CA2636916A1 - Methods for treating hepatitis c - Google Patents

Abstract

The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.

Description

METHODS FOR TREATING HEPATITIS C
CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of Application No. 11/331,180, filed January 13, 2006, which is a continuation-in-part of Application No. 11/180,961, filed July 14, 2005, and of International Application No. PCT/US2005/024881, filed July 14, 2005, both of which applications claim the benefit of U.S. Provisional Application No. 60/587,487, filed July 14, 2004, U.S. Provisional Application No. 601634,979, filed December 13, 2004, U.S. Provisional Application No. 60/645,586, filed January 24, 2005, U.S. Provisional Application No.
60/665,349, filed March 28, 2005, and U.S. Provisional Application No.
60/675,440, filed April 28, 2005; this application also claims the benefit of U.S. Provisional Application No.
60/758,527, filed January 13, 2006, the entire contents of which applications are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.

BACKGROUND OF THE INVENTION
An estimated 170 million people worldwide are reported to be infected with hepatitis C"
virus (HCV), the causative agent of hepatitis C. Seventy to eighty percent of HCV infections lead to chronic liver infection, which in turn may result in severe liver disease, including liver fibrosis, cirrhosis, and hepatocellular carcinoma (115).
HCV constitutes the Hepacivirus genus of the family Flaviviridae (106), and contains a positive-stranded 9.6 kb RNA genome. The features of the HCV genome include a 5'-untranslated region (UTR) that encodes an internal ribosome entry site (IIZES) that directs the translation of a single long open reading frame (ORF) encoding a polyprotein of 3,010 amino acids. The HCV ORF is followed by a 3'-UTR of variable length, depending on the HCV
variant, that encodes the sequences required for the initiation of antigenomic strand synthesis (79).
The HCV IRES and 3'-UTR both encode regions of RNA structures that are required for genome translation and replication_ The HCV polyprotein is posttranslationally processed into at least 10 mature viral proteins, including the structural proteins core (putative nucleocapsid), El and E2 and the nonstructural (NS) proteins NS2 to NS5B.

