"--
39 " c:_')-' 0 ,, 4,' ',,rcg,t-Y..õ 875
it
40=897
. Li

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41 911
"
42 911
43 = 911
'rc4 "
44(irk- ,)-cc)-p-e-trv, 863
õXto
45 (2-4õ rh,"
863
46 863
47 O-4r1 897
48 trc5rVo., 897

49 C - 5,5,,f 895
,j0co
50 ffrer)--.Yrk¨. 895
51 " (L'''9C2-e" 849
,,,cocco
52 883
53 " 869
"
54 O-9CQ-2-0;c5griµN-k., 835

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C01 Xr \ ""
55 C' )-4r,' 01 'N * ,YYZO .3 849
Li
H,C 01:c ..-
56 ( r&11 0 * ' r s-1µ JZ

849
57 (1)--4õ' * *,NrjNc:51-1Acõ,
883
õ,001X.3
58 rsreZ., 883
---. H
59H Cirt,,' 0 V 4A., 835
"
60835
* õNic5r(A.,
,03 0
_11;0 ---/
r ,
0
61 ._. , N r-H)L
me2sc,--i5""%\ * \ IF . I=r\l'rN \ 864.3
H FiaNC H Lj
0
5L'o/
62 H N
N \
= 1,J\ * lis?NL'Ol
7,1
838.4
F H . -)..._0 H
H3C
0 N
5) )0 ---/ 0
H F 07i.--- rEsil)L0/
63 ,N Nu \
r's-SI''''Crsil 856.4
H3C F
---/ 0
0N0' )LO
F)---/ H IIII r
IN)
64 H N F 4, ckcir N 856.4
iiiiii " N)._o H
H3C
0 y -../ 0
-0A-N---- '
F 07,---1,1A-0-
65 H N N \
F H _1:ii 874.4
.)._.0 H
H3C
-0)N---c F 0
66 H ,N Nu \ A-6. / N 7¨,N, 874.3
wi NICNI)
L---/
H3C
0
---/
(3 /
F N 0
67 H N rs,1 \
F4J¨Lirl CI . iNCIsii7--N)`. 874.3
H3C

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-0,1---N---f . Fa4 N 0rri)L0z
68 H N N \
vN * ¨ irsi'lrfil 874.4
H3C -F
-0,L-N----)
H N N \ F / N 0r rt)L0''
69 F P...'N = * Nr'l 0 891.4
1-13C F
0
O N./
F
70 C)=
?NO . . / r,\, 0
856.2=

N'' Fr-LOI /
2-0 =F
0
N./
/ --/(
F
71 874.2
1:-ILC.3 I
N
F 2-0
0
/ = N----o
ic:),.,.,,,F 16.60 ' N ?
----- A
72 856.2
F N
2-0
0
O N.,
F
73 ,N, ,
FIL-1.""ii N ? 891.4
F F
X \--
74 <15-4. 0 V ,qõ,,zocõ, 897
8 "
.,..ix. õ_.
75 H (-4,-. * ,; * .Y.'c4)''-eZo., 847
.,..qi...
76(1'''' c'PcriZoo, 881
.,...1X. ..._
77 (1r% * ;', * rqv,j(..., 847
78H -.....4.
(-, . 0 V.t)%rYZo., 847
<1- "
- ---
.,..1,Xe
865
<1- "

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.,..q.r. F
80(I' - -& N * N * :,,i, X\ ,1-1Z0 c õ , 865
P "
.,001,Xe F
81 L m $1;roe :õ__(c)q.,1-1L 865
Nz
, r_1µ2_06_2__fikorri
. _x
82 ?
F
\-0 F
N3C014;c N
a
N,--- \ ¨ \¨
83 S- N * ,, \ / ' P --µ/' 916
F
'PhO ' C 4'
F
84 1/ 0
0
/ N /.'A
a.
F (M+1)
fAN)c 9
/ N 0rk
d_o
85 C-N\ 101 N . 900.5
-F 0
(M+1)
0-k)
' )(
F / ri 0
86 N 0 N it N'Ll..3 / 918.3
6-0
0--11
/ N---0 ,O.,,_,,,Y j
F
87 917.8
Flit-) '''':---CCI4'1'' 1
6-0
/
0j)
, r 0
88 F4-) ""(N 0 N lit N'Ll_Nj / 935.8
F 6-0
0-J(
/
89 F._7cly...eN,N \ ao N it ws....0 0 935.8
F 0

c

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?--1(N-c,

F
,N. N \ /
F---) "r&N ' = IF N'ILCIsil / 935.8
N
6-0
0---(4
H3C0)-r µ, , HN \ \/
91 ,,iyN * * ,/,_Nlis 0 3) 901
F _Lt5, HN
e0 0
07
H3C0C3L:t;ik HN \Z
92 ci,;(-õ, = ,. . , NHQ5, 900
tettl HN,r0
e0 t. 0µ
H,C0C31.1 HN NZ
H N ,
93 FRpm N 01 * ,/,r1S17: 900
eo
R
co51--S-e
H3 H %N,rt, 0 Y
94 FW''' N IgQ * I/J-Ni5Eµic0 900
e 0µ
,o,tx.
c".-(,?---(3c)-2-crNo")---)14 NA
cr "
¨
_I-,------,-->
96 ,, ..0 H N . N 0)--5__ 0 NA
,o
i
6-
N
F H
n--
97 r, N 0)-5.___ 0 NA
N
n--<
-C-
9 NA
8
/02ii:,
99
/0,..e-0 NA
--(
Ot-
F
\
0,1,0 Ci.._
HN
100 -.0- NA
oPN[,1
' Ni = N, H " µ\;--11)LC(
F Ntl'. tO
\
0,100_
HN
101 CNY'll o¨ I=1 -./ C.NA
N F 110.01
I,1=3

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t;y = -
102 (---,,,AT, 0.__-=) ___/ 0 NA
"Ti/ = N* H 0-re-cl
F I NN1
N V="'
\0400
HN
0..rti
0_1,11 H N
103 µs. N-11::::N NA
cf
CI
-----.(
HN
0.={1
FN H H N
N
104 :-tP-S--N
N NA
0
FF
\O-,e_- --- - cj,,o/
HN -
o
0,.(11
cl,lLiil H N
105 '' Ni1Crfl 9-(':'.% NA
cP
0 --( -,./
0 0...,,,
cN,F4 H N
106 NA
c3-0
CI
0 0..(11
FN H H N
107 ---µ' NI:li-l-N NA
N
j--0
\
0_40711_cc..P Hrc N 0
0¨C-11
108 N NA
1-,::,
N
HN
0...(11
109 H N
C 1-1CNA
d:" 0

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--% (3õ0/
HN 0 0(1
cr-t H N
:!Lto_cc,,,_c_,T.3
110 NA
k
,(7-0
F
\040
0
,. YO
0={11
111 c,...1.11 CI F 0 is,1_,ID NA
N
N
6-0
\O-4)___- ---,..1 01,...0/
HN 0
r-N H H N
112 i3
NA
N
,c7-0
F
O--< _t-
HN 0 0..01
cr.11;11, j_II__cci_j_c=DN
113 NA
N
c=-0
F
\ 0
O--(HN-
-1 YO
C%11:41, j_i_i_c cµr_c),,,IH t,,it_:.D/
114 N NA
-0
FF .
_,( 0,,c,,
H 0 0. \/11
C1`,!LI):_li_icc37
115 N NA
.-0
FF
\O--<H N_ ____/ 0 /
''. Y-0
0.{11
116 cv.i.,0 CI F 14 is_.1,1_:i NA
N
6-0
0
/ HN
o4 ---0
N H
117 ,. in, 14_irj
N WI N Ilr: N NA
Cr
.

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¨% 5õ0/
HN 0 C)711
c

J N,1 N H ,1
lri _3
F-1,.: 1 1
118 NA
F
,o-(0
0
HN-0
o-C-ri
cri14 H N
119 s N N N NA
F
0
0/
H O 0.(11
C:H\ -.....t.:NNH 1 NA
0 NA
¨ v ¨
ci
\O- e
FiN--
0
Y-- /
0 0
..(1
CslciiiNFli_cc\>_c____)4,,_1;03N
121 NA
N
d-0
H-t-0 0
--CC
N
CI\ 4
__(H F H r,_ri_..,D
122 NA
N
,c3-0
F
\0-11:_t- /
- Y-0
0...Cti
cr`
,1µ._131 F 11 Tit_01
123 N NA
N
c3-0
F
n--(N
N hi 6 .
124 )____00 -..= N w N \
HN-- eo=0 NJ NA
0¨
o ,
H
0) --0/
H 0 0.-{11
iN H H N
125 Niji-CC Ni-240,4-N
N NA
F ff
F)7P

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\O--: .-- ----.( 5
i
--0 0-C11
CLI,
126 ' N / ,-7-CC)-N NA
F-c7-
F
0
HN---0 /
'-0
0..(1
CH HsroN
N
127 N NA
F
>c-0
F F
\
o
N H N
128 ' N 1,--1-1C-N NA
F -/P-CD
0
F F
\ 0 --e_ -----( IL 0/
HN 0 () (1
cNq41 H N
129 NA
53-0
\o--4:_.- --- 5,7
0-,/1
130
1NL,i:iirc3N
NA
N 0
CCI
\O--(H0
N__
0..(11
C,(1,:ji_ccy_c_)_tit,y_01
131 NA
0,
, 0 ___/ 0 ,
(3-1-'iN-0
0..{1
CLI,,,rjr_103N
132 NA
:
\O-1 ----- )0'
0.(11
cl'----,Nr,(:,:ii_cc.c)_ciH Hri cDN
133 NA
N
Y-0/
\ 0--< -
H 0N ¨ c,
0 ..{1
NHHH N
134 NA
,rir
F

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\0 -
---::, y-- --,/,
--c, 0-cr-N
4,,.0/ ,,,j_cc,õ ,i3N
135 NA
F-ci-p
F
, 0
0--(
0)\--0/
MN---0 0-- ri
---
N m H N
136 1.:).___.....,
NA
--' T%--
N
\040
HN--0
^ Y-0
C
LI: I.,1_. , ,NHij_c_= N
137 NA
----,--_-,..).¨, ¨
= 0 ,
138
Cs,.µ1%N
NA
N
,.....--0
Q
\O¨<`)
---0 -- 5-0/
O 7---N
H
MN
139 0_111 1,i_Tj. NA
N.1¨CQ--2--*_ki
_Fd-0
F
\ 0
0--- ri0)
0--(HN-0
../."-
C-,H_If,y.oN
140 NA
N
:6-0
F
0
''. Y-0/
0-(HN ,.----0
0...(-1
H N
rc,L1:_i_ccµi_p_c
H
141 N NA
N
\04
--0 ---.( 0,--0/
HN
Oarri
H
CN Hi:_c3N
142 NA
N
\O-40___ ----.{ 0y_o/
HN 0 N
H

(,,,s
r-N H H N
.NA
,*i¨

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0 ,
)-0
0.{-1
C'''u, . VC4D
144 NA
N
4
F
o
0)4
r.--0 0..(1,,
(41-(11 H N
145 N ,.--1-9--<IN NA
p
\o--e --/ 0)\--0/
o-(11
"N-cp,,c.,, :ii_c:Q__c:i__<_.,FH ,voN
146 NA
d-
,o_to
--- )-0/
""--0 0.{-vi
r-N H H N
147(,,,, I:1i _on_ 2 _CIO.)
N NA
P
) --0
0...(11
CN-fil H N
148' ,N-11CC)-2-CN NA
(---c.
,0
,4
---' 0).--0/
0-Cri
H N
149
C NVI-1-1CCNi-94µ.4-1-N NA
N
,n40
---- Y-01
...{-11
C,7_1)1lcD"y
150 - T - NA
F F
0)-0/
HN--0 (:)----H
151 CO

,tri,
NA
c__OF
\ ____/ 0 /
- ,--0
0-(- õ
152 0. _ _ _ _I_ __.(.1.DI
NA
c.s.N or

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k0 ___/ 0
= >--,c
-{1-1
153 C'.-c: NA
N
\CI-C
\C'ON-0
C'rg
154 Co-CQ-ci--LIT1) NA
Cr
'4.._. -% 5L,,,
0-01
155 C\--,c-14--
NA
6--
.
0-{-4
156 C7&C) NA
CE
F F
3_0/
0..(1
157NI ,J--CQ-2-1,- NA
CC
F F
158 Cf.5-CC),-9-6 NA
0-0
159 C:i!'l. NA
F 'D
160 (_5'n_ '4-Ln ' NA
F
10P F
F m
FFCe',1 . = P4) '0
161 >,....0 6-0 ...),..17,õ( NA
N:
162P '''C''. -''_\ ¨ NA
c :I

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01.1!:(0
163 , . oi . ,,c,1,,00,1_ _.
NA
8_.
N.
r 2--c
.
NA
164
NA
6
*
05`Xr.0 F 0
ri<0
165 I Hc:_>' 9, ,,-cc:',--P--C,I-L-c:3 -
, NA
,
,c,_,:>__ ___.(3,so
166
U-CQ'4 ri:)_<, ._,---r-S,J
. NA
N
\O-< __- "---.( 3,..0/
HN 0 0-1.1
167
NHHk N
NA
N
\O--,0N >--- -- 0)L0/
---.0 0..(11
(-õNµH 1_0
H N
168 NA
N
F
04 --- 0)-0/
HN--0 0={1
(-.,Nii ,._i_i_cc \)_9_cH To
H N
169 NA
N
F_,---0
F
= Y-0/
170 '
c-N H H N
N NA
\--,0
`045-
/
HN--__,. ____ .
, )--0/
...{-1
171 c.-1:11 NA
,1 F r,Ti_)
N
N

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0
RN
- )--0/
uN H H N
172 - Nif-5"-C,CY-2-<.-.1 N
NA
p
\04R0N_t- 0 /
0.-Cti
N141 H N
173 ' N p-1-1::C;,----c}-<!-4-N NA
c-cp
P
`0-1
4,,---
0 --- 0).
0 /
-(13
174 Cr:i."T<I3 NA
RN 0 0.=(-11
CN H
, \IN )___.....N___zNHT.(,h3N
175 - V N.-PI NA
F F
\o_e-.3 -- 3_,./
.¨
04.(1RN-
176 CI:1,1- NA
0..rti
177 CLi."-1 NA
N
(_OF
\O-S --- Y-0/
N--.0 0.-Crf
178. .
C NI4J-Crµi-c17)--<.% NA
.,
,,:___t--0 --- 3-0/
0..(-1
179 C\___ftj F riy<
NA
N
6-0
_
HN
0..(11
C:`1,e1,,_3.i_ccHT, _04
1 80 NA
d_N 0

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271
,(, N.
H N
181 N NA
\--cF
F F
---
r1
Cs7.1:N. ii_cc \r_p_CIN F:CD
182
I
N NA
c.
F F
--- 5n-0/
Oss{11
183 0_114 olir<Di
NA
N
\0_,(c_OF
\O-4
O ----(
.
0..ctil
184 CLe 0 11 frO NA
)_.
0_,Z,Xõ,
-Z.
185NA
F __________________________________________________________
N
FFQ:j'N
186 NA
I. N . /[13 '0
''': Cc 5:(
---- H
0._.,0
,014)c. Nz
F 0 s 0
187;_). :c-,_Lcirr,-k.- NA
Cr
5V-r
188 .-1,_(--. ,$),X,,_
a' ="'r, NA-ci " , NA
ONON_v
189 ,.,NA
7-zrixr.

190 a.i. ,g,,, ,,,--,,,,_._,:;c,,,,__c-_).__,,-,,-
,,,,,,O, H
NA
i,
CY',r'Z?
191 C-5''''')Lo H NA
. ,F
0 ,_

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272
N7
,7-=-NA
192Cl) ..õ(rr-L-c_54 H ? NA
6 'F
NV
?Illic
193 (3, ..õkrti.t...-,:), . ? NA
N7 _________________________________________________________
194 c3 õAI, ,"-A, =-ci,,__c::)-(1-
4,......:N, . , NA
do "-c
N,
i J),X.0 ,= o
195NA
CN) ""17CIPCJ C1C ''F
ic J140 NZ
i- 0
0 ,
N sr--õ--(0
196 F-CP)' ."--Lc:_5 " ' NA
cco
r Q
197NA
F H N / H
6-0
0 ______________________________
F N,
198 Th- p4, F N n
(.=----p T -ci-Lcji H NA
F H
Cit
ric-.0 NZ
199 NA""Cl \ ,----CC:r-CD-CPIF 'L-01 H 1
NA
6-3 *
0

,i)c,0
200 .rj, .0,,,i,,..f.), . ?
NA
NZ
0

'') N CYµpj
201ci.õ,kr, ,.1::-..,?_9¨cli,Lc_34 H ?
NA
6 'F
NZ

c

202X_15" " k t 1,-11-(," L - C5' " ? NA
,
d
,
9-ZrX 0
e'---/
203 (Ndo
, ? NA
_ ________________ _ _______________________________________

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273
.._
204 ''?-cc:;-0P-f4 '-'.,rY.- NA
9
L ,?
205 ¨0CoN.1 10 -
pA.: 84_0 NA
206 )., H N N 0)-1_1 NA
/0_ki: 6-0
N
C)¨(
207 NA
,0A,:" -8--01- -
, N H
HLt1-0C,11CoN00-
208 P-<: NA
,>-/
L,0
FIN,?'
209 (74i,, ji, NA
(\,F0
210 NA
\ 0
0F14 ?..,..
211 <::^1( c1;1 0? _...4 0
' -o= NA
1 = * H '17141
F NN>_<31
rik. j
List 'N
= ! s i
212 __.(001-1 - * N N\
NA
= eo 0 N....,
p
05L'r,(
\ H
L-Nr 'Llierk/___Q___CN
213
NA
HN._,( e0 o0 N---/
/0
\ H
0
----' -- 0/
0..(1
N H H N
214 cµv...1.D
NA
N
/0
CI--)

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274
`0-4:,_ --- L'
0..(11
_I.J1 H N
215 NA
cr
.
,o-(0
0
HN-t z
, )L0
0...C. VI
cNv_i_ Ill H N
216 NA
c3-0
F
cLciNiiii_c_iN
217 NA
---------2;_0),--
Q
0-r-r,
218 cN\ ,..1.41 H_.,_.c.iN
NA
' N ,sliCC`r-2---(,LI i's. "---
0
el
OR:
0 0...(11
CI\_1,14 H N
219 ' N-11C: C')-1 -2-('!..-.1N NA
c:--0
F
%
HN
0.={1
220 cs%o CI F rjrch.31
NA
N
N
6-0
\O-F1:- __/ 0
_ 0z
, Y-0
0...(1
cNLvil H N
221 NA
c3-0
F.
H 0 CI.C11
cN\ ..1,14 H N
222 NA
F
\O-e
HN--
0
0=={11
r,rj _c_DN
223 N NA
- 0
FF-=\

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275
\0--(H:__
0..rtil
cNL1 J41 H N
224s' N-1-1C: 1C---c:)--<1N NA
FF
F
225 cisy CI F 14.1,1
NA
N
N
6-0
0-4
/ II N--.
cN,...(1,1 H N
226 s' N--1---N NA
CI
0
,(N_ ___/ 0 ,
, Y-0
0..0
c,t_cr.41 H N
227 '' N-1-C,..-N NA
c..-0
F
,0e_
HN 0 0...0
0...1.11 H N
228 '' N-1-Cc\i-ci 7)-(1-N NA
F
\ 0 --e ---- y_ci
HN_0 0..0
(Ni4 H N
229 NA
N
CI
\o<0
--HN-0
0..0
230 CLei¨Cn-2-111.¨ NA
N
d_o
\o_<oN__ __,,j,-(1
H
r-N H F H N
231
NA
F

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276
---- y-o'
0-(11
C\ _....i. 0 F O_Tiii:i
232 N NA
N
p..t0
r.õ...,N
N
/
233 _o N w [sil--.,õ\
NA
eo 0 N_,
0_
H
0 0
----{ ci¨d
..(1
N H H N
C,\....,e)
234 NA
o
FF),F
0-(----ri
Csr's 23----cl N N
235 NA
5=11_0
_/ 0
-, )\---0/
H 0
c>7-11
C-Vil H N
236 ' N p-t-ICQ-cl-N NA
F
õ,COYLX ,.,
" N,_....)4 \ \___.
237 k , *IP rypiL 918
0 = F
M N.,___((
238 F--' r-1 01 NJD-c-r\r ,-(N4 954
40t C
239. _.., j,,, 0 * /), .(,), , - - - i ,,i' -IL 835
=õ
' __________________________________________________________
240 cl,tt\ *14 7 ').13,ni/Z.õ 853
H u
F
H3COINXe
241 ,-)-CO., 861.4
<r÷ L?F
H3C01,,Xe
242" c'--f=:-CEN,-0-(1' ,r .)--CC., 880
h"
..___ c)/,

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277
243 " 804.4
244" 0
* 818.4
LI
245 " clfo' *748.4
H,c01õX õ
246 , "D¨er 837.5
NA = Not Available

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278
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+H] Designation
0
.rj, 7- ti -
6,r6
CN¨T0H HN,r..4õ
".1 F 0J`
H iii
247 ¨\
N ,
Y.---.
N
Mixture of
\ N 0.003 1.4 0.1 0.004 8
984.15 985.1
isomers
4-0
0
0
j Ord
6
...e," A ,ro
F
N 0 HN 4
,,..õ.,
\ "..7-rj O'''
248 N , ..,,
111D N\ * \117.1.)1 Hi
'F 0.013 2.54 0.005 17 948.05
948.5 Mixture of
isomers
4-0
p
6sr
HN,,,,ls,
C:$
n-1.1 I F H NTh
249 N ti 0 \ ip \N-c,
).....0 N 0 0.009 0.8 0.004 4 958.11 959
Mixture of
isomers
NH
C,'
$
,0
0
0 A
j r....
0sr0
\ N 0 HNse.,/,µ
F
250 N .-. 14.7).1 0.013 0.3 4.05 0.003
36 966.04 966.7 Single isomer
IP N\=\ IN
4-0
p
o
_ _j_ r-
A
0,ro
HN
251 N
A, F * C:o
H tii--\
N N\=sT"'
\ N 0.003 1.12 0.004 25 966.04
966.7 Single isomer
4_ 0
p
0
_L, r...,-;
6.ro
(NH HNsr..,4,
N ,õ .41. itTil
252 IP N\ IIP \ N 0.024 9.9 1.15 0.011 15
956.12 957 Mixture of
cr0
isomers
0
S
0

CA 028116 62 2013-03-19
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279
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la I aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
F
N,
\11
_,---
14 ' -1_
OH l'
253 -o
_II 00 N 1, HN _.0 'Y
0.. 56.000 500 918.02
918.6 Single isomer
HN \ ...,iiih. o
---\' N--N (pi
---7
F
F
\ 7 N
254 -o ao N\ *
HN 0
o.. 127.000 489 918.02
918.6 Single isomer
0 ___.? HN \
---- WN
F
___ 4 oNr6
Oro
c---N-c," HNj,µ
0:1
N F
, .41_ 14,.X1
255 11P- IP " IN 0.008 3.2 0.28 0.004
4 984.03 985 Single isomer
N,
(iii-0
0
F4
F F
j, or6
6).0
CN-4611 HN ,,...õ4,
..14 F
0.007 12.9 14 984.03 984.8 Single isomer
256 N , Atis..
IIIP 111 "N
F
0--"F
F
_j, oNrd
6,ro
HNõ(
F (:)'
H lil, F
257
0.030 0.44 4.73 0.003 110 1020.01 1021 Single isomer
40 Noil.
"N
eF
0-1
__,. 0r6
N
6ro
FIN(
IA
M ',.., F
N Cl. .
N--\
258 \
40 N . "N 0.003 3.94 0.003 46 1020.01
1021 Single isomer
cr0
o
F4
F F

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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb
2b [M+Hr Designation
CN-rON 0,r0
HN,r_iõ,
"..--/1 F
0:::
259 11, 958.11 959
N , 0 !ki--\
Mixture of
O rk 40 N\ ri...../
isomers
clo
o
--C
... 0j, 1-....ei
N 0 HNZ,
\"'.7-11 0J=
N_- ki HTh
I. H IP
Mixture of
260 \ N 983.15 983.9
4-0
isomers
0
HNO
)
0 ,s'
.. 1-....
\"
õ..--, H 00
Ni o HN,,,/,µ
A--II
F
0J=
N ,-
40 N\ 1,
\ N
Mixture of
261 0.010 50.3 0.918
0.009 21.5 1001.14 1002
4-0
isomers
0
HNO
)
--J, 076
. N
e" _i
'r
N 011 HN,r,/,µ
\...1 HCA.
F .Ty....)
262 N ,-
N\ . \N H 0.011 1.2 0.005 3.6 944.09
944.9 Mixture of
isomers
4-o
0
(
¨4 07_6
=/--N 6)00
CN--µ`0F1 HN,roiN
i Od=
N _,
263 40 N\ 1,\ r"../ 8.1 0.55 4 954.15 955.1
Mixture of
isomers
4_ 0
o
---

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EC50 EC50 EC50 EC50 EC50
Obs.M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
- ____________________________________________________________________________

6,ro
HN(µ
CDN.--\
F H
Mixture of
264 N Fri al \ * =1--,.-i--/
1 0.009 6.7 0.411 0.008 6.9
916.03 917
isomers
...\*0 "W" N osm N
NH
0,
e
,0
OH
, ____________________________________________________________________________

Osro
HN,,,,4,
.0
H N--\
Mixture of
265 LW ri rip \ = \lei ,,--c--==, 0.012 6.39 0.2 0.005
3.3 926.09 926.7
.....(.0 "qr," N 0
isomers
NH
(:)
Cr
,0
0
6,ro
HN,,..../N
(:)
n4.11
Mixture of
.009 4.8 0.35 0.006 4 1002.17
1003
266 N ti 0
iii \ ID \N-c-/
isomers
NH
(:)
,0
0
6ro
HNsej,
F,14
Mixture of
0.006 0.5 0.459 0.005 40 1038.15 1003
267 Li.; N ft \ * \N-ri-4.-/
isomers
).....?-0
0
ONH
,0 Cl$1/_/--O
0
___.1 0N
r6
6sro
H
CO" HN,j
,
N
268
CA
, N 01 F H
N']'
N
N\ 0 -1(.4.../
\ N 0.009 0.6 0.205 0.005 1
984.15 985.1 Single isomer
cr .
0
0
_ _ _ , , 07_6
6=ro
N-rorl FIN/,
C,--rJ
N ,
269 IP N\ I, " 'N 0.004 10.86 0.3 0.004 16.8
984.15 985.1 Single isomer
4-0
0
0
I ___

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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cm pd # Structure Calc.M.S.
la laY93H laL31V lb 2b IM+Hr
Designation
0
... r.,
2---N Oro
HNse...&
.0I''.
270 N ,- ,.b F 0.027 0.9 6.659 0.006 47
948.05 949 Single isomer
IP N\ =&'''')"
4-0
p
___!, or6
-,---N 6,ro
F.,,sN _40
(:) . H
tki
\,.. /,
.Sr-Itil
N
271 N õ.. 111 .. .-r---1 0.006 2.2 2.222 0.008
32 948.05 949 Single isomer
ir N ....)IN =F
4-0
,0
, ___________________________________________________________________________
0 6
F ..:04 6,ro
N 0 Ht,c,,j,
F-'

Itli
nN_-
272 Ak. H ,F
Mixture of
976.10 977
IP N * \NI- ¨
isomers
4-0
o
--C
6=ro
HN)..,,õk
F i.1 N---\
N N iii \ iyi N1,--1/4-7
273 ).....(0 ""er" N .mri \ N
cl 0 988.14 988.9
Mixture of
NH isomers
C:1
,0
0
,o
0,ro
HN,e,õ(
'CN--N 1 F N.
N N iii \ ID \l'i^F
274 )....o .41v N
4-0 994.09
995 Single isomer
NH
(:)
,0
0
S
6sro
HI.co,j,
C:i=
N
L if 'N ai \ 'ft -il"--f=F
275 )...o -w-- N sw, \ N
(10 1019.13 1019.9
Mixture of
isomers
Ol'IH
,0
0
HN=0
)
,

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283
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CalcMS
la 1 aY93H I aL31V lb 2b
. . . [M+1-11+ Designation
0,r0
HN,,...õ1\
0:3
LN1- 11 0 \ = \%-ir.'"=/'F
276 )....0 N
cro 0.045 2.1 11.9 0.014 98.3 1037.12 1019.9
Mixture of
NH
isomers
0=(
p
o
0
HN
)
,r- N 6,r0
CN-4011 H1.4....,
....,--M
(20 -
H
!4---\
N õ
940.12 941 Single isomer
277 0 N\ 11, N'''''./
\ N
4-0
0
--"-
,....4 7.-...
..:CH 6,r0
CN 0 HN....,/,
"..7-1C1 40'*
278 401 r \i 1,
" N 940.12
941 Single isomer
4-0
0
--K
- '
0
.../, r-,..,,-;
211 6,ro
L./4 0
A F HI%c..,j,
C:1
N
= N\
\ N
279 1001.14 1002 Single isomer
4-o
0
HNO
)
_i Ord
õ N 6sr
CN -1-0M HNse,j\
F Od'
280 4-0 1001.14
1002 Single isomer
0
HN-0
)

CA 028116 62 2013-03-19
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284
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la I aY93H 1 aL31V lb 2b Calc.M.S.
[M+H] Designation
___/, 07_6
6,r0
CN--1-014 HNsr,õ/\
IA ii0r\
281 40 ,Ni 11,''''''v
\ N 0.003 58.4 0.7 0.006 13.7
956.12 956.8 Single isomer
cr 0
0
ct
.. j, Ord
6
_71

CN,r0
0 HN,,,,,/,\
1-41 0'4
N
282 0 ri
\ N 956.12 956.8
Single isomer
4-0
0
0,
6sro
HNsr..,d\
F
-ri rii 0 \ 0 Ile--
283 .....c) N 0 \ N 958.11
958.9 Single isomer
NH .
C:,
C--"
,0
0
S
¨
6,ro
NN,eõ,,(
(:)
284
.....0 N
\ N 0.026 24.3 0.007 9.4 958.11
959 Single isomer
c3NH
,0
0
S
6,r0
HNx.j\
F H
0
285 N N \ *
>....(\-0 N
1
\ N 0.015 3.4 0.005 47.7 994.09
995 Single isomer
NH
0-<
,0
0
S

CA 028116 62 2013-03-19
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285
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
6sr0
HNse,/\
F H o'N, .__\
N N 0 N\ . N`V
,0
4_0 0.016 5.8 0.4 0.006 14.6 972.14 973.1
286
Mixture of
\ C
isomers
C)NH
,o
p
-)
6).0
HNse.,/,
ir)
N vii-6\m
\ N
...-0 '"I N 01'w
Mixture of
287
4- 0.028 0.7 0.009 9.8 984.18
984
isomers
ONH
,0
0
q
HN,,...J\
ON
288
1 H .
N 11 s'w,
a \ Nse"==/.F
\ N
....( 0 "qv N 0
Mixture of
(11 0.006 0.3 3.9 0.005 32.4 1020.16 1021
isomers
ONH
,0
0
q
6,r0
HN/...,/\
uo
.
N N0 N\ s \ -1(---,F
Mixture of
289 )....c)
4-0 0.058 0.4 9.7 0.010 > 100
992.10 993
isomers
iDNH
,0
0
S
q
6,r0
Hi.c.,/N
C2i .
n-44 1 H N
N iri ii \ 4-i \N Y)
1
Mixture of
0.016 10 1.2 0.010 11.6 940.12
940.8
290 ....\/0 -q N oµmw., N
isomers
NH
(:)
4-
,o
0

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb
2b [M+Hr Designation
HN,,....JN
F N (:)!'I
Th
N N rah \ N-K''../
Mixture of
0
291 .....o " lir N W \ N 998.18 999
NH
,o 4--
isomers
0
C)
HN,,....
0'( .
292 N ifti
)....0 ..4r N 0 \ N 0.015 13.5 0.3 0.007 13.7
954.15 955.1 Mixture of
H
isomers
oNH
,o $
o
1
d ord
6 o
sr
CN-1-0111
"..,--M
F H r \
N .,..
293 401 N\ 1,N.K....'
\ N 0.008 1.3 0.003 7.1 958.11
958.9 Single isomer
4-0
o
---(
_4 oNrd
6,ro
Hre,j,
C...):1:0
294 N .õ-
, N F
Ii.,T,t...)1
=N\ =\ IN 0.013 18.9 0.6
0.005 18.9 958.11 958.9 Single isomer
4-0
o
¨(
_. o ri
1, r- ... 6
cNH H Nµ,..,
"'.,--11 (:)
N , II r \
1001N\ = -1(4'../
\ N 983.15 984
Single isomer
295 4_ 0
o
o
HN
)

CA 028116 62 2013-03-19
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287
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
--J, 0r--0
6
f N sr0
rN-40H HN,,,../N
- riCi
N õ .. 1:11)...)1
N
296 IIP N\ 1 I * \ 1
4-0 983.15 984 Single isomer
0
HNO
)
0
.J., r6
CN--t2 6 ,ro
HN,e0(
"..7-11 F (:)
297 N õ. ..... 14.1)1..
IIIPN\ * " IN 944.09 945 Single isomer
4_ o
o
___./ o ,-..,
.-,.-N
_i H 't
CN 0 HN,,.../\
"A--/1 0'( -
F
,... Ak. 4,1)!...)
298 N
RIP- N\ Ill \ IN 944.09 944.9 Single isomer
4-0
o
(
6sro
HN,r0,/,
"*.4j
N-110
299 N 0.009 40.3 0.004 14.4 954.15
954.9 Single isomer
4_0
o
0rri
......1 =-=
-,,.-N
__i 6sr0
C. N H 0 HN,e.,/,
..-ij
N ,
300 IP N\ I. \ IN 0.014 5.1 0.7 0.004
12.4 954.15 955 Single isomer
4-o
0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure CalcMS
la aY93H aL31V lb 2b
. . . [M+FIr Designation
HN
,ro
N N *
N
N
301 0NH 0.013 5.5 0.005 8.3 1002.17
1003 Single isomer
0>(
,0
0
,ro
HN
N N *\ = ,
N N
302
1002.17 1003 Single isomer
C:oNH
,0
0
,ro
NN
I N, .F
LI`r stil \
N N
303
0.007 0.1 0.006 69.4
1038.15 1038.9 Single isomer
(:)NH
,0
0
=ro
HN/,
=F
L-Nr¨til
N 0 N
304
0 0.026 0.5 4.3 0.007 50.4
1038.15 1038.9 Single isomer
(314H
,0
0
HN
,ro
HON
n---('N
N 110
N N
305 0
984.18 985 Single isomer
ONH

CA 028116 62 2013-03-19
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289
. _.
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+1-I] Designation
6,ro
HN,r,/,
H
N l'il is, \ ip \Nõ,c).....0 N 0 N
306
($ 0.007 4.8 0.3 0.006 6.6 984.18 985 Single
isomer
C)NH
,0
0
q
6,r0
HN...õ,/,,
0:, .
LNI¨ril is \
307
\ N
.....0 N 0
C.- 1020.16 1021 Single isomer
C:1NH
,0
0
q
6,ro
HN ......,/,
F,r\__ P I
L-N' H
308 .....o
NH N
4-0 N
1020.16 1021 Single isomer
p
0
q
6,ro
HN,,...õ4,
F,r,k_iN 1 F (:)
L H
_TiLD
W- 'ri is \ N is ,
\ N
NH
(:)
$
,0
0
0
HN
)
6,ro
HN,,...j.,
(:)
F H_T,
N N T.....)
õ N
111) \ * 1
..... N 0 \ N
NH
(:)
$
,0
0
S-0
HN
)

CA 028116 62 2013-03-19
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290
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure M
. .
CalcS.
la laY93H laL31V lb 2b [M+Hr Designation
'0
,-,,
- NH
ykr0 Ht50
N 0
N
311 C)---<'N n 1102.05
Single isomer
\ . N-
-Tr---N \___
cri W N \ N cTh j 0
Ftc!)kOH d-C) tho-
6,ro
HNz.j,
F HO
N---\
=F
N ri
312 ). ft \ = \N--('---"
i
...0 -w-- N N
0.01361 0.04242 2.006 104.5 1024.12 1024.9 Mixture of
0
isomers
NH
0.(
4--
,0
0
,o
6,ro
HN,,...j,\
O' 'N
Mixture of
H -\
0.01139 22.11 0.4472 5.979 898.04 899..1
313 L-N' ri th
isomers
\ N
).....0 "', N c;mwf
NH
(:)=.
6
,..
OH
j., Orr6
sr
F.,,"N...CH
1 0 HN,,,/,µ
"..411 CA
N, H V.'F
314 NT-'...../
\ N 0.05816 1.466 2.87 87.12 976.10 976.7 Single
isomer
4-0
0
.--
_ j, Ord,
F.CNI1 0,ro
o HN,r,/,µ
',
315 N
Illr N\ N "F 2.532 90.01 976.10
976.7 Single isomer
$0
0
6,r0
HN,,...,/,µ
13
F
'4 11 Ai \ Ail
316 ).....c) "iv- N osi=ri \ N
0.005 18.02 0.36 23.24 988.14 988.9 Single isomer
NH
C)
$
p
0
53

CA 028116 62 2013-03-19
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291
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
1M+Hr Designation
6).0
HN,,,,/,µ
0
F

N 11 111 \ ilk "--T-------",
317 )_(>O-mr-- N ow \ N
0.00817 1.184 0.195 6.912 988.14
988.9 Single isomer
ONH
C-
,0
0
,0
6).0
HN,r.,õ,(
N C)
F H N--\
0.015 0.5 0.3209 13.88 916.03 916.8 Single isomer
318 1--N¨ri di \ * N'Tr'-**/
\ N
......0 w" N ow'
ONH
6
,0
OH
,
6=r0
HN,õõõ.1,
FO'N---
319 ni ti \ *- M-.1,-..../ 0.004 41.02 0.3329
9 916.03 916.8 Single isomer
L, ap ,
\ N)....,0 N ow
NH
0
6
,0
OH
___ j Or6
,
F 11 6=ro
-\---N 0 HN,,,,j\
F ....r.1),I...).
N/, ,d.h 11 = F Mbdure
of
IP
320 N\ I. \ N 0.01128 0.1398 1.207 87.61
994.09 995
isomers
4-0
0
-c
or_6
-,õ= N N 6 0
C_TH -I-
"..r-M F 1::
itri...)1
0.00982 2.132 0.195 2.146 944.09
945.1 Mixture of
321 N õ .....
IP N 110 \ N
isomers
4_ 0
p
6 0
---,-, ,
rN 't
CN-40 HN2...1\
Hy....)N
Mixture of
322 N ,
* N
0 N '
" N 0.0162 0.4183 0.1426 1.192 942.07
943.1
isomers
,-(::= -0

CA 028116 62 2013-03-19
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292
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
1M+Hr Designation
,
0ro
HNk
(:)
F,.r.v.11 1 FN
N-..(1.-0
323 1--'ti 40 N\ . \ N 0.01563 0.02 2.674 68.32 980.07
981 Mixture of
>,...(0
4-0 isomers
(:)NH
,0
0
6=ro
HNsr.õ(
0'(
F H N---\
324 Lnir I 40 \ ii =i-ir--./ 0.02436 6.242 1.81 25.43
948.05 948.9 Single isomer
)....0 N 0 N
NH
0.
d---
,0
,0
6,ro
HN/,
F H
325 N N 40 N ID .4--c.-- 1 100 100 100 948.05
948.9 Single isomer
)....(0
4-0
NH
1:3
,0
,0
0=ro
1414....,4,
C3 .
F,,r-vil
H
326 LW 'N 1110 , IlD \N ir,,--r"F
)..(3
c$_.3 0.02664 2.77 49.99 976.10 977 Mixture of
isomers
NH
(:)
,0
0
S
6,ro
Hhcojs,
OJ'
n---<1.1 1 F H !.I--\
Mixture of
327 N 11 40N ak ,N'e'"' 0.01 2.3 0.1873 1.328 946.12
947
isomers
....0 N 0'w ' N
NH
0=(
(1-
,0
,S
0,ro
HN,e,,,4,
Fõr-vil 1 F H (:) !,1..F
328 1-147¨N 40 \ IF N-e.""/
N \ N
..... 0 4-0 0.01029 0.04 2.205 73 1008.12
1009.1 Mixture of
isomers
CZoNH
,0
9
---)

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
[M+H] Designation
, 6,ro
HN,,...õk,
$Z)
F,r.A. _3
\
H1)....)
L-1 .1 N
Mixture of
1. N
329 z\......(0 H 1101 N 0. \ IN 0.0056 1.517 1.656 18.49
984.03 985
isomers
NH
(:)
4-
,0
0
F-7(
F F
. .
0.ro
HN,rolõ.
F
M = l''IM
N N ii \ \ -g--,-"--=
"w". N
330 NH
(:) 0.003 1.486 0.2152 7.645
1050.21 1051.1
C---
Mixture of
isomers
,0
0
0
d
6,r0
HN,,....,1\
(:)
331 N N ii \ \NI ,N--,-,-"--/ 0.004 7.523 0.2071
4.54 928.13 928.8 Mixture of
isomers
.....0 -w- N o'w
NH
(:)
(1--.
p
,s
0,ro
HNsejs,
(:)
F H II--\
332 Lri N iiii N \ . \N-C-'
>....c. ,
4_ 0.01225 43.76 0.4942 17.35
972.14 973 Single isomer
0
NH
(:)
,0
0
1
0sro
FiN,e,d,
F -4
r--µ441 H
O14
y.)
333 N 5\ N
, . \ , N
Kir 0.01234 1.19 0.195 5.178 972.14
973 Single isomer
0
NH
O.<
,0
0
¨)
6,ro
HN(
0J,
334 N ti 0.005 52.66 0.2183 12.86 926.09
926.8 Single isomer
...0
OrkiH
($
,0
0
_____________________________________________________________________________
_

CA 028116 62 2013-03-19
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294
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+H] Designation
6.:3
HN,e0/N
335 Lti N S\ . .1.-,,,r=-/ 0.01505 1.8
0.2346 0.37 926.09 927.1 Single isomer
,....0 N 0
0.(NH
($
,0
0
C
H
N 0-
1M-4 1 HN_40
" N N
336 0 \ . / NHO
\_to Mixture of
N
6-0 N"
NH 1..(> ¨11\r- 0.01157 13.82 0.1904 5.211
906.06 907.1
isomers
/ '
1:)
p
6,ro
HNzoj\
F H '1---\
337 N
Lt.; N 0 \ = \ -1,--`--/ 0.0035 0.1841 0.195 7.701 948.05 949
Single isomer
N 0 N
ONH
$
,0
p
61:)
HN,r.,/,
F H 1;4--\
" F
338 N N 0 \ ,N-il----= 0.01346 0.3647 0.195 7.558
948.05 949.1 Single isomer
.....0 N 0`ou \ N
NH
0-<
$
p
p
6sro
H Nz..,
F__(1)1 ON
"F
L 4 .. til 111. \ --ir."."'
339 ...o .4iv N o'sw \ N
0.953 100 100 100 1019.13 1020
Single isomer
NH
4:0
$
,0
0
0
HN
)

CA 028116 62 2013-03-19
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295
EC50 EC50 EC50 EC50 EC50 Obs . M.S. Isomer
Cmpd # Structure
1 a laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
0sro
HN(
(:)
F,r-viN 1 H F
[-if 'ril ith \ 14-7(""/
\ N
340 ).....o -iir N osw
1 100 100 100 1019.13 1020.2 Single isomer
(21NH
$
,0
0
HNO
)
6 .
sto
HN,r,,..
ot:
n--14 H
)0
N -.1
341 N til di \ di \ ,
.....,0 0`.=1 N 0.01328 54.63 0.2997 11.13
940.12 941.2 Single isomer
(:)N H
$
,0
0
S
0r0
HN,,,,,,(
(:) '
342ri
)....0 N 0.01308 2.627 0.2881 2.418
940.12 941.2 Single isomer
o
(:)N H
,0 $
0
S
6sro
HN....,
N Or)
F
F
L-NI µri iii \ 4-i -e=-=
... N `.E' \
4-0 0.02634 0.07918 3.088 61.91
1020.13 1021
343 .0 ,
Mixture of
N
isomers
(:)NH
,0
0
0
Oro
CNH
¶../-11
344 N 15.9 469.9 724.87 725.5
Single isomer
0 N 11, i
\ N
6_0
: 1-- =-= 6
:12-N ,r0
0
Nl H N,e,,,/,
0:) .
O
NI M
345 A , H f N * i....../,N
" N 0.01349 8.592 1.789 31.37
926.09 926.6 Single isomer
4_0
,0

CA 028116 62 2013-03-19
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296
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
6,ro
Ht.l(
Cr(
C¶ \

di\
N N = \NITN--/
4
346 )....o .4-V N -0 0.01386 6.028 0.4267
2.64 970.15 971 Single isomer
(:)NH
p
0
,0
6).0
HN....,/\
(:)
H N-\
- F
N N ak \ -m- N-e".=/
\ N Mixture
of
347 .....c) =.= N 0,1w 0.028
0.1566 6.892 188.4 1006.13 1007
isomers
NH
(;)
$
,0
0
,0
6,r0
HN....,/N
0:t
F
\
348 N
I* \ -gr."/ 0.01713 7.981 0.4534 2.465
966.04 967.1 Mixture of
isomers
NH
O.<
$
,0
0
F-(
F
6,r0
HN... L _IN
Fõr-µ_14 i
1:1
\H
Mixture of
ii
349 ....o ..w N
4-0 0.01237 0.2279 2.721 84.03
990.13 991.1
isomers
(:)NH
,0
9
¨)
6).0
HN,,...,,&
350 N N iii \ 4ri \F
, 0.01097 0.8042 0.7204 8.253
930.06 931 Mixture of
0 ''m N osw" N
isomers
(DNH
,0 (17
p

CA 028116 62 2013-03-19
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297
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b
Calc.M.S.
[M+H]
Designation
6sr0
HN,õ..õ1,,,
Od`N, ..._\
F..r.vil 1
H
Ny--1/4../
Mixture of
351 LW -1.1 lii \ =\ , 0.02156 0.4577 0.1775 9.245
930.06 931.1
isomers
0`3.ri N
0:3NH
$
,0
,0
Osro
HN,r,/,
(:)
F
352 L-N¨N io N\ . \NHI 0.00976 0.04956 0.5672
9.561 978.05 979.2 Mixture of
isomers
....0
c)-0
NH
0.
,0
0* 6sro
c1=140 HN,r,IN
IA ,r3
353 N ___- Alv. 11.1 8.626 366 824.99
825.9 Single isomer
Illgi N\ 111 \ IN
<3-0
04-- 6,ro
CN40 HN,,,,/,µ
ii )n
354 1.179 678.1 824.99
825.9 Single isomer
6-0
6,r.0
CNH HN,r,4,
IA (Zobil ._
355
1, 12.16 110.2 724.87 725.8 Single isomer
0 N i
\ N
d_o
, or,
Chrlroti 6,r0
HN,.....4,,
0'4
356 N ,
0 N\ 4, Hwy.õ14...),
\ N 0.01505 3.088 0.2035
2.379 926.09 927 Single isomer
cr0
0

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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
1M+FIr Designation
j. 07_6
6sro
c NI-011 HN,,...,4,
"'si'll F C:0
N ,
m...i.y..) 0.0162 20.67 0.3557 2.697
942.07 943 Single isomer
357
IP N\ II, \ 6
7$0 -40
. .
j or6
N.1)...)
6ro
_11 s
-----
\ N 0 HNz...4,
"..,--M F 0
111
358 N ,
ID '
I. N\
\ N 0.02086 1.514 0.03596 0.5689
942.07 943 Single isomer
,c.--0
6r0
HN,õ....,/,µ
Fvil 1 F H (:) !,I.
L-Nr 'N
359 ).....0 N
4 -o 0.02836 0.5365 4.157 76.52 1024.12
1025.2 Single isomer
ONH
p
0
,0
6sro
HN,,....4.,
0J=
F,,r-vi i F H !,I.
LI(
360 >...0 N
_o 0.01321 0.06267 2.885 111.6 1024.12
1025.2 Single isomer
ONH
p
0
,o
6,r0
FIN /,
(;) .
F
361 N N 0 \ =
4-0
)..._0 N \ N 0.01345 20.71 0.572 33.65 998.18
999.1 Single isomer
ONH
,0
0
0
6yo
HN/,
n-44 1 F
0
362 N ti \ = N--,-----7
.....,,O N 0 \ N 0.02602 2.432 0.07 4.6 998.18
999.1 Single isomer
ONH
$
,0
0
0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
6,r0
HNse,,d\
N ril la \ 1 p \i'l
1
363 ....(r) .=i- N N 0.018 43.3 0.4796
10.63 954.15 955 Single isomer
0
NH
C:0
4-
,0
_?
)
0sr()
HN(
N 0'(
\ N
(:)NH
4-
,0
_t0
)
6,r0
H N
(7)
F,T_A_IN FH
-N la..F
365 ).....o .... N
4-0 \ N 0.00804 0.04587 2.188 68.84 1008.12
1009.1 Single isomer
NH
(:)
,o
p
¨)
6,ro
H1.1...õ(
Fr-1,1 i F 140
N iip NP'F
366
4-0 \ N 0.0389 0.2949 2.96 79.37 1008.12
1009.1 Single isomer
CDNH
,0
p
6 .
H1.1,..,/
0'(
n-14 1
N N iii
mixture of
N \ N ,....?=c) -.4e-P-
4- o 0.01121 5.385 0.2396 7.747 954.15 955.2
367
isomers
NH
c:)
p
p
6,r0
HN,,.....,(
(:) -
F H NTh
368 Lri N 0 \ ip t4-----
>,...\/0
isomers
ONH
,0
0
--c

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
0 0 6
---!. r
= N
, _CH 6,r0
,-
\ N 0 HN,,...,õ/õ.
-SA 1::
369 N , .4,.
IP N\ IP \lilil
0.02 15.21 0.112 3.65 928.07 929.2 Single isomer
4-o
p
0 0 6
__.):, r 6 0
=
i
-. H N
, µr
\ N 0 HN2.õ4,
"A-M F 1401)....)1
0
370 N .. ,. N\ IP 1
\ N 0.01857 7.238 0.028 0.55
946.06 946.7 Mixture of
isomers
4_(;) .
,o
_j, oc6
6=ro
C.-.1-0"
HNxõ,(--
371 N , 147,1
0.4...)
40 N\ =
\ N 0.01427 2.28 0.2345 11.7
944.09 944.6 Mixture of
isomers
cr o
,o
o ,4
jµ 7¨

= N
õ
N 0
Co
\17-11 F
372 N , Itrt...!
0.02522 1.79 0.055 946.06
947.8 Mixture of
lir N\ * \ IN
isomers
4-o
p
--1-11 6.r0
CN 0 HN,,,(µ
H
F 0'4N
N , ..ii.
NY)
373 IIP N\ * \ N 0.01613 5.214 0.2444 5.925
972.14 973 Mixture of
isomers
c$0
o
---
6).0
HN.,...0(
(:) -
F H H.--\
Mixture of
LH N di
.....0 -mr-- N `mv \ N
c$_(:) 0.0105 8.422 0.3063 8.9 974.11
975
374
isomers
Or4H
,o
o

-

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb
2b [M+Hr Designation
6=ro
HN...,1\
0
F4
H N
375 Lõ,, -ri \;(....,µF 0.09597 1.528 6.8 198 934.02
935 Mixture of
isomers
(:)NH
p 6
OH
60
HN,,...1õ.
(:)
F H !kim
Mixture of
N

4_0 0.00973 2.25 0.035 11.21 972.14
973
376 ....0
isomers
ONH
,0
0
6=ro
HN,r04,
I:)
Fõrvi F H N'--\
377 LW =N a \ = \N ;,--r-i-----
>_(:) ""w"" N
4-0 0.00736 0.025 1.792 59.8
1008.12 1009 Mixture of
isomers
oNH
,0
0
S-
0 A
6,r0
F.c., N_roN HN,,...õ1\
..-41 F Od=
378
N , aki H
NP=F
4-0
0
¨ç
-/

6sro
F.cN_LH
0 HN,),/,µ
'.7--111 F 0j`
N , lip' F
379
ID N\ 11, \ IN 0.005 0.0098 2.687 71.51
994.09 995 Single isomer
4-0
0
---
0 0 6
---t. 1,r
CN-i-o-H 6,ro
HN,,...õ4µ
li-14 CDNI _..
380 N , 1,
101 N\ ..(-.."M i
" N 0.01344 3.12 0.1024 0.4612
928.07 929 Single isomer
4-o
0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
6r0
HN,,...õ(
CA
F,,r¨vil F
381 LNI¨N 0 \ .\Nlr-i---/F
0.04486 0.3468 3.283 71.4 980.07 981 Single isomer
) .... 0 N
4-0
ONH
,0
0
0o
HN,,...,õ/õ.
(:)
F,T....µ j'i i F H
382 LW- 'N 0 1,\I = " ,N 0.0036 0.0181 1.202
57.74 980.07 981 Single isomer
)....0
4-0
NH
C:)
,0
0
0sro
HN,,...,4,
Co'
n-14
383
NH
(::
KJ--
,0
OH
6).0
Hhc.,/,µ
(-1
.n--<1
384 N N 0 \ .\N-,-----/, 898.04
899.1 Single isomer
NH
0,
6
,0
OH
6,ro
HN,,....j,
(Zo -
385 L-Nr¨N =\ = 4,,,--r
).....0 N
.c¨c) 984.03 984.8 Single isomer
ONH
,0
F40
F F
6sro
HN,,,,/õ.
(:) .
F,r_A J`l
H 1:--4
N-. !=D
386 1-1( 'N =. I* ,
....0 N
4-0 \ N 984.03 985 Single isomer
NH
0=(
,0
0
F4
F F

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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EC50 EC50 EC50 EC50 EC50 Obs .M .S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
6
.r0
HN,,...j.s.
F,T-"1,4
\
H ti--\
387 N
)....f.>' 0 N ap N . \ --(4.."/ 930.06 931 Single isomer
ONH
$
p
p
0,ro
HNi,/,
F, .1 1 140 Ns -\
388 Lti N ilo \ . \ -1(--- 930.06 931
Single isomer
....(0 N
cr
NH
0
p
p
__.1 Ord
CNA
0 FINI..k
,--0 0
389 N , .
Hy,t1...)
N
1
\ N 926.09 926.9
Single isomer
4_0
p
j. or6
A
C 6.ro ,
Hikc...Z
N 0
C) "
"..,--M
390 N , 40 ID ki N--\ N\ -1(''..../
\ N 928.07 928.1
Single isomer
c-o
p
H
N 0"
NHorY\
_70 N
4-0 N---.1> r 954.08 955
Mixture of
391 \
/ 'NH õ, isomers
(:)
P
p
6,r0
HNõ,....,4,
(:) .
F.% ><N F F
392 1-147¨ti 'lw 14-T,--
1002.02 1002.9 Mixture of
\ N
)...._0 "'IV N o
isomers
C3NH
$
p
0
F-C
F

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
[M+Hr Designation
,
6o
HN,r,l,
<:)
n---14 H
393 N ri ii \ ilk Nyl..,,, "F
Mixture of
984.03 985
\ N
..... 0 ". N o'w
isomers
C:oNH
($
,0
0
F-7(
F F
,
6,r0
HIsl.../\
(:)
F
,....µ,0oN'w isomers
c:)NH
($
,0
F40
F F
6r o
HN,,...õ4,
0;)
F H
395 N ihi dig \ ilk N N P"F
Mixture of
1002.02 1003
\
....0 .1w- N c7w
isomers
1:)T4H
C--
,0
F40
F F
0r-...
: ,-;
CNI0H HN,....,4, =
"-S7-11 F 11(:) -NI -.-
0 N . 1.4....../,
" N 944.09 944.8
Single isomer
396 N ,
4-0
p
0 6
---f r
_./
CNH 'r-. -N
0 6,ro
Higx.õ1\
1-11 F HON
N õ. . ...r)...)
397
N
01 N\ 1
" N 944.09 944.8
Single isomer
4_0
p
j 07_6
6sro
C(N-1-2 Hiklx,õ(
),--M
, ,A,,,,. 926.09 927 Single isomer
398 N
I r N\ I I , IC )11))
4-o
p

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
_ 4 Ohird
CN:r
oH 6y.0
' cr-
HN...\-
.-141 04 .
H N
I --
399 N õ,õ
1.I N\ . h..,
\ N 928.07
929 Single isomer
cro
p
6sr
HN,,....&
04
H N---\
N ril gli \ *I \ 1
400 ),....0 ""ir, N os"w" N
970.15 971 Single isomer
014H
$
p
0
p
6,ro
HN,,,,j,
04
n--<1 ifQ
N N = N\ * N
4
401 )_.o , \ N
970.15 971 Single isomer
NH
c2i
,0
0
,0
,
6,r0
HN,r,/,µ,
04
F,CN-4.1 1 H N--\
N ri lb \ * N-rrA"/
\ N
402 ).....o -w---
1006.13 1007 Single isomer
0,NH
$
,0
0
,0
6,r0
HNI...õ1õ,
F,n-14 1 ON
N N It \ = \ -itr-/
4
403 >,...o 1006_13
1007 Single isomer
CDNH
,0
0
,
,0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la ,laY93H laL31V lb 2b Calc.M.S.
[M+Fl]. Designation
6,r0
:Jr&
NNF,..,-=, ri 1 40 \ 10 \
H
Ny...."' F
404 . ....(0 N 0 N 992.10
992.9 Single isomer
NH
C:)
<1$.-
,0
0
S
q
0-ro
HNs,õ,/,µ
(:)
F,T_A_21
H
NP. F
LW- 'N 0 = ,
....(o
4-0 \ N 992.10
992.9 Single isomer
405
C> NH
,0
0
q
6=ro
HN,,....(
F oCt -
N N
H.7_11.).
= F
406 0 \ .1,1,4
).....0 N 0 976.10 977
Single isomer
NH
0
($
,0
0
S
0,r0
HN,,...
(:) -
F,r-vi 1
H N
407 1-1. 1C
1¨N 0 \ ip \
>.....0 N 0 N-1C)" F 976.10 977
Single isomer
NH
(:)
($
,0
0
S
6,ro
HN,e,/õ.
n¨<PI F H N- \
408 N \ .1-ir--".-' 946.12 947
Single isomer
N 0 *
.....(\==0 N 0 N
01.1H
(1-
,0
,s
6,ro
HI .1
ICI -
n---1.1F H N
409 N ril ip \ = \Ny--), 946.12
947 Single isomer
N
NH
(:)
(-1
,0
,S

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
0se:3
HN2...õ(
0
F,n-14 1F F
H N
N ri di \ -m- \N--?--), "
410 ).....\ 0 ""mr--- N 0`.E, N
1020.13 1020.9 Single isomer
NH
(:)
(1...-
p
o
0
6(:)
H Nz_i,
FN F H
0 In.
411 "--ri Fri 10 \ 411 ,14--,1"'"/ 'F
.....0 N 0 "lw s N 1020.13
1020.9 Single isomer
oNH
(1-
,o
o
0
6=ro
HN...,(
0'(
n-44 1 F H r\
412 N rii al \ a '1-iiN 966.04 967
Single isomer
)..._0 '"Ir, N 0 `'w1
NH
0
(--1
,0
F40
F
0,ro
HN...,,
(:) '
F H r\
413
).....?-0 .-., N
4-0 966.04 967
Single isomer
0
NH
(:;,
p
F40
F
6,ro
HN..õ,/,
(:) -
iii \
HN
414
....0 , N 0 954.15 955
Single isomer
NH
(:)
<-----
,o
o
6).0
H N,,...,õ(
O
L-14' ri a \ 0 0 -,:-,)0
415 ....-0 .- N 954.15
955 Single isomer
NH
C)
($
,0
9
-->

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
6).0
HNse.,/,µ
F,,r¨vedN 1
ii
416 N
L-Nr¨ti \ * ,
....c) , N 0 \ N 990.13
990.8 Single isomer
NH
4:::
$
,0
,0
6,1.0
HN,,,õ/,µ
C:) .
II (1101
H
417 1.4 N\ . \141 11 .134)"F
)...e'0
4-0 990.13
990.8 Single isomer
NH
(:)
,0
0
6,r0
HN,,,j,
F H
N
N
418 NH 1050.21
1051 Single isomer
0-(
$
,0
0
0
d
6).0
HN/,µ,
Cr(
N pi iii
....\(:) -..r.-- N
419 NH 1050.21
1051 Single isomer
0-<
e
,0
0
,
0
d
6,r0
HN,,...4..
C) .
14 i 11 'I---\
n--<
420 N ti * \11-"-= 930.06
931 Single isomer
....e-0
C:oNH
$
,o
p

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b
Calc.M.S.
[M+1-11+ Designation
6,ro
HN,r,1õ.
04'
r, . . = v . . 4NN I
421 \ NH 930.06 931
Single isomer
>...t.?t,L- ' -0 õ 0 N * \ rt
ONH
C--.
,0
,0
0 id
''r---),-0
422 '0,0!/to tii 0 N\ * \N N1040.19 1041 Single
isomer
0
Ss
---,a)
0-- H
\--J--rN,o,
=::),,i__.
1
N 1 1,---.,
423 0-- \ L /4 H 0 \ * " 1040.19 1041
Single isomer
N-C3 N \ N
H "=. 0
Qmik s
MI
6)O
HN,v0,4õ
0J= . _._\
=
n-14 1F H
Ny 1:-1=,
424 N N 0 = , N ,
>...).-0
d-0 0.00389 27 0.6629 6.776 972.14 973.1
Single isomer
0.,<NH
,0
0
_e)
6=ro
HN,,,iN
F H
1:)...._\
H Hi [I\WT.-Z./I
425 ....0 N 0.01474 1.047 0.1416 16.74 972.14
973.1 Single isomer
NH
(:) '
4-
,0
0
1 ,
6,r0
HN,r01\
(:)
F Hi, 1..,..1..)..F
N
L 1.1 'ril al \ = 1 0.00649 0.2636 10.16 977.05
978 Single isomer
426
.....c) ""w" N \ N
NH
CI::
,0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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310
- _______________ -
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb 2b
[M+H] Designation
Fõr-\.... .j.1
ap \ *
N 0
427
O NH 1-101,0 0.002 3.4 9.8 0.001 44
865.40 866.5 Mixture of
isomers
,0 Hisf'---(
9 0
,
6,r0
HKõ,_,,I\
Fõr-\21 1 F HOJ,Ni
428 Lni .11 0 \ =0 !I-Tr"' 0.012 7 5.3 0.001
6 897.40 898.5 Single isomer
N 0 ` N
CoNH
t
,0
6,r0
HN.,..._(\
(:)
Fõrõ--\\_i 1 F H V----\
0.003 0.8 5.9 0.001 41 897.40
898.5 Single isomer
429 \ ii \N ,z,----/
0`'wt
C:1NH
,0
6,r0
HNiN
Fõ N (:)
F
Mixture of
0.010 2.7 9.8 0.020 17.1 883.40
883.9
430 rC)--N1 idl=
isomers
IW N\ II. "N ' -
-0
(:)NH
,0
6,r0
HN,,,,I\
N (;)
431 n..,., , ii F . N H -Tr."--/
N"--\
0.010 11 0.7 0.020 2.4 865.40
866.2 Mixture of
N N .
-w-- N " N
--0
isomers
ONH
,0
6).0
HNrc
N 0
F H 10
432 F,Q4 -41,11 \ if 0.004 3.55 2.14 0.001
11 883.40 883.9 Single isomer
1101 N 01. \ N
NH
(2)
,0
6.r0
HN.r.,1\
F, N Od'
F H II-)
433 Qi ''''<'N1 \ N-,,, ----, 0.001 0.2 4.86
0.001 69 883.40 884.5 Single isomer
-0
NH
,0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V, lb 2b Calc.M.S.
[m+Hr Designation
F,n-J*1 1
N
--0 1 4 '
434 ol- ill-D 0.011 4 1 0.001 10
865.40 867.2 Single isomer
NH
,0 HNr
o0
F,C.1 1
N N iti \ = , N
kvil,
435 ci 0.002 0.5 2 0.001 32 865.40 866.5 Single
isomer
(DNI4
,0 Hike'-r
,L.
9 0
:)rd,
6,r0
ON 0" HNz_c
436
N , F HCI \ II, 1 N, "." 0.002 30 1 0.001 5
865.40 866.5 Single isomer
re*--.3
. N hL
\ N
---0
0 '
--.õNr. 6,r0
ON oF4 HN,,..,k
437 A
N ,- F
H N.--\ 0.003 6 1 0.001 2
865.40 866.5 Single isomer
N
40 N\ 111 "N11.---/
-0
F,
Q¨<' 1
N 0 \ i. , N
>....0 N
tO N--..:) mixture of
438 0.008 45.6 10.38 0.003 37.4 879.40 880.5
NH
O
J
isomers
,0 HN '1,
o,L.0
. .
F,.r,\_p 1
Liki 'II 1110\ 11, / N
)...0 N 0 ri---s)
439 (:)NH
Oy N 0.014 540.8 7.4 0.002 6.1
879.40 880.7 Single isomer
,0 ) ,
HN ..'1
o0

CA 028116 62 2013-03-19
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{¨

EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
1Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb 2b
[M+H] Designation
,
,
, F,,r-ss_p I
0
440 NH H>0.002 24.2 4.05 0.001
52.7 879.40 880.8 Single isomer
C)
pHN -1--
_ j_ ord
6sro
CN--(3t1 NN,r_i\
"..;-14 F ON F
441 N ,
IP N\ IF " 'N 0.010 14.2 0.020 22.9 911.40
912.7 Single isomer
-0
c) ,-;
_rj, r-
6 0
-r
Cri:DH HN,,....,/,
"..SA F!sl---\
11(Y(
442 N ,
N
\ N 0.010 18 0.020 151.8
911.40 912.7 Single isomer
0
,
,
_ _
.
F,,r...-vii 1
0"I=rf 1-41": F
Mixture of
443NH 4:)-.,- N 0.019 1.95 42.864 0.008 883.40 884.8
)
isomers
,0 HN ''''i
o0
0*
C..(.:4HO 0 CA
, N
N ,
Mixture of
444 IP N 11 \ IN 1.320 14.582 2.81266
0.792 6.101 792.40 793.4
isomers
c, -0
iki
0*
(N40 ...k
"AA 02
N,... li r\
isomers
c(0
, q
,

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CalcMS
1 a laY93H laL31V lb 2b
. . . [M+Hr Designation
... . 0Aj. 7--.... 6
,-. ili r0
\ N 0 HNse,,,/,
'..---A Cr(
N õ H In
Mixture of
446 N
* N\ * -ir-.
\ N 1.000 4.26 1.95 0.200 2 906.40
907.4
isomers
,.-40
\--Ai
-4= Or
d
C= N
H dsr=O
N 0 HN,r,/,µ
Nõ 4,6. H
447 \
Ny=-=14.'.../1
ID N * \ IN 1.950 1.95 1.95 0.200 2
939.40 940.4 Mixture of
isomers
<to
0,
,..../ r-
.---- 11 Ciro
N 0 HN,r,,/,µ
\....ril
ON
N_- õ H I
Mixture of
448 N).)
0 N\ o*
\ N 2.830 1000 212.36 2.400 1000
925.40 926.5
isomers
(4-0H
0
CNH
'i7-14 14;14,)
N
449 ID N 1, \ N >2000 > 5000 592.30
593.3 Mixture of
q-c:i
isomers
N
0*
c-N-40 ..,(
Srm .J)
N , 46.. 111,11...)
450 IP N\ 1, ÷ N 365.116 5099 811.40
812.3 Mixture of
isomers
k-0
\---C-OH
0
0-(7.
CN-10
02N
451
04'
N õ H !'1---\
N
451 I.1 N\ 1, ir'.../
\ N 131.553 670.918 788.30
789.7 Mixture of
isomers
gs -0
N

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CalcMS
la I aY93H 1 aL31V lb 2b
. . . [M+Hr Designation
0*
F..\---,,,r400
$0!%1
ID
N , li .,F
452 40 N\=-iT"'
\ N 909.000 >5000 828.40 829.3
Mixture of
isomers
g, -0
N
0-*
Cti-40 ..(
N õ 41.,t.
453 IP N\ * \ IN 294.000 > 5000 824.40 825.4
Mixture of
isomers
ci0
HN
occ;
6
=ro
HN,,...õ1õ,
454 0.064 N\ II) 11--.../
\ N 0.064 145 9 0.011 24 938.40
939.3 Mixture of
isomers
HN,
0*
..
gliii4u0 0
04,
N ,...Ak. It TILI...) Mixture
of
455 IIP N\ IF \ IN 293.000 659.44 810.40 811.4
isomers
cfo
0 NH,
0-*
CN-40 .(0
....--11 0./,
N..- Ai,.. 14...(11...)
456IN 72.699 588.56 850.40 851.4
Mixture of
cf0
isomers
HN
)>
04-
CN-40 ...(0
""i-il 0
N , HN
SiN 1,
N
\ N Mixture
of
457 ct-o 140.477 1225.95 854.40 855.4
isomers
HN
?
OH

CA 02811 662 2013-03-19
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.
EC50 EC50 EC50 EC50 EC50 Obs M.S.
Isomer
Cmpd # Structure Calc.M.S.
la 1 aY93H 1 aL31V lb 2b
[M+Hr Designation
-1-*
C._H -0
, N
N , 41,L. H
Ni
458 ir N\ IP \ IN 188.892 227.88 788.40
789.7 Mixture of
isomers
,-i:3
\---%
6sro
e"N0 HN,,..õ),,
r-M (:)
N , NHYN)
459 40 N\ * i
\ N 0.246 19.21 18.4 0.027 200
968.50 968.8 Mixture of
c-0
isomers
HN
?
OH
H
-4 0 , N
N ,.,... it,,--n
Mixture of
460 Or N\ 111 \ IN to 512.000 >20000 838.40 839.4
isomers
0 0 )c_
0 =
-Nt
-0 N ni 11
H - = H n
,
Mixture of
461 N ir N\ 11 \riColt---N-1' õ. 0.097 >200 14
0.151 99.105 964.50 965.5
isomers
o
0 .- H 0-
c.-N le
-
,C 0 NP1 H n
462 5 N\ ollt '1Ini-o 0
N
0.018 > 200 88.9 0.022
76.8 882.40 883.4 Mixture of
isomers
N-1
0 * H 0-
-0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer .
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
ONx---c....
N , , P.,,---n \____ Mixture
of
463 up N\ * \ 'N tt__,,- 0.024 > 200 0.4 0.014
41 952.50 953.5
0 , o
isomers
o N-1
0 0_
*
-N,
_
-,
J4
L-14_ N
0 u c-0 mixture
of
464 A--- 485.000 2619 881.50 882.1
isomers
HN
I H tkl, - \
1--1=1 _ N ag iik wir1/4-/
""iir" N \ N 0.073 >200 0.27 0.033 0.2
970.50 971.1 Mixture of
isomers
465 C
N-8 40
N
6,r0
HN,r.,/,µ,
F,n¨<''
p
e .F Mixture
of
466 N
N IF1 di \ * , 0.005 0.2 3.2 0.002 49
942.40 943.4
\ N
isomers
.....0 ""w" N 0`w'
0=(NH
g:
,0
N
6sr()
HN,,,,,Z,
L_,,i ri 0 \ . \NI,-..7,
467 >..,...0 N 0 N
>1 >100 >100 0.130 >100
995.50 996.5 Mixture of
isomers
ONH
,0
C-0
HN
N-

CA 02811 662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
6,r0
HN,r,,,,/\
468 N it \ Al
.....\)=c) ...w- N `I=rf
0.073 24.86 1 0.063 26.5
939.40 940.5 Mixture of
N 1,
isomers
ONH
,0
(4-NH2
ItH
6=ro
Higs,,õ
N C)'
c"" 1
N 111 \ 1 I p \14 0.090 18.89 7 0.011 >100
924.40 925.4 Mixture of
469 N
.....tp -w...." N
c4--0
isomers
NH
(:>
,0
0 NH2
.c:=
Oa'
n-44 1 F N !,1--\
470 N \ = N--,
oc. , 177.000 1884 810.40
811.4 Mixture of
N ft \ c
N
<4-0
isomers
A-
N
HN,,,..j,
0'(
n---(14 I ii ,l--\
Mixture of
N ftN swi=ft " N
471 N \
,...0 -,
c0 0.006 6.2 0.2 0.006 1.9 949.40
950.5
isomers
Or4H
,0
0
cisro
Filisej,
n-1
0'4.11 F 4N
Mixture of
472 N N iii , i-K0.002 1.31 0.22 0.002 7.5 924.40
925.4
)....i3 Mr N ow \ N
isomers
ol'iN
g=
,0
sN
6,r0
Hikkr...õ/,
Cr(
I ti N---\
473 N ft \ * ic-,,-../
).....-0 , N
,.-0 \ N 0.003 0.88 0.19 0.004 2
963.40 964.5 Mixture of
isomers
NH
00
,0
\ --1,1.'s IJ.1
0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+1-1]* Designation
L-N' N ft \ ip /N
=::='0
474 \-0 1-1-1.1>--.N 208.000 19 ..
716.30 .. 717.4 .. Single isomer
/\--- Oi-N
>1,0
LN N 0 \ = , N
.._0 N
\--0 N--.1)--eN
475 NH (:) ,N 0.010 11 0.363 0.003 1.929
830.40 831.4 Single isomer
0=<
).= ,0
HN .'1,-
476
I=1._ vi ii \ ip / ri
-w-- N 8.400 10000 707.40 709.4
Single isomer
0 u \-0
N ti, ip \ ilt, / ri H -,,.....
N\-0 N N F 0
H lr'-' -k 0.023 97.1 95 0.013 >
100 821.40 822.5 Single isomer
NH 0 r4 Cr
0.(
,0
6)o
HN,r,L,
04
H!4
\ =

.--\
478 N
)....tflo ti 110 N . \ itc....=/ 0.004 18 0.41 0.004 4
906.40 908.4 Single isomer
NH
0.(
g-,
,0
sN
6,ro
HN,,....,/,µ
00.
!4--\
n--<-.1 1 M
479 N rii 0 \ * \ -,,,-;--/ 0.013 66 > 100 0.005 7.6
906.40 907.4 Single isomer
).....0 N 0
(DNH
,0
C-,
N

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
Cµ)----<clio; 0 N * /r.1115.11
480 #44#1414t 1227.6 691.30 692.3
Single isomer
\-0 0
=ic-
.
N
,r. 1.4 ,,,
481 .....0 nk_ow . m
j.1--5.0
-),--\i? 0.124 62.1 109.9 0.012 110
805.40 806.4 Single isomer
p 0-
ONH
,0
6sro _
H142....
482 n --1N1 1 0
N
ft \ft---
0.028 0.382
0.014 2.7 738.40 739.3
Mixture of
..._\/0 No
isomers
-CDONH
C-i4
0
/N
oir) H N
483 \-0 rfir'll>.0 609.000 >1000
721.40 722.3 Single isomer
1-
N ri = \ ik , r
)..._.0 N\-0 11.-111.)-0
484 NH 0N./ 0.026 11.9 17.3 0.019 >100
835.40 836.4 Single isomer
t).
) ...-
,0
6=ro
HN,,,õ/õ.
cr(
11 v--\ Mixture of
485 N 11 ill \ 1* \ 1,--c" 0.012 22.58 0.23 4.35
936.40 937.4
isomers
....0 ""ir--- N ow/
NH
(:,
p-0
,i.,