Three distinct elements have been shown to be involved in HCV IRES-mediated translation: (1) integrity of the global structure of HCV IRES, (2) the 3'-terminal region of the HCV genome; and (3) trans-acting cellular factors that interact with the HCV
IRES element and assist in translation initiation (35).
The initiation of protein synthesis in eukaryotic cells predominantly follows the 5' cap-dependent, first AUG rule (61). However, an increasing number of viral (6, 12, 28, 31a, 50, 95,97, 98, 105,128) and cellular mRNAs (18, 39, 45, 78, 91, 130) have been shown to use an IRES element to direct translation initiation. In 1992, an IRES element was reported in the 5' UTR of the HCV RNA genome (129), indicating that synthesis of the viral protein is initiated in a cap-independent fashion.
A bicistronic expression system can be used to define and evaluate the function of IRES
elements. This test system harbors two different reporter genes in which the 5'-proximal reporter gene is expressed by a cap dependent translation mechanism while the second reporter is expressed only if an upstream sequence inserted in the intergenic space contains an IRES
sequence element. Using this system, a putative IRES in the HCV 5' UTR was unambiguously demonstrated to function as an IRES involved in translational control of viral proteins (133).
In vitro translation, RNA transfection, and mutagenesis studies provided further evidence that the HCV 5' UTR contains an IRES element (23, 41, 42,108,129, 132,133, 134).
Both in vitro and cell-based studies demonstrated that the HCV IRES guides cellular translation initiation factors to an internal site of the viral RNA (56, 58, 120), thus functionally demonstrating the HCV IRES activity. Taken together, these results demonstrate that the HCV 5'-UTR contains an IRES element that plays an active and crucial role in the mechanism of internal initiation for HCV protein translation.
The IRES is one of the most conserved regions of the HCV genome, reflecting its essential nature for viral replication and protein synthesis (13, 118, 122).
Although both 5' and 3' sequences of the IRES appear to play a role in the control of initiation of translation (42, 109, 110, 113, 136), the minimal sequence requirement for HCV IRES function has been mapped to a region between nucleotides 44-354 (40).
Biochemical probing and computer modeling indicate that the HCV IRES and its 5' sequence is folded into a distinct structure that consists of four major domains and a pseudoknot (11, 42, 122). Domain I contains a small stem-loop structure that does not appear to be a functional part of the IRES element while domains_ II, HI, and IV
contain the HCV
IRES activity (43, 111). The=relationships between secondary and tertiary structures of the HCV IRES and their function have recently been established (5, 55, 56, 99, 124). Both domains II and III consist of multiple stems, loops, and bulges and are important for IRES
activity (23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131, 139, 141, 142).
Domain II can induce conformational changes on the ribosome that have been implicated in the decoding process (124). Domain III has the highest degree of structural conservation among the different HCV strains. It comprises the core of the flavivirus IRES and has 6 subdomains (40). Various studies have shown that subdomain IlId forms complex secondary/tertiary structures and is critical for initiation activity (55, 56, 57, 124, 129).
Domain IV has one stem-loop that spans the initiation codon and is specific for the HCV IRES (41, 122), but the precise role of domain IV in IRES activity remains controversial (41, 112).
The role of the HCV IRES is to position the translational machinery near an internal initiator codon in the viral inRNA. The translation initiation mechanism of the HCV and other viral IItES differs significantly from that of 5'-cap-dependent translation initiation (7, 21, 31, 35, 61, 71, 72, 81, 88, 96, 114, 123). =Most cellular capped mRNAs utilize a number of initiation factors (eIFs) that are required for the translation'initiation process. The initial steps of the process require proteins that interact with the 5' cap structure and recruit the 40S
ribosomal subunit to the cap-proximal region of mRNA. This complex then scans 3' of the cap, until reaching an AUG codon at which translation will initiate (21, 114).
However, in the case of HCV, the IRES funetionally replaces the 5' cap structure, allowing the 40S ribosomal suburnit and eIF3 to bind directly to the RNA. Subdomain IIId of the HCV IRES
harbors the binding site for the 40S ribosomal subunit and the only initiation factors required for translation initiation are eIF2, eIF3, and eIF4E (15, 58, 94, 100, 120, 124).
The polypyrimidine track-binding protein (PTB) and La autoantigen are noncanonical translation initiation factors that bind to and enhance HCV IRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB, a 57-kDa protein involved in RNA splicing, is also necessary for efficient IRES-mediated translation initiation of picomavirus mRNA, and some cellular mRNAs (10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 kDa double-stranded RNA unwinding protein, also increases the activity of poliovirus and cellular IRES (38, 85, 86). Other cellular factors involved in HCV IRES-mediated translation initiation include proteasome a-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9 (24, 25, 100), and hnRNPL (33).
However, the role of these RNA-binding proteins in HCV IR.ES-mediated initiation of translation is unclear. Receintly, it was reported that the activity of interferon (IFN) a against HCV replication might target HCV IRES-mediated translation initiation by causing a reduction of La protein levels (117) Some HCV proteiiis, such as NS5A, core and NS4A/4B, also reported to be involved in the HCV IRES function (143-146)_ Thus; an inhibitor that blocks interaction between the IRES and the noncanonical factors might efficiently inhibit HCV
replication and lack cytotoxicity.
Currently, only interferon (IFN) a and the nucleoside analogue ribavirin, in combination, are marketed for the treatment of HCV infection. However, these two agents are immunomodulators and have limited efficacy, relatively high toxicity, and high cost (80, 83, 84, 138). Although the treatment outcome is variable among the six major HCV
genotypes, only about one-half of all treated patients respond to therapy, suggesting that the virus encodes protein products that may directly or indirectly attenuate the antiviral action of IFN. IFNs are naturally produced in response to virus infection, and cellular exposure to IFN leads to the induced expression of a variety of IFN-stimulated genes (ISGs), many of which have an antiviral function. ISG action can limit virus replication at multiple points within the replicative cycle.
There remains a need for an alternative means of treating patients afflicted with HCV.
Specifically, a need exists for novel antiviral drugs, for example, that have no cross-resistance =
with existing treatment modalities, and which demonstrate synergy with other anti-HCV
agents.
All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.
SUMMARY OF THE INVENTION
The present invention provides compounds, pharmaceutical compositions, and methods of using such compounds or compositions for treating infection by a virus, or for affecting viral IRES activity.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 illustrates the HCV-PV chimera construct. The cloverleaf-like RNA
structure of PV; an essential cis-acting replication signal ending with the genome-linked protein VPg, is located at the 5' end of the genome. The solid (HCV) and open (PV) boxes depict open reading frames encoding viral polypeptides. The position of the HCV core fragment (the frst 123 amino acids) gene is denoted by 0 Core. Overall, the HCV-specific sequence in the HCV-.
PV spans from nucleotides 18 to 710 (139). ' DETAILED DESCRIPTION OF THE INVENTION