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
_.
ON
H --\
VI 0 \ * \14 ir.--(7"/ Mixture
of
486 c:i 0 ""lr, N 934.400 >1000 822.40 823.4
-0 isomers
)\---
-0----,
N
r \ 44 1
= , ri
N N"...' 4 =N
487 9_ \-0 605.000 >1000 806.40 808.3
Single isomer
7\-- 01,N
.._1,0
,
6,ro
HN,,...4,
0'"N
n-14 i H--\
488 N N, di \ * \N-g-,--`.--/ 0.011 114.2
1.62 35.93 931.40 933.2 Mixture of
.....<0 w.'" N
isomers
0
NH
0.< N-4
,0
µIi4
,
n--P '
1.1µ_0 N-...2. ..,o
489 NH (:) -N 0.860 115.2 236.2 >1000
835.40 836.3 Single isomer
Co
HN-1,..-
r--V_P 1
)....0 N\....0'w
490 NH 0N 0.090 51 65 234 920.40 921.3
Single isomer
0=<
),....
,0 HN ..)
9,.0
6,ro
HN,,...õ,/,
,C)
F H !J--\
491 N til di \ ilk \Nii----- 0.010 9.02 0.42
10.9 924.40 925.3 Single isomer
NH
0=(
C0
-
9
N
- -

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V , lb 2b Calc.M.S.
[M+Hr Designation
6sr
HN ,,...,4,
C:1
n---14 F H N¨ \
492 N N \ . .1 i,--,i-"--/ 0.010 21.62 0.17 12.37
924.40 925.3 Single isomer
0
""le, N
,
p
-0
0=(NH
µ----i4 _
, _)1 1
F
N pi ii \ . , N
N.3õ= 0,F
. .....<)'0 "w" N 0,-.4
493 NH
'<- 0,N F 0.006 26 16 0.003 >200
943.40 944.4 Mixture of
isomers
(HN
), ,.--
,0 *-1
F
\-- l'a CM IS N 1. /N -11,
\--0 N 0
494 )4NH 01,N 0.005 19.2 4.3 0.000 410
863.41 865.4 Single isomer
Hi.(
¨{ L.6
495 1---If
ni', m_p- > 0.2 2 5 0.008 973 885.45
886.4 Single isomer
0 N\ * /31 ("
. )---(--
60 pi
\ 0
(:. 6=ro
>....70. HN
crZ
496
_ci
N t....<7 m tsD 0.010 <100 0.009 233.7 921.45
922.4 Mixture of
isomers
0 N\ * \ I
6-0
O6
--"Mr 6=ro
HN õ(
497 ;--N
u_lito 0.019 5.2 >2 0.190 227
895.44 896.4 Mixture of
isomers
UP N\ II P "N
-0

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b [M+Hr
Designation
\
N N 0 \ =
).___O N
\ / N
-0
JJ
H1-D-F Mixture
of
498 ioNH OTN > 10 > 1000 > 1000 >2 >1000
837.40 838.4
HI(''(
isomers
,0
o10
r0
HN2 ,õ(,
F
0.N., _\
F,r......p 1
H
499 LI,i ' ri, s \N.,r-.../.,F 0.013 1.55 0.005 10
975.30 975.9 Mixture of
isomers
)_(;) N çt0 N
.NH
(:) S
p
CI
-o
,..,4
=-= NH
yky0 m
CCF
500 F N 40 N\ lip ,` H 1._ --
N 6' ---s' 0 0.028 0.2 2.826 0.022 50.6
1018.38 1019.0 Mixture of
go N-1 isomers
H
¨ 0-
S
1
'N
-0
O d.
=== NH
F
,O.1 ...4NN 1 001 F
N -
isomers
M-1
¨ 0-
-S
0
-0
r.4
=-= NH
)="'Cr0
CC
F
14 I*
502
0.007 1.5 0.005 17.1 941.35
94t9 Mixture of
F N
.1*.11' N WI., N L
\ NH 0H0 0 isomers
J-0 N-1
Ho
c,'S

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la I aY93H I aL31V lb 2b
[M+1-11+ Designation
'0
O NH
H
CC
N N
( F
503 F4---/ " \ lii' - 0.012
011*o
N 1.021 0.007 31.4
1018.38 1019.3 Mixture of
isomers
g-,... s
¨
,
=-.. N
1-,'
=-= NH
o F
F
504 N iim \ m--, 0.031 4.391 0.007 33.8
955.37 956.4 Mixture of
F
isomers
`14-11PF N oWl \ NH 0.-- 0
N-1o-
c -
-0
f-v4
=-= NH
)r 0 ri,' ro li
505 N is , is /1,1
0.110 >100 42 0.023 863.43
864.5 Single isomer
oIr,
HN ..1"
o'LO
+
HN 0
Il
O...,4N 1
0 N\ */ N
506 11.___õ,
\-o H >2 109.9 109.9 0.157 110
747.38 748.2 Single isomer
OIN-1
HN r
'0
,=,,
`-' NH
0
LI
507 N a_ , i p , N
0.080 > 100 43 0.029 57.9
863.43 864.2 Single isomer
01.N
HN'..----r
o'Ci C)
7

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
'0
¨ NH
t
508 N \ = N
41113-v N > 1 > 100 > 100 0.154 > 100
747.39 748.2 Single isomer
0.),N
>c,NH
¨ NH
OFINr0
509 N \ 111
0.070 > 100 > 100 0.026 > 100
793.35 794.3 Single isomer
\-0
01,N
HN
kl
H2N LI Y"'
510 N \ N
N1..0 0.015 > 100 25 0.017 99.5
820.37 821.4 Single isomer
\-0
1 re-4
HN
9 0
çs
HN 0 H
N N
Oci.-4
511 N \ = N
N 0.020 110 50 0.015 69.3
845.33 846.3 Single isomer
\-0
01,N
)
HN
0
-nro H
"
512 NS 0.043
SN 0.043 109.9 44.71 0.020
110 859.35 860.4 Single isomer
\-0
HN
0
0 H
N
cNµ
_i....
513 N \
N 0.140 109.9 109.9 0.030
110 859.35 860.4 Single isomer
\-0
9,L=0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la I aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
'0
rt.i.
- NH
0 H
ciN ....4NN
514 0 \ * / r,
0.040 109.9 15.53 0.022
110 .. 835.40 .. 836.4 .. Single isomer
"14,--' ikk-0 N
03-11-D
HN .."(
-0
i-,J.
=-= NH
O....-0,Hro
14
4 N
1
515 A \ 11, / N
"1,1% N 0.088 109.9 40.23 0.060
110 835.40 836.4 Single isomer
\-0 N
Of---;)
,
,,-,-.s
HN 0 m
--1 N
9 CY-4
516 N ill \ 11, / N
"41r-- N 845.33
846.3 Mixture of
\-0 01"---)
isomers
OTN
HN ."(
9 0
72
0
-o-A.N o H
O..,,<!'' 1
517
µ-0 N di \ . , rõ
>1 > 1 0 0 51.2 0.118
>100 834.38 835.4 Single isomer
""6-7' N N--r-D
OTN
9-0
0 <-'>
'0-1(r-TO Icl
6..04 1
N a ,
518 Riir N
\-0 N 0.314 > 100 > 100 0.067 > 100
803.38 804.5 Single isomer
0--I'D
HN '."(
9 0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
'o
- NH
---i(niiNr
N 11,
41112" N / N
N4._-\,\ 0.038 > 100 8.7 0.034 > 100
821.39 822.4 Mixture of
519
isomers
\-0
01-14-2
HN \
-0
rv4,
=-= NH
icro
HO 6..õ<7.1
520 N *
N
0.165 1.6 0.082 > 100 807.37
808.4 Single isomer
\-0
HN ''.1
So
NH
oH
UN
521 111
'11111-P N / N
0.044 > 100 4.6 0.020 > 100
835.40 836.4 Single isomer
\-0
HN
,L0
rNH
_re 11
Li.".4N1
522
t\l\-ol*N
0.054 > 100 24.1 0.022 > 100
833.42 834.4 Single isomer
N µ
o0
0
H
H O... 4ry
N di \\2w, N
523 N N 0.085 > 100 27.9 0.040
> 100 817.39 818.3 Single isomer

-
CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+H] Designation
'0
"J.
.... NH
Li.."4
524 N Ai \ * /N
'11111P N 820.40 NA
Single isomer
-0 M
0-it\D
HN '''r
9,L0
LnF ,
HNC) H
525
U.-4N1 0 r,\4 * / _c\
25.000 1000 592 1000 923.45
924.2 Single isomer
N
\-0 H
) ,...-
HN )
9,L0
n, ,
H2NO ti
N
526 N a , * , r,
"Illr N 1.680 377 195 823.40
824.3 Single isomer
TN
HN '"(
....o,(Thci
ON
A
CI
527 a 0 \ . / N 0.050 13 0.7
15 949.34 950.2 Single isomer
N .3
c3-0 H
HNAs'r
nF ,
HNO H
--I N N
F1=1 Ou.õ,<, 1
528 Nrill \ -M-- / r.,
0.420 143 108 >1000 880.42
881.7 Single isomer
4111r" '-o
0.T
HN ."(
c:,(:)

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H I aL31V lb 2b Calc.M.S.
[M+H]. Designation
, j,õ
iiikio H
N
529 N 40, , =, N
0.057 42 11 246 881.40
881.7 Single isomer
N N
"0
\-0
J.
HN -1,...
9,-0
N 6,r0
HN.r,1õ.
530 HN-.0 H
)'(N, ¨\ 0.060 69 29 210 939.41
940.6 Single isomer
\--0
o ,
0N0 H
'27-11 V
N ,
531 0 \ . N.
/ N 961.49
962.5 Single isomer
_A
4 N
c3-0
Hc4c, tliD
HN(
9)=0
)._soN
d-o ti =
532 oi-111--- 921.48
922.5 Single isomer
NH
O
,0 HN"..""r
9,1=0
_..%,
=,--N 6,ro
HN,,,,/,µ
533
N ,
lc 1:0 0.001 8.4 0.2 0.001 7
895.4 896.4 Mixture of
isomers
6-0

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Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+I-Ir Designation
rj, Ord
Oro
__il----"
\ N 0 HN,,,is,
"..7-11 0'(
534 N , il...r. jkl.....) 0.013 12 9.11 0.005
9 901.5 901.8 Mixture of
isomers
d_o
__,, ore,
6,r0
CN-t-011 HN,r,4,
535 ,--11 (:)
N 0.020 27.82 1.1 0.002 111
859.4 859.9 Single isomer
, H r\
40 N Ilik ....../
\ N
>40
H r\
536 Ld N di \ * Ny--"--/
sw' \ N 890.530 10000 767.4 768.4
Single isomer
)-0
/\--
0
60 cr
HI=c.,,t,
N 0J=F0
n___ i
537 11,1, 0.013 109.9 18 914
915.5 Single isomer
N N di \
=,
)....\0
>-0 \ N
-0 NH
C.
0
,0
0Th
538 b ci-ri ',I 0 \ . \N-ir1/4-/ 0.006 0.9
0.020 0.2 965.4 966.4 Single isomer
-114-)4D N = N
H

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Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+H]
Designation
6sro
HNsejN
(:)
539 r-N_I" ti=I
H H NTh 0.180 >100 93 >1 824.4 825.4
Single isomer
=

N'ir""V
oCo N . \ N
e0
A-
..4
a.?
540 `--4 N =0lyN" 0.500 >100 71 >1 824.4
825.2 Single isomer
,i3_0
0,H
p
cij
o)..
541 LN" N 40 478.000 >1000 >1000 360.000 763.40
765.0 Single isomer
..,.?-0 " N
1,--0
CO
0
_. Ord
CNN Oro
FiN,r,/µ
542 õ...tio
ci(:) 0.003 19.19 1.815 0.002 44.5 868.4 869.6
Mixture of
isomers
IIP N\ 111, \ IN
?-0

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Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
IM+Hr Designation
ii-i.,\
(0 ri Mixture of
543 =::,NH Oy N-1 0.005 12.18 4.748 0.004 3
834.0 834.7
)
isomers
,0 HN --17
,
j or6
6
(N--2-0 ,r0
HN,,,JN
544 N1- , ..
0.005 2.26 1.724 0.002 1.1 888.1
.. 889 .. Single isomer
111P N\ * \ IN
6-0
_
6
,--, H
_11 ,0
,....14 0
Ase.,,/
1:)
545 N , ClCI H N--=\ 0.004 4.69 0.5041 0.002 1
908.5 909.6
Mixture of
isomers
01 N\ = "/
\ N
d-0
0 6
6o
H Cr
:CH sr 0
A N ...,./\
Mixture of
546 N' 0.006 m....r)...)i 0.006 19.64
0.6745 0.003 1.3 874.1 875
isomers
IIIP N\ * \ IN
6-0
0 g
....i, 7--...
= N
_C 0=ro
CN 0H HN.r,/,µ
547 .,--11 CI F 0
N--\ 0.005 16.84 0.619 0.002 8.7
898.4 899.4 Mixture of
N ,
isomers
0 N\ Ili 1111.
\ N
<?-0

CA 02811 6 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b [M+Hr
Designation
_
N N 0 * , N
).....c.
\-0 F 11-j ,
.- Mixture of
548NH 01M--7 0.013 31.05 2.474 0.003 > 100
823.9 824.8
O
)
HN ,- isomers
,0
l
o0
j Ord
Oro
"-.'N-1-0 Hnise.,
549 \-.,-11 F o 0.003 1.97 0.9988 0.003 1.3
864.0 865 Mixture of
N , Avb t0
isomers
<?-0
Oro
CN-1-0 HN..,,,õ(
""7411 0'(
Mixture of
550 N , = 14 N-\ 0.009 66.79 1.92 0.004
890.1 891
isomers
. N\=ir"."/
\ N
7.4-0
(0-)
1,i , gip N
, * , .
C(I 0 N-c,"\
551 NH O
0.061 7.42 6.055 0.009 > 100
818.0 818.8 Mixture of
---rIT.N../ isomers
0.,1,0 Hie",i--
00
r-N___(,1 i F
L iki ril 110
.....(0 N
?-0 M-1.1)
552
ON 0.003 2.15 1.334 0.088 3.1
852.0 852.7 Mixture of
CoNH
)isomers
,0 HN ..)
9-0

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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CalcMS
la 1 aY93H laL31V lb 2b
. . . [M+H] Designation
¨'07-0,
-= ),0
\õ../4 0
0.010 101.1 16.66 0.002 78.1
886.4 887.2 Mixture of
CI F ii n
,,
isomers
N
0 ri
"N
to

N
L 4 ti 0 N\ ip ,m.)
),....\).0
d_o
554 NH 01,1.1...) 0.001 27.79 0.767 0.002
7.7 900.0 901 Single isomer
0=(
), ,0
HNi
o.0
0 g
\---N -roN 0sr()
HN,,...õ/,
555 "..1c:1 -
Mixture of
F 0.002 20.77 3.175 0.001 9.8 852.0 852.8
N ...- 14 N-- \
isomers
0 ri
\ N
?-0
-'07-0,
r
CN¨I- so
011 HNk
556 .,--IZI ci Fir) - 0.002 47.82 5.848 0.002
27.7 886.4 887.2 Mixture of
isomers
IP ri IP "N
to
0 g
6
sro
HNse,,k
IAON
557 N __a. 1.(0( 0.017 93.26 2.586 0.005
51.2 938.1 938 Single isomer
. 1.\I IP"N1
6-0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure .
CalcM.S.
la laY93H ,laL31V , lb
2b [M+H] Designation
--/, Ord
Ili Oro
F o HN,r.õõ(
558 F CA
il !kl F 0.001 3.04 2.004 0.001 33.6
936.0 937 Mixture of
N , i .F isomers
40 N\ * \ ,--
<?-0
L 14 vi iip \ ip ,1
>....0 N
d
559 NH OTN 0.003 25.61 0.5109 0.001 7.2
882.0 882.9 Single isomer
0-<
,0 HN r
n-41;IN
F
N 14 0 \ *
)....0 N Ilj\r.) Mixture
of
560 NH tO
0.007 44.8 13.09 0.002 26.8 852.0 852.8
o<03-N
isomers
,0 HN y
c-Lo
___,, or.6
6
ro
HNk
'...-tl 0' Mixture
of
561 N , 4.6,. ii...r 900.0 900.8
isomers
6-0 F
0 A
.....? 7--... 6
\---N-(DM ro
HN.1.....4s
562 .S,--14 c)õ, 0.012 167.4 10.22 0.005 13.6
866.0 866.8 Mixture of
, isomers
)
N F )
\ N
4-0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure CalcMS
la laY93H 1 aL31V lb
2b . . . [WM+ Designation
01
_...µ .-- A ,..
6=ro
HNsedõ.
563"....H
/ N F 00 - 0.001 12.15 1.339 0.001 4.5 866.0
866.8 Mixture of
N , 11,1 isomers
lir N * " 'N
_to
j ord
ri 0.ro
FIN,r,L,
-
564 F m 1/4-- 0.005 48.97 11.08 0.002 17.9 864.0 865
Mixture of
N õ isomers
40 N\ ="N
.(--0
.....µ Or6
Fi...õ, _t--q 6=ro
N o HNd.s.
565c::=
i, vF 0.002 0.93 1.06 0.001 61.1 918.0 919
Mixture of
N -ii
isomers
0 N\ * \ -im,'
<?-0
-0 11
i0-1.c._43
566 N "'lLilte- 0.022 > 100 33.97 0.006
> 100 858.0 858.7 Single isomer
Mr N W
6-0
0 '
__,/ r...n
cH
N 0 HN,,....õ4,
567 or,i 0.033 >100 12.3 0.003 >100
902.0 903 Mixture of
IP
N , F
" mNy...
isomers
0 N I
4-0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure .
CalcM.S.
j 07_6
=,--N 6).0
HN,I.ol.,
\ 1__H Mixture of
C:)
568 , N F !,I---\ 0.011 0.22 11.63 0.001
43.7 902.0 903
N , isomers
= N\ . 11-11-
\ N
_to
6=ro
HN,,....,/,
0'
Mixture of
569
\ N 0.023 >100 11.76 0.010 60.5
846.0 846.8
isomers
NH
'<-
0
,0
4. Ord
F..,N_ill 6,r0
0 HN.r...4,
570 \''..,41 F 4;) 0.012 0.2 12.86 0.001
76 888.0 888.8 Mixture of
N ,..- 13 !,1.
' F = isomers N\ * -ii-'
\ N
to
Oro
HN,,,,j,
.::
N
571 11 0.001 4.02 0.3006 0.001 3.7
882.0 882.6 Single isomer
-14 ri 0 \ "N
),....?-0 N
NH6-0
(:)
,0
F
.
572 NH <2-0
N-.> 0.003 22.65 1.359 0.001 2.6
864.0 865 Single isomer
(:)' OI
,0 HN .-i--
9,L0
0 ,
HNis,
573 N_- .d,,. vi .0 .s.r. 120
882.0 883 Single isomer
IP N\ IP \ IN
d-O

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. .
CalcS.
la laY93H laL31V lb
2h [M+Fir Designation
, 0
0-"<N
1-1-4 N
\\-cf
N
574 ri 0 0.010 > 100 43.2 0.001
336.4 793.9 794.5 Single isomer
)

HN ...-
.-1
9-LO
...j, 01_6
6)=0
F N..c. A
e HN...../
575 ,- .t)) 0.019 0.81 19.86 0.002 44
884.0 884.6 Single isomer
IIP N\ * \ 6
4--o
F,r-vi 1
....0 ....r N
11.... F
576 NH t 0
0- N 0.011 0.41 45.42 0.001 90.8
870.0 870.7 Single isomer
CD
). .,
p HN
,
07- 0
7-
F
A,-/tri 0)0F \,,..(N
577 A r C:) !=1 F 0.004 5.64 1.526 0.001
104.4 938.0 938.6 Single isomer si Th,
N ,
_to
F N
F
578to
0,N-/ F 0.002 1.09 5.191 0.001 102.9
923.9 925 Single isomer
0 NH
),

p HN -1.,
9,L0
j or6
Oro
F,orto ri HN,,,,L,
579 --1:1
N , 0'(
F 1:1 tr\ 0.011 26.56 2.158 0.009 918.0 919
Single isomer
I.1 ti ol,
" N
d-

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+H] Designation
..._r-N_
Lk rii 0
0er N
580 NH <1-0
0.1,N2) 0.005 60.12 5.531 0.002 2.2
846.0 846.8 Single isomer
0=(
),
,0 HN -1
j, or6
F _:T1 6,ro
.C.(N 0 HN,r,04,
581 A F ON
r( 0.020 0.39 11.49 0.001 70.5
902.0 902.8 Single isomer
N , ii ---\
0 14\1
\ N
4-0
F,r-N. ji 1
F
* / ri
).,..0 N
ri
N H --.F
582 tO
01-Ni> 0.013 1.11 83.06 0.002 93.9
888.0 889 Single isomer
(:)
)
,0 HN -1
r F
"-1.1 M INI,141
).....0
1-0 11....l.>
583 NH <
864.0 865
Single isomer
Cli OTN
,0 HN .."(
,...4, 0N7.,6
Oro
P.c=S-a
.N_T-H
HN,,....4,
584 N F '_, ,,,
H...r.,:c.).,F 900.0 900.8
Single isomer
0 N\ * \N ;=1
<--0

CA 02811 662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b
Calc.M.S.
IM+Hr Designation
F,r-v ji 1 F
t = -14' 11 0 .) \
N---.1)-F
585 c:INH -C)
J ,, 0.014 0.2 23.5 0.007 64
888.0 888.8 Single isomer
,0
HN '
9,L0
F N
F"----N-- I
-14 N 0 \ = , rl
586 NH ?-0
0,, N--/F 0.002 4.2 1.4 0.001 41.7
906.0 906.7 Single isomer
0.
). õ..,
,0
- - __________________

F N
N N 0
..._()
587 NH 0N--/F 0.001 14.82 2.6 0.001
95.4 906.0 906.7 Single isomer
0=(
),.
,0 HN,..-
,
-4 or-6
_:1--N 6sr
HN,,...,,k,
588 Al F 0::
H .1TheIF 0.002 7.68 1 0.001
41.4 923.9 924.7 Single isomer
N ,
0 . = \N-,,ii-----F
__..
_ . .
,0 .4
_ 7......,
, 6Nro
Flõ../4 0 HN,...õ,Z,
589 ),--M =F 0.001 14.23 2.5 0.001 158.6
923.9 924.7 Single isomer
to

-'07-0,
_,-/-N sro
F1,...(N 0 HNk,
590 A F (;)
14 NTh,F 0.003 24 1.7 0.001 59.4
938.0 938.7 Single isomer
N _._.
40 N\ 11* "Ti."'
4-o
__/, or6
__-/--N 6=ro
0 HNse.,/,µ
591 ),--M F (r)
H !4M,F 0.002 43 1.6 0.001 159.4
938.0 938.7 Single isomer
N ,
4--0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
F N
F"---- I F
-N N
=(ft \ . , ri
)....0 "W'''' N )
592 NH ?-0
0,,N F 0.007 53 4 0.001 151.3 923.9
924 Single isomer
C:)
J.
p HN,..-
"1
o0
F N
F,¨ i F
= /N
N Firl.===\F
593 NH tO
0,,N---TF 0.003 59.04 9.4 0.001 209.9
923.9 925 Single isomer
0..(
J

p
HN -17
9,L0
.. j, 07_6
= N
F 6,ro
1C-)11 HNse.õ,/,
ON F
A 0.002 9.6 1.3 0.001 3.1
920.0 921 Single isomer Th,
N...
40 N\ 111) "N
4_0
, 0 6
¨I, r 6
F,., 7- N sr.
Flõ../1-:0 HN/,µ
595 N (:)
H N--\.,F 0.001 0.9 0.001 5.4
920.0 920.8 Single isomer
6
Fµ, z-ti ,ro
Flõ.p 0 HN.,,...,õ(
596
F F
0.005 9.18 0.001 134.8 936.0
936.7 Single isomer
mp
141P N\ 11. \ N F
.<-0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
1a 1aY93H 1aL31V lb 2b Calc.M.S.
[M+Hr Designation
F
N
L-14 Ni 0 \ =
597 NH 4-0 H0-1N-> 0.002 31.3 1.18
0.001 5.7 866.0 866.7 Single isomer
0
).
,0 HN, -1
9c,
_
F

111
-4 ri ii
.....0 -"w" N 7 N
1-13''''
598 NH ---tc 0.õN--) 0.002 35 0.5 0.001
2 866.0 866.7 Single isomer
O
).,,..-
,0 HN )
.....i or6
tõ.., _-i--ri 6=ro
Fv. N 0 HN,,....,1µ.
599 ,--11 =:-. - 0.020 6.69 0.001 168.7
938.0 938.8 Mixture of
F H !*1(F isomers
N ,
_?-.0
FFrrrOHN 6sr.
FiNse,,/,
600 >,--M cr
F ii !.I,F 0.001 2.53 0.000
111.3 936.0 936.8 Single isomer
N ,
0 N\ * "N
--/., Ord
6
F, A sr0
Flõ,..110 Hkrols.
$0
601 N', F ii Vm,F 0.078 6.53 0.001
251.8 936.0 937 Single isomer
0 I* F
01-N--.
<?-0
_j_ 07_6
F, :Cm 6,ro
F1,.../4 HNse..õ/õ.
602 ),--M0 F =::!,1--% F 0.017 19.79 9.6
0.001 58 938.0 939 Single isomer
li
N
40 N`i 11, "N
_to
_,,....g
0
F, z-ri 6).0
F1,...N 0 HNf,
603 SA
ON F 0.013 18.78 7.4 0.002
517 938.0 938.6 Single isomer
F H
N ,..-
\ ¨ N
4-0
'

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la I aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
F
N
Lii
604 NH t 0 7),N-> 0.014 0.008 852.0
852.8 Single isomer
t::)
). ,..-
,0
9,LO

Lt4 N ii \ * ,N1 ..... 0 ""w" N
ti---)
605 NH 4-0
0.003 21.58 1.9 0.002 2
848.0 848.8 Single isomer
Ci=(
),
,0
=
¨ ____________________________________________________________________________

__/ 0,...0
6,ro
CN-1-0" HN(
606.--14 (:)
H N 0.002 15.22 2.1 0.001 2
834.0 835 Single isomer
N- i \ ,dNWa N3)===
lir N 1,1 1
to
Lni Vi
=ft \
.....?-0 -.., N N '...=\
607 NH ___?- 0 H
01, N---/ 0.001 16.54 1.7 0.002 7
848.0 849 Single isomer
0-{
),

,0 HN,..-
-1
___4, oNr0
6 0
c....rH sr
<til 0 HI.1.....&
608 I'll cy(
H N
14 0.002 4.62 3 0.002 12 834.0 834.8
Single isomer
- rilli \ N3-1..
qir N \IMV 14 I
t
F
"-14 ril ral \ . 'Nil
>....0 "== N N...µ \
609 NH to

H
0.1, N-7 0.002 24.89 8.6 0.003 71
852.0 852.8 Single isomer
0-<
).
,0 HN =-1
6=ro
iiNsej\
r-N___,-- V F (:) N---\
Mixture of
610 M 0.009 35 1.4 0.003 3.9 900.0
900.9
,-.4 ri, 40 \ . "N "'"/
isomers
....0 N 0
lo,NH
d-
p

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1aL31V lb 2b Calc.M.S.
[M+Hr Designation
, Oro
6sro
(N-40 HNk,
611 ,--/1
N õ
my.i.D1 0111.950 27.45 1.95 0.200 12
884.0 885 Mixture of
isomers
ID N\ \ N
2-0
N' µ14
C-12-1-1 z
r * IN
612 N-TO ri--..- 1.950 241.5 7.47 0.200 200
846.1 846.9 Mixture of
---TIL-NH 0.TN-,/ isomers
0
a, HN y
9
90
0 6
6 'r 0
CN---(0-"
HNI....4,
613 ,--/1
N õ ,a,.. H
0
N,r10 0.023 359 10 13.2 884.0
885 Single isomer
lir N\ lik \ 'N
2-0
14' µN
\--/
j,
,
HN,..õ4,
\õ,=1 0
A 0-(
.4,. 0.004 12 10 9.8 884.0 885 Single isomer
614 NV.-
Ir ti IIP "N
/4-0
N' µN
C?-l-1 / N
r *
615 N,r0 N-1 ...= 0.016 190 9.11 0.003 46
846.1 846.9 Single isomer
NH ,J.
cyr.i.,...
---r'.--
J. HN y
09
00

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la 1 aY93H laL31V lb 2b [M+Hr
Designation
N /,N
, *
616 Cr.iL0 ri--,.. 0.003 23 14.92 0.003 58
846.1 846.9 Single isomer
NH
ON..)
--1,1- )
Oj'9 HN -T-
/N
617 111.Th 703.9
704.9 Mixture of
-r 0r14_, isomers
(LI<
>r0
'0
C:0 d
..../NH 0
HN\.../
Mixture of
618 o 1.000 152.82 832.0 833
0,( \
Cil...,1,N.µ11/ *..!l . Itri,...3N
isomers
\ i
' N
ciL --0
(:) Mixture of
619 ,---,N; ,m *
N I:) 717.9 718.9
isomers
'MN /11,(1-01
\ I:I
N / N
620 F.-d-c= 0.024 6.22 32.8 0.003 >200
882.0 883 Mixture of
0,-N.y-F
isomers
--(1NH ..1
09HN .-r--
,t '
9 0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb 2b
[M+H] Designation
'0
C:1
NH (:i0
)"** HN\..."
621 o
N 0.004 34.08 14.7 0.004 43.5
832.0 833 Single isomer
0 '
---.1 , ii pjyri
\ i
' N
'0
.0
NH c:i0
o HN\.../
622
N 0.005 >200 9.9 0.003 47
832.0 833 Single isomer
C) x
sTh-NN
\ 1
' N
N /,N
, *
623 d-o ti--==== 0.006 >200 6.6 0.005
92.2 832.0 833 Mixture of
0,- N../ isomers
'-===NH .1
0J,0 HN y
9.t0
N , *
/ N
624 d-FOI il-1=.=µ 717.9
718.9 Mixture of
isomers
-r __.
()I< /-N
>r0
.>(
ON
625
411 N\ * \14 > 2000 > 20000 557.7
559 Mixture of
isomers
N-- 6-0

CA 02811 662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb
2b [M+Hr Designation
FC?-11
N.TO ili....\F 0.007 41.8 5.3 5.000 >200 904.0 905
N H Mixture of
626 F
05,14,./=F
isomers
---r-
0J..0 HN y
MN = N
1
627 F(12-1 , 0
/N
Mixture of
789.9 790.9
rs
0.1<
,,F
F N,r0 isomers
0
>co
6)00
H Nµr...,4,
(:)
i'Vf F !,1---\ Mixture of
628
`4 N a \ . !-ii----x 0.296 >200 29.1 0.066 >200 864.0
865
isomers
>.....0 "gr--- N ' N
NH <?-0
(:)
,0
ll
0 N\ IP,-r----N L.
629 N 6-0 \ N cj-cN--10 . 3.000 1086.62
614.7 615.8 Mixture of
H
isomers
0-
,....../V * N
11 / N
/ * i
630 F"cµN.T0 0.045 1.45 45.877 0.005 >200
868.0 869.1 Mixture of
isomers
---1,-- NH .
00
N r * / N Mixture of
631 F'el IP 1.1--"' \_ >2 >200 > 200 >2
>200 753.9 755
isomers
't o wy-F
0-1 I'
>ro

,
CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs
. MS. Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b
Calc.M.S.
[M+Hr Designation
N , *
632 Ct,?:-. [4-..-\ 0.003 >200 2.1 0.004 54.1
832.0 833 Single isomer
0,, N.,/
-Ill NH -I
01.0 HN y
9-k0
633 thl ilj.,.\ 0.003 82.89 14.2 0.003
53.1 832.0 832.9 Single isomer
0,,N,./
0.1.0 HN ",r-
9-k0 1
634 F-Ce1-0 Fili""\.. 0.036 1.87 89.97
0.009 >200 882.0 882.9 Single isomer
0,-W./ -F
lel-NH ..J.
04'9 HN y
9..k0
N ' 0 / p
635 F"Cr4 -0
ON0.277 1.26 35.724 0.008
>200 882.0 882.9 Single isomer
,./ F
`-r1- NH ,1
0J..0 HN yy
9-k0
* z N
Fd- o636 F ..T.T.,
NH
0.1.0 Nj.),F
0,...N F
--I
HN y 0.012 86.77 3.2 0.004
>200 904.0 904.9 Single isomer
9..0
F(Thi--N
637N 0
NH
04'9 N"--D,F
0,... N F
,i
HN ",r 0.003 78.42 22.7 0.002
>200 904.0 905.1 Single isomer
0=ro
H Nse..(
Fõ r..-14 1 (:)
s 4--
638 H
F 0.050 4.6 21.7 0.007
47.6 920.0 921 Single isomer
L-r,c 'N di \ 11.--7
N
/=.t0
ONH
,0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V, lb 2b [M+H]
Designation
6sro
HN ...,,/,
C:: -
F4 1
639 MP' F 0.008 26.9 0.005 41.9 920.0
921 Single isomer
Lri 'N
)_.0 .4.. N \or' "N
0.< N N
p
O
1::)
>,.. NH
0
/-N H
F''N.==L-04 * N
640 N / z 4 / N 868.0
868.8 Mixture of
ti24.%
isomers
ot.N.../ F
..1
HN ",r-
9.t0 1
'0
(:)(
>,,../NH
0
c"....ii_ MI * õN
Mixture of
641 N * / N 832.0 832.9
HiCr- \
isomers
0,..N.,/
.1
9-LO '
'0
sCi
>.,../NH
0
N

F,C,,ql, * N
642 N ' r 41
/ N 868.0
868.8 Mixture of
isomers
io.,,r--
NF
HN "
,I.
,
00
i
b
c:,
.., ..,NH
0
F'C"---/ * rt'l
Mixture of
643 N ill / IN 868.0 868.8
isomers
-I
HN y
90 .

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
[M+Fi]
Designation
'0
0-(
>,," NH
nOH
F".-=\-N * N
644 z N
r4 / 7 . , 868.0 868.9
Mixture of
isomers
N.--..).
01õ,N F
HNi '''r---
00
I
O
0.<
),..iNH
0
cl,* , pi * N
645 -1-4 / * -- N 832.0 833
Mixture of
isomers
0,,./
N
HNJ.
'''.---
I
O
(:)
>,. NH
o
(NL=rm *
N
646 N 7 0
,/ N 832.0 833 Mixture of
isomers
0,, N..../
J.
HN
90 i
b
0.<
>,.. NH
0
cN).....114 *
N
1
647 N / 0 / N 832.0 833
Mixture of
isomers
N-.="
0,,N...../\
J.
HN y
'0 N,n
C:.,NH \ 'r4 N.1..._ ...L
648 '0H iii . HNf0
H
14 N "411P-v =N 0 1
0.340 38 34 0.006 67 882.0 883
Mixture of
(-"
isomers
I 6-0 0-

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b [M+H]
Designation
6,r0
HN,,...,4,
o
u _n
14
649 0oll* \ I; ¨ 406.000 2295 882.0 883
Mixture of
0-
H 0 HN-to
C-
/ N r"----
N-A-eil
isomers
. .
F
0 NN)
... _;...i
,,,
650 ro , al \ =
ti O `
HN 0 $##t 274
--r 918.0 919.1
Mixture of
isomers
,,L....<, I6-0 0,
F ' N
0.<b ci
....INH '0
HN,.." ... Mixture
of
651 )-o 0.003 2.42 20
0.005 46 836.0 837
( .". ,m/ I.N C.1- \
isomers
-1-1 0 Ply-c3F4
\ i
F s N
NQ
\ 1
0 HNi
652 -o II) 0 N 11 4-lt' > 1 > 100 > 100 0.022
> 100 882.0 882.9 Mixture of
isomers
0 .....0 HN \ 6o
--S N-76N
c)
6,ro
HNL,
0
n4.1 1 H
Ny-14.)
653 N ri di \ iii \ , 0.002 0 0.002 4.5 966.0 967
Mixture of
.....0 "4117- N 0\lmv N
isomers
NH
0-c.
$
,0
0
F4
F F

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[WM Designation
.0 N,,n
04,NH \,,
'Ili 7..,_....L
.cro ti imi *H 0 1
654 r-N N 4w N HN...t0 0.037 > 100 37 0.003 65.2
882.0 882.9 Single isomer
l____õ)¨<=pi I d- 0 0-
04,NH
655
r-N N '11w N . 11 o'¨f-'`
HN_To 0.673 > 100 42 0.011 >100 882.0 882.8 Single isomer
I 6-0 0,
Oro
HN.....,/,
0'4
F H 10
Nõ(- Mixture
of
656 Lt.; N 0 N\ * \ IN 0.006 5 0.2 0.003 1.9 930.1
931
isomers
).....\0
4-0
(:)NH
,o
,o
6=ro
HI.c...,(
4;)
F
Lt.; N 0 \ ilk \11,,--(it\ Mixture
of
0.007 4 0.2 0.004 22.8 984.0
985
657
).....\/0 N 0
isomers
NH
(3.
.C-
,0
0
F4
F F
6,ro
HN2..õ/
140
F,n-141 I F _ ii)....)
',F
658 N N iiii \ \ N 0.004 0.2 1.6 0.004 30.5
1020.0 1021 Mixture of
......0 ''= N
ow isomers
NH
C:1
4-
,0
F40
F F
6rO
HNr./N
F4 1 0N\
LN, ri ial \ * xlic,./..F
Mixture of
659 j\,...\o ..= N
4_0 0.006 1 7 0.002 42.9 1002.0 1003
isomers
ONH
,0
0
F F

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
O
0-(
NH 0
Htl\.....,
660 o 0.006 8 5.7 0.005 43 836.0
836.9 Single isomer
CM,a* ,N 0' x
-Th-N * ii,r_c3N
µ i
F ' N
-
O
(:)
>,..,NH 0
HI.1\....,/
661 o 0.004 >100 11.8 0.004 25.2
836.0 837.1 Single isomer
,c,,11, µ III = N 0' '
-Th-N , * itr,c3N
\ t
F ' N
F
,o
N :-1
(:)NH \ 'r--"'N
662 'Yo
N Cr \ ip
,- N 440"-- N 11 CdTh.'L
HN 0 0.260 62 59.6 0.013 > 100 918.0 918.9
Single isomer
.L___,---<\ 1 <So 0-.
F ' N
6sro
HN,rod,
F0'(t.1
ML
, --\
== F
663 Lri N ii \ . \ N-c--/ 0.004 1 0.3 0.004 14 966.0
966.9 Single isomer
....0 "'w" N
4-0
NH
0.<
,o
p
6)-0
HN,,..õ/N
664 Lri N 0 \ m- ;----/ 0.002 16 0.2 0.002 8.3 966.0
966.9 Single isomer
)...0 N ow
NH
0=(
Cr
-0
0
F4
F F

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
[M+Hr Designation
6..ro
HN,,....4.,
(:)
n4.1 1 H N---\
665 N ri iii \ -. \N,T1-.--/ 0.005 6 0.2
0.003 2.9 966.0 966.8 Single isomer
.....-0 w.". N 0 '=E'
4ONH
C7
O
0
F4
F F
,
N,
ri &Th,-L
666 -o Ill
0 N\
30 HN 0
-1"
0, 1.000 > 100 > 100 0.000 > 100 918.0 918.8 Mixture
of
isomers
0 .H0 HN \
---";
F
.....1 or 6
6=r0
HN,,,(
- )7-14 0-'4
H N--\
N , Mixture
of
N 940.1 940.9
667 =ir"`""
\ N
isomers
4-0
0
F
0 N,õ__...CS
04 NH \ 7- N
668 \i"Kr0 H b. , *
11 0J-i `
HN 0
-f 918.0 918.9 Single isomer
FL('N I 6-0 0,.
__,, 01_6
6
=ro
C.N---torl FiN,/õ.
F (:)
my,...)1 0.005 0.6 0.2 0.003 0.7
930.1 930.9 Single isomer
669 N..- ,Ai.,..
IP Il . "N
4-o
p
j, or6
6,r0
C(N-tc;Fil HN,,...../N
0'(
670 ...Nil-, ...õ F H
IP N\ IP.4_.r.1..): 0.006 5 0.2 0.005 2.9 930.1
931 Single isomer
4-0
,0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V , lb 2b Calc.M.S.
[M+Hr Designation
0 A
-r
HN/,
N_- .Ai. up,F
671 IP N\ =\ IN 0.016 0.6 2.4 0.005 52.5
1002.0 1002 Single isomer
4-0
F40
F F
--J, 0r6
,,N 6'r
0
F, ..4 11
N 0 HN,r,j,
\1-14 C:.
NI.- H !.1.,F
672 01 N\ .4, "../
\ N 0.006 0.22 2.1 0.005 26.8
1002.0 1003 Single isomer
4-0
0
F4
F F
HN.../
673 F
Lri iii a \ . =i-,,---,N - 0.00685 1.4 0.1408
948.0 948.9 Mixture of
isomers
..._(0 ''= N
0
4::)NH
,0
F
0,ro
HN
o0 -
Mixture of
H N---\
0.01579 7.862 0.1396 930.1 931
674 LN' M gi \
isomers
o
w \ N
(:)NH b is
,0
F
,
Oro
HN,r,õ,(
0'
1
675 ti \
ft \ ft N-c,
),...0 -, N o'mv 0.01313 5.192 0.1423 980.2
981.1 Mixture of
isomers
NH
Ci
.C---
,0
0
C)

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb
2b [M+Hr Designation
Oro
Hkr.õ4,
(:=
r\
Lii pi
o ft \ = \N-r,----/
)....( -w--- N
4-0
Mixture of
676c;,NH 0.01146 9.211 0.2883 1032.2
1033.2
isomers
,o
o
o
d
6,ro
NN,/,,
F,r-v3 1 F 0J,
H !4Th.,F
i-1N1
677 .....?-o
NH
4-0 0.02203 0.1319 3.906 1078.2
1079.1 Mixture of
isomers
c:)
,o
o
S
o
b
6).0
HNsr.õ4,
F H
)..N' 0 II 110 N\ IP \N-11N)...)1
678 4-o 0.02197 5.034 0.3629 1042.2
1043.1 Mixture of
c:)NH
isomers
p
o
o
o
_4. oNr6
6,ro
F.\., _TH
N 0 H Wr.õ4,,
IA 0J= . __\
N ,
N...f.-Z./..F Mixture
of
679 ir N\ . \ N 0.01418 0.1566 2.77 990.1
991
isomers
4-0
0
S--
, Oro
6sr0
---'"r-11
C N-40 H Wr..4,,
,--II F C
680 r(
N , Aõ,.. usi h).4..)
0.01 43.4 0.5746 972.1 973
Single isomer
4-0
o
S--

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b
Calc.M.S.
[M+H] Designation
ONro
6,r0
CN-I-roll HN/õ.
F
N ,
681 0 ,=\4
\ N 0.00981 4.784 0.2061 972.1
973 Single isomer
4-0
0
S-
6,r0
HN.,....j,
03 .
F H N---\
682
4--o \ N 0.0088 3.58 0.1225
974.1 975.1 Single isomer
CoNH
,o
o
0,
6)(:)
HNse...,
(:) .
F H N--\
LH' di \ \N_It.../
,
683 ).....c)-o N -w-- N 0,w, N 0.05331 18.5 0.3538
974.1 975.1 Single isomer
NH
0.(
4--
p
0
S
q
11 0-
- N N 0 \ * / NHO Fr:I-P\r
\ 4H
684 =

N
0.00554 0.09471 0.02844 954.1 955 Single isomer
/ µ.1.
(:)
p
,o
M
H 2-
I F
=/ NH07...-y
685 \__zNH
o N 0 14---1 0.01215 2.5 0.16
954.1 955 Single isomer
/ '
(:)
p $
,o

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
0.(:)
HNx.,,(
I F 140
ON
" F
686 LW ri 0 \ * \ IN
0.00799 0.01904 1.958 1002.0 1003 Single isomer
).....0 ""Rr N ow
(:)NH
,0 $
0
F-1
F
0,ro
HN.z.õ(
F ON
687 LN' N ii \ = \ 1-1.--/,F
)....0
4_0 0.02801 0.197 2.78 1002.0 1003 Single
isomer
NH
o-
,0
F_(0
F
6sro
HN,,...õ(
0'4 .
IH
688 L-N' q iiii N \ .
,
4_0 NP'F
1
\N 0.00919 15.96 0.9876
984.0 984.8 Single isomer
NH
(:)
,0
F40
F F
6sr()
HNseõ,(
(:)
N--\
689 N *I \ = \N ,,-f` F ...-'
)....(0 ..w N
4-0 0.00254 1.935 2.455 984.0 984.8 Single
isomer
NH
0=<
,0
F,(0
F F
0sto
HNI....4,
F4 1 F 00
yi...)/
690 Lni ri ii 0.00529 0.6467 0.9878
1002.0 1003 Single isomer
0H =N
N 0'w'
0NH
.C---
,0
0
F4
F F

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 pips . M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
(m+H)
Designation
6=ro
HN/,
FN 1 F HON
691 Li'l 11 N
N
0 \ . \--r-- 0.00274 5.758 1.067 1002.0
1003 Single isomer
.....ID N 0
NH
O.(
$
,0
0
F4
F F
6=ro
HN,,...õ/õ.
.0
F
692 Lri ri so \, Ny--
N -/ 0.01126 0.3635 0.7222
1002.0 1003 Single isomer
\
>.....0 N 0
ONH
Ct
,0
0
F4
F F
6sro
HN,,...,/,.
0'4 .
F
=F
693 N\N-c--
).....0 N
(1 0.00297 1.13 0.5323
1002.0 1003 Single isomer
0
NH
,0
0
F4
F F
6,ro
HN/N
1:1 -
694 1--N' N 0 \ ip .11,-- 0.00191 1.68 0.4014
928.1 929.9 Single isomer
).....\)-0 N 0
0.(NH
Ct
,0
,s
0=ro
HN4.,
¨(11 I H
695 nN \ N
11 0 * \ Ir'"'"/ 0.00523 1.498 0.2222
928.1 929.1 Single isomer
0.(NH
Ct
,0
,S

CA 028116 62 2013-03-19
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359
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la , laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
6sro
HN,,...õ(
F.

1 H
(:)
696 N ri di \ . \NP.F 0.7761 14.77 9.446 934.0
935.1 Single isomer
1
C:INH
6
,0
OH
6õro
HN,õ...õ/õ.
F,n-1.1
697 N ti iii \ = \i=J'F 0.2843 0.8465 13.44 934.0
935.1 Single isomer
os'w
NH
0,
6
,0
OH
cio
HN,,,k,
(:)
1.1 N0 \ . \/li,--ri
...?\.0 -,-- N os÷"
698
<1--- NH
0.02305 48.17 0.1533 1032.2 1033 Single isomer
(:)
p
o
S
o
d
6=ro
HNseõ,4,
II
).....0
c_o
699NH 0.02112 11.47 0.229
1032.2 1033 Single isomer
,o
o
o
d
6).0
HN(
F,n--(14
700 N 1.4, ai \ . Ny"-",/ 0.02385 0.4835 2 978.1
978.9 Single isomer
....o "gw" N \ N
NH
0'
,0 0
0r0
HN,)....d,
(:)
Fõr,-vi i F
701 1-1,1
N
4-0 0.02913 0.1689 3.14 1008.1
1008.9 Single isomer
ONH
p
o
----

CA 028116 62 2013-03-19
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360
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
0õro
HN,,,,,/,
F,r-vi 1 F 10 -
H N.--\
702 LN¨N \Nii--"--7
)....c.
4-0 0.06167 0.06878 1.535 1008.1
1008.9 Single isomer
0.(NH
,0
0
S---
coH
703 b 0y 0-N4 40 \ . , --i,;=-=
N 0.130 0.52 0.094 1058.2
1058.9 Single isomer
S
O
1110
'
0 H
[ yO,
!
140 ., .1 1
F
704 0-14 L-14' -H 401 \ = \ )1---N 0.031 0.4 0.036
1058.2 1058.9 Single isomer
N
0
S
--C3)
1101
6r0
HN,,,,4,
Cr( .
F
HTõtol
n-11 1
Mixture of
705
N N ift \ `'w N , 940.1 941
isomers
\ N
$::/NH
,0
:..:0
-pi N N
).....0 N 0`mr÷ ti-j''',1>
706 0.007 58 3.447 0.002 11.9
902.10 903.4 Mixture of
0:1NH
HN ,..- )-
isomers
9)..0
-14 N 0 \ = , N
).....0 N 0 ti-j...)
707NH c, ,,N 0.017 3.414 0.001 8.3
902.10 903.4 Single isomer
C:1
8' J _.-
,0 HN ..1

CA 028116 62 2013-03-19
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361
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. .
CalcS.
la laY93H laL31V lb 2b
[M+H] Designation
-14 ri
,.....(0 N 0 ilj..)
708
80N 902.10 903.4
Single isomer
ONH
).
,0 HN -(90
=r-N
6,ro
HN,r4s
)7-0 0
709 H 1 --1.1 0.008 91 1 0.005 9
860.00 861.3 Mixture of
N , isomers
"Ni
c?-0
,
-OA *
1_9
0.
11
N 0
NI_ --- 0 1
710 N , 0.050 >1000 21.6615 0.016 890.515 977.42 978.7 N\
IP '
Mixture of
\ N
isomers
6-0
0 6
0)00
HN,r .1.µ
711 i-il
N _.Cr(
m . 0.019 5.02934
1.9555 0.002 25.9449 909.45 910.7 Mixture of
isomers
\ N
6-0
j A
.0 1¨
o0
CNN H
10N sr0
N,r,,õ/,µ
....--11 04' Mixture of
712 N , 131.D( 0.019 2.93552
1.9555 0.007 22.3421 909.45 651.8
isomers
40 N\ 41"N1
d-O

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
362
EC50 EC50 EC50 EC 50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la , laY93H laL31V lb 2b Calc.M.S.
[M+FI]* Designation
'0
n.4.
=-' NH
Nr.''Cr0
N N
(
713 -1i--' N 0` . / 14.
N 0.019 11.559 3.693 0.002 37.251
849.40 850.7 Single isomer
\--0
0,N
).
HN ."1...,
o,L.0
'0
,-,-4
=-= NH
N N 1
714 -li--' N 0\ . / II
N 925.43 925.8
Single isomer
0,N
J
HN -1
9,L.0
'0
,,J,
=== NH
),"Cr0
N N
r 1
7150
` I* / _,
N
N 0.002 18.59 9.11 0.002 85.53
925.43 925.8 Single isomer
0,N
).
H N -1,
9,L0
0sro
-qi 0 HN,,,,/,µ
716 4
_, H
0'4 n 0.016 > 50 27.49 0.006 15.61
909.45 910.8 Single isomer
N
1, N...r---..v
01 N\ "N1
6-0
HNse,,,(
c:.
717 r=I '-,11
li v--\ 0.005 6.23 981.72 0.005 130.23
909.45 910.8 Single isomer
\ N
6-0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
363
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
,
.>(0
N 04,r
-------<, I H "\
Mixture of
718 -N N a \ . \NT:-"=/
N 6.200 17 441 795.41 796.7
(:)0 -.--zr-
isomers
6-0
A-
, N
t-N N
111P \ =li,
(:)0 _ N
Mixture of
719 6-0 N
0.-r.1) 574.000 996.05 811.39 812.2
)\-- -1.
isomers
>1,0
09
C<N-1,0 ..(
720A o-? 302.830 10000 801.36
802.2 Mixture of
N õ..
.i., myis)/
isomers
11P1 N 111 \ N
6-0
02
CN-10 Clc)N)
721H P 2.000 36.79 890.43
891.7 Mixture of
.. .
N
isomers
1-1P N\ 1110
cso
=
(N 0
--I N N
722 Iv N 0\ 111, /1 1.950 188.88 989.51
990.9 Mixture of
N
isomers
6-0 N-
N).ii>
0
4 1
-(c)
ON
c_.)-- 1 H
N-
723
N 0 N\ IP 667.33 668.3
Mixture of
\ 6
isomers
6-0

CA 02811662 2013-03-19
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364
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
HON---
724 (r N 5
Li \ . N.T.".../1
\ N 945.51
946.3 Single isomer
N..8
, jo
n¨,!4, 949.39 950.6
Single isomer
725 b_10 N 0 N ik \ . ,N ,
'LIPP" N \ N
N'8 6-0
M,i'...., 803.36
803.9 Single isomer
726 N ri di \ I* ,
\ N
8 --.."" N 0
e
6,r0
HN ,
Or
H 5
727 n_NI li n 825.36 826.7
Single isomer
... o N\ II* \ 11- -
6 _ 0
NH
0.<
,0
c,)..a
-13),-0,
N
728 s c--Nr-N a 965.44 966.7
Single isomer
H
.1-111r N w \ N
ti /Th, 6-0
\--0)
Mixture of
729 L-ri Fri di \ io \ ,r,---/ 0.013 47 12.2 0.009 12
915.41 916.4
isomers
)....0 *---- N 0
0-(NH
6---
,0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
365
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V, lb 2b Calc.M.S.
[M+H] Designation
6=ro
HN ,
OX'
730 0.016 > 100 1.6 0.009 0.254
853.39 855.4 Mixture of
N [I aki-ri----/ isomers
/\...0 -.-ar- N
6_0
NH
(1'
,0
CQ 11
731 1-14 ri ilk = /1-il-4-/ 0.013 4.287 0.2 0.012
1.031 923.43 924.5 Mixture of
\ N
isomers
).....0 --04,- N ow
014H
6.--
,0
732 Lt.; II a \ ip \Nii------ 0.029 55.72
0.39 0.019 2.354 913.46 914.4 Mixture of
isomers
)....\,0 --'-mr" N
6-0
Or'iH
,0
6).0
HN,,..d,
00 -
0.371 >100 44.8 0.035 32.027
766.36 767.3 Mixture of
isomers
L it til Oil \N lc'', /
0 cs.0
6,r0
HN,,..õ,/,
0'4
H N--\ Mixture
of
734 r . . . . ,,,_ ...eNN 1
N 0.008 0.71 0.19 0.009
0.9 923.43 924.3
'0_10- IL: H 410 N\ 110 "NT "....f isomers
N--ru
H

)0

CA 028116 62 2013-03-19
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366
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
, la laY93H 1 aL31V lb 2b
Calc.M.S.
[M+H]
Designation
Oro,
FiN__Ny
.::.
735n-441
N N \ H

N 0.008 19.11 0.008 1.911 913.41 914.4 Single
isomer
c3-0
-C) NH
0=(
,0
0, 11
111714.5
736 b_10L.i.01.41 0 \ . N
s 1 0.005 49 1.7 0.006 41.4 933.45 934.7 Single
isomer
N s N
q --,
__i-0
0 ....1
6,r0
HN,..õ J,
0'
N 1 H !,1-- \ 0.018 11 0.2 0.010 913.46 916.4
Mixture of
(Ng
\ isomers
0 N 111, \NIX4-4.%/
6-
N ,
HC),T)13
, 1
N
738 b--µ0 l'Cr N 40 \ 1, , 965.44
967.5 Single isomer
N \ N
N d-0
0
j 0,6
CN 0 HNz.õ---
-il
739
N , .,. mO
909.45 911.4 Single isomer
IP N\ * \ N
d-o
A Oro
Coi'H H1,1...õ.
.zC
, N
H
0 ikl-- 0.007 32 1 0.004 16.8
909.45 911.4 Single isomer
740 N-
N.-{,.../
0 N\ * 1
\ N
ec,

CA 028116 62 2013-03-19
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367
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
4 H
F47.1)15
N
741 b_--/\'
id-N" 1.1 illp N\ * \ ;,4 0.011 97 > 100 0.005 60 877.39
878.3 Single isomer
N
H ', <73-0
l>
0,ro
HNs _..j.µ
742 r---__<1,41
c,4,) 0.016 7 0 0.007 5.2 915.41
916.4 Mixture of
b-Nd.--C) = \ IP \ ;.1
H
isomers
)..,__µ__ c?-0
%__.1
.>(0
0'4
ril 4111 N\ lip %.--1-1-'"=/ 128.990 678.6
767.38 768.4 Single isomer
0 u 6-0
A-
0,(:)
HN OH
N N "---1-i observed
",/, > 1 > 100 85 > 1 > 100 885.38 Not
Single isomer
0 "...." N \ N
HO e0
OK
,0

CA 028116 62 2013-03-19
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368
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b
Calc.M.S.
[M+H]
Designation
b_i---a. C H 4\ * /N
N(- N\-0
745 H ",-- IND 0.014 3.18 0.8 0.010 5 847.40
848.5 Single isomer
) O HN .õ-
'."1
o0
0C¨<1
0 r.\i ip N-tõ , ,
746 N , -0 ,... \
HoINJ 0.082 3.45 0.4 0.038 5.9
889.41 890.5 Single isomer
0
O cr3 -pro-
b_0-14 N 0 \ = /N ,
µf4--/C) N
747
-0 11"--- H -,
i> 0,,N) 0.014 41.65 9 0.010 <100
803.38 804.4 Single isomer
J
HN -1..,-
. . _
-4 ri 000
).....(c) 11-1-2.>
748 NH 0.022 92.12 2.3 0.017 16
837.38 838.4 Single isomer
-0
0.(' ON
0 HN ..,r
9,.00..
Oro
NN4r
r--v..(P I =:).N
Mixture of
749 Li,i, Fri 0.020 20.05 0.3 0.007 6.1 897.42 899.3
,
isomers
-0 NH
(D
6-
,0

CA 028116 62 2013-03-19
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369
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
n441,1
=

tip ak,
0_102/to H
N , 1.1\-0 HT0N
750
CI ,
), ,,, 0.030 6.3 0.007 38.1 831.41 832.3
Single isomer
HN 'µ
9,,.., ¨
r--s___11
b_ick-ito 40\ . 'NN
751 ti,O-
_01N->r,
0.055 3.5 0.3 0.044 1.6 917.44
918.5 Mixture of
isomers
00
...7 0
(LW _ il ahm N
N8j \-0 N 1-)
752 C 0.227 > 100 1.6 0.038 0.6
869.47 870.3 Single isomer
oN )
iLli NI 0 N\ lp / ri
'-0 ti )
753 C 0..,,N_
,.., 0.021 1.5 0.013 4.5 837.43 839.3 Single isomer
9,I0
'4 N 40 . . , N
\_0
754 _ 10 N¨ 0.026 5.3 1.4 0.750 15 847.40 848.3
Single isomer
01'1H
p N 0
0 H
NI
c4LN'o'H 4 N * /N31, .,,
755 C tO HM.
0 14-> 0.200 >100 0.85 0.120 0.52 897.51 899.5 Mixture
of
isomers
1 )
W. ,

CA 028116 62 2013-03-19
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370
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
CirD
01'
H N---\
756 LN' N di \ * N=e"'"/ >1 >100 51.6 >1
>100 763.35 764.3 Single isomer
\ N
"--."" N o'w'
co
e
Oro
HI=1......,
0'4
757
N N 411 \ . !III "t"\ 0.009 16.2 0.85
0.410 33 853.39 854.4 Single isomer
\,...0 N
d-0
40.(NH
p
0)00
HNsed,
CP4N .
r<!4 1
758 ItrA. 0.036 1.3 0.12 0.120 0.36 923.43 925.5
Single isomer
b_16---NL. N 00 N\ ip " ,N
N--ru
H ,....,,, cr
,
6,ro
HN,,,j.s.
0'(
ti tit \ m_ 1.:,,, 0.015 13.5 0.33 0.090 1.5
897.42 899.4 Single isomer
\....c) ---"," N c7
-6 NH
0,
e
,o
0 H
iN44 C1,11..
760 Lni N 0 0.028 3.3 0.076 0.021 2 923.43
924.5 Single isomer
C3NH
e
,0

CA 02811 662 2013-03-19
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371
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
0sro __
HN,___.F
("N___j4 1
761 H r\
0.025 5.5 2.1 0.350 11
895.44 896.3 Single isomer
' ri ti ,,
itN =\=
),...0 ---..w
d
-0
O( /\
p
0(:),
HNs___Y
03
762 c>4.1
N ria\s Ny--""==/ 0.030 2.1 0.43 0.026 4.2
897.42 899.4 Single isomer
\ N
).....0 " N 0
fr:oNH
e
,0
0 õ
,r ,--0,
N
763 , 0-- 0 N 0.027 71.5 7.5 6.300 >100
961.49 963.3 Single isomer
k _.)0 H
MP.' N \ N
\.._..? %_..)
F
FO H
',.r-No,
764 b cv-r.; Fri a \ . \i. 0.010 14.3 0.21
31.2 1033.45 Not
Single isomer
observed
---mg," N
õt0
H r__\,.
\--,2F U
F
H , pi 1 p FF
0 E\ 10 CN, 0 ,
765 ,t_o ti--i 0 . 0.024 >100 11.9
0.004 15.3 873.40 874.3 Single isomer
A-N2),--o,
N
H
0
HNII ---( 0
766 N ,- di \ m- 11241-0 1.950 12.67 1.95
0.200 3 921.40 922.5 Mixture of
isomers
4,1Er" N \lwi "N
s

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la laY93H I aL31V lb 2b Calc.M.S.
[M+H]
Designation
N
H
0 4,1
--.-/ 0
767 N9 , 11.124-..{ 11 0.019 1.95
1.95 0.096 11.879 921.40 922.5 Single isomer
IIIP N\ cf
raL 0
1411P-
b_10,....
N
H
0
Hii
768
0.019 12.546 1.95
0.057 139.906 921.40 922.5 Single isomer
o
giL o
410-
e"o
Nt-
0
769 N .-- 0 N\ = \II ,,,,Fif 0 m 0.021 62 10 11.1
921.40 922.5 Mixture of
isomers
NN,
GT
. .
-0)4 0 N
N =
770 IN r.,N 0
\-0 PI NA.,11 1.950 17.34 1.95 0.200
178 831.40 832.5 Single isomer
),-o,
o
0
H w
, N
N c\N-i(C)--6
IP N\ 1110 \ IrN H
Mixture of
771 o 24.000 774.73 899.40 900.3
isomers
4
s ,
1.

CA 02811 662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
*0
OLNa F
H H
N H c\N,(0.-6
40 N\ H
772 0> 2000 > 20000 995.40 996.3
Mixture of
4110.
isomers
S.,-
0 .1
0.
OHO'F
-;r14
N ...\N=10--(.-
ID N\-4µ H
Mixture of
773 0 > 2000 >20000 935.40 936.3
isomers
S
*q.
o F
N cµN--( --f-
N\ * \ H
Mixture of
774 0 >2000 >20000 953.40 954.3
isomers
F
.>( N
0
775 10 N0 165.000 >20000 751.30 752.3
\-o N 11-4/}4 0
H

F 0
-0 ./.1 0 N =
,
N H
"HF:t6
0
776 '410 0.036 1.8 3.8 0.005 46.59
1109.40 1110.3 Mixture of
isomers
'0*
0,
F 0
-04 je H N
0 i0,41 N, "N H 0
Mixture of
777 4 0.007 0.6
0.8 0.003 28.18 1067.40 1069.0
isomers
s
F *

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
, la laY93H, laL31V lb 2b
Calc.M.S.
[M+H] Designation
F -.YO
H N
PO so \ la \ 6 H 0 14
F 0
Mixture of
778
* 0.005 2 0.4 0.004
27.47 1049.40 1051.0
isomers
s
_0 " ii, ,õ,,
AO N\ 11,
779 \ -0 8 pi 1.953 454.2 865.40 867.0
b41-11),-o,
o
.4
02
F,r-- \ 1 1 H
N-(11)
780 Lri N ft \ ft , i
ci0 ,-- N `sw" ' N 10.308 30.4 861.30 862.0
Mixture of
4-0
isomers
A---
O\ _,O
__,
F -YO
,_.? H r 4
I ,
0 .. . _ Ni i 1 ! T ( t 11-1'44.-r1"- .
0 N\ 11* \ 6 Mixture of
781 F 4-o 0.060 2.2 41 0.004 >
200 975.40 976.4
isomers
O' ¨,O
__.
/ 0
F --
sr_RNH N 1
782 -o 0.270 > 100 41 0.059 > 100
957.40 958.4
isomers
0\_,o_
---e, o
,
,iµ io \ = N H
,\,c\iN ,,,,,,;-0 N''-o'
Mixture of
783 d-o 0.161 > 100 31.96 0.053
38.607 939.40 940.4
isomers
O\¨..O

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure C,a1c.M.S.
1 a 1 aY93H 1 aL31V lb 2b [M+Fir
Designation
o-ANI=4 I
il
L) ri as 11; H 0
784 c-o 478.067 3990.18 825.40 826.4
Mixture of
isomers
0 o
\__,
_
F
0 N
OA 11 .4 I H \p,i._,O.--K..
NO N io N\ = ,,,_ii..; õ õ,
-1 A
Mixture of
785 .... --o 70.262 1071.01 843.40 845.4
isomers
0)40
\__,
F,__,
N
H
H 01
\ N. H 0
N 0W \ N Mixture
of
786 256.000 1270 841.30
842.3
isomers
IPrig s
F
101
Mixture of
787 F 0 903.000 1251 859.30
860.3
isomers
N
miL s
1.111-
F ----/ 0
-0 NH 0
- i 111.41ri)L -
o - N
ol. \ 'N Mixture
of
788 F 0.008 0.2
2.8 0.004 15.382 973.40 974.4
s isomers
(10

CA 02811 662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb
2b IM+Hr Designation
F -"0
H!.1 1
,.. \ Hpp.:4; q -
H 111D i,i olle \N
Mixture of
0.005 0.227
0.003 0.761 955.40 956.4
789
isomers
4P-
,irL s
.>(
0
F,r...-\ _11 i CI H 0, !kJ-
-Nr--NN-11
Mixture of
o0 ''w N \ N 619.000 1000 908.40 909.4
790 L
.-0 isomers
)\--
-N 0
,
1._
F t,r\ NH
1
I4N "2.(,TIIN i ilai \
/4.141-11:\."'C Mixture of
791 ,r0 H ir
6_.s-- 0 N 0.015 0.2 0.195 0.006 0.353 1057.40
1058.4
0, F
isomers
F (NH
til._3-4' it..,?...00
M
HN sr 0 n 401 N\ *
, H 0 Mixture of
isomers
=
F
11AH pi 1
CI
Am \NiN H 0
iiir N 1.7 Mixture of
793 F c-o 0.024 0.1 > 100 0.006 18.45
1022.40 1024.4
isomers
F --'0
NH Fl
pi i
p N
N H ..e----o=
0 4.,, \N, o r.
lir N W Mixture of
.794 F 4-o 0.031 0.04 > 100 0.008 10.43
988.40 989.5
isomers
-N\_/0

CA 028116 62 2013-03-19
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' EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. .
CalcS.
la laY93H laL31V lb 2b [M+Hr
Designation
'
i,
F ---µ 0
-02r11AH !,1 1 11,,--.' N)L-0.
F
795 13-- 1 1101 N ill \ 'N 1.69 1005.40
1006.4
o
Mixture of
isomers
4P-
F
N
itita
H
796 F "IlW N
O \ N >1 >100 >100 857.40
859.4 Mixture of
isomers
41P-
O
F
-0)rilsr.,00 !,i 1 ' )LO.
11,T,N-.(11
Mixture of
797 1 j'N * N * ' "
\ 0.023 2.234 0.26 987.40 988.4
N
o isomers
VP.. s
F H
I HIc\Nf-IN--
H L.5)4 so \ = N i H 0
798 N
O \ N
>1 >100 >100 839.40
840.4 Mixture of
isomers
ril S
WI
i-1 =ro
FFr N-40 HN,õ...,õ4,
799 - Ni
N , F C:i
H P:1,: 0.018 13.2 2.1 0.006 380
971.40 972.6 Mixture of
isomers
0 N\ 1, N-11-'-'.....7µ
\ N
6-0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
I a laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
_
F, )11 0r0
F
N 0 HN,,...j.,
Mixture of
800 N , F ii VM,F 0.005 9 9 0.004 > 5000
971.40 972.6
0 * " I,' isomers
cr
¨/0V 6
, I
.-til 6,ro
\ õ.p 0 HN
801 >4 o2..N., 1.100 403 63.5 0.020
138.3 902.50 903.2 Mixture of
14/.....- Ily.,2
isomers
ii \ N
0 * i
to
N
e i
N
0-1 0 N
802 r) \-0 ... F
0 N >2 953 1091 >2 430 727.30
728.3 Single isomer
'Pk

,=,,,
9 -
N
I
rii nal \ ip ,N 1
41111-1 N
\-0 H
803 01-N
). ....- 115.000 334.42 597.30
598.2 Single isomer
9 ...
-----
n-1.1
N 1.1 ip \ = , ri
....0 N rl-j":>.F
Mixture of
NH
804 ?-0
OTN 0.012 6 17.62 0.012 22 867.40 868.4
0.(
isomers
,0 HNY
1o0
F,,r-vi4
LW 11 0 ) \ ip , N .....0 N N ,
H-rj.: F Mixture
of
805 NH ?-0
OTN 0.031 0.6 32.69 0.010 85 885.40 886.4
(3.
isomers
,0 HN1"
9,1.00,
=

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b
[M+H] Designation
/N
q-c. N
VIH:}F
Mixture of
0 NH
806 to
0.1..N 0.021 11
16.84 0.016 12 883.40 884.4
-0.(
isomers
,0 HN'Llr
0,L0 0.
F,,r-v4N 1
Lli II 110 \ lik ,N 1
() H N.,:)..,
F
Mixture of
- NH
807 OyN 0.065
2.76 39 0.012 <100 857.40 858.4
0.(
)isomers
,0 HN ====1....-
9,L0
0,r0
HN,r,/,
C:,
808 n--1;11 , N
N 0 N 0 N\ . µ143,-L..õ)'F 0.009 11.82 10.9 0.009 92
839.40 840.4 Mixture of
isomers
-0 H
\-0 N
C:o
p
Fi..r 1
"ri N ion
809 )....0 N tO
Mixture of
11--.ii> 26.800 314.1 794.40
795.4
0 N
isomers
0.(NH
1-
,0 ____,0
F,n-1/4 1
N v, 0 \
810 ).....0 N M')0.036 14.18 58.24 246.6 849.40
850.4 Mixture of
NH t 0
0 N 0
isomers
t:)
,0 ,v...1-1 0
. , ri
>,..<0 N
811 --4:)
C:$3 N ---' 0.011 17.84 35.03 169.9
865.40 866.5 Mixture of
0.(NH
isomers
,0 HN ."C
o,.0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la 1 aY93H 1 aL31V lb 2b
[M+H] Designation
F,r_Nal I
1-14,¨N 0, \ = /N
),....?-0 N 11-..1)
Mixture of
812 ?-0
0.045 3.576 5.465 10.04 893.40 894.4
c:=NH isomers
,0 N =-=
H
CC03 5?-fs-
/N
ok) N
813 A- ---(:) :: F
l-
o ) N õ, isomers 1.160 11.25 794.40
795.3 Mixture of
HN ..1
o'co
IN___dki 1
b&0 N
N
814 N /___\.. to ii-1.->F
0.r., 0.035 1.72 4.1
). ....- isomers 0.21 893.40 894.3 Mixture of
\-0) HN -1
n--(41,1
b 0 N0H 0 \ = "N
-1N-7\- N
',
1> ?- 0 11-.1)-,F
0.020 3.76 36.2
) ,.-- isomers 150.3 849.40 850.3 Mbcture of
815 H
HN ..)
9,L0
n--(1'41N 1
O
.,...,,o N
N-ji>.F MiXtUre
of
816 -0 NH
C:7$ t
0,,N 0.042 2.57 12.3
). ,..-- isomers 42.46 867.40 868.2
0 HN '-,
910
j, o
Nrc;
6=ro
CNI-01-1 HN,r.õ/õ.
817 ,--II
, F
N C:)
H .,F 0.001 0.4 2 0.001 5.7
896.02 897.0 Single isomer
\ N
tO

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
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.
EC50 EC50 EC50 EC50 EC50 Obs M.S.
Isomer
Cmpd # Structure CalcMS
la 1 aY93H laL31V lb
2b . . . [M+H] Designation
0 --
-
H0
N N ao . s , NH 0,__(N-40
818 ....\0 / "
N N----1,01 )- 0.019 12.462 0.003
49.8 886.03 887.0 Single isomer
\-0
ONH
,0
.....µ 07_6
C 6
isl¨t ol s0
r
HN,,...2,.
819 1-14
Nõ, F m01).1...). .
F 0.012 6.5 11.269 0.002 18.7 885.98 887.0 Mixture
of
isomers
0 N\ * \ IN
to
p
>\,0-61.11-_,N
HN
Mixture of
820 IP N\ 110 \N-1,1c01-0 101.700 581
788.35 788.7
isomers
9-1-0
N
o FIN- - N \
,.. ,
Mixture of
821 ip N\ 111 \ 7,,'õii___/-- 140.019 1.9555
1.9555 0.003 2.06206 902.39 902.7
94-o "0 -N...to
isomers
H 0-
tki.,N
Nfr
0 0
Y 11
822 N glii \ tM4 0
Mixture of
,.r----ri
4111r N W/ \ NH04-0 208.251 1170.9 824.35 824.8
isomers
9_2-0 A'
iii6 N
VP-
-..co
/I O!sl¨\
F,7,--<,
..
1-1,1 N Si \ 11-1
Mixture of
823 432.198 1102.4 824.33 824.8
00 N \w/ \ NH
isomers
9.1)-0
A---
N

CA 02811 662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
[M+Hr Designation
01
O.
NH
"-f---Nrci 11
Mixture of
824 (.1:5-4N I N ,C7.1 0.004 0.27 0.19 0.003 0.8
938.39 938.7
.1 N\ o. \ -i--'
isomers
NH 0 , 0
N--/
S4-- H0IIIII
H F
.0
F, '¨'r,....\_....24 1 j
Pt.)--
825 ).___-0 ""1"-'= N sw' = NH 0 . o 0.004
19.5 3 0.005 76.8 938.37 938.7 Mixture of
S-'

Itio-
isomers
ciNH
o---
C
M C
826 ).___.o ...ir-- N \ mu
''' = 0 'WI 1.953 19.5 938.37
938.7 Mixture of
s7()-0 isomers
oNI-1 H0
cr,,N
o----
r rUl F
lip \ ip
F
\ NH H
Mixture of
4.037 19.5 624.22 624.8
827 N 411r, N
)-0
isomers
cIN
14 11 n
ci-<-' al
-,-- N\ lit \N-
14 NH Mixture of
828
s-,()-0 5.131 624.24 624.8
isomers
iik N
LW
'0
nd.
- NH
'-i---",r0 Li
829
fo....: i
NAi \ 4M. N...--re 0.013 80.1 0.674 0.011 0.74 902.39
9023 Single isomer
411111P N W \ NH 0 , 0
s4--0 N-1
H0-
4),N

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
r0
'NH
Nr-Nr 0H
(_14.1,21
830 N iti \ 0.015 6.149 1 0.013 0.881
902.39 902.7 Single isomer
4Ir" N ow/ \ NH cr- 0
s4- N--1:,-
ciN
NIL-
(D=r0 H
N N CI
\N--icin0 N 0
831 N > 1000 1480 884.32 884.6
Mixture of
isomers
S ,N
*
..):)
'
F 04NTh
,r-vi 1
1-1,1 -N di \ it N.1.-^".7 Mixture of
oc:= w. N \ NH 518.300 1953 860.33 860.6
832
isomers
s4-0
A-
11/0
'
14 11
c_iN I I n
(1101 N = \N-N H 1-1
833
=t0> 1000 3481 684.22 684.6 Mixture of
S , N isomers
01
/1 11F
Ft--4N fib
-"r," N\ 11* N
¨ \ - NH Mixture
of
834
s4-0 > 1000 7347 660.22 660.7
isomers
fi& N
1.11-
'0
,-, ,
=-= NH
F
835
.111.,---('N 1 \ N ;--jt. \ 0.008 0.15 2.7 0.007
35 974.37 975.2 Mixture of
F * N o* '-' ----
'\ NH o . isomers
N-i
s-st H0 N
VP-

CA 028116 62 2013-03-19
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,
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
'0
- NH
NriNr0 ti
c_t_ils___14 1 CI ----
' 'N di \ = 11,,,-N ,___ Mixture
of
836 qg-P N \ NH d-- 0 0.008 4 0.2 0.007
15 998.37 998.6
isomers
r=t0 N-1
H 0-
S , N
,s2
=-= NH
NrINFO H
1.1.õ1/--N ..._ Mixture
of
837 1101 N oIP \ NH cH 0NO-
0.022 6 > 100 0.009 2.549 964.41 964.7
isomers
t--t
S ,N
*
'0
ri. (
- NH
'`relNr0 ti
N N
838 (.)---<µI H40- 0.033 9.27 54.7 0.010
<100 835.4 836.3 Mixture of
N
* N\ 1, / NH 0,,_4N 0 isomers
1.1 ,1),1 ,-
)--0
OH
,
HO, N
N N 0 \ * / NH
0 H N Mixture of
c:.
839 i-o Ni:N.,7-r- \ -OH 5.900 212
737.35 738.2
o
A--
isomers
..,..,0
*
0 0
'f. H
N N
c=¨=)--4 I
840 v N illi \ *
4111r N / NH
N-J-.1.
isomers
-\.OH 51.000 991 721.36 No M+H Mixture of
isome
)-0
ol-r4--7-
C
HaN-4 11 1
N N 401, \ .
841 .....(0 N
-o /iNH o40,3--
0.027 28.07 95.17 100 851.4 6.3[(M-
16)sMixture of
)
isomers
(:)NH
OH
,0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure CalcMS
la 1 aY93H I aL31V lb 2b
. . . [M+Hr Designation
H LI
ciN
N *I \ * , NH
Mixture of
842 N N4..u3 32.000 1000 521.25 522.2
.-0
isomers
:
OH
Fõ 11
N N - =\ * , NH
(:) ik
0 N r-k,,,...\
Mixture of
843 )- 0 1 j-,OH 895.000 1000 739.35 740.2
isomers
_____O
Ho, 11 r s
b 0 N N =0 \ = , NH 0,,_4"
844 -o N ii""-,' 'NH 0.990 5.99 17.58
99.99 935.42 0.3[(M-16)4 Mixture of
H = )-0 1:: isomers
QOH
0
,--
O.
NH
NT--"Nr0 H
845 N N ,
Li....4N ' =NQ
L). \ M N..1., Nt ).__ 0.032 10 2 2 939.09
939.3 Single isomer
41111-4" N ow/ \ NH 04-- 0
WI
s-2- H0_ N
VP-
0
r-
aNH
)---3Nr 0H
,Nµ N
L j....4 I n
846 N Ili \ 10 0.020 5 0.09 0
939.09 939.6 Single isomer
\ NH0
4111!'" N
s7to N-1
H0 N

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb 2b [M+Hr
Designation
'0
O J.
- NH
N,---1,,0 H
Mixture of
847 .iiii...,4NN 1 11_4 - 0.530 5 415 999 853.39
854.3
F 01 =\ / NH 0",....c_o
isomers
N"--",..."
1-0
6H
'0
(DNH 6Y0
HNI.1.,
848 s7-1=--ro h
Mixture of
isomers
1 1 31 843.97 844.3
ct 0
N ill \ N...-re,,./
411111}P N wf \ NH
1-0
CI;IN 1
849 vi H / NH Mixture
of
278.000 1000 529.26 Not Obs
,-0 r.1..M
isomers
`,..4
N L 5)
Mixture of
850 -L-N),_orii is \ ,m, rt.1.1-- -. 212.020 601
729.36 730.3
N W \ NH
isomers
0 )\¨ )-0
0-
11-40 .0yMrC5)
00-1).-0 ti
ci<7 0.040 0.21 0.11 0.56
927.43 928.3 Mixture of
851
N lii--- \ 4. isomers N......r)---,
4111." N \IW \ NH
1-0
'0
-o0'( NH ekr.0 -
12.
/ H1.4. õ
"..0 H
852 N N 0_..14,) 0.010 8.14 0.64 2.62 875.4
876.3 Mixture of
N
CY-4r.1 a isomers
* \-NH
N
)-0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure .
CalcM.S.
la laY93H laL31V lb 2b [M+Hr
Designation
0 '
jr
Cr:OH
"..),-11
rc853 N , F 0.005 1.4 3.7 0.001 18
910.04 911.0 Mixture of
"Ill=diI \ isomers
Ur N * - -N H1
0"o
II-10-
0 ,-;
... rso
11.
(N OH
854 .7-11
N , .. ----c 0.010 1 2.6 0.020 7.7
922.05 923.1 Mixture of
isomers
N
0
IP N\ 11, =I.-(;---(0
6_ N-1
H 0-
õ,Z
.e.,
=-= NH
)0 H F
855 r.N,.._<,N I F i---0.010 0.5 1.2
0.020 8.3 954.10 955.1 Mixture of
N..<-4
isomers
4111P N o\IW/ \ NH cr-c 0
11-10-
0,-(11-1-__ CrP
?
/1 0 -N
856 HN ,
di \ N.F > 0.2 > 100 63 >0.2 369
839.99 841.0 isomers
Mixture of
mr'' N . \ -
NH
0
p.-iOt
i, Or6
6 0
----.rN
CN'40 HN,õµõ/õ.
F 0'4
N-\
857 N , 0.002 619.1 0.79 0.002 9.4
940.10 Mixture of
941.1
01 N 0, illr'.../
÷ N
isomers
1,k , * *
/ NH 0
858
F 'el ICI) r4-1,,-0 >2 < 100 > 102 >0.2 >2000 735.91
736.9 Single isomer
'T
0,i<

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la I aY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
H 0-
M / *
/ NH 0 N-,<
859 F"Ct.10
0 N----t,õ.õN)) 0.026 >2000 36.47 0.001 696.3
850.01 851.0 Single isomer
"lel NH
j or6
(---N-c, 6,r0
HN,,,,,(.
860 .i'll 10 14
F (:) 0.003 360 0.76 0.002 3.4
936.11 937.1 Mixture of
N , ,._. H
-1,-
isomers
Ir 11, "N
p-Ori
_rj,07-...= ....;
11 0)0CN 0 HNõ,...õ4,
A-1.1 F (;)
861 N
myy....) 0.002 210.3 1.73 0.001 8.4
908.05 909.1 Single isomer
, .
IP t.i . " IN
to
o
_J, 0r6
'N 0,ro
,NTH
-0 F HN
N
862 "Si.. ll
,. 0
H !4"--\ F
., 0.002 1.8 0.001 156.8
946.08 947.1 Single isomer
N
40 ,\, *"N
6-0
F,,r-v11 1 F
* , ri
-0 ti"--) mixture
of
(:)
863 IN 0.005 4.1 1 0.001 14 926.09
927.1 NH
isomers
,0 HN --c--

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
[M+Hr Designation
N NI ) NH C) 0 \ ilp
- .
Mixture of
864 110-3- D 0.002 5.6 1 0.002 2.2
890.11 891.1
O
isomers
0 HN .."(
9114.
-0 pl 0 N,iki
g - N
865 40 IP \ C --.'L
0 0.005 31 4.2 0.001 13 940.10 941.1 Single
isomer
gH \
0-
F N
F"--N- l
tipi \ 11, / N
N
\-0 ri
NH o --..)
866 y N 0.003 4 1 0.001 42 841.92 842.9 Single
isomer
sO
).
,0 HN '1.õ,
9,(:)
_j oNt_c;
6
=ro
041-0"
HN,,..õ(
(;) -
NI --- Mixture of
867 N ,...- I* 11,(\/ 0.002 194 1.6 0.001 4
924.07 925.1
AO N\ o i
\ N
isomers
Fe
F
i Ord
,
CN6r0
-(0 HN,e,/,
868 '..../1 F Co' -
II NM,F 0.002 6.3 1.4 0.000 79
859.91 860.9 Single isomer
AO N,_011"
0
....0 " N pril.==, \F
\-0
869 NH OTN--fF 0.002 3.3 2 0.002 68 841.92
842.9 Single isomer
Co
,0 HN '."(
9,.0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la , laY93H laL31V lb 2b [M+Hr
Designation
F N
M (1
N N 0 \ . -Tr--111 j
870 )...... \ 04----1, ¨
0 N N
\-0 HN 0 0.003 0.6 1 0.001 106
871.92 872.9 Single isomer
NH 'I
C:) 0-.
p
--/, 07-6
_rtii
FN 0
871)i-Fil
N , F . /10 0.027 7.64 31 0.002 2 899.98
901.0 Single isomer
N N\ 10.-.1.0,--,
`-o
HN 0
't
0,
Or6
N
_CH 6r0
CN 0 HN.,____(
872 , H
F C:1 NTh F 0.034 >200 91.9 0.008
200 817.83 818.8 Single isomer
i;--N il ,
N...- r.\i\-- olp
L 4 I.4i io . /N
N\_0\-r, N
H
873 or'-;D > 2 >200 200 0.045 200
730.87 731.9 Single isomer
Hte--y)
o,L0
C'l
N m 0 N. ip ,N r,
\-0
874 1.10-0,1, > 2 > 200 200 0.034 92.8
732.89 733.9 Single isomer
HN-1---1"
o-10
N
n..4
N /1 0,*
\
HO N\_0 Vir--
Mixture of
875 0,14--/ 0.115 >200 200 0.031 200 812.93 813.9
isomers
HN;LY
,o
o-1.0
[

CA 02 811 662 2 01 3-03-1 9
WO 2012/041014 PCT/CN2011/001638
391
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb 2b [M+Hr
Designation
N
876 Ci>1-0.W 0 N\\-011* /N--_,\r'l
(I7:1õN-1
-- > 2 >200 200 0.033 200
780.94 781.9 Single isomer
HN)Ar
9 0
N
I
/N
877 c:)NH 1.10.1-D 0.354 >200 200 0.123
200 839.96 841.0 Single isomer
0 HN;'--lr
N
C<' 1
N N 0 \ = , ri
N\-0
878 HN NH
Y Nol0 > 2 >200 200 0.070 200 760.86
761.9 Single isomer
0
Ht.r1r
9,Lo
N
I
N 11 =, \ = 'N
0
0.7---.N'lq \-0
879 , 0.0 > 2 >200 200 0.037 200 788.87 789.9
Single isomer
hi--.
H 0
HN;--)r
o0
N
Cr,j N H 1 a , = ,,,, IL
0 -
\-0 H
880 0.,14 --) 0.316 >200 200 0.028 200
819.97 821.0 Single isomer
.:3Nli
o HN;--Ir
-7c
9-Lo
N
21.4N 1
H ao \ . /11
1,1._(:) N ,.,.--\
H
881 OH 0.777 >200 200 0.030 200
720.84 721.8 Single isomer
HN---(
c0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
392
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+1-1]+ Designation
N
n..4 1
N NI / ri
0 N
\-0
110-1TIDIõ > 2 > 200 > 200 0.463 > 200
846.01 847.0 Single isomer
882 Cr?:0
.1
FiN'LT.
ci,-0
/N s
883
\-0 N'.0
N > 2 > 200 >200 0.098 >200
834.00 835.0 Single isomer
HN
)

000 HN ...i.,,,-
/\--- 910
N
n-4 1
N ri
884 11"-D
-0
Y-N 01,N >2 > 200 > 200 0.022 > 200 858.96
860.0 Single isomer
0r NH
HNsL-(
,..Co
9)=0
Lni rf ft \ IF ,N
, N
885
\-0
ii Yl>
N N
CIY- >2 > 200 200 0.036 >200
758.84 759.8 Single isomer
NH, J .."
HN -1
9,L0
1
L0 ri ii \ t. /0
.() "lir' N \ ¨ 0 N-,',,rõ\
886 H2N 0.(14-/
)õ,- >2 > 200 > 200 0.056 > 200
733.88 734.9 Single isomer
HN "t
9).0
1
N ri is \ -m-- , ti
..0 N\_1:7/
H ...)
887 H6 0.-1.1
) ,.., >2 > 200 >200 0.020 >200
734.86 735.9 Single isomer
HN '"1
9.L0

CA 028116 62 2013-03-19
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393
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure CalcMS
la 1 aY93H 1 aL31V lb 2b
. . . [M+Hr Designation
n-1.1 1
N 11
goN\ iip , II
....0 \._ 0
N ',._.>
888 ,NH OyN
).. , 0.500 >200 >200 0.116 >200
745.89 746.9 Single isomer
HN '1
o0
LH' 0 ti A \ =
"'
J
\-0 H 11..>
889 0,,N 2.037
),875.07 876.1 Single isomer
01-4,P1' HN '"I,
HH
L-1,1
i__0 ''= N\-0 3
H
890 11)
YN N
- 0-
J , 816.88
817.9 Single isomer
Or NH
HN '''I
-0 9,.0
Liki ti
0 11101
891 ci--c," \
ci \-0 H I ....)
OyN
J. 822.76
823.8 Single isomer
HN .-1
C-J'I
N ti,
õ..0
-0 N --0
892 NH 0.,,N 777.89
778.9 Single isomer
(:)(
,1
,0 HN -1
n-.11
N\-0 il
H r
893 NH 0N-.J805.94
806.9 Single isomer
(-)
),

,0 HN '),
,.. 0 0 H
v `--.I,
\-- 11)
894 NH 0,,,N 0.018 42 16.1 0.010 112
819.97 821.0 Single isomer
CD.
)

,0 HN, ..)
,0

CA 02811662 2013-03-19
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394
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
[M+H]
Designation
-14'
\,,.,0
895 01-N 0.014 7 6.5 0.013 96
791.92 792.9 Single isomer
IDNI-1
)
p HN ..-1
9).0
___/ N 0 ri 0 \ o ip ,
rt
N
896NH OyN 0.013 32.89 10.1 0.007 1.166
819.97 821.0 Single isomer
O
J
p HN, ."1
o,L0
n'i 1
\-0
H ..
0
897 c::.NH 0.1- 218.024 2408.33 834.04
835.0 Single isomer
0 HNµ4.---(
-X
/31
898 , \-0 .,,
8 ..r!,_)
01,
..) 32.000 401 782.95
784.0 Single isomer
9 HN --
N N 0
\-0 H 11.)
899 ' NH .01.1 0.004 43 3 0.002 51.1
819.97 821.0 Single isomer
4:3
).. ,
p HN )
o--c,
"--4 0 N 0 \=, N
00...)- -
NN -
\_0 H ..)
900 0 i'l H OyN 0.233 > 100 93 0.070 > 100
924.08 925.1 Single isomer
0 ) ,
6 90

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
395
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
n.....<,N 1
0 ,--\ N N A \ ii / N
J
___,N 0 ".r."- N\-0
H 1µ..>
901 0,N, 1.910 591
-1 ,..- 951.15 952.1 Single isomer
HN .-1
902 IP \-0 H
OyN 53.000 1891 809.98
811.0 Single isomer
N-
HN"---r
9,L0
N
C\)....., 1
,___?-o
Ito N-4D
903 R____,NH OyN 1.910 285 761.89 762.9
Single isomer
Hie---r
Cbi
4,4 .
904 v_0 '0
N
b 0--OT 2.000 532 852.01 853.0
Single isomer
HN'Y
,0
N
n'4 1
CN->.1.)'
N ri it jr_14,
/
"4,13' N
905
\----- \-0 H 0
0,
HN------,-- 2.000 258 868.03
869.0 Single isomer
F
,0
/H0N--,0
,
906 0 2.000 586 853.99 855.0
Single isomer
Hte-s-vr-
o,L0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
r_. \ N i
LW-4N . 40 \ = , N
.J1
q0 H 1.
907 1\_0FLO 7.000 2977 809.98 811.0
Single isomer
-11 HN-----(
9,1=0
n-J4 1
N N
c) al \ . , N
_ -w-- _;'w Nj,
H '
908 F( c
F k..)NH 0 0.032 96.78 29.62 0.020 > 100
845.89 846.9 Single isomer
,0 Ht,r."1"-
N N a \ * Niõ
2.8)
\-0 H '1 ' D
Mixture of
909 14 0i-N
1 ,- 2.000 493 809.98 811.0
isomers
HN .)
N
N N
iiiN
\
910 N 0 = , N
"...--
\- 3,
,_.b 0..0 24.000 1061 852.01 853.0
Mixture of
:
isomers
HN)'---(
9.L.0
,-- ft \ 40 , N
4 N
3
214 0 "mr--- t=k_o
H T.)
Mixture of
911 OyN
). ,,,,
isomers
F HN .)
o0
r,..\ N 1
LNi.."4'N.
IW

0
CN 0 " '',-0 N
912 "--N 0 o''>5.700 1854
..f933.05 934.0 Single isomer
-0 H
Hi.r..--(
o0
J

CA 02811662 2013-03-19
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397
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
1M+Hr Designation
-
1--t=i ril a \ ip
3
N.Fi2N - \-0 H I.)
913 0.,(N 533.300 2192
J..., 733.92 734.9
Single isomer
HN ..1
,k0
,
-4 N 40 \ = õii,
\-0 H I.)
Mixture of
NH cl
914 .õ-N 43.100 1355 791.96 793.0
O
Jisomers
,0 HN ''µ,-
9'0
N
n_..e
,...0
915 oyN 0.020 > 100 12 0.010 89.2
819.97 821.0 Single isomer
(3NH
,0 HN"--(
9-0
1
N N \
4...__O 14,_0`m N
F
916 i1/401, 0.010 81 >100 0.009 831.86 832.9
Mixture of
0-(NH
,0 HN-L-1"
isomers
9'0
N N 0\ = , N
N
F
917 NH 0 P IsiD4i, 0.020 > 100 26 0.009
831.86 832.9 Mixture of
0.<
,0 HN------(
isomers

CA 028116 62 2013-03-19
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398
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
[M+Hr Designation
b _O.' v., io ,. \, = , r,
N = N
\-
918 1-1-- Ilili0 0.131 109.9109.9 0.019
110 914.00 915.0 Single isomer
0 H1.1)-1'
0-1
0-
0\----' 0 0-0
'
N
N NI io \ = , r,
ti,1-0
919 NH 0.300 >100 >100 0.088 789.94
790.9 Single isomer
-
HN)---(
9,L0
N
N iii 0
o =NL.0
H
920 N
c --\ 0r'0
HN'----(
0-1'0
N
N= , N
i
N--6 \--0 H
921 H
0,10 0.136 109.9 109.9 0.016 110
855.96 857.0 Single isomer
OH Hi,(--)r
n
N ri 0 \ ip , ri
H r) N
N \-0 11 -.1>
922 ,o---Is . 1,4
OTN 0.154 109.9 65.72 0.034 110
895.00 896.0 Single isomer
IA HNr
9,I=0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H I aL31V lb 2b Calc.M.S.
[M+H]
Designation
N
N 1
rii a \ a , ,
o'--- =..,m-ii,õ,._\
923 0,4-1 690.81 691.8
Single isomer
HN'---(
0,L0
f/i rif ,,,
N-i-U \-0 i
924 2,-----\ "-:=N -> 838.03
839.0 Single isomer
(
___./
HN )-1, --
N
n..4 t / N
( ft N io N\ . ,
14-)______' CI N
925 (
ti) j-c. HkrD
01-N
HN"----r- 866.09
867.1 Single isomer
9-(:)
N
N ri 0 \ ,
= , N
J-0
mixture of
926 N
C -\ f:01:1"-/
7. 832.07 833.1
isomers
HN;----r
9).0
N
N N ao \ = , N
3
J-0

C -.)- 832.07 833.1
Mixture of927 N-\
isomers
HN)---1"
o0
Cl'i 1
N N io \ = , ri
-5....0 N)- o N
mixture of
928 -0 NH
C) --' 0-111- 850.00 851.0
isomers
0 HN'---1'
o0

CA 028116 62 2013-03-19
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400
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
N
n..4
ap
929 H J-0 H0
Ni 860.03 861.0
Mixture of
isomers
HN"---(
9'LID
b-:
,0-14 N
930 H N,,-0 H0
Cy 876.03 877.0
Mixture of
isomers
0 H14'..i.
..40*
.>(
Cc_uo
02
931 N , >10 >1000 >1000 >2 >1000 734.86
735.9 Mixture of
RP N\ 41 01;
isomers
H N_t0
2 0
CN-roti 6,r0
HNr,/,µ.
932 A
N , mO
0.362 >1000 524 0.205 >1000
862.99 863.8 Mixture of
isomers
\
1001 N * "N
02-C3
,NH
04-
F,.\----14_40 _..40
933 N' 04, , 14 ..1":õ13...F
> 10 >1000 >1000 >2 >1000 770.84
771.7 Mixture of
isomers
H N-[
2 0
0 A
___.µ r=-=
F.cN1H
0 HN(
934
H I. > 10 465.092 >
1000 0.100 > 1000 884.95 885.9 Mixture of
N ,- 1 'F
isomers
N
40 N\ 410 ****!,"/
\ N
H2 N-2-C)
0

CA 028116 62 2013-03-19
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401
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la I aY93H 1 aL31V lb 2b [M+Hr
Designation
/4
/0 4-...,
---', ti 6(.)
HN
935 A 0 ;0 1950 1000 457.51 0.200
1000 848.97 850.0 Mixture of
N .õ. .,a. 14
isomers
.
11. ti * "N
H N -2-C1
2 0
*
Osr 0 -=4 0
N,N I&
936 si,r---/..,, 'N "740Cri,ti_ 836.09
836.7 Single isomer
N \ N
\-0
OT
NH
ci,ro .
937

(N ._N iii ,,...., HN
> 1 > 100 92 0.407 > 100
950.19 950.5 Single isomer
S---: M* (:) .
N
H
140 N\ 4 Ny.D
\ N
\-0
5Cfm(i14"..._
- ,,N -N
" - FIN , F
938 0 0 4 N\ * \N-NH 0N--(--- 0.004 23.48 1
0.001 5.504 919.40 920.4 Mixture of
H-10-
0
isomers
5-0
F
F F
,-,1
- NH
y'CrO H
c_Ni..,,14 1
939 N 0 / NH
N N
isomers
0.002 5.61 7 0.001 25.107
851.40 852.3 Mixture of
t-0 .--..=,\..F
HN0,-N---/-
). \,...-
910
-0
- NH
NrCro H
_r_,1_7_47 I H 0-
940 N 0 N., V, NH 0,.4N-40 0.006 8.63 1.83 0.002 5
901.40 902.4 Mixture of
isomers
/0
FF F

CA 028116 62 2013-03-19
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402
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure Calc.M.S.
la 1 aY93H 1 aL31V lb 2b
[M+H] Designation
- ___________________________________________________ '
kl
40'4 1 F
N ON 0 \ NQ
941 N 'WI NH ch( 0 0.008 79.27 12.87
0.002 162 939.40 940.0 Mixture of
6-0 NI-
r
isomers
\r"-NH
c) ,.,
-1) 141 HN¨N ..c>
942 4 N\ 11. N.,i, N ,\__
\ NH cj----c 0 0.008 6 2 0.003 4 913.50 914.5 Mixture
of
c0-0 N-1
isomers
H 0_
'0
O d.
- NH
tt
(r:11....zi F
Mixture of
943 N al \ *
0.003 0.4
\ NH 0H' 0 0.001 2 919.40 920.5
isomers
_?s-0 N--
H 0_
____________________________________________________________________________
..
9.,--c_irtri-
-CI 11 HN--,"
944 11-1-P N\ * \NIN 01--ro 0.010 48 2.1 0.020 11
913.40 914.5 Single isomer
.(So
tNo-
____________________________________________________________________________ _
9ili..
0H1 -N
- ..n
945 40 N\ 4i N,I., N
\ NH 01--c. , 0.010 4 1.1 0.010 2.1 913.40 914.5
Single isomer
<0-0 P.1-1`-'
H 0-
S'ILT 1 tirt
N N 4 \ lik / NH
)_4'.0 N --
946 .(-o 0.010 > 100 6.4 0.020 111.9
957.50 959.4 Single isomer
NH
1.1)1 y
0-<
,0

CA 028116 62 2013-03-19
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403
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b
Calc.M.S.
[WM. Designation
1 14
I H40-
1--N N 0 \ * , NH 0,414 0
947.(:P.1-.o ri---)1 )- 0.010 39 4 0.020
35.9 957.50 959.4 Single isomer
C)NH
,0
0-----
F..01=_10 ..=;)
, 0J=
/,.---N
HN ,..- N
alb ,- F
948 332.501 5099 823.30 8234.3
Mixture of
MP N\ * \ NH
isomers
0
0*
F..04.4=0 .> o
---
/----N Cris
HN ,õ.- 11 can N,;0"F
Mixture of
949 12.500 57 843.30 844.2
RP N\ \ -NH
isomers
c___2s--0
GI
F
SC-cri F
õ, 6 ,
950 lie N\
c) ilp 'I,4' 01....1.--0 0.011 0.4 5.3
0.007 17 937.40 938.4 Single isomer
c, .s-- 11-10-
F
51.-fm(114
H 0 -N
- HN ,- CC \
951 0.020 9 4.6 0.049 23 937.40 938.3 Single
isomer
II-P N\ * \NIH. 0%-li 0
c, CO
Ho

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
404
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
F,. M
n....4N'
952 di . 14--rZ,1 \.__
..... 0 "".".- N\ 0.005 0.09 0.6 0.007 9.11
999.40 1002.3 Mixture of
NH S µ H '
0-
isomers
0=t' '
;0 *
F
9 14
:c...1(._
-0 pi 0 -N
HN ,-
953 . N\ iv \NINC-CoN,L0 0.512 15 589 0.047 275
923.40 924.3 Mixture of
isomers
)-0
Cs
j or6
6
=ro
F.Rd-011 HN ,,..../õ.
N (:)N. _...\
Mixture of
954 HN ...,
N'1"-,i, '--./1- F 0.008 0.2 4.492 0.004 6
957.30 959.2
NHisomers
c-s-0
CI
F, 11
955 \N--- NH 0-A ,
Mixture of ..--
).....o ----- N ----
14-10 0.012 0.09 2.9 0.011 49.1
1000.40 1001.3
0
isomers
NH 0-
(:)
0 1
, N .---
F
03,--cpr, F
-0 14 0 >=41
HN,
956 N-feC .... 0.015 0.26 11.4 0.011
93.988 923.40 924.3 Mixture of
II N\ lik \ -p, N 0N----c' 0
isomers
ces-o N--t
0-
-0
O J.
- NH
H
)N
957 F 1.1 N\ oI,
\ NH cH. 0 0.007 1.6 0.006 19.7
1000.40 1001.0 Mixture of
isomers
N
H-10_,
g, S
-,- 1
',. N

CA 028116 62 2013-03-19
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405
EC50 EC50 EC50 EC50 ECM Obs .M.S. Isomer
Cmpd # Structure
1a 1aY9311 1aL31V lb 2b Calc.M.S.
[M+H] Designation
,..,2
- NH
ykr0 N F
N N
_)""µi41 o , Mixture of
958 4 N\ = . -----1," N ..--- 0.008 1
0.003 8.4 963.40 964.4
\ NH 6.---i 0
isomers
0
aes-
6=ro
HNse,õIN
H
F,,n_.µN 1 00
.1.5:!),
Mixture of
959 N N di \ m., N- F 0.005 >100 1 0.004 7.8 937.40
938.4
isomers
>..0 "it." N o'llirl \ NH
c:)NH
c:e-S--
,0
,2
=-= NH
)µ=iNr0 rj F
960
ON akr, 14,õ=.(1 ._.. 0.010 12.19 22.82
0.007 >100 957.30 958.3 Single isomer
F Itir N\ W \ ''
NH d-""( 0
_?-0

cs
CI
-0
J.
,
'-= NH
)="*Cr0 N
CCN N
961
Fhl 1 /411" \ 11, \N.,-rii= ft..1....0 0.003 4.03
0.492 0.004 43.878 957.30 958.3 Single isomer
ce-s--0 N-1
H 0-
CI
Ni--
0 0
'r 14
cr, N
Li
gib , ....4 1
n
962 N \ * ,-,, It_
114.400 322 807.30 NA Mixture of
'AP" N \ NH 0 0
isomers
c_s-0 A----
CI
'0
4NH .c:)
0j`N
N N
963 ci...
N a 1 , -4 i i Nlei-D"F 0.492 54.5 0.158 110
862.40 NA Mixture of
isomers
tr.' N \INF \ NH
0
____ 1.. ____________________________________________________________________

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
406
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b
[M+H] Designation
ca'?
- NH
i'jNr0 H
964 -s crq), 414 0- 1.100 36 823.40
824.3 Single isomer
N \ / NH 0,_,-(0
\-0
- NH
965 1%ric) 0- 1.100 40 802.40 803.4
Single isomer
N Cy.
"= N. /N. j....c."NH
00
to
CN-10 NH
"A-41 00
N
966 1001 N\ o
N 1.000 89 52.7 0.760 84.7
805.30 807.3 Mixture of
isomers
çs
CI
- NH
yisy.0 H
N N
967 (2-4
N N\ =Nt5 0.010 0.13 0.2 0.006 0.9 919.40
920.3 Mixture of
isomers
0 \ NH cjs 0
c)s-
-10-
1-14/)N Nle0
968=o N \ NH > 1 > 100 > 100 > 1 > 100
843.30 NA Single isomer
cs-0
CI
____________________________________________________________________________ _
.

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
407
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. .
CalcS.
la laY93H laL31V lb 2b
[M-4-lir Designation
.>((:)
ON

4,
N,
969 N = -
o N \ NH > 1 > 100 > 100 > 1 > 100 843.30
NA Single isomer
?-0
cs
Cl
'0
- NH
970 CI:12-4N N 0 0.016 0.3 >100 0.009 0.315
921.30 921.2 Mixture of
=N\ I,NH 0
isomers
0
Ho
CI
0 0
971 HNO H 0.010 8 37 0.015 76.656
946.50 947.5 Single isomer
N N
1140-
N N\ / NH R___k 0
\-0
HN50 H
972 9 -C
IU N4 H 0_ 0.467 > 100 <100 0.146 <100 846.40
847.4 Single isomer
-
N N\ / NH 0,___(N-40
\-0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
408
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b
Calc.M.S.
[M+Hr Designation
'o
O J,
- NH
-Ssrcro H
973 N N 1440- 0.009 43.48 4.3 0.007 21.9
837.40 838.4 Single isomer
N an / NH 0,_( 0
Mr N\-o N--"Lo. 7--
'0
- NH
H
974,N,..,,4N 1 H40- 0.057 109.9 20.563 0.013 110
837.40 838.4 Single isomer
\-__/ N 0 N\ lp / N H 0L4N 0
Ncl3 )¨
\--0
'r0
HN,õ1õ
n--.4 1 F
N N a \ , -ft- N.,
0,
975 .....o .111-W N W \ N H
:go 0.020 3 0.008 50.2 1000.40
1001.4 Single isomer
NH
()
0
I
'N
(-:'
=-= NH
)='''r0 N
U
,N N 1
n
\--I N ali \ S. N..-.1., N L Mixture
of
976 'liar 0.007 2.7 0.2 0.005 2.3
964.40 965.4
isomers
WI_
I
N
r:
=== NH
y=Cr0 H
977 rrsi,.,.<1:1 ,
n
, N ilk \ ft N,Iss- N 0.018 1 0.009 2.1
887.40 888.4 Mixture of
isomers
'14-11P N W \ NH cj-S' 0
?-0 N-io-
c's

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
409
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
[Whir Designation
0=ro
HNsõ..../N
H
F, N " " \ 11, (:) N
i - \
978 n--4 1 N 923.40
NA Single isomer
,, 40 \ ''
.._0 N
_?--- 0
(:)NH
--c2S
,0
n
Htil,r0 H
979
9-40,N,....4NN 1.1
1 CCO.<NH 6
0.029 0.383 0.294 3.2 1041.30
1045.1 Single isomer
F al \
W N W \ NH cFb
cs-0
0
CI
,
'0
il,
- NH
),"r0 F4
C)C
(Ns, N
414 am \ 44 N,r,. N ,\.....
980 F
W N oW 1000.40 1002.1 Single isomer
it-0-
-..,
gr¨S:
0,ro
HNse,õ/õ.
H
F, N (:) tl
,ri...).
981 n--4 1
N N 0 \ 11, N- ' F 923.40 924.2 Single isomer
....0 N \ NH
c-JNH
c,9
,0
OH F
N
982 F an N--,;("11 ,...õ,
W N \IIri \ NH 0- 2 81.700 167.19 161.6
297.56 839.30 842.1 Single isomer
cs-0 0
CI

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
410
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
0 g
6sro
>--11 0 FiN
1
cr)
Mixture of
983 N
myy....) 0.026 0.49 8.1 0.001 67 966.40
966.0
',
RP N\ . \ IN
isomers
8
... 0147 _ 6
6,7,0
c . . . . .1 = Vii I 4 HN
0'4
CI

984 N , H N---\
0.006 29.88 0.7 0.002 57 930.40
930.0 Mixture of
001
\ N isomers
8
-14 N
)....0 N 0 111-1) Mixture
of
985 OyN 0.003 8 1 0.002 15 896.40 896.5
NH
8 ,
isomers
,0 HN -1
9,L0
_j_ ord
,--- __til 6sro
\õ..c...H0 HN,,...,,i,
0'(
/ N CI
986 N , 1,
0.003 20.8 0.27 0.001 6.2 946.40
946.2
Mixture of
40 N\
\ N
isomers
tO
0
C.,
n--14 1
N N
)......0 N
o likl-j1.> Mixture
of
987 t
OyN 0.004 8.8 0.8 0.004 1.9 912.40
912.4
ONH
0 ),
isomers
,0
(15' HN .'"1
,k0
0*
C. i 4 0 .. (c
14/ (Dr,i
988 -- \ .ai M_11)õ..
> 10 275.009 35.1221 >2 156.107 802.40
802.4 Mixture of
IMP N lir \ N
isomers
6-0
CI

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
411
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b [M+H]
Designation
0*
r-r.ii 02
Mixture of
N ,- as. itil
989 RIP N IP \ N 16.000 95.7794 77.0776 > 2 845.40 845.4
o
isomers
II
_
\ ,
N
_ ___________________________________________________________________________
0*
N_ H
ik0
990 RP N\ * N
\ N 143.510 1000 544.35 23.770 456
834.40 834.4 Mixture of
14-0,....7 isomers
:NH
0*
(N-'0
li-11 02
N_-
RP' N (DID \ 'N mixture
of
991 98.590 1000 412.46 21.370 374 860.40 860.4
isomers
C{N
NH2
(NH
"-Sril
N_-
HID i.,
RP 11, \N IN Mixture
of
992 o 349.000 > 5000 645.30 645.3
isomers
11,
-N
C_NH1,1
N ,..- 13 !rii,
St* \ i4 Mixture
of
9930 3.000 > 5000 660.30 660.3
isomers
NH2
0 6
6).0
cN 0 HN(
NAl
, ki sir--
r\
994 * N\ ID
\ N 1.950 10.44 1.95 0.200 2
974.50 974.7 Mixture of
,0 isomers
'--N
NH2

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
412
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure .
CaIcM.S.
la laY93H laL31V lb 2b
[M+H] Designation
0 '
rc) 6sro
ON 0H HN,.....(
A (:)
N , Ai. 14;0 Mixture of
995 IV N\ 1, \ N 0.010 >100 10 24.8 948.40 948.3
isomers
\gO
.1,4 NH
7--..,0 ri
0sro
CN-10 HN,,......(
A I:)
N , al. lisletot Mixture of
996 RP N\ OIP \ IN 0.007 40 10 9.8 959.50 959.4
isomers
=
\ ,
N
C:0"---
CN-40 ..
"",-11 013NTh
N
L
õ..-
\ir/
ri-o 139.157 3562.44 861.40 861.3 Mixture of
997
isomers
vl-l't
14=k1
NH2
"
0-k-
CN-400
..--Ill WI'
N ,
998 I I-P N\ il* \ IN 3.900 52.94 27 0.218 > 100
844.40 844.4
o Mixture of
isomers
*
=
0-*
C/4 o
o
i.. itr 1:o
999 11.1 N\ oil* \ 325.000 > 5000 875.40 875.4
Mixture of
isomers
*
'/0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
413
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la . laY93H laL31V lb 2b [M+Hr
Designation
04"
CN-40 ..
.7-1;i1 02
N ,- alb" H
NY1')1
1000 IIP N\ * \ IN 189.210 1230.32 828.40 828.3
Mixture rsof
isome
o
so *
p
crk-
IA 02
40 ll*
\ N Mixture
of
o
1001 592.717 >20000 981.50 981.4
isomers
0
b
_.,.. Ora
N
00
\ N 0 HN,,,/,µ
1002 N ,- H
0 N\ *-1/,...ft,/ i
\ N 0.004 1.48 0.005 0.3 942.40
942.4 Mixture of
isomers
0
b .
p
---"r1 6r.0
CN-40 HNj,
H
N ,
N...1- Mixture
00 f,\I =

oll, 1 Mixture of
1003 \ N 0.007 2.76 0.5 0.005 11.9
1094.50 1094.5
isomers
. 0 .
0
b
¨/, 06
6 0
õ..-. iH 'r
\ N 0 HNsed,
N ..,- kt..(01
1004 W \ IN 0.003 0.19 2 0.003 12.9
989.50 989.4 Mixture of
N
isomers
PIP
11,
¨
iN / R

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
414
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CalcMS
la 1 aY93H laL31V lb 2b
. . . [M+H]. Designation
, 0 6
Nr-
,--- --/-14
00
N 0 HN,,,,,/\
, ..._\
N_- ask. HONN....r.,/
Mixture of
1005 kr N\ o. \ N 0.003 7.89 0.3 0.004 1
958.50 958.5
isomers
*
0*
CN-40 ..(
"..,-.11 02
N , m H---\
1006 140 N *-1(....f
\ N 230.000 >20000 853.40 853.3
Mixture of
4-0
isomers
11--(j
CN--.161 0sr0
HN,,,,d\
1007
N _. m .... N-- \
sir./
0.006 25.94 0.2 0.008 7.6 959.50
959.5 Mixture of
\ N
isomers
O
CN
0 6
6
CN-'16-11 ,r0
HN...../
1008
N lit 0.004
0 N\
\ N 0.004 52.2 0.3 0.006 16.869
967.50 967.5 Mixture of
isomers
Q)-0
_1.--0

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
415
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CaIc.M.S.
la laY93H laL31V lb 2b [M-4-H]
Designation
CN-10
17-14 02
H 1,4
N
N\ l*
N
1009 o 920.40 920.4
Mixture of
isomers
N-40
N Itr14..)
1010 14,1 N \ N 864.40 864.1
Mixture of
isomers
S
0-/c
CN
N
00 N\ *
N
1011 c70 986.50 986.1
Mixture of
isomers
0 IF
CNH
N
11,6
0 Mixture of
1012
720.30 720.1
isomers

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
416
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
O 6
6
=ro
H Ikl.,, j\
441 H o;()
-(
N _, a,
N
RP oil* \ ig Mixture of
1013 0.006 2.1
0.256 0.003 3.3 1034.50 1034.5
isomers
IIP
IP
O 6
,-----"If 6,r0
Lfi 0 HN.t. _v.(
Cr(
N , aab, lirt
1014 .)
IIP N oll* \ 0.003 2.3 0.2 0.002 2.2
978.40 978.4 Mixture of
N
isomers
11)
/ S
--
O 6
6,r0
H
ON 0 HNõ,_ __I\
--;,---13
ON
N _, r)
RP ri* \ i., Mixture
of
1015 4_0 0.004
32.2 0.21 0.005 6.8 1100.50 1100.5
isomers
N
c..-1,j
-C)
0 ir,
04--
rN--40 .>k
,--il 02
N ,... ..., H
"F
1016 11-1, il * \ i4 225.000 1390 846.40 846.4
Mixture of
isomers
0
0 0
p
M-k
o
Cell .(NH
0'
_..r11....
Nif__ ...- M
1017 0.274 1.63 1 0.129 21.3
844.40 844.5 Mixture of
isomers
0
b 0
p

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
417
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b [M+Hr
Designation
0r¨

ri
_../\ =
C6ro
N-10 H N.,...1,
C)
r(
Hy.1%)
1018 ....tr-,11
N
0 Noil* 1
\ N "F 0.007 0.69 0.004 7 960.40
960.5 Mixture of
isomers
b .
p
6
F.../, __-r- N sr0
N 0 HN,,....õ4.,
\17-11 (:)
1019 N ,
0.006 1.17 0.497 0.006 0.512
960.40 960.5 Mixture of
114 P N\ . \IY")
isomers
0
0 4Ip
p
0* 6).0
C1 = 1 -4 0 HN,,....j.µ
,-111 C:0
N , H
RI
N,?N Mixture
of
1020 P N\ . \ IN 1.111 403.99 885.40 885.4
isomers
0
0 *
p
0--(-- 6,ro
F..cpi_/0 HN,,...jõ.
.i-1741 0'4
H1
1021 N ,. 2.045 ..- .4. li
N...(.)1
Mixture of
r N\ l* \ IN 520.8 903.40 903.5
o
isomers
b 0
p
0sr()
cNii HI*1...õ/\
(3-(
1022 N õ.
IAP t\/ 11, \Iiiii...H4 7.490 1228.75 785.40
785.4 Mixture of
isomers
0
p.
0-
F..cNH HN,,...,õ4.
14, N
1023 2.836 700.87
N , al, H YN)
Mixture of
803.40 803.4
isomers
o
0 0
p

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
418
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H . 1 aL31V , lb 2b
Calc.M.S.
[M+Hr Designation
___/, r--
=,---N 6,ro
C N-1.0 H HN,,,./õ.
"..7- /1 C)1
1024 N , aim
RP 1.\1 * ,..1N):,....), 0.003 25.32 0.2 0.003
4.1 942.40 942.5 Single isomer
0
'0 .0
p
0 6
),--14 HN,õ..,/
6)o
,µ
, )..DN
1025 N , aim N
I=P \ 1 IN - 0.003 0.68 0.31 0.002 0.2 942.20
942.2 Single isomer
0
b *
p
o-*
' H
N _-H N.--\
. N =

O. hi-ir Mixture of
1026 \ N 16.000 443 893.40 893.5
isomers
*
--- NH2
0
CNH
- H
'7,----N
N ,...- ,r, H 11.10.14)
RP N\ IP \N N
Mixture of
1027 o 693.30 693.3
isomers
*
--- NH2
o
H
\----N-10 .>(
NH
N , , in
1028 .N oll, N-ri--
Mixture of
\ N > 1 > 100 > 100 > 1 > 100 843.40 843.5
isomers
*
\ ,
N
',
-011_6
6,r0
K='
L_IN 0 HN(\
N ,
1029 = N 1, \ 6 0.004 3.17 1 0.008 3.8
1007.40 1007.2 Mixture of
isomers
o
/S
--- NH2
0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
419
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
1 a 1 aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
-
il*
CN--(0 ..4
NH
"A-11 0J'
N , 11_1, Mixture of
j..4...)
1030 kl, N 1. \ N > 1 > 100 > 100 > 1 > 100
842.40 842.5
0
isomers
*
IP
_ .
0-*
C
N-10 _>(
"",--11 F199.700 606 02
I
N ,...= Mixture of
1031 RP N 0. \ 'N 846.40 846.4
isomers
,0 *
0-
It*
CN-40
H
F 011
H
N , _Alb.
N))1.
Mixture of
1032
RI N II \ IN 1.000 > 100 > 100 1.000 > 100 844.40
844.5
isomers
0
0-
0 6
fr 6,r 0
HN.,.... ..).µ
.--24 F C:o
itry,D 0.006 2 0.2 0.005 0.7 960.40
960.5 Mixture of
1033 N',
RP N 0. " N
I isomers
,0 *
0-
141---
...
C=rµIio NH
04,
, N
N ,..- H
1034 IIIP N =11* " N 0.030 82 13 > 1 51.11
844.40 844.5 Single isomer
,)--O
0-Q
p
11*
C.:(Fio ..(
NH
N,
O'r
N '
\
õ
1035 Si N\ ll)
\ N 0.247 11 0.066 6.15 844.40 844.4 Single isomer
o
O *
p

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
420
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la 1 aY93H laL31V lb 2b
[M+H] Designation
0*
CN-10 ...40
N , 0.1)....),
14-P N\ 111 \ IN
Mixture of
1036 4_ 0 219.000 628 874.40 874.5
isomers
0
1-6o
--t 0,r0
(---
1 N
.( 0 HN sed\
- A 0;)
N , Ai. ii_rtl..)
1037 II-IP N\ 1. \ N 0.010 3.2 0.005 10.4 988.50
988.5 Mixture of
0 isomers
0
b
0
CN--10 HN,,...j\
1038 N sip N\ = \NI--)..) 0.024 0.4 0.009 0.2 984.50
984.5 Mixture of
isomers
0
0 *
9
0 0 6
---Nr 0sro
CN0 H N ,,...j\
Mixture of
1039
0.009 12.1 0.007 0.6 958.40
958.5
N 40 N\ t,..../
isomers
0
0 0.
9
0
"
6,ro
CN-I
0 HN(
A 0
N1)
H.10,1,
1040 N ,..-
LIPI N\ ll, \ IN 942.40 942.2
Mixture of
isomers
o
0 .0
9

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
421
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
. la 1 aY93H 1 aL31V lb 2b Calc.
M.S.
fM+Hr Designation
M-k- 0sro
C/N-40 HN.,...k
H
i";--N (:) .
N ,...- ab. H
I
N,;&)
Mixture of
1041 WI N . \ IN >100 39 74 884.40 884.2
isomers
0
b is
p
0).0
(9N-2;' HN,,....4,
....-14 ONrk .
N.,- _., . m,
1042 r,i..,,)
0.020 58 0.96 19.80.
976.40 976.2
Mixture of
RIP N P " N
PI
isomers
p.
o-
0 _2.- 6sro
C.._ o HN,,,,/x.
1043 N' 11
\11.1)..):
Mixture of
NIP N\ ll. 0.022 72.2 0.28 994.40
994.3
o
isomers
b *
p
C,N-40 HN,,....k
..--1,ii
C) .
1044 N ,
LIPI N * .11:11211...)
0.024 3.5 <0.195 <0.195 974.50
974.2 Mixture of
isomers
0
,0 ilk
0-

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
- .
-Jõ 07-6 6 0
õ
N H HNsed,
\ l-Il A NI =--
1045 N , HC
N-c..," >1 >100 7.2 >100 914.40
914.4 Mixture of
140 N\ 101
" N
isomers
_
HOd-0
OH
so*
F.\----N...4.0 _>(0
, alk, H
NY:4)
1046 N ItIP N\ 11, \ N 330.000 325 864.40 864.3
Mixture of
isomers
o
so 110.
p
o*
CN-40 _(
1,--M CI H1.1
021 --- Mixture
of
1047 N ,
0 N\ * .1-....,N 1
" N 319.000 527 780.40 780.3
isomers
-C)M......cp
(9N --I0 n u
"..s,4 ,-
1048 N
Ho,,,t5
, ai. Ill-P N\ IW \N N 0.030 0.43 0.03 0.13
1026.50 1026.6 Mixture of
isomers
P
0 0
p
.
_....1 07.4
= N
,-.. _r- H 0=ro
\ N 0 HN sr...4s
0.004 10.5 1.1 0.001 21
944.50 944.5 Mixture of
1049 N _.-
IP N\ IIP "N
isomers
0
f

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CalcMS
la laY93H laL31V lb 2b
. . . [M+Hr Designation
CN.--:12 6,r0
HNz....4õ
1050 --M
, CI H
0 n 0.039 < 100 12 0.003 113
910.50 910.4 Mixture of
N
. .
N-.r...." isomers N\ 1
\ N
0
0 rs'
... .., r- s-=
=r-N 6µro
F. ('N H
CN 0 HN,,...4,
"..--II00
CI
Ni, au 11 Mixture of
0.030 0.4 9 0.001 129 980.50
980.4
1051
IIP ti 1, "N
isomers
C

-0
N m 0 \ = , ri
).....\/0 N
Nj..:.>
Mixture of
1052 ciN1-1 IN., 0.007 48 5.5 0.001 85
876.50 876.8
isomers
p HN .-1
9c,
__, ,4
,o 1-..,
6
õ
)00
r N "40 H HNx.õ1õ.
1053 .,--II
N ,..- CI icr
0.005 37.5 1.1 0.001 19 896.40
896.0 Mixture of
isomers
\ N

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la I aY93H 1 aL31V lb 2b
Calc.M.S.
[M+H]
Designation
L4 N so \ * , N
0-,
1054
J
mixture of
7N 0.001 2.1 0.8 0.000 50.6
910.50 910.5
C:.NH
isomers
,0 HN '''r
9 o
F,In4.1
N N 0 \ ip /N
).....?-0 ^ N
I
(4-0 1-1-j _>,F
Mixture of
C::. NH
1055 0 N_ 0.002 0.2 11 0.001 12 946.40
946.4
isomers
,0 HN '-1,-
r-N44 1
* , N
o ri-j-.)
1056 oy N 0.020 52.58 1.3 0.001 15
876.50 876.5 Single isomer
0.<NH
)

,0 HNõ, ''l
910
N
N iii \ =, N
O -,-- N
N-'..
1057 C:),N) 0.004 5.11 2.5 0.002 81 876.50 876.5
Single isomer
NH
)
,0 HN '''lõ,-
o-.0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+1-1]+ Designation
n¨(14 1
N ii
0 401 \ = 'N
N 0 N"..')
Mixture of
0.001 10.73 0.771 0.001 10 862.50 862.5
1058
C:)NH 0.TN
isomers
p HN r
o0
-.4 ri 0 \
....0 N 0 ri-ji>
1059
i-_- 0.003 27 1 0.001 2 910.50 910.5 Single
isomer
C:)NH
p ,HN(
Lni N 0 \ * / !,I
)..... 0 - N 0
1060 (:)NH 01-N 0.002 1.5 0 0.001 2 910.50
910.5 Single isomer
,0
HN ,
J- , -1
F,,r_v_p i
LN¨N 0 \ ip /N
0 .0N
N-1Nr
ID .,=\
1061 NH
<1 yF >0.2 0.8 25 0.001 15 946.40
946.5 Single isomer
p !III"(
9 0

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
[M+Hr Designation
Fõr-vit i
LW 'N 0 \ * /N
,....\-0 N0 r-11
C:1 .1: F
1062 NH
(4-0! 0.003 0.19 7 0.001 45 .. 946.40
.. 946.5 Single isomer
HN
,0 y
9 0
-4 N 5\
0 N--1.,::.)
H O _
1063 NH 0.010 90.3 4.85 0.001 11.1
862.50 862.5 Single isomer
0=<
TN
,0 HN r-
o0
).....0 N 0 tri'''
1064
0.000 67.2 1.32 0.000 10.9
862.50 .. 862.5 .. Single isomer
0.(NH
),
p HN '1
O0
0--(-
ON-40
, 11,1
1065 40 t.' \ i * i
N 130.383 494.969 864.30
864.2 Mixture of
N
isomers
JO
CI

CA 02811662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la laY93H I aL31V lb 2b Calc.M.S.
[M+H] Designation
L ti N 0 \ if , N
oci N N-'1,.
Ar- 0 Hop
Mixture of
1066 >10
>1000 >1000 >2 423.891 889.40 889.5
isomers
N--N
, NH2
N
n....., 1
N N =\ ip
0
1067 Jo H "0 >10 >1000 >1000 >2 >1000 796.40 796.4
Mixture of
A-- 01-N
isomers
>1'0
ij'l 1
N N 0
JN
CoC:1 H H3
0õ0
1068 > 10 415.367 > 1000 >2 > 1000
830.40 830.3 Mixture of
isomers
0
>1
CI
n-1.1 t
N Ni *I \ I* / 14
).....?-0 N 0
NH NO-NT 1)
(;)
1069 0 HN r 1.950 13.99 1.95 0.200
2 1003.50 1003.2 Misixtomureersof
s)-L0
NH2
/N
cNON N3,
0(:) H
A- 0
1070 1- > 2 4508 978 1179.3
873.40 873.4 Mixture of
_õ0
isomers
n-ji 1
N N *\ * / N
N
(:)c) H 0 HA"0
A- 01,N
Mixture of
10711 >2 4801 1681 1342.2
888.50 888.4
rs
isomeN
L NH2

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+FIr Designation
0*
C/N-to .(0
A CI CA
144 )
IIPN\ 1, \ IN
Mixture of
1072 7.301 642.739 896.40
896.3
isomers
,-;
-4 N go \ , N
>,....?-0 N 0`1=,/ rt".")
NH 01,N
Mixture of
1073 o.(
) 1 0.006 19 9.11 0.005 9 987.50
987.4
0 HN '''i...-
isomers
o0
n
.(N
n-ki 1
N N gli \ I. / ju,
.111- N
0(:) "
1074 267.000 777.33 854.40 854.3
Mixture of
>1,0
isomers
q
N N
).....\/0 N
cto0 11"...)
1075 c:)NH OTN 0.008 36.28 148.08
0.003 > 5000 968.50 968.4 Mixture of
,0 HN ..,,r-
isomers
00
q
0*
C/N1-(0l'ill >(o
Al Mixture of
1
1076 OA
N , ii V"--\
1.I N\ IP 1....'--/
\ N 27.260 45.888 898.20 898.2
isomers
JO
CI
n-44 1
N
0 11-jr.)
1077 NH
c:I 0-N
) ,..-
isomers
0.628 >200 200 >2 200 955.50
955.3 Mixture of
isome
,0
0H HN I
9-0
4-
0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+Fir Designation
0-/c
CN-40
(;)
F
N õ..- ,I,. iiift)
1078 IP N\* \ IN 455.503 1819.04 848.40 848.3
Mixture of
isomers
JO
CI
= .
n-J.1
N ri ip\ft/N
0\w/ Nõ,,,
J
1079 A- o.1-11.--/ 7 156.944 831.55 911.40 911.4
Mixture of
isomers
Cto
9
n-14 1
N ri 0 \ . , ri
....0 N
.<NH
1080 o CD.N
). ..- rs
0.061 >200 10.5 0.009 14 953.50
953.4 Mixture of
isomers
,0
HN .'"1
o NH2
n-J1 1
N ri =\
).....\)'0 N
4_00 m-,..:)
0 N
Mixture of
1081 ONH
HNr 0.010 87.6 4.6 0.015 2.1
981.50 981.2
,0
isomers
9,L0
-11
..(o
Od'
r"\_,õP 1 F H
01
Lii rii io N\ *N;
\ N
0 0 c(0
Mixture of
1082 A- 33.936 30.1 868.40
868.1
isomers
oH
,--1H
.1 0 HN -,-
-0
Mixture of
1083 110 . // 1.000 >100
>100 1.000 >100 806.40 806.4
-0 Pi .i.)
isomers
01,N
.1,
HN r '..1
.L
9 0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H 1 aL31V lb 2b [M+Hr
Designation
r0
o N HN,,,,/,,,
-0>%1 0 HN r .0
1084 1.000 >100 97 0.188 97.3
882.40 882.5 Mixture of
isomers
401.1 \ . -1('...../
\ N
6-0
'0
CoNH
OH 0 / N
,---N N 'my" N
1085 t_'.1,1 I `-0 Njj-i> 1.000 > 100 > 100 0.159 >
100 806.40 806.7 Mixture of
isomers
01-N
J

HN ,..-
...1
9-10
6.ro
0 HN,,..,/,
(:)NH (D1.1, -\
Mixture of
1086 H 0.074 > 100 45.5 0.010 22.24
882.40 882.7
)"..Cro H ai \ M N-e,../
isomers
N N
, "i'Llir N \w/ \ N
6-0
' N
P Q-N 14 / NI
1087 Lss.)¨ I N \--o n''''') 0.478 >100 >100 0.430
>100 841.40 841.3 Mixture of
0.TN
isomers
HN '"(
c.,0
6).0
HN,,....,/,
1088H N
...111-Vo ,-, lik \ I.. .N-11-)...)N 0.417 > 100 94 0.237 > 100
916.40 916.4 Mixture of
isomers
p Or N N 1-11P0" N \ N
L_ __

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
431
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la .laY93H laL31V lb 2b Calc.M.S.
[WHY Designation
n-14 I
N N ap \ . , ti
,i,õ.\
1089 A-- OT.14---/ 194.000 2153 897.40 897.4
Mixture of
isomers
HN .'"(
o OH 9-L
iik , ri
)......?-0 N
1090
NH OyN
.k isomers 0.028 5.99 2.9
0.011 9.181 940.50 940.5 Mixture of
,0 HN( -
HO
CPI 1
N N 0 \ * /N
c3)'0 H N --11
c:(00 H
i\-- Oy
1091
HN( 549 952.50 952.5
isomers of
rs
0)k
/--N
)
,-,4 N 0 . . /N
o0 H N NA
4-0 H0
A--
Mixture of
1092 HN '''( 409.900 2306 967.50 967.5
isomers
9'0
HN
?
,N-
L-4 N ip \ = õ ti
o(:;= H N N-'',.
4-00 H
A--- 0yrrID
1093
HN)-..'r 74.178 1252 966.50 966.2
Mixture of
isomers
,0
(N,
0-/
n--44
N 11 0
)......0 N o FreNr)
OIN
Mixture of
1094 O
NH
p HN"( 0.013 21
2.7 0.013 2.2 1009.50 1009.5
isomers
\ _./
0
/-N
)

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
[M+H). Designation
r-\44 1
Lti
tos.w'
0 N
0=(NH
1095 2..---
0 H"1 0.041 >100 2.8 0.016 2.1 1024.50
1024.5 Mixture of
isomers
9'0
co
HN
--4 ii 0 \
0,NH OTN Mixture of
1096 pC HN ..-f- 1.000 >100 77.9 0.127 > 100
1024.50 1024.5
isomers
o0
i0
c N\
0-7
c--0 ri-j.-:>
1097 (:)(Nti (3.-^1
). ,..- isomers 0.008 > 100 0.8 0.005 6.9 940.50 940.5
Mixture of
,0 HN '''I
).
00
p
CI'l
N ri iii \ = / N
C) N wk
o .,
40 H t!i.,)
Mixture of
1098 A--- OT 2.020 196 883.40 883.5
isomers
HN y
9,L0
p
,--14 H 0-
N..- N-4
1099 40 i. Ilk /V),--_ 0.012 3.2 0 983.50 983.4
Mixture of
c--0 11 N
isomers
p

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
1a 1aY93H 1aL31V lb 2b Calc.M.S.
[M+H]
Designation
,
0 0 6
_& r
(Nc. N
õ..m
N ,õ 11- n
1100 . ri . -ir-N L
0.010 19.2 1.56 0.006 3.51
956.50 956.5 Mixture of
" N cji' 0
isomers
cr. M-lo-
9
Oro
HN,,...,,JN
N
4:: .
F
1101 n..4 1
Noit.,.14.eiN,D"F 0.002 1.26 7.719 0.001 50.2
881.40 882.4 Single isomer
N \ N
NH ,60
(2.
,0
F,CJ4 \ F
= /T
....0 N)-0
11N ..
1102 NH 0,- .P0'F
0.002 1.95 19.68 0.002 >100
873.40 874.4 Single isomer
0.
)
,0 HN
910
e j, ord
_ O)0r
Ft_11 0 HN,,,..(
1103 ),41 F0 - 0.007 17.1 1.542 0.006 23.4
899.40 900.4 Single isomer
"N
<?-0
-J O1...0
6
F, :11 sr 0
F LIN 0 HN(
1104-)--11
NI, F 0
H r\ 0.004 2.26 0.588 0.003 23.7
899.40 900.4 Single isomer
0
Nr9"1
\ N
<?-0
F N
F- )--- 1
-N N ft \ = , N
N.
..11
N
H
Co'
).
HN -1....-
,0
=

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
1a 1aY93H 1aL31V lb 2b Calc.M.S.
[M+H] Designation
-
F N
F-n¨e 1
N N 0 \ = , N
"mr--- N
1106 (34-..) 0.002 1.95 0.637 0.001 31
855.40 856.4 Single isomer
ONH
).
,0 HNõ,, ..'1
1
O0
6=ro
04:10-ON HN.2.../N
1107 'ir-11
N ,...- 0.1,4. 0.005 1.95 1.591 0.001
18.3 923.50 924.5 Mixture of
F
isomers
11101 N\ Ill \ IN
d_o
_, oro
6'ro
CN1-.011 HN.,..../,µ
A, F 1:3 .
F4 I.,F isomers 0.003 1.95 1.521 0.001
19.3 923.50 924.5 Mixture of
1108 N
0 N\ . N-11"--/
\ N
d_o
6,r0
HN,õ...,4,
C:t
F,r.--\...4N 1 F
LN, ti ii \ * 14,.(114,), ' F 0.020 43
1109 0.3 0.001 52 899.40
900.3 Single isomer
....\/0 -w-- N \ N
NH .60
t:)
p
6=ro
HN,,..õ,/,µ
(:) .
1110 n-1 1 F
N N 0. \ m NH.101.01, "F 0.001 1.1 0.9
0.001 9.4 909.40 910.4 Mixture of
isomers
....0 ÷" N `..' \ N
d_o
NH
,0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
Oro
HN4.,
F . .
HC:o!,1
\ . .
1111 L
, W N iii \l'i'F
0.002 0.8 1 0.001 9.7 963.50
964.7 Mixture of
isomers
(:)NH
61-0
0 r
r\_,.,41,4 F
L N' 11 al \ / N
....(0 ""ir swf Nkr-\ _
--0 H F Mixture of
1112NH P4--
o r 0.003 4.108
0.001 8.5 883.40 884.4
(D
isomers
,0 HN =-,
9,.0
CN-ro 6..ro
HN,,...jõ
A 0'4
F 40
1113 N ,...-
0.003 11 1.2 0.001 12 941.40
942.8 Mixture of
Fi o*
" N
isomers
Fe
F
F N
N\-0 N
1114 (:)-10,- 0.002 1.2 0.4 0.001 76
859.40 860.4 Single isomer
0.,(NH
,0
HN,,-
1 =-1
910
j or6
HN2õ,õ/N
1115 .
N ,..- H ,iTh. 0.064 92.5 64 0.004 64 863.40
863.7 Single isomer
= F
N
0 N\ -11-.....7
\ N
.<--0

CA 02811 662 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
, la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
_
_____________________________________________________________________________
0 A
_i_ r... 6
,ro
'
" 0 HN,,....(
1116\1,1 ,z) . 0.010 0.8 2.4 0.020 20.9
863.40 863.7 Single isomer
N ,- H .,, F
* N\ * 11-'...../
\ N
<?-0
.. 0A7-... 6,r0
er0. r.1 HN
0 z../N
1117 , II
N ,.. u
!,I..F 0.023 19.7 4.8 0.001 7
891.40 892.7 Single isomer
0 N\ *
\ N
d_o
0, 6
___!, --
- --trk 60
\....1.0
---N HN,,...,/,
O'k
1118 N , 11. H 0.003 0.5 2 0.001 23 891.40
892.7 Single isomer
IP N\ \ IN
d-O
0r-
ri
j
,r-N 0sro
CN-40 H HNx.,õ(
1119 ,-.14 o !,i. 0.011 8.8 10 0.001 31
877.40 877.7 Single isomer
N
1101 N\ 1,
\ N
cy--0
07 i, .-....A
..,-N 6,r0
CNH 0 H Nx õd\
1120,--14
N _- ON
,F 0.003 0.5 4.8 0.001 21
877.40 877.7 Single isomer
*\
N * "N
cp 0

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
'
...j,0 7-0
=,-N 6,r0
F..,N_.0H
\,...11HNx..1\
0
1121 N ,- H Ni --- 0.030 20.2 17.5 0.001
23 877.40 877.7 Single isomer
N..r.../
0 N\ 110) 1
\ N
cy-0
,-;
j 0re,...
,
,-N 0,ro
.,,
FN_.µ0H HNj\
x
1122 \ ,--M
N ,- 110
N---\ 0.002 0.8 4.9 0.001 27
877.40 877.7 Single isomer
"N11.--.-.../
c-0
,F _iN 1
F ,N,__Fri /N
.....0 N r-ij.
0 .)
Mixture of
NH (:)
1123 ?-,N 0.002 6.4 2.9 0.001 22 869.40
870.2
O
)-
isomers
,0 HN ."1õ--
910 .
F N
F'---- 1
),....0 N
0 N--i..)
Mixture of
1124Co-N 0.002 2.8 1 0.001 6 883.40
884.2
0.(NH
).
isomers
,0 HN '').,
io0
N m 0 \ = , ri .....0 N
-C) NH 0.002 of
1125 ON¨ 0.002 13.5 1.2 0.001 5 847.40 848.2
CDNH
)
isomers
,0 HN .'÷ \

CA 028116 62 2013-03-19
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EC50 EC50 EC50 EC50 EC50 Obs.M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[m+H]
Designation
--b--<1;1 1
N oil 0 \ * /N
N
1126 >.--NH (0 N-.1>
0.018 46.74 26.5 0.001 142
873.50 874.5 Mixture of
Crc., ).. .,..- isomers
HN 'I
o0
6õro
HP1...../õ.
F N
1127 Ft-4 1
. _.1,1....4.2
0.003 12 12 0.001 49 881.40
882.5 Single isomer
N N a \
NH ,60
1:::'
,0
j Ord
FF,,,N 0 _-/-1
HN,,....,4,
1128 0.002 0.8 0 0.001 9
917.40 918.5 Mixture of
isomers
d_o
F N
F-------
-N N * \ ig , r
....0
1129 to
0,14 0.003 3 2 0.002 14 869.40
870.3 Single isomer
NH
)..,0
HN. ..., "1
o0
'
F N
F---¨<' 1
/,......0 - N
..
1130 NH (0 N--=)
ON 0.001 2 1 0.001 37 869.40
870.3 Single isomer
(::)
,.
p HN -1õ,

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
439
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
[M4-1-1].
Designation
n-14 1=
N ril 40 \ 4. /N
......0 N i:;/ ri--.)
1131 ciNH
OyN
). 0.003 29 2 0.002 5 847.40
848.4 Single isomer
,0 HN ..'1...,
o0
n¨(14 1
N N) 40 \ - N
--(:) IN-1111)
1132 (:)=KNH OyN 0.003 3 1 0.002 3
847.40 848.4 Single isomer
p
HN ''' \
F N
F-n¨e
N N 0 \ lp > /N
0 N-'..)
1133 c..(NH Oy N 0.004 27 1 0.002 16
883.40 884.4 Single isomer
p )HN. .,..-
-1
F N
F----- I
- N N
-,) a
1134 NH 0--3,N1-).' 0.001 1 1 0.001
17 883.40 884.4 Single isomer
c:)'
p
HN 'I'
... _i_ 07_6
F 6, _11 ,.0
F--\... 0
HN
,
11 ,,,,,<
'(
1135 N õ, Fi0 tril.D 0.003 17 0 0.001 26
917.40 918.4 Single isomer
6-0
j. 07_6
6
FL._ _t-N )00
Flõ..s7_14e HNse.õ(
0'4
1136 N , H !.1---\ 0.002 1 0 0.001
11 917.40 918.4 Single isomer
N
40 N\ ID"N
d-o
o --"._._41.C-1.4
-0)1 0 NN
0 N\
1137 60 HT "µ\ 0.002 19.1 4.23 0.001
40.6 857.40 858.5 Single isomer
---/
)
HN -1 _.-
9.0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
440
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
_...1 Or6
6sr0
CNll HN,,,),
"AA " N 0'4N
1138 -
, m
N ---\
0
0.003 18.7 0.26 0.004 2 958.50
959.2 Mixture of
ii
isomers
0
IP
_
N /
j Ord
6=ro
(-µN-roll HN,,..õ
,-M C.)...
1139 ( .
,i
N , As,. 11
Mixture of
IP N\ ll \ N 0.010 1 1.1 0.020 1.1 957.50 958.5
isomers
o
I*
11,
......1 076
CNA6sr()
0 HN,,...õ/
1140 ....
1.100 2 1.1 0.020 1.1 921.50
922.5 Mixture of
111P ri oil* \ ;=4 isomers
IP
II
F
.
1141 to
0 14
y---=} F
0.010 2 13 0.020 12.4 869.40
870.5 Single isomer
ONH
).p ., HN .-1
9-LO
F
40 \ m , r4
).....0 " N s2WI VI \ . _F
NH
1142 tO
01,N--T 1.100 11.2 0.020 45.1 869.40
870.5 Single isomer
Ci
)
,0 HN ..)
00

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
441
EC50 EC50 EC50 EC50 EC50 Obs .M. S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
IM+H]. Designation
iõ Or-6
= N 0,r0
x
õ
N 0i., HN,,,,/,..
\"'si'll
F ON
-
1143 N õ... . li N.,F
0.010 > 100 7.7 0.020 10.2 963.50
964.5 Single isomer
\
140 N\ -11--......./
c=3-0
j 'Nor6
0sr
CN:10H HN..,/,õ
F 00
m, 1
1144 N _.- ,7õ0
0.010 2 1.1 0.020 26.5 963.50
964.5 Single isomer
IP N\ =" IN
go
_
F N
F-n-- 1
....0 N
to N
Mixture of
1145 0.019 5.764 2.511 0.054 457.395 897.40 898.4
NH 0-3-r'D
isomers
,0 HN
o0
_ 7-O
F, _11 6sro
ruN 0 Hisis,
1146
0.019 4.6 2.4 0.070 318.37
895.40 896.4 Mixture of
N õ... .4,õ.
isomers
IP N\ IP Or;
d-o
----- TH 0)00
\ N 0 HN,e,ls.
ON
N , il !=I--\
40 ti oil* -ir.'"*"7
\ N Mixture
of
1147 0.019 1.9555 1.9555 0.002 1.9555 1033.50
1034.4
isomers
*
4110'
IP
j, r....
=,..-N 6 0
µr
F,..--,N_10H HN,,...õ/õ.
\'' 1 .0 -
1148 N Mixture
of
,,...
il,
N ' F 0.019 1.9555 5.39248 0.002 67.2647 981.40
982.4
0 ri o -T(*"."/
" N
isomers
_I
c. 0_

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
442
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
0--.
.>40
RI ,,
Ods
N _.-- m 1,4--"\
1149 * N\ 0* 1...'''
\ N 124.000 640 845.40
846.3 Mixture of
isomers
*
1.1' \
\=N
0*
..4so
0(0
=N\ l* NsTr"'-7
\ N
Mixture of
1150 o 298.500 >5000 883.40 884.3
isomers
*
, N
N,_
Ojc
C4N-40 ..k
)7-11 02
1151 N , ,A.
IP N\ * \IN.
m µ14,...)
53.000 248 781.40 782.3 Mixture of
isomers
r-,0
0-*
o -(0
¨SA 04
1152
N..- = 488.700 764 873.40 8743
N-r. 1.--11..)"F
Mixture of
\ N IP N\ '.
isomers
0
*
1 0-
CNH
,--ki m HH--\
N-
* N\ * 11---'..../
\ N
Mixture of
0
1153 245.000 >5000 645.30 646.3
isomers
*
N' \
\--N
CNH
N4I
H HH--\
* ki-g-1---'.../
1154 9.300 > 5000 683.30
684.3 Mixture of
o
*
isomers
/ 11
N

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
443
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
O ri
I, 7--..= 0r0
C14-10 HN,,...õ(
1155
N , itr 1:tt...)
Mixture of
N N 0 \i li) 1
\ 0.030 16.31 3.4 0.023 11.75
959.40 960.4
isomers
o
IP
__/, or6
CN-10H HN,e0(
CA
" .N-r
. -J41 H
N i:1=.
Mixture of
1.)
1156 01 Nsol, t
\ N 0.016 26.75 2.4 0.011 4.4
997.50 998.4
isomers
4W
N
0 A
F.N_40H
I HN,,....4,
CI,1%1
A -
1157 N , µ,..
'F 0.007 0.27 6.6 0.004 32
987.50 988.5 Mixture of
1.
isomers
0
IP
1 o-
O 6
j., 6.ro
CN:roil HN,r.õ,/,,
CA
Hy..1...)1
ts il,
....,-14
IP
1158 N N\=\ IN 0.032 15.22 1 0.021 4.92
989.50 990.5
o
Mixture of
isomers
II
_
N
O 6
0õro
F.CH1-0H HN/N
1-il F Co
1159
N ,
1.I \i . N-11--....../
\ 0.005 0.2 4.6 0.005 20.1
1012.40 1013.3 Mixture of
N N
isomers
o
A
1,

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
444
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
0---.
F.0,1_40 ...(0
A F 0'1,
N , m . - N¨\.,F
1160 40 N\ so1"--./
\ N 922.301 724.584 897.40 898.3
Mixture of
isomers
*
0---
F.oN_40 _>(
'2,---M F 0-?
,.. 1:1 !4
N- Th..F
0 N\ 11,
sir..
\ N
1161 8.766 5099 973.40 974.3
Mixture of
0
isomers
lik
Ilk
A
F....." JrN 60
\ N 0 HN,,...,/N
F .C)
N
=,No
\ N Mixture of
1162 0.006
9.111 9.111 0.005 14.818 1087.50 1088.3
isomers
A
IP
A
0 A
6 0
-r
HN..õ,(
"..,431 0-4
N õ..
1163 0 N\ il) -il----....*v
\ N 0.004 58.732 9.111 0.004 9.111
957.50 958.5 Single isomer
o
A
4110'
0 6
õ7,--
-
.---, -tH 6 0
r
\ N 0 Hikise,/,
-11
.., 0
N '(
li N---\
1164
\ N 0.006 9.111 9.111 0.005 9.111
957.50 958.5 Single isomer
o
0
___

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
445
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
01¨_,
....j. A
6
F, jrri .ro
HN,,,,k
'ON 0
A Cr( N--\
1165 N ..-..,,L Ilyõ,)==F Mixture
of
tir N\ . \ IN 0.005 0.13 889.65 0.003 99.34
1023.50 1024.4
isomers
0
IIP
ip 0-
..... 01 r A ..,
6
=,-N sr.
F.cN_joH HN,,,,/,µ
(:)!.4
N , H ---\.,F
0N\ ol* N11-......'
\ N Mixture
of
1166 0.005 0.09 9.11 0.003 25.34 1069.50 1070.4
isomers
411
4
IP
O ,=4
_I, r-
6
F N H _IN ,ro
N,,,..õ1õ.
'...41
F
1167 N , .. H
N-.1)...) 0.015 0.2 685.23 0.002
>5000 969.40 970.3 Single isomer
IP N\ lit \ IN
CI
O 6
=ro
F.0%,:c0H NN,,,/,µ
A (:) .
F
N
0 N\ olik T--......./
\ N
1168 0.005 0.19 0.9 0.006 8.6 1087.50 1088.4 Single
isomer
4
IP
IP
O 6
.7 - -
_ill 6sro
F
"CN 0 HN,,....4,
.,4j (:) .
IP
1169
N.-_ m V--\.,F
0 N\ -ir"."--/
\ N 0.049 0.64 9 0.002 49.8
993.40 994.5 Single isomer
P
4
4

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
446
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la I aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
O A
.,./s A Oro
F
\,.. N 0 HN,õ...,&
04
N , .avi. ii....i)....
1170 )1 "F
IP N\ * \ isl 0.002 0.2 2.3 0.003 25.3 993.40 994.5
Single isomer
0
110
=
O A
j
=,-N ,r0
F.\= NjoH HN,r,(\
IA c:)
li !4
N- ---\..F
40 l,
\, o
r. -if.'
1171 \ N 0.015 0.67 5.5 0.003 51
1069.50 1070.4 Single isomer
ilk
0
41
O 6
1,
6 ir .,----- _7- H sro
F
N 0 HNsr,/,µ
\ ,--tj F
Cr4
N .õ. H r-\'' F
0 ()IP
1172 \ N 0.025 0.76 10.7 0.005 37.6
1087.50 1088.4 Single isomer
4
411
*
O A
...j, 1-....
6(::1
F.\---N-roN
Ht./.....i\
(:) -
N, m1,1
...)1.'F
1111P11*
N\ \ IN
1173 o 0.002 0.19 0.6 0.003 11.5
1087.50 1088.4 Single isomer
4
4
4

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
447
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
[M+H]. Designation
j 07_6
0,0
F,cteo-ri HN,,/,µ
H 0J'N.õ
, N
ily.õ2"=F
1174 F
IP r.; ll* \ IN 0.016 0.38 6.5 0.004 61
1029.40 1030.3 Single isomer
o
4110'
Ilk
F
0 /4
...../. 7---,,
6=ro
Cl'cl.140 HhIsej,µ
N (D N
---\
'_,... F
1175 10 NN 0.022 0.25 6.9 0.002 36.5
1047.40 1048.3 Single isomer
o
*
F ill
F
F,r-µ_p 1 F
\ ""ir." N s=w"
1:1-11>
co F Mixture of
1176 NH
0.,N 0.004 0.2 21.3 0.002 90 901.40
902.4
CI
). ,..--
isomers
,0 HN -1
9-LO
'
0
_j_ 1- ....A
F..\---"N=11 6,r0
,< 0 CI F HN,,....õ1µ
Mixture of
1177
N , 0 II, H
(:) rNi --'../ 0.065 0.3 23.8 > 200 935.40 936.3 \
....N 1
\ N
isomers
6sro
HN,,....,/,µ
F.r.....v)4 1 F H
001.4, ---\
1178 LN, rii , --m- ,N-Tr'.../"F 0.007 0.4
5.1 0.002 28.8 935.40 936.1 Single isomer
N c7" \ N
(:)NH
6¨

,0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
448
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
6).0
HN,,,/,..
Fõr-vil l F H
1179 L-14' µri 0 , ,N.i.r..../F 0.002 0.1 4 0.002
27.9 935.40 936.1 Single isomer
iDNH
6---
55(
6,7.0
HN,,,/,µ
F N
ri"--- 1 F
1180 0 N \ . ,
.....?-0
\ N 0.002 5.4 0.004 39.9
1012.40 1013.0 Single isomer
0
C3NH
*
N-
6)5.0
HN,,,,/,,
F
rõN
N , F I:) .
H N.,--\_F
1181 pi tap \ = .1--,, ,/--
0.003 2.71 0.005 20.8
1012.40 1013.9 Single isomer
)....-0 N 0 N
(DNH
*
,0
_
\ ,
N
6=ro
HN,,....,4,
F N
r-.7--<' F N--\
N ri 0 ,,, = \ ,N,
1182 ....c)
0 0.003 1.245 0.004 27.4 1042.40 1043.0 Single
isomer
01'1H
*
14' \
60
HN,,..õ4,
Fõr-N___.(N 1 CI F 0'4
1183 I-4 =0 0 \ 0, NHpi 'F 0.250 >100
>100 973.40 974.3 Mixture of
isomers
)....0 N
" N
4::/Nli
144
7.,
p

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
449
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
6,ro
HN/,µ
Fõrvii 1 (:)
F MiXtUre of
1184 ii ,
F 0.011 0.2 28.29 0.009 53 899.40 900.5
Lri N 0 \ = \,,ri---,7
isomers
).....0 N
(:)14H <1-0
,0
F
Lti ril 0 \ * , r,
,.....0 r=i_c, irc,....\__-F
1185 0.),N;/ 0.045 0.59 39 0.005 61.2
901.40 902.4 Single isomer
NH
,0 HN ..)
o..0
F,T..11 F
/ N
LNI-
0 N )=F
1186
01-N 0.008 0.19 22 0.005 61
901.40 902.4 Single isomer
014H
,1 p ,.., HN .)
9-LO
6,ro
HNsr.õõk
F 0J=
H !,1--\,,F
L 1,1 ril 0 \ = N -tr--"'"'"f
>.....0 N \ N
0
NH
1187 t:>
* 0.164 3.5 16 0.043
> 100 1252.50 1253.8 Single isomer
p
0*
H _pH
HO
F,T....\_14 \ F
L1.1 -NI 0 \
6, ft /N
....( N "lw vi--INI.,õ\__F
1188 tO
(21.1'is--/- 0.014 0.2 49 0.005 41
887.40 888.4 Single isomer
0-<NH
)

,0 HNõ..-
.'"\
o,L-0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
450
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
F,1-4 1 F
- N. ri 40 \ . , N = ...0 N
11:11..)-F
1189to
03-N 0.006 0.2 28 0.004 82
887.40 888.4 Single isomer
oNH
)
,o HN .'"(
9-LO
6,ro
HN,,....,(
F Cr(
H !.1---\
1190 LN N iii * ,,
F 0.220 >100 71 0.006 74.4
899.40 900.4 Single isomer
F' \ N-Irk-/
...0 ..., N w \ N
0.(NH <?-0
p
6).0
HN.,,,,(
F
F,r,-,\_(1/4 1 ON
r( .
1191 LN, N iii \ w 11,ff,L,õ)" F 0.008 0.3 17.9 0.005 56
899.40 900.4 Single isomer
....\0 N \ N
C2iNH .(-0
p
6,r0
HIelx.õ/\
F II)
N---\=,F
1192 La N imi \=.-,,..../ 0.007 2.365 0.005 48 1011.40
1012.4 Single isomer
....\/0 `q No`urf \ N
NH
(:)
15'
p
=
6sr0
HNx.,1\
F ir
ON

F
1193 Lri N di \ * --e-v 0.037 0.9 11.514 0.004 60
1011.40 1012.4 Single isomer
)....0 "gr," N ow \ N
ONH
*
,0
=
.>0
HO N Cld,N_.\
1194 .1 1 CI F II ,1õ2-0H 533.000 943 803.30
804.4 Mixture of
N N 0 1,1
(ollb \ 11;
isomers
of3 H
)\---

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
451
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure .CalcM.S.
la laY93H laL31V lb
2b [M+H]. Designation
,
0,ro
Hlkiii
HOõr--N C)
I CI F
Mixture of
1195 H N--\.,
OH 0.135 1 68.9 0.010 > 100
917.40 918.4
t-1,1 'N 0 \ ip \NC."/
isomers
?-0
0NH
,0
_
HO,,r-v14 1 F
L-- iki NI 0 \ = , N
.....0 N
11-jr:>014
Mixture of
1196 (0
C:IN 0.150 8.2 95 >100
883.40 884.4
IDNH
),,
isomers
,0 HN ..")
c:,-0
...o
0'1,
1197 Lt=I '11 illi \ 11
M
,:::0 '"Iv-' N \ N 608.000 >1000 867.30 868.3
ixture of
4-0
isomers
/\--
p
6,r0
HNs,....,,(
0
CI
H N-\
- F
Mixture of
1198 LW- 'N\wl - N-e=-=7 0.058 0.75 4.7 95 981.40
982.2
isomers
\ N
4-0
CDNH
,0
p
0sr()
HNseõ(
0'(
I
F,N H N
u
1199 LN¨N 40 , sk \ N,.(4...., -F 0.130 0.92 2.9 85
961.43 962.4 Mixtre of
)....0 " N N
isomers
0
ONH
4-
,o
p

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
452
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+F11. Designation
6,r0
H N...,,i
F,T...-11 1 HO (:)
H !.1--\.
Mixture of
1200 L-ri 11 il \ -M Ny''...""/'F
2.500 25 432 498 963.40 964.2
\ N
isomers
.....0 "= N o'sw
0::.NH
(17
9
p
6,r0
HN,,...,
F,,r - i!`l 1 * (:) .
H !=1--\.
Mixture of
1201 Lt.; 'N iii \ = \N-R-7,F
0.320 4.3 4.7 37 1023.50 1024.6
isomers
)....0 .11V N
4-0
ONH
p
p
6,1,0
H1.1....j,
Har-\44 i soi,1 -
LN, ri th \ Ily,..), 'OH 0.360 32
1202 66 >1000 913.40
914.4 Single isomer
)....\/0 "=iv N ,w/ \ N
d_o
NH
0=(
,0
5L-c_
-0 N
0 -N
1203 , \ = N----Nn 4fi
H
HN 0.002 98 2 0.000 6.5 881.40
881.7 Single isomer
SI N\--o,rL
\
HI_
0 ,
--.Z Osro
C
N 0H HN_,
(
1204
*..,--11 . o- 0.011 26.4 3.8 0.001 36 845.40
845.8 Single isomer
N.N-\
1001 N\ = -1T--'..../
\ -N
\-0

CA 028116 62 2013-03-19
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453
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
¨ ____________________________________________________________________________

6Yo
HNrk,
1205 N ON ili \ M- -11 0.002 0.65 0.195 0.001 12
829.40 830.2 Single isomer
).---
NH "le' N \I'v \ N
\-0
c)
p
N N 401 \ ta \ N ' õ 11,,,L
1206 \W n
\-0 - 0 001 1.16 0.222 0.001
Hk 0 9 817.40
818.2 Single isomer
'I
4::=NH
0.-
,0
0 6
(---,-"11 0 0).0
1207 ,õ..c_llo = HNõ,,,,J\
(:) 0.007 51 8 0.001 48 911.40
913.2 Single isomer
N.- Al,
. iti.
ID N\ \ IN
\-0
N
0-4 1
' N / ri 0\ =
, N
\__70 N\_
Ir..)
1208 .NH 0
0 OTN 0.004 1 1 0.002 22 817.40
819.2 Single isomer
p HNµ..---(
o0
* , N
1209 / \--o .NH 0.1.14--fF 0.002 0.48 2.9
0.000 98 853.40 854.2 Single isomer
(:)
pNN'"----(

CA 028116 62 2013-03-19
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454
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H. laL31V lb 2b Calc.M.S.
[M+Hr Designation
N
0--4
N 0 0 N IP / rA
1210 oTN--rF >0.2 46.31 24 0.098 374
696.30 698.2 Single isomer
HN'----1"
9.L.0
_
, N ,
0-4 1
' N N Ojos., /Nic,,,\
v_to
1211 / 'NH Hoi,N--/ 1.100 2 1.1 0.020 5 893.40
894.4 Mixture of
0-(
isomers
P Hr,e1-----(
9,L0
6.ro
HNI,../,,
N
1212 1.100 2 1.1 0.020 44>0-- 1 ki
tr\t- Mixture of
.2 905.40 906.5
" N oN = N\ .1, \ IC '''.=
isomers
)4- d-so
NH
c::.
P
6To
H1.11,),
1213 N \ ,,--ri,--, 1.100 2 1.1 0.020 3.1
893.40 894.4 Single isomer
N =
>4-0 N ii "
NH
(3
p 6-0
F N
F-n--(' 1
N N 0 \ . , ri
1214 __o r4\_0 tii--i 0.010 134 123.5 0.760
982.1 697.30 697.2 Single isomer
NH HN.,4
C:,
p
F N
H (1
N ril ap \ m, sl.1-1,----r.n
1215 )____o N\_0\w/ \ N o'---z:/--- 0.010 8.48 1.1
0.020 82.3 853.40 854.3 Single isomer
NH HN---f0
0=( 0-,
p

CA 02 811 662 2 013-03-1 9
WO 2012/041014 PCT/CN2011/001638
455
.
EC50 EC50 EC50 EC50 EC50 Obs M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
,
0
ONH
----r0
N N
1216 4-i r4 110. / r, 0.019 2.16 1.95 0.002 32
937.40 938.2 Mixture of
N fr..=,õ isomers
d-O
01-N--/
HI,e4-T-
9)=0
_
0
ONH
---r0
N N
.----(' I
1217 4-' N 01.
0.019 4.366 1.95 0.003 29
937.40 938.6 Mixture of
6-0 11---..'µi=
isomers
OTN--=
HINI.'-.1.-
I" N N sit N \ N 01
----4----,7--
6-0 HN- .10 0.019 8.242 1.95 0.003 76.7234 937.40
939.4 Mixture of
1218 (3
isomers
C:0NH
0-
p
-tir"- --P 1 14 (1
'
1219
__>')10 0 AO N\ . \ i.-r-01,)-
Mixture of
d-o Hh o 0.019 50.879 3.065 0.002 58 937.40
938.4
isomers
' 14H -f
0 0-.
,0
F, N
\ l'! co'lL
1220 \--o Hh o 0.019 1.9555
1.9555 0.002 36.2983 835.40 836.2 Single isomer
f
oNH -
0-
,o
Fps 1
N 40 N
11 (/
\= \ = r-1_,)-
1221 /---c. 0 6N0 \ Hii- 0 0.019 1.9555
1.9555 0.002 911.40 912.2 Mixture of
NH
C.) -1.
isomers
0-
,o

CA 028116 62 2013-03-19
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456
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la . laY93H laL31V lb 2b Calc.M.S.
IM+Hr Designation
>ro.4
ON HN -N
1222 r--\_(!'l 1
at 4.725 352.297
50.7592 0.301 >1000 877.40 878.0 Single isomer
gp-
o>-0
C>-4'
N N 0 \ . 'N
1223 00 N \-o
tij`r-D 502.760 1000 1000 > 100 1000
691.40 692.3 Single isomer
A-
...,.,0
-4-- 1---
00 N .-
I
-N
0-k- HN _
1224 CN-40
''....H *
(:)N-µ 180.440 1000 1000 15.920 510
1002.50 1004.0 Single isomer
N , 46. 11/ M?,.,2
RIP
\-0
_.(
(;)
CI
CI Ali \ * 1
Mr N \ N
1225 o it#1/ 645.63 1000 >100 1000
835.30 836.3 Mixture of
11, isomers
_
HN ,N
0
CI
CI
= ri oll, Nr......"/
\ N
1226 11, 129.300 > 5000 635.20
636.2 Mixture of
isomers
HN .. N
HNS

CA 028116 62 2013-03-19
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457
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+1-1)" Designation
0
H ON
1227 r--\_111
>2 >5000 3844 4709 991.40 992.0
Single isomer
1-1,1 r.f 411
1101 N\\-01* Ci
NH
0-(
,0
HN
=0 Pl-(
HN -N
1228 >2 >5000 4660 > 5000 1059.40 1061.0
Single isomer
=
b_co. H 101
1.1 N\\_0HN
4)
-
CI
CI idw
N N Mixture of
1229 0 8.600 1254 792.30 793.2
isomers
HN , N
HN
6,r0
HN (
O'k -
Cl
CI
1111-r N N Mixture of
1230 0 >2 1827 404 948.6 951.30 952.1
isomers
HN N
0
0
HN
1231 C NH 501.958 5099 702.30 703.3
Single isomer
HN
N Myr)
IP N\ \ 6
\-0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
458 ,
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b
Calc.M.S.
[M+Hr Designation
0
-0-1(i.ir
H 0
HN -N 00
HNs.,,J\
1232 CY-1.1 .:) *
H N--\ 0.025 > 10 9.11 0.020 9.11
1173.60 1174.5 Single isomer
N 11 ilki \ 1110 N'ir".
\ N
NH
(:)
,0
0 6
\---.(NO HN,õ,..._(
- A
N ,õ my.,01
\ 14
mixture of
1233 o 0.059 29.393 9.111 0.029 9.111 1173.60 1175.4
isomers
*
N y. NH
0
0 6
CN0 ..0
, > 2 381.08 156.186 0.075 211.543
824.40 825.3 Mixture of
isomers
1234 N'
=N It"N'IrAfti
6-0
0-k 6,r0
( N 0 HNs,õ,_(
(:)
1235 N -
, __--)14 ..,-IIõ .4.,,.. N 0.270 155.87 65.774
0.025 81.879 824.40 825.4 Mixture of
isomers
6-0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
459
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2h Calc.M.S.
[M+Hr Designation
ea
g70
r`pi
1 6 c--/
k, (3
0
N
1236 ,__, o 1,4 \ HN.t. ___(µ
0.037 49 11 0.019 28 1058.50
1060.3 Single isomer
, H
O'k
N , m NTh
\ N
or6
r0
NH2 HN_(
rp 0 N\
1237 - A c::= !=1--\ 0203. 13 83 0.008 219
897.40 898.3 Single isomer
40 ,:,\_01"
" N
o)-c= H N
\-0 irrD
1238 )\-- TN > 1 >50 76.7 0.036 987.75
748.40 749.3 Single isomer
Hr.e----(
N N ap N. . , 14
8
1239 \_0 N-j.'2.>
OTN 0.112 >50 >5000 0.004
164.09 766.40 767.2 Single isomer
HNM"-
o0
'

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
460
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[WM+ Designation
-N. N ip \ . , r,
7
1240 N\_0
o ,o 01-N 0.606 > 50 > 5000 0.039 745.66 762.40
763.2 Single isomer
HN's---(
r-\_41,41
-14 N so \ = , ri
0 N\_0 ti-J.=:>
1241 0.071 >50 > 5000 0.014
325.09 763.30 764.2 Single isomer
ONH OTN
,0 HN(
,--N N
0 N
\-0 11-j
Mixture of
r..)
0.1.,N 0.510 > 50 9.11 0.024
1248.86 788.30 789.2
1242
0 NN
isomers
N----1--
,0
Q-1<
%0
0
N N
(-__ 1
1243 I.1 N\ * /ic 0.320 >50 9.11
0.021 1564.83 859.40 .. 860.2 .. Mixture of
isomers
01-N
HN't"
-N N
..,0
1244 H2N N\_0 0.366 >50 >5000 0.025
1457.91 747.40 .. 748.3 .. Single isomer
0
HN....--(
9,10

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
461
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
. la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
N pil =\ * /N
0
1245 OTN 0.266 > 50 >5000 0.019
614.1 .. 777.40 .. 778.3 Single isomer
HN
`1 HN

9-10
N
N 0 N
-0 N---.:.>
1246 )3-1(o 4 OTN 0.023 >50 9.11
0.004 103.13 853.40 854.3 Mixture of
isomers
HN'---1--
õgb>L-0 N\-0
rt-H) Mixture of
1247 H ol-N >2 >50 612.51 0.012 217.17 853.40 854.4
isomers
Hre---(
9,40
,
n¨J4 1
N ril 111 \ 11 p / N
\--03
1248 Halõtrip > 1 >50 9.11
0.053 281.25 754.30 755.3 Single isomer
HI.e---(
9-LO

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014
PCT/CN2011/001638
462
,
EC50 EC50 EC50 EC50 EC50 Obs
.M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2h
Calc.M.S.
[WHY. Designation
0 A 0 )Z._
,--,N ..2"N N_,Cri
\
"-S Nr410 =NH
__.
1249 / N
0 1.\1\-0. -1 0.045 >200 43.2 0.004
57.81 1078.50 1060.4 Single isomer
H
O TN
Hhr---1-
9.L0
11 HN 69--NH =r0
('oHN.
1250 _mo 40
r.....4.,
2.633 > 20000 > 200 0.192 >200
937.40 938.5 Single isomer
N , H !sl--\
0 N\-01* %...
-c$
o=< NH6,r0
HN.r
. 0'( 0.037 >200 10.1 0.004
>200 1010.50 1012.4 Single isomer
1251 r-
L-N=
___.0
\-0
ioNH
p
)1--
0 1 0
e
H 0=ro
1252 CN 0
'..,-11 &HN.j .,
Cr( 0.019 >200 17.8 0.004
>200 1010.50 1011.5 Single isomer
0 ri,_0111
\ N
-0 H
)14,. 1,1
0-( ip
0.,=,\-0
1253 0TN-7 3.974 359.7 > 200 >2
>200 758.40 759.3 Single isomer
HN'Th"
9,.0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
463
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cm pd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
6 OHNI-
,L
--=,µ 2f.
HN - - 6,ro
C N 0 HN,_
1254 ... 4111'
N 4;) 4.765 1234.4 >200 0.177 >200 978.50 979.4
Single isomer
,
\-0
NH2 0sr()
HNs__(
* $:)
1255 c.,___.<,NN 111)41.4 0.043 46.8 200 0.022
>200 910.50 911.2 Single isomer
0 H = 11\_011 \ NI
ONH
,0
H2N 0O
HN s......,(
* .C)
1256
0.100 >200 >200 0.014 >200
910.50 911.1 Single isomer
1-N N r¨H * N * 14111/44.1.--\
\-0 \ N
NH
(:)
,0
HNt 6,r o
HN 'N HN(
1257 n-)41 H N--\ 0.020 >200 200 0.092 >200
1020.50 1023.0 Single isomer
N 11 a
"w N w \ N
\-0
NH
0..(
,0
0 NH
L.10
HN-t 'r0
HN -N HN s___/
C3-
1258 * 0.041 >200 56.12 0.028 12.5
1093.50 1094.9 Single isomer
LW N di \ AK Ile"'
)._._c) -,-- N .mr, \ N
\-0
ONH
,0
0(:)
HN
02NH 6(:)
HN,...,
c:) -
1259 * 0.064 >200 20 0.005 12.7
1025.50 1026.0 Single isomer
Lti N m-
>4'0 ''mr N ''w \ N
\-0
NH
4:3
,0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
464
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la I aY93H 1 aL31V lb 2b Calc.M.S.
(M+Hr Designation
6
HI,!...õ4
0'( '
NH 6).0
HN/N
1260 fk O'k 0.119 5.7 >200 0.013
>200 1067.50 1068.1 Single isomer
L'N' ti ill N\ * NIT---"==/
\ N
)-t0
=z)
,o
_J¨n
0 N
N *
1261
y_..ic, m 0 . , N 0.030 82 8 0.008 991.50
992.5 Single isomer
01,N
0NH
,0 HNTh'
-/-4!.11
0 N
=
F,,r_v_pi
1262 L-N¨ri 0 \ m /N 0.300 59 >100
0.030 1027.50 1028.4 Single isomer
1.1\_(:)/
NH OTN:
0.(
,0 111.1.'-(
o0
m_ JO-
0
M
fh
1263 Lri 8 0 \ = , N 0.130 >100 >100
0.005 1025.50 1026.5 Single isomer
)___ 0 " N
\-0 reNo
NH 01-N
(:)
p Hre---1-
't)
ckNH
''../.0
HN 6)00
HN,,..../.µ
1264 g 0"( N 0.020 74 20 0.007
1067.50 1069.3 Single isomer
H
L-1,1 tii li \ \N-.1.-1,..)
1
,._.0 '"ir--
NH
1:)
,0
,05N(,p
H 0 )_.
--N 6
HN sr0
HN,,,,_ j\
1265 F,,r.,,, _pi = oJ,
mp.F 0.116 0.6 0.31 0.080
1 1209.60 1210.0 Single isomer
\ N
,...0
NH
f::)
0

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
465
EC50 EC50 EC50 EC50 EC50 Obs.M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b
Calc.M.S.
[m+Hr Designation
_ .
H2N
/NH
6
-N ,r0
HN.s_k
* HOJ, -,i_..\
1266 I
n--1.1
N ri 0.458 24 37.72
0.103 47.239 962.50 963.5 Single isomer
0 . ip wir-../
\ N
N\-0
N
.0 H
,0
N,
/---` w
ox
g
1267 '--ri ti, 0.079 82 8 0.013 1.875 1010.50
1011.0 Single isomer
r=i\-0 ri-J.D
NH OTN
0-<
910
H2N
/NH 6
¨N sr
\ s
HN, js,
F,r-N____P I
N * (:),4,._\..F
1268 1.000 > 100 > 100 0.423
> 100 998.40 999.0 Single isomer
0
L; ri 0 141,-',./
N\_0 \ N
C.NH
,0
f-'0j \ _J
0
1269 '--ri N 0 \ . , r, 0.093 3.57 19.5 0.006 107
1046.50 1047.6 Single isomer
CI N\_0 ilt-1.: F
OTN
C;1NH
p HN.---I'
9-c.
6sro
HN,,,õ_k
'0 * Cr(
H N
NT ri \ ip
1270
N..(1,..) 0.039 60.65 18 0.010 34.6
911.40 912.4 Single isomer
L-¨ 0 \ ,
N\_0=N
(:.NH
0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
466
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
= o=ro
HI,c_k
* Cr(
r'N___<,11 14,1).1.)
1271 N
Lii N 0 \ ip , 0.094 50.63 25.7
0.009 58.827 957.50 958.5 Single isomer
y4-0 '4Iv NI\_0 \ N
oNH
,o
= 6,r0
HN(
* (:)
1272µmw, N H --(:
F 0.005 1.826 0.004 5.138
993.40 994.4 Single isomer
Lti µri, ,f.
NH
C:i=
p
6 0
-r
HNI-1,
N
O---(' 1 F ,c) N. --\,,
1273 N 011 A \ = 14--,1-' 0.002 3 0.789 0.003
27.939 847.40 849.3 Single isomer
)---
NH "=mr N\-0 \ N
(:)
p
,
' o o,ro
HN -N HN,... .../N
* (:)
1274 0.056 72 7.5 0.013 29.2
1104.60 1105.4 Single isomer
NH
(:)
,o
o or-
o ,ro
117- H6Nxõ,
1275 N ,
0.044 99 0.9 0.013 15.1
1024.50 1026.4 Single isomer
N
).___O "gr, N = N
\-0
c;INH
9

CA 028116 62 2013-03-19
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467
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la , laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
(ThNH
Osro
HN -N HN,,,,,õ(
= 0'4 -
1276 > 1 > 100 > 100 > 1 > 100
1004.50 1005.4 Single isomer
>4=0
\-0
OrkiH
p
,, =?2.1-INH
WILO
0,.._/-j , H
Oro
ti HN.,/,
1277r--1,4 > 1 >100 >100 0.597 >100
1136.50 1138.5 Single isomer
\___ itriN
L-ri ti iii \ * ,
.4, N \ N
\-0
IDNH
p
M('L6
- - Osro
HN - N FIN,s_k
1278 r¨,' 1 /.
ii, >100 >100 0.023 1161.60 1163.0 Single isomer
\ N
Lri N isi \=Ny-A--/
\-0
c=NH
p
iSIHH
N
(----/.0
HN 6)00
HN4õ,1õ.
1279
. 4:) ' 0.052 34.3 15.803 0.026 84 1056.50
1057.3 Single isomer
N N
AI
"gr.' N \ N
\-0
NH
c:,
9
6Y0
HNI...-I,
, N ,
6).;,..).
1280
0 \
N * \ IN 0.011 21.3 4.007 0.020 110 869.40
871.4 Mixture of
isomers
/ vIINH <(0
010
1281 _(:) N 0 \ N ^ , 4---7--
s" : 0.026 2.3 13.4 0.009 >100
875.40 877.5 Mixture of
NH
--f
isomers
0' 0-,
,o

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
468
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
>L 54 ,
FI-"1 pi 1;1"Ni
1282 )__0 ri SI N\ 11. ir--......
\ N > 1 > 100 > 100 0.177 > 100 806.40 807.4
Mixture of
isomers
--(3
ONH
,0
F,T....\_4N F M (I
Li.; Ni_
_.0 \ N o'----/--- >1 >100 >100
853.40 854.3 Single isomer
1283 )__
Hi4 0
NH --t
(:) 0-
,0
F,r,v_41.1 i /1 (1
L-4 N 0 . T--14,1 1_
1284 )----() N '..' \ N o'--,----
0.020 1.2 10 863.40 864.4
Mixture of
NH ?-0 HO
.1 isomers
0.< 0-
p
6 0
-r
HNI-1.,
N
>f.p-- , 6),,,,,.,i3, Mixture
of
1285 N 0 tl 0 \ , 0.010 1.9 1.3 857.40
858.4
isomers
> `wi \ N
?-0
4:::NH
p
'o
04,NH
---r0
N N
Ã1-4N 1 M
1286 H .1 \ 11. /11
N 0.002 1.2 0.2 923.40
924.5 Mixture of
4-0 ti- ===:)
isomers
OTN
HN'Th."
P ,,=0
0 .
g? r,r-\-
LW =N N 0 \ * N-iy-N-'
1287 ___o -w-
4-0 \ N
24.000 110 217 884.40
884.7 Mixture of
NH
isomers
1:1
,o
,o

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
469
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CaIcMS
la 1 aY93H I aL31V lb 2b . . .
IM+Hr Designation
>I. ,
NRIP
4
1288 >4'0 N `1.w \ N 3.000 202 125 866.40
866.8 Mixture of
_,õ
isomers
0:1NH
,0
,0
>I,
N , 1.,---
1289 Lni ri ft \ . \N ,-,--,
)___.0 "w" 13.000 408 378 788.40 788.8
Mixture of
NH
isomers
?-0
0
,0
F,,rAdi 1
List 'NI
>___µ,0 N
\ N 04---,-^
H 0.010 0.23 0.31 941.40 942.6
Mixture of
1290 0 0
isomers
NH
C:)
,0 * 1.1-I
0-
,0
No 0
i 1 i = ATI = - . . . -, zi'7, \
1291 )--4.'00t---,---
Mixture of
41 0 .020 1 0.14 923.40 924.7
isomers
0=<NH
,0 * --t
0,
p
N
/1 (.1
N N 0 \ --m- -Tr-111 1_
1292 ).___0 N `Inv \ N 0"----/¨'
Mixture of
0< 0.. ?-0 .,i. 0 0.010
""-T
0.. 7 1 845.40 845.8
isomers
,0
. ,
,fEV--.44 1
/_L.'
N
0 s.- o N T.:}F
Mixture of
1293 t
OTN 806.40 806.8
isomers
HN''.'"(
,L
9 o

CA 028116 62 2013-03-19
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470
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
- f,i_oril el \ Ilp / N
N
0 X-- ri¨..
1294 to
N..>_ 788.40
788.8 Mixture of
isomers
Fipc-r
6=ro
H N,,,,,,
1295 C:o
'::D--<1.1t
0 = PIP. F
Mixture of
884.40 884.8
'.1--coi \ i
N \ N
isomers
O)\. 4_0
p
Yk .
F,n--(ri 14 1 F R r;,--\
1296 __eo \
11 0 N 111 \N Ti-A...
902.40 902.6
Mixture of
4_0
isomers
(:) N H
p
p
54 .
F R nn
1297 )___,/0 ti 0 Mixture
of
N 10 14.11
\ N
884.40 884.8
isomers
= NH c-0
,0
p
6=ro
FIN." k
:.
Mixture of
1298 - N 0D1 110 N\ . N-ii=-"'"=/
\ N
isomers
0 (1._0
p
N
/ N
' N N 01 \ .
N
1299l>.F
isomers
HN'----r
9,i,0

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
471
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
, la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
N t
* / N
N
1300 to ri .õ
l..) Mixture of
ol-N 688.40 688.8
isomers
LW 1.4, a = mi -.EY/ /N, , . _, ,Cy
> _ . , _ c ) 4 . I --- N ow \ N cal-,. Mixture of
1301 0.080 0.14 0.19 11 983.40
983.6
NH isomers
NH
p.. ,o
,o
'--.4 N 0, \ * õ - Lc)
1302 >---C N \ N 0
0 NH 0.060 1 0.02 0.3 965.40
965.6 Mixture of
isomers
NH 01,
(:: p. -o
p
N
C=5__.4 1
N N iii \ M--_,---1-, 11,...,0
1303 >----C "qr." N "wi \ N 0 .
0.060 1.8 2.3 1.3 887.40 887.8
Mixture of
NH ?-0 01, NH isomers
0-K
-o
-0

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
472
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
H.4
0'
N0
00¨\FO
kr 5.1 _(,Iti 0 -0 \ * 1
/ N F
Mixture of
1304 N 0.020 0.18 0.7 2.7 905.40
905.7
?
OTN
isomers
Ht,e--1-
,00
H_4
0'
N0
Ora-r0
N N
Mixture of
1305 Clil 1001 N\ it /-r.4 0.020 1 0.2 1.7 887.40 887.8
toM 0
01.N
isomers
Ht4M--
'0
Cr(NH
N N 1
....--,(,
1306
"grv" N / N 0.010 0.4 2.1 13 863.40
863.8 Mixture of
isomers
tO NiiNr.,\...
H F
OTN---f-
HNs'Y
'0
(:)NH
---rt3
N N
(j-41.11
1307 0 \ /1 H N * 0.010 7 1.6 11 845.40
845.8 Mixture of
oTN
isomers
Ht4M"
6,r0
HN,,,/,µ,
, CA
Hp
Mixture of
N
1308 c-Nr.... 1 F
N 'F 0.004 20 1.11 0.003
855.95 857.0
N 1
isomers
)--0
NH
O.<
,0 \

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
473
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la . laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
A Cisr0
HN
F-__71 0 srok
1309 Al
N õ..- F CD'
0 r-- 0.002 4.03 0.1997 0.001 24.3
936.012 937.0 Mixture of
isomers
0 N
\ N
6-0
0 r;
_.....! r-
Fl_il 0 FIN2...,,,(
1310 A
N , F m0 1411 =-\ 0.001 0.46 0.019 0.001
12.3 936.012 937.0 Mixture of
isomers
JO
O A
6
CN H
:c:- , sr0
N
02.01.,
1311 i'll
N , F m
N'
' F 0.001 0.2 0.6 0.001 9 918.022 919.0 Mixture
of
isomers
"6
\
0 N Ilk
6-0
=
0 6
6
-1:2," 4r0
C6
HNris,
1312 ,--/1
N , F ir
I:4,41)
' F 0.004 5.4 0.7 0.001 42 918.022 919.0 Mixture
of
isomers
140 N\ = \ IN
6-0
O A
6sro
c14-1-- (-3 HN
F 0 /..õ4,
m
!41....' F 0.016 7.6 3.8 0.001 10 910.042 911.0
Mixture of
1313 N .- -isomers
0 N\ = -ir."
" N
d-0

CA 028116 62 2013-03-19
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474
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la . laY93H laL31V lb 2b Calc.M.S.
IIVI+Hr Designation
o
__ r-A
6 0
'r
---N-r0N HN2..õ4,
1314 \I-11
N ... F 0
H i'l. F
, 0.001 0.3 1.1 0.001 31 910.042 911.0 Mixture
of
N isomers
40 N\ * ir-"*"."
\ N
d-O
O A
j 7--- 6 µr 0
---- 1.1
N 0 HN,,,/,µ,
\1-11 0' Mixture of
1315 N õ.- H ,ITh.,F 0.009 7.7 3 0.001 6
924.069 925.1
isomers
40 N\ IP N-ir'.."
\ N
d_o
O A
j r.... 6 'r 0
---- _tH
N 0 HN/...4,
,1 ir
pi . Mixture of
0.002 0.3 1 0.001 30 924.069
925.1
1316 N ....- 'F
isomers
RP N\ 11* \ IN
6-0
LN q 0 \ = , ri
.....,0 N
6_0 1:11.)
Mixture of
NH =::=
1317 -N 0.020 <100 9.94 0.002 100.2 932.218 933.2
o=(
)..isomers
,0 HN ''Iõ--
c-1:(0
. .
0 6
F r 6,ro
FN OH HN.r.jõ,
1
1318 --;,-11
, Cr4 4,1.11.) 0.010 59.96 3.6 0.020 19.9
924.069 925.1 Mixture of
isomers
N
IMF N\ .
0 \ IN
6_

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
475
EC50 EC50 EC50 EC50 EC50 Obs . M.S. Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
-
0 6
F'UN 0 HN2.1õ,
1319 '2,--11
õ if
N
N---\ IP 0.010 2 1.1 0.020 26.1
924.069 925.1 Mixture of
isomers
\ N
00 N\ '''''
6-0
'0
CS-NH
r0
N N
( ?---<' 1
1320 Si- M 0 \ ir / 1
N
N0
isomers
0.018 105 10 12 890.136 891.1 Mixture of
<?-0
isome
OyN
),

HN ,.., ''',
9,L0
-0
rd.
=== NH
).='0
iõ1,1,N i
1321 Iv M 0 \ *
N=0.014 208 10 72.7 892.152 893.2 Mixture of
-0H>isomers
OyN
)

HN ,-
-1
9,.0
L-Nr-4N= a \ ilk "----4--
0 \ NH0-----k=
11-1 0.019 1 3.6 0.003 89
1000.48 1001.5 Mixture of
NH o-
isomers
C:i
94 ,\
J070
F :CH 0)00
N 0 HNsej,
H NTh
Mixture of
0.005 0.47 9.6 0.004 9.7 970.457 971.5
N
isomers
1323 N-
=N . -1"--/
\ N
6-0
CI

CA 02811 6 62 2013-03-19
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476
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la , laY93H, laL31V lb 2b Calc.M.S.
[M+H]
Designation
O A
_.....µ 7¨
6=ro
F.., _4 H
N 0 HNi,
--2;-M F 0 -
N ,...- 4ab. mi...10.
' F
1324 14-P oliP \ I N 0.009 0.43 10.2 0.007
26.3 1016.1 1017.1 Mixture of
ti
isomers
11,
NiN \
O ft'
F - A 6sr
'CIN 0 HNsejs,
--- H
1325
;7--N
N F 0t
,..- ii iklF
40 1,\ * \ N 1"-----/
0.003 0.19 1.1 0.003 8.1
1021.12 1022.1 Mixture of
J
isomers
6-0
0
O A
6
F.,---= _11 sr0
\_IN 0 HN,,e,õ,k,
H
F
0--)
F
N ,
N....r11"
1326
IIIP ni IIP \ IN 0.006 0.38 9.11 0.004 25.14
1019.15 1020.2 Mixture of
isomers
6-0
c)
0
r-
A
=,--N 6).0
F.cN..40 H HN,,,,/,µ
**-.. H 0
/7-14 F H
N õ.... Ai.
1327 II-P N11, \N PIN ' F
0.007 2.51 9.11 0.002 17.64
1042.14 1043.1 Mixture of
isomers
0
lik
1,
0,
jo7---
r;
-,_N 6).0
F4 H
o HN,,,j, \
F Cr( .
N...- ii N-- \., F
1328 140 r\i ol, -171.'-/
\ N 0.007 0.36 88.43
0.006 180.29 1046.13 1047.1 Mixture of
isomers
IP
, \ 0
N7 -
.,, '

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
477
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V. lb 2b Calc.M.S.
[M+Hr Designation
J070
FrIl 6ro
o FIN,e4,
(:)
Mixture of
1329 N ,
0 1,
0.003 0.09 70.44 0.002 >5000 970.457 971.5 N\ N-Tri
\ N
isomers
6-0
CI
j... oNrd
Oro
F...õ--, _ril
HN/,
'CA
N , F pi VM.' F
1330 40 H olP -Tr---'
\ N 0.006 0.19 1 0.004 18.3 1068.2
1069.2 Mixture of
isomers
11,
IIP
S ,
Oro
HN,,,,k,
F 'CI
H H--\.
' F
1331 \=\N`----'
)....o , N
60 0.005 0.8 0.004
10.04 1021.12 1022.1
r
Mixture of
N di =isomers
C)NH
,o
(-N\
o--/
Oro
HN,,..../\
Fõ(...-IN 1 CA
CI F
Mixture of
1332 \ 14_,(10-F 0.037 0.3 7 0.002 51.1 976.505 977.5
L-riii 00 N =1
isomers
\ N
)....\/0
6-0
ONH
,0
F,
r"---N I F
'--14 N 0 \ = / N
/).....0 N
d-o-F
Mixture of
1333 NH 0,-N 942.06 943.1
) 7 isomers
c)
,0 HN ..)
9-0
. ,
Oro
HN,/,µ,
Fõ 0J,r-\...) CI F F./ H--"\,,F
1334 LN-rii a \ . \I%-rr. 1010.52
1011.5 Mixture of
).....0 ---," N
0
isomers
CiNH II
,0
4

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
478
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b CaIc.M.S.
[M+Hr Designation
0sro
HNõ...,4.
F' C:.
n--1.1 1 F H
1335 N N di \ . \N-e-----, 0.017 >100 18.1 0.008 1.248
976.077 977.1 Mixture of
....y=0 ---- N 0 N
isomers
(DNH
I
,0
4
0,ro
HN..õ,(
F,,r,.-."1 F ir) -
11,;0..F
1336 Lri-11 di \ ilk , 0.032 15.67 5.4 0.008 2.38
1051.15 1052.2 Mixture of
\ N
....\/0 ''''-w N ow'
isomers
0.,<NH
C--
,o
(--Nµ o-
o--/
F
1-14/¨N a \ . ,N
NH (:)
3
.....(c) -AP--," 1,1\_0'w"
H 0-F
1337 ,r'l 0.010 0.5 19 0.007 167
859.913 860.9 Single isomer
o<
p)
p HN,..-
i
o'Lco
n-1 1
N N
,.)0 N,,_\
1338 -0___. NH 0 0,1`1-1 0.009 53 1.7 0.008 26
821.941 822.9 Single isomer
C.t
)0
HN-,,..-
-
I,
i-j_.,0 NI\-0 H
1339 P 0 N' 01:0 0.040 52.8 4.88 0.017 110 843.951
845.0 Single isomer
Ci,i )
o,L0

CA 028116 62 2013-03-19
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479
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la 1 aY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
n¨<14 i
N d =\ M /N
-4
w N
o .....\
1340 o" µN__,,c)
\--_, A OTr4-,1 0.022 64.7 13.98 0.017
110 819.925 820.9 Single isomer
0-
HN '(
9,40
6,r0
HNse.õ4,
F,n-J4F c:) 1:4
) .
N
1341 N N ali \ 44 N-fr"----/
....\ -0 ''''Ew
1064.19 1065.2
Mixture of
isomers
CoNH
,0
(NI\ 0-
N-7
L-4
1342 0 N\-0 ...JJ,
'
N 0 ii
\--_, -1 1:0-1/1-"D 0.036 42.2 29.15 0.023
110 819.925 820.9 Single isomer
0- ).."
HN --1
9-10
n.1 1
`0_10 N 0 rii IN \ 11, oi,..
N \-0 H
1343 0.026 40.3 6.48 0.015 36 840.947 841.9
Mixture of
-"N isomers
HN --1
9..0
'N N 0 \ ilk /3!
it_ N
\-0 H
1344 = "-49_? 0.:NrID 0.012 109.9 19.1 0.009
110 857.978 859.0 Single isomer
-NN

HN =-1
9,40
N N
oN-''-r----\
\-0 H
1345 -1311)1-- "
c:,-N--1
), , 0.054 109.9 109.9 0.018
110 789.899 790.9 Single isomer
HN 'I
9-.0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
480
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la , laY93H laL31V lb 2b Calc.M.S.
[M+H]
Designation
n-J4 1
N Mr ilkH . / N
0 143
\-0 H
1346 N..8 - 01, .1
>2 109.9 48.617 0.126 110
851.971 853.0 Mixture of
isomers
HN ..'1
o)=.0
n-.11
N ri
1347 is
00, N\-0 N '0
N..8
03,N >1 >100 >100 0.238
>100 851.971 853.0 Mixture of
isomers
HN'(
N ria\i ip
0 --, N / N
A
1348 HF3\-- \--0 N '0
oCoNH 03,N 0.008 >100 6.1 0.010 55.2 821.941
822.9 Single isomer
p HN 'I'
n-J4 1
N ,..,N 0 .3N
H (3 " N
\0 H -
,0--ioN
1349 0,-.0 0.691 >100 90.1 0.107 >100 923.05 924.1
Mixture of
-
).=
isomers
9* NH HN 'i
0)`0
N ri 4 \ = /N
lil 0 N
\-0 Hjj
1350 PP 7-0 0µ.-1.0
) 0.051 > 100 > 100 0.015
> 100 805.898 .. 806.9 .. Single isomer
HN(
0-C)
N il 0 \ . / 11
M.__/ co N\- 1F1 . 0
1351 ,0--,< ', 0
0.018 78.9 4.1 0.006 54.2
869.986 .. 871.0 .. Single isomer
J
OH HN...-
l
0-L.0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
481
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b
Calc.M.S.
[M+FIr Designation
,
N u \-0 H
1352 H 01- 0.017 > 100 21.3 0.023 25.9
845.926 846.9 Single isomer
N-N
lel
9 0
N NJ
>....0 --,-- N
6_0 )
Mixture of
1353 NH (:)I'l 0.004 13.96 1.16 0.006 53.67 926.17 927.2
C)
) isomers
,0 HN ,."1.õ-
6sro
HNsed,õ
F,r.--ss_p 1 (:).
1354 NH....(1.1,./" F 0.051 >200 31.6 0.010
>200 919.997 921.0 Single isomer
Lig' q 0 ii * " ;ki
)....µ 0=>-o
0 NH
.1._-
,0 -N
¨ -- =
0-k-
0 .-c:.
1355 N _...
110 N\ 11,iti)...)1 .1 .F
\ N >2 > 200 200 >2 >200 805.892 806.9 Single isomer
0
_.1
-N
0-/S-
0 _.=(0
14 Cri=
1356 N ,
IIP N\ .\piy,11.4 >2 >200 >200 >2 >200 769.911 770.9 Single
isomer
)-0
_'1-S
N
E
F
N
H .7---
1357 't() 14
0rN H / ' 4 \1471---N 1_, 0.178 12.01 71.7 0.004
>200 868.005 869.0 Mixture of
N CiLl'
isomers
-0 HN 0
--t
0,
0
0
'1)-14N0 0
1358 H N N
.f, 2.4 I 0.20 1.14 1.54 0.16 80.00
922.04 923.30 Mixture of
714 (0;4
isomers
F 11 40 = * õ ),_
Ni-0 rl "r!) H Cr-

CA 02 811 662 2 01 3-03-1 9
WO 2012/041014 PCT/CN2011/001638
482
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure .
CalcM.S.
la laY93H laL31V lb 2b
[M+H] Designation
OµJ)i,n4
0-
Mixture of
1359 r ,N 4 1
ea 7PI--4 0.12 1.10 0.29 0.07 6.35 922.04 923.30
F--7 N 40 = . /N -,--1 0
isomers
JJ, ---
i N
HN
F.Q.,A \ AA . * '45)'''.(N F
1360 cr5s_N 0 HN < 9.92 413.00 465.00
0.81 955.00 891.00 891.70 Mixture of
isomers
0(3
0' \
-0 *
0-NH N 01-0
..,, / % , N
1 liki ..õ \ ak ' w N -C-7
Mixture of
1361 0 N lor N 0 3.01 269.00 159.00 0.05 475.00
855.02 855.50
isomers
*0-
1
0 NH ci , N
1362 * 1 IN Y \ alL
N0
s_y 11 my ,..., Ho N
=... 0.03 10.40 0.03 119.00
840.39 841.30 Single isomer
HN <
OC:)
\
-0
(:)--TH N
0
Or-fli 7 \ ,fti ''' * /V16:0-0 Mixture of
1363 0' N iny N_0
0.22 231.00 0.09
245.00 819.93 820.30
isomers
HN <
0(:)
H N,.._<,N 1
1364 C---' N 0

H , 962.17 963.30 Single
isomer
so N\ * N 0 ,
,-k 0
e0 H N
rj rc,_
,
1365. :i
\0 914.04 915.50 Single isomer
\ - H 01 N\ * /N 0 0
rill"oi N4

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
483
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+FI]
Designation
0
/0--11_____0
----/ 0
)\--0
cm r 1 1
11 ,N-i
1366 N / ISI \ *
N \ 1.-1-Vj 0.00981 0.567 1.38 0.00765 32.2
966.16 967.0 Single isomer
4-0
0-0
00
-- ...." 0
' 111----0o/11 --,.._
`
F-Cc /1 F M___,N-1
1367 N / * = ilk , fr,, N.--, 0.00734 23.7 0.397 0.00568 4.85
984.03 985.0 Single isomer
N
<17$-0
F
0-4-F
F
Cr.)-14N I 0 \ *
1368 8-1
1 4 õ , o N 0=ti-ko
0.00574 15.3 0.297 0.0105 10.8 930.06 931.0 Single isomer
,1)
<iCt ---(I""`NH
1:1
0
()
- )1-0
011 \
(-1 i HF
N' \
= *
N
\ N
1369 4-0 0.0449 0.0706 7.05 0.0124
63.3 1018.16 1019.0 Single isomer
0-\--0
o-
o
o--i. __ _/ o
/ k---0 ---= v-0
F-C1,4,Y1 F H ,NTh
N" *I = if \ 'F
---ir---\_1
N
N
1370 4_0 0.133 49.2 0.52 0.0896 64.3
1054.15 1055.0 Single isomer
0-Th
\-0
\----b-
o
p--140
,___
H
QNThi... m
F It _LN-1.=='
1371 N / * = it ,,,---),-1
0.0282 16.4 0.358 0.00711 7 1038.24 1039.0 Mixture of
N
isomers
4-0
_.0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
484
EC50 EC50 EC50 EC50 EC50 Obs .M.S. Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+H] Designation
0
0-- 0
' 1-1------0
(:),/--N
F-C.1c11 F IL,N1
N / 01 \ 1, \ 10-"''' F Mixture of
1372 N 0.0146
2.35 0.162 0.00674 0.888 1008.12 1009.0
4-0 isomers
0--\_\
0
,0--kco ____( S-0-
O--N µ
ciLir ii
ii ,NTh
1373 N / 0 \ . sir----V.J
\ N 0.0041 24.9 0.14 0.00852 2.65
948.05 949.0 Mixture of
N isomers
Fe_o
F)-0
0 ___/ 0
53-14N-C,:µ,
H ,.= F H = H
N NH N
1374 .,)- / 40 \ * \ 11-,
N N 0.00352 1.12 0.0433 0.00799 0.587 946.06
947.0 Mixture of
do isomers
p
0
0_40 )..o, ----/ >Lo
O r4
---- µ
' tlic) F H H
N
r"..\_,,N", ram \ ia, \ IN-0
Mixture of
1375 ---- N 1 lir N \w/ 0.00699 60.9 0.324 10.2
946.06 947.0
o isomers
Q
p
0
P-14N-00,/-tii \
r N M F It
*
1376 L...----(\ / 40 =
N N 0.00595 1.8 0.0607 0.00453 1.55 944.09
945.0 Mixture of
d-0 isomers
p
/.....< 0L0
pi<oN = , ... _
H---.00/-
rN M .,,,.. F m N
/ \
1377 -1r-3
`---)14 WP \N . N 0.00739 0.222 0.00448 0.00577 0.48
944.09 945.0 Mixture of
4-0 isomers
p

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
485
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
(M+Hr Designation
-
0
ii0 _._. ' 0 ,../ )\--0,
F ",---N -k
9 141.--0 0,, H
N
r
L----. M /
1378 )---
N AO N 0.00577 2.87 0.0649 0.00497 3.3
946.06 947.0 Mixture of
0
isomers
d-
p
0 ,0,e
9-4D1-0 H0,2--N
--4& \
F N N
Cl.:!."N t taw \ \NI*3
1379 N i tiiir N \w/ 0.00754 25.3 0.211 0.00462 8.25
946.06 947.0 Mixture of
do
isomers
p
>Lo
' .1---o 0 ----( N \
c.N.L.ri, pi
F H._ _, N
1380 N / 101 \ * \N T1 \ -"jI 0.00556 0.798
0.0467 0.00628 0.874 948.05 949.0 Mixture of
isomers
N
0
F .
0--
0 ____
0--
___./ 0
' Fl----0
07 ril '
cµIsti. 4
F
1381 N / * 11 ,N--,
0 \="ir\--J
\ N 0.0283 44.6 0.519 0.00798
11 948.05 949.0 Mixture of
N isomers
0
F,
0-
____
N ---(_(-0
o
,4 m_r_c3N
1382 N / so = . , k 0.00634 2.27 0.106 0.00699
0.147 930.06 931.0 Mixture of
N isomers
0
F II,
0-
,O--C),.._t
N ____./ 0
H
Cc li
M_ __1
1383 N / so = * , ii,-, .--, 0.0205 56.4 0.419 0.0139
61.8 930.06 931.0 Mixture of
N
isomers
0
F *
0-

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
486
EC50 EC50 EC50 EC50 EC50
Obs.M.S. Isomer
Cmpd # Structure
, la laY93H, laL31V lb 2b Calc.M.S.
Em+Hr Designation
0
' N-----0
ctru
1384 N/ 10 \ * \ irr-4-µ-j
N 0.0112 2.85 0.0125 0.00672
6.99 980.19 981.0 Mixture of
isomers
00
0
-----i 0>\._
' 1:1--0 02-F1 9
(-N.L.T14,
vdtc,
N /
40 \ . , IT:, \--, Mixture of
1385 N 0.0137
4.95 0.21 0.00649 7.2 980.19 981.0
4-0 isomers
00
---( 0,..n
11-0 0 /-11
-,t2.!__Trii
F 11_,N1
N /
, 0.--, Mixture of
1386 N 0.00878
2.21 0.341 0.00578 19.1 972.14 973.0
4-0 isomers
0-1,_\
N t --( c'
ec o,
0
ru
F 11_,N1
N / 40 \ . "N N.--,
Mixture of
1387 N0.0175
18.3 0.371 0.0104 7.62 972.14 973.0
4-0 isomers
0-1_1
0
0.--,
,
N--
H ---0
c.N.Ltrii
F M ,NTh
N / 40 \ . -ir-VJ
\ N
N
Mixture of
1388 4-0 0.0117 10
0.294 0.0107 20.3 1018.16 1019.0
isomers
0-\--0
\--\
0-

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
487
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la , laY93H laL31V lb 2b Calc.M.S.
im+Hr Designation
0
0--. ___( 0
' 11----0
ctst.r. ii
F 11..r_oN
N / 0= ,ip , iN
N Mixture of
1389 4-0 0.114
0.502 3.47 0.0139 66.6 1018.16 1019.0
isomers
0-\,,.0
\----\0-
0-i0
' --0 - -=,_ >= L0
0,, m \
F*-Ct.Lill F H N
N-r--0
N" 0 \ ik \ IN ' F
N Mixture
of
1390 4-0 0.00529 0.0155 1.85
0.00728 59.1 1078.21 1079.2
isomers
0-\,,0
0
00
.--
' 11---0 - )^ L-0
oD--N `
FC,t'l=Lrill F H--1---Z3
N
N" io = * "N ,F
NMixture of
1391 4-0 0.0236
19.2 0.217 0.00556 16.3 1078.21 1079.2
isomers
0-\-0
0
00
---t
' rtt- ,,__ )^ µ-0
0,, M µ
c.N.L.Trm
F
1.1 / IS \4, \ 11N-\-)
N Mixture
of
1392 4-0 0.00813 0.894 0.0845
0.00329 5.01 1042.23 1043.0
isomers
0--\
s--0
0
0
,/ 0
HN-t-0 ___.
CiLrim
N' LIP \ lik sirA...J
\ N
N Mixture
of
1393 4-0 56.8 252
457 3.62 934 1042.23 1043.0
isomers
0-\--0
0

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
488
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CaIc.M.S.
la laY93H laL31V. lb 2b [M+H]
Designation
\N--0
clµcm
F 11 ,N-,
95811 959.0
Mixture of
1394 N / T,
40 \ 40 , -- \ --.J .
N isomers
4-0
0-
0
0--
' N-----0
F-C.N.L5M F11,1_34 .
1395 N / 40 * , ir,, , F 982.10 983.0
\ Mixture
of
N isomers
4-0
S-
0--iO= ____.( 0
' N-t
H>L0
Of NI \
F--C.I.tr [k14 F H N
/
\ N F
111" N
1396 4¨o 1086.19
1087.2 Mixture of
isomers
0-µ
LO
LO
0---
0
'
4.-0
H
ctirm
F 11_ _ilki
Mixture of
1397 N / 40 \ * , 11,-, \ --,i
942.07 943.0
N isomers
0--J
0
0-- ..__/ 0
' N----c.
H
O1 141 \
F.-C=Ic NI Msr_oN
N' 40\ * , 1,4 ., F
N
1398 4¨o 1068.20
1069.2 Mixture of
isomers
O-\

-0
d

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
489
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CaIc.M.S.
la 1 aY93H laL31V lb
2b [M+Hr Designation
0
' ttt = >L0
cN.L.5.1.41
F Ity_oN
Mixture of
1399 N / Of \ * \ NI 980.02 981.0
N isomers
c---0
0-7-F
F
t_
N ----/ 0
o
cf,,m
N
.0)-0 Mixture of
1400 1000.17
1001.0
isomers
0
P
o
0.- _/ o
' 11-----0
F -.Cc 11 itr_o.N
N' el\ =\ = F
N
c___0Mixture of
1401 1036.16
1037.2
isomers
0
0..:
P
,0--13...___
N --- C--0
H 0
F''Cl4Lr tl F li..roN
1402 \ N
i'll / I* \ Ilk i 1002.02 1003.0
Mixture of
N isomers
eo
F
F F
00
0--.
/
NY
H
o,/ N \
/---!! ii
H N
-=="" -T,,:i / ril
111 N " N " Mixture of
1403 Q4)--o 1024.24
1025.4
isomers
0--\s_o
0

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
490
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
0
Co-- ____/ 0
F(.,,P.1)rM F 11,_4NI
N" 40\ 41, , ii,õ F
N Mixture of
1404 4-o 1054.15
1055.0
isomers
0-__cp
---\
0-
0 0,*-N \
F=-Csi'l=PJ F tLy_s,DN
N / (110 \ 1, \ IN ' F
N Mixture of
1405 cro 1054.15
1055.0
isomers
0.-\-0
\---\
0-
,0-to,____
N - "--0
H 0
F.P.I=rM F M ,NTh
N / 0F N
, . Mixture
of
1406 N 1008.12
1009.0
4-0 isomers
0-\\
0-0t
' N¨-----0
H s )L0
F'Cr.l.Y1 F 11....ro= N
N / 11101 \ 11, \ ;si , F
Mixture of
1407 N 1008.12
1009.0
4-0 isomers
0--\__\
0-0i. ....../ 0
' N------0
H - >L0
O--M \
F.1.1.Lr NI 11_,N-.1
1408 N / \ lik \ 10"-j' F
N 990.13
991.2 Mixture of
1110
isomers
4-0

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
491
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure CalcMS
la laY93H laL31V lb 2b . .
. [M+H] Designation
0
0--,
' 1..14
F'CN=Lri P.11 H ,N,
N
1409 N / \ ek. , 1--- \--1, F
N 990.13
991.0 Mixture of
40
isomers
4-0
..
H---",_
o
etr, ii
N /
M_T...s3N
\ N
40 \ cip i
N Mixture of
1410 cro 1024.24
1025.4
isomers
0--\\--0
0
00
---
/ Fit----0
c.,.....iim
H--r-ZD
N
N / *I \ *1
" N
N Mixture
of
1411 cro 1024.24
1025.3
isomers
0-\o
0
r ...../ 0
--,__1-0 (:)/ 11 `
(-õN.L.,iim
F
1412 N / lb 1-;-, \--, 930.06 931.0
Mixture of
N isomers
d--0
P
0
0--
, ./ 0
itl--- -
(3,7 m \
QN,LsTru
F M._ _,Ni,`"--1
Mixture of
1413 N / 110 \ * \ ir,i- µ-'1.,,,-) 1038.24 1039.3
N
isomers
4-0
_.0

CA 02 81 1 6 62 2 01 3-03-1 9
WO 2012/041014 PCT/CN2011/001638
492
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la I aY93H 1 aL31V lb 2b Calc.M.S.
[M+H]
Designation
0-0
/ 11------0
QN.......rjii
F 11_ _iN -1 === --I
Mixture of
1414 N / 1101 \ * \ ir,i- \---J.,,,-) 1038.24 1039.3
N
isomers
4-0
-0
0
0--- _._/ 0
' N----0
C) 231 1
F,Lr 14 F 11 ,NTh
N" 10 \ * \ 'F,.---
N
1415 4¨o 1086.19 1087.2
Mixture of
isomers
0-.,
LO
LO
0
03.-
' N-
4---c)
O1..11 1
F=113 F M....._,N1
N
Mixture of
1416 4-0 1086.19 1087.2
isomers
o,
Lo
LO
11 F
/hi 1`11...,
1417 \O--i 0 g N_.> 930.06
931.0 Mixture of
0 'cl-. -NH isomers
-0 ci-'0'
...
N
H)0 0/1 1
F.--,=1=LrPJI 11..7_0N
N / IP\ * \ ;,4 = F
N
1418 4¨o 1068.20 1069.3
Mixture of
isomers
0--\-0
d

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
493
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure Calc.M.S.
la laY93H laL31V lb 2b
[M+H] Designation
0
' N----0
H - \--0
F.'ec ICI M ,N--,
N' si \ *\ -TrA.....1
N ' F
N
1419 4-o 1068.20 1069.3
Mixture of
isomers
0--\
s-0
(-_-.
0
' N-----0 0, ti \
P-C.1.1=M F M...r_oN
1420 N / * \ * , 'N 984.03
985.0 Mixture of
N isomers
0
Cr F
0-4-F
00
.--
' N---c.
H --1. --,0
0,/ q \
F.'1-
,rr,1 F M._ _71-1
1421 N / = \ * , 14- N..-.-J 984.03
985.0 Mixture of
N
isomers
4-0
0-4-F
F
-0 -..
0 0
0
0--t ...._/ 0
' N----c:,
H --,_ )LO
0,/ N ,
F-Cicil F II T,N-,
Mixture of
1423 " / le \/A--I'F 982.10 983.2
N isomers
4-0
S-
O
' 473H
F"ClcM F M ,N-,
Mixture of
1424 N i * \ le. -r-N.,..1,
\ N F 982.10 983.2
N isomers
4-0
S-

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
494
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure
la I aY93H laL31V lb 2b Calc.M.S.
[M+H] Designation
i 0
'
F M r,N--,
Mixture of
1425 N / = \ *
N ..J
\ N 978.12 979.3
isomers
cr0
.9,0
0 \
--( C)-0
= N.-"0 0 NI \
04
F 11.,_,N-1
1426 N / * \ * \ 14 µ===== F 1002.02 1003.0
Mixture of
N isomers
Fd¨O
F F
F ,Nm 1
F
0-4 0 0 '.._
N\ *
N Y,)
1427 ' ' -O0 N
948.05 949.2 Mixture of
6
isomers
NH
0
co...0
,
0.-0
-t
' 14-t
H
F--ec 11 F 11 ,14-,
F
1428 N / \ *I \ * .J.
N ' 1016.00 1017.0
Mixture of
N isomers
<____:--0
N"-F
F
= N 0 ¨,c'>-
0
0,r31 µ
crll
Mixture of
\
1429 N / 0 \ * -In.--J N 948.05 949.0
isomers
N
0
\O *
F
0
0---' --
1 1
, --( CL0 --0
0,/---N \
cttrici
1430 N / ao \ * , gi x.--, 942.07 943.0
Mixture of
N isomers
tj0-3

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
495
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1 aY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
0
0--t.
---( (:)--0
' ilt-0 C:1/1 \
cistril
1431 N / IP \ ilk \ [iv-) 942.07 943.0
Mixture of
N isomers
,
0-3
0-t
' 4-0
0,/-1 µ
(-õN.Lirm
F
1432 N/ 0 \ =
N -11-\...J
\ N 978.12 979.2
Mixture of
isomers
4-0
.So
Ci \
N - v-40
0 (-
F 0,21 \
N...r.)N
1433 / 1.1 \ la 1
\ N 980.02 981.0
Mixture of
N isomers
c---0
0-7--F
F
___,./ 0
c
0 O<-/--N \ l.....6_ m
1434 N / * \ lik \N 11,-TIA-J 980.02 981.0
Mixture of
N isomers
c--0
T-
0-F
F
00
--'
i....../ 0
HN't , -0
Cc m
H-r-ON
N
N' 1101 \ lik \ NI
N
4-0
1435 1000.17 1001.0
Mixture of
isomers
o
o
?
0

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
496
EC50 EC50 EC50 EC50 EC50 Obs . M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la laY93H laL31V lb 2b rfti+Hr
Designation
,0-- _. __..,/ 0
N )\--o
o
cit,c4
N
\ N
N
d-0
Mixture of
1436 1000.17
1001.0
isomers
o
o
P
____
N 0 ---/;__ %
0 tii \
F-C.Nyl ItroN
t=I ' * \ it \ ;,, . F
N
Q,)-0 Mixture
of
1437 1036.16
1037.2
isomers
o
co
P
N 0 -(
--,_`>L0
oiN' ec rj 1:LroN
\ * , ;,, ' F
N
d-0 Mixture
of
1438 1036.16
1037.2
isomers
o
(:)
p
11-0
cµIt m F ir It _,N1
1439 N / so \ * , 0--,.. 1002.02
1003.0 Mixture of
N F
isomers
Fd¨O
F >1)
Q¨J'IN 1
ICI,.__
N-' Mixture
of
1440 /c1.--µ eo
01,N¨ 912.07 913.0
o isomers
---T--- NH
-0
o9

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
497
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la 1aY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
. ¨
Q-14N1
0 10 N` * 'N'Aõ\
1441 ,o--NU_
o ..,,)-o 51,14..../
912.07 913.0 Mixture of
isomers
NH
-0)-- --r.J.,
o9
,
'0-N6:3 0-
1442 H -4
N 341 1 .
4
/ r 0 0 0.03 25.59 0.53 32.02 914.04
915.50 Single isomer
o
c--111=N\ lik N-iNirj4 4140_
eN
1443 / N
141 . \ * 1 4:VP 0.10 100.00 0.33 0.04
0.20 946.22 946.50 Single isomer
N WINO NO
11
)-0 H
0
,
1444 PI ,N"1 1
\....., Pi 4 ' 0 \--
/ ri,1 ,¨;:. 0 821.94 822.40
Single isomer
N0 ri-Yi4 ro-
t*
O
ct,4%c N
1445 5)
942.19 943.30 Single
isomer
c3-0 N N is.D
i0)
'.05?i,4 r-0,
'-( 4 \ ' r4 40 H N N
1446 4_ ' ' o -/ - 978.13 979.30
Single isomer
t1 N =
N--cO tii 0_
d-0
0
---.N"----fH. O
1447 4-2---`'Ll /
I tip ti O)/ 958. 959.30
Single isomer
-
0

¨o H \

CA 02811 662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
498
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure CalcMS
la laY93H laL31V lb 2b
. . . [M+Hr Designation
o
o
0 No
H N
x5..4 l (-0)
1448 F N H 0 \ = , ti (3._._.\ -1.0 1040.19 1041.40
Mixture of
isomers
N
0 rii--.), N-440
40 .
_ .
0
---'N-Nr0
F-2 N t dk.
1449 Fl up \ * / N (:) 1038.29 1040.30
Mixture of
isomers
N
0
\
(101 S F
(0-\
_ \ .__.c p
Mixture of
1450 -0 N :!:--`-, 14, 140 \ . /N-11--, N.' r 0_
0.02 1.36 3.03 26.54 894.02 895.70
N
isomers
I ,
_
F
(0-
OLO0 0
N \
1451--0)Lri ici-1--4n 0 \ * intil,c2m)I-1(0_ 0.05 1.10 4.56 0.04
9.70 894.02 895.40
Mixture of
ro
,0
,,,....) 0
N r )0
0 - - 1, ,
Mixture of
1452 -0 14 '1.,.,-,i-iirl 0 \ * ,,,,,,-c4,-0._
936.06 936.40
N isomers
'F
co-.) 0
CS--t N\0N =

1->
0 \¨'õ
1453 -0 NY-pi 0 \ . , t4 prN' -it-
...= H N rii-Lti H 0- 936.06
936.40 Mixture of
isomers
F (0
7C0
-f N\ 0 ).--,
1454 , N )--, _ir
_,T,..ri . , _. _
rii-cci. rii 0 794.93 795.30 Mixture of
isomers
F r1-0

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
499
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
,
C.--
HN \ 41
H0,.(N
N --- NH Mixture of
N---.< 2.22 1.32 76.29 162.61
938.03 938.30
1455 itto 0 )---_,
isomers
,
n 11 ..--N.)., F
0 u _-_,, 6
0 0
0
-NMixture of
1456 HN ......
N...fe
isomers
l" OH 496.26 999.00 999.00 999.00 733.88
734.20
SON\ 110 \ NH
/-0
CI / 0
¨1,4-0'
-0 p-t;
N 1;1 C)'-' H
1457

_/I' )oH
isomers1 " Mixture of
0.06 4.20 37.15 0.03 260.00 847.98 849.20
.. is , N
N lik \ -NH
1-0
4oH o-{---
<," 0-
)...rN!' is ,..,
Mixture of
1458 965.20
965.40
\ NH isomers
--c)
,,,i..s
0 eD 0
0
HO OH14 C) 14
r 14,....r_N
Mixture of
1459 L.--/ N ...i&,-
WI \ . N,./41-...)
N \ NH 987.16 988.20
isomers
N,1-0
_E. g-i.;"
04 ,---
1460
,Nµµ.."-11
L---/ N ilk N,...1,,,-...)
N Mr \ NH 967.26 967.30 Mixture of
isomers
id.
0
X ---(_ NS-0'
-0 r.,---;
(:).µ= H
N N
14
F...'1./
1461 H 140 \ ilp sN..
't.'1)" F
N = NH 975.10 975.20 Mixture of
isomers
N-)-(:)
9
W-

CA 0 2 81 1 6 62 2 01 3-0 3-1 9
WO 2012/041014 PCT/CN2011/001638
500
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
1M+Hr Designation
0
)L 01-0-
04 H
N N
i....141
=1462 F
H "" ib
w" N\ '4
* .71..11'.2' F 975.10 975.20
Mbdure of
isomers
N,---(:)
,4 S
WI-
' .
h....0
'03
NH
NH ._hi_ i N 131'''r
Mixture of
0.02 18.45 11.59 60.56
848.02 849.07
1463 o j Ni al \ -*- / ,,,,N
isomers
0 N NI.0 N
/ (0 H
_
'o3NH
NH N , N \
1464 0 c___7--(ri 0 \ * / 11 Z. T 0.03 94.59 25.51 50.60
834.00 835.05 Mixture of
isomers
/0
(0
-......p
'03
NH
HN _ i\N I,4 \ N
Mixture of
1465 O=r<Li-ril 0 \ = / )3....__N 0.05 26.35 91.54 142.92
818.00 819.05
N N U
isomers
(0 H
'0INH
, , ar71 \ N (31...Cr
Mixture of
1466 0 14" \L'1 7-.-N 0 \ lik /,?-c^_i) 0.77 277.13
123.04 220.76 818.00 819.05
H
isomers
N
(0 H
.--...0
'03
NH
NHS. 11 \ CN, .1,,
1467 / - to \ * /,,,IL h.,' I 0.10 261.86 103.84
486.23 789.99 791.04 Mixture of
N
isomers
-0
'05?
NH
Aim_ "" r,4 \
N y='-r
Mixture of
1468 IF c!5---([41 io \ * / ...õ,ti 0.21 227.84 121.41
138.16 837.04 838.09
N N -,_.)
isomers
(0 H

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
501
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure M
. . .
CalcS
la .laY93H laL31V lb 2b
[M+Hr Designation
0...-C)----
0
L---) 0
'0A. NH I Mixture
of
1469 N.1." 1. N \ 0.05 30.90 6.04 0.03 7.10
907.05 908.10
N Y.. isomers
00 c_i-'dN 0 . * /
H N NJ
/ (0 H
0.,,C)---
Hl.k.._1.,
1470 0 -(:).NH 0.06 17.50 8.05 0.03
19.15 921.08 922.13 Mixture of
/
N11." ,N N \
isomers
(:)
1110N \ =
isomers
o< 'c__7
/ (0 H
0
--0ANH
N
M
1471 73 O..Ati\ ,,t,07,... 3.33 414.70
116.89 0.02 378.28 Nom 881.16
isomers somers
N N U
( H
0
'0ANN
1472 7)N u.N ..,k N m\ io \ it , N,,7.7.1*.IY 1.29 455.20 93.80 0.03
233.68 881.10 882.15
i Mixture of
isomers
N N U
)--0 H
(0...1
L--( 0
'09
NH
1473 HN N ,z \ N YiY 888.05 889.10
Mixture of
0:30 N
/ U." N go \ * / %õ N
isomers
N ...2.,..
--.0
*
0
'01NH
N Mixture of
/
1474 _IN 6....ei is * , N
isomers
' N 01,...T, 878.10 879.15
\ %,
N N
(0
0-
N N \ct_cNH
1475 0. N 0 N\ * ii,ijU r 676.83 677.88
Mixture of
isomers
(0 H

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
502
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H 1 aL31V lb 2b Calc.M.S.
[M+Hr Designation
N\ * N 0
Ft) N
1476 \ ---14 (SI * N,ro
-; Fit,..< 896.11 897.16 Mixture of
isomers
o49
, C
,
tit / e,, .0
N\
Cr'IL N * 'Ns,õ..0
1477 N al
-} Hi..1-< 896.11 897.16 Mixture of
isomers
P . NJ ctO
/ 1.µ1,.
N\ * N
1478N
--14 cil * ro
--,- ft) N
1-1:H 896.11 897.16 Mixture of
isomers
o . NJ
o
/ C
/2 i4
I )o
mr_ N 'Am
1479 N di. N CYHr
ci" ti\ / , N 919.15
920.20 Mixture of
isomers
N N
?- 0 H
LN)o
HO
WI 0
'OA NH
o Mixture of
1480 .:,._7)4riµ 401 N\ ir , T,,. z.ky- 896.11
897.16
Mi isomers
N 'L?
(0 H
+
+M ,,Oy 0
1 N
1481 o.ro N , * N ..C_-_7 244.15 984.80
999.00 125.00 549.30 763.90 764.95 Single isomer
6.4 \ * N 0
- N
. 6
-1-
-4-li oyo
1 ,,.>õ N ,
0 0
1482 -f N \ , * N "C_/.. 342.79 999.00
924.54 251.00 999.00 795.99 797.04 Single isomer
...iiii...km * N
jo
c.-11
0 Ito \,-
31-
-0
11 0 , ,0
1483 r ) i 4
/
14 1N¨c 14 --' - 878.01 879.06
Single isomer
¨1-N
ao

CA 028116 62 2013-03-19
WO 2012/041014 PCT/CN2011/001638
503
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la .laY93H laL31V lb 2b Calc.M.S.
[M+Hr Designation
co_j
r ,o
-09tio 0
r

N
1484 lqyA-i-N, o'
962.08 963.13 Single isomer
N / .II \ ft I pi N
N -
e 0
H
N
C4r.i 1
0 / N H
N - 0 i., It N,-J, ,
1485 --)- -0 0.05 13.40 2.73 23.00 945.50
946.50 Single isomer
O(
ol,,,,
,0 HN . r
.,
? 0
/1
0 N 0110 \ * / N H
0
\-0
1486 NH
N N'.4...r--\
1,14-/ 0.40 32.00 1.72 117.30 888.40 889.30 Single isomer
0
0 HN .="(
M N CI
C---')-('N ab,
1487 H wi \ lit z N
N 580.14 581.19
Mixture of
,.0 N-j121
isomers
o
'03.r=0 .. r ,o
m .r...N..)_4NN 1
...) 0 Mixture of
1488 F H 401 N\ IP / NO--r0--
,7 A 0.06 0.15 0.03 1.90 1062.15 1063.20
isomers
...qt-,,ii
0 li
\.*
-F
0_
-05z.Xeo
...,,N,
1489 F-'s 9 =
H 140 N\ IIP / puy. H 0.03 0.08
0.99 52.10 978.08 979.13 Mixture of
isomers
tl->4
F
0-
-cil ;co
H c..Nti 1 CI
1490 / po
0 N\ * -,- 9
N)(0, 0.02 30.00 3.68 20.00
894.48 895.53 Mixture of
isomers
N--,., H

CA 02811662 2013-03-19
WO 2012/041014 PCT/CN2011/001638
504
EC50 EC50 EC50 EC50 EC50 Obs .M.S.
Isomer
Cmpd # Structure
la laY93H laL31V lb 2b Calc.M.S.
[Whir Designation
o
H c..N._..NN 1 CI 0 Mixture
of
1491
r A 0.02 0.03 1.00 978.56 979.61
isomers
H 14110 N\ * / p0.1õ-..N 0,
N-Ce H
---N---e- 0
ci,:y(!4 I
0 Mixture
of
1492 rl 0 N\ o* / No N.-, 0.13 13.60 0.10 0.03
0.19 1006.27 1007.32
isomers
N - ',
\ . *
0-
---)-00
1493 111 0 \ 216.06 999.00 815.95 817.00
Mixture of
N o. iNit 0til-o l< isomers
F-&0\
I
xture of
1494 43. /Fri 615.72
616.77 Mi
isomers
F-.&0\
o ..
II C441 9
1495 N CYA'N.L0'. 0.02 48.10 1.03 0.01
1.23 930.06 931.11 Mixture of
n Olt \ fi, , M
isomers
0
H
F_as
,
,OINIt r.
C.) 0
H c,f,N 1
- A 1014.13
1015.18 Mixture of
1496 0-
isomers
1 140 N\ oS ltill n

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
CONTENANT LES PAGES 1 A 504
NOTE : Pour les tomes additionels, veuillez contacter le Bureau canadien des
brevets
JUMBO APPLICATIONS/PATENTS
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VOLUME
THIS IS VOLUME 1 OF 2
CONTAINING PAGES 1 TO 504
NOTE: For additional volumes, please contact the Canadian Patent Office
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Representative Drawing