A. Compounds of the Invention One aspect of the invention relates to a compound of formula I
R x Rl ' \ \
Y I
N
Z
R2 ~

wherein:
X is:
-hydrogen;
-a nitro group;
-a cyano group;
-a -CORa group, where Ra is:
-a C, to C6 alkyl, -a C6 to Cg aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COOR,, group, where R,. is a Cl to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a hydrogen;
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more CI to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;

-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;
O

O
~

(CH2)n N O
- Rb , where Rb is a hydrogen or a C, to C6 alkyl, and n is 0 or 1;
. I .
\ N -where is a hydrogen, a-CONHR,,, where RX is as defmed above;
or an -SOZR., where R,, is as defined above; or \i~
N~~~
O
- , where Rd is a Ct to C6 alkyl or a C6 to C8 aryl;
-a -NHCORe group, where Re is:
-a C, to C6 alkyl;
-a C6 to Cg aryl optionally substituted with:
-a Cl to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOORX group, where R. is as defined above;
-a -CH2O-Rfgroup, where Rf is a C6 to Cg aryl;
-a -NR.gRh group, where Rg is hydrogen or a Ci to C6 alkyl and Rh is hydrogen or a C6 to Cg aryl optionally substituted with an alkoxy;
-a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a C1 to C6 alkyl, optionally substituted with a C6 to C$ aryl, -a C6 to Cg aryl, optionally substituted with -COOR,, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR,, group, where R,e is as defined above, or -a -NHCOOR, group, where R,, is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a Ci to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more CI to C6 alkyl(s), -a -NR;SO2R,e group, where R,e is as defined above and Ri is:
-a hydrogen, -a C, to C6 alkyl, -a -CORX group, where R,, is as defmed above, -a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:
-a C1 to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more C1 to C6 alkyl(s), and R; is:
-a hydrogen, -a C I to C6 alkyl, - a-CORX group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N}=N- group, or -a -CORI, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Cl to C6 alkyl(s), -a nitro group, -a CI to C6 alkyl group, optionally substituted with:
-a -NHSO2Rx group, where R. is as defined above, or -a -NR,,SO2RX group, where Rx is as defmed above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COORX group, where R,, is as defined above, -a -CORm group, where R., is:
-an amino optionally substituted with one or more Ci to C6 alkyl(s), where the one or more CI to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more Cl to C6 alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rõ is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or .
-one or more alkoxy(s), -a -NRoCORp group, where Rp is:
-a Ct to C6 alkyl optionally substituted with:

-a halogen, -an alkoxy, or -a C6 to C8 aryl, -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more Cl to C6 alkyl(s), -a hydrogen, * ~ or Z p and where Ro is:
-a hydrogen, -a Ci to C6 alkyl, -a -COR,, group, where RX is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen, -a C 1 to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR,, group, where R,, is as defined above, and where R, is:
-a C6 to C8 aryl optionally substituted with:

* f - . .
N

O
~---N
-a C i to C6 alkyl, -a haloalkyl, -a -ORs group, where RS is a C6 to C8 aryl, or -a -COOR,, group, where Rx is as defined above, -a C, to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, -a C6 to C8 aryl, andlor -a -COOR. group, where R,; is as defined above, -a -COOR,ti group, where R,, is as defmed above, -a -NRtCOORõ group, where Ru is:
-a CI to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 tO Cg aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a Cl to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a C, to C6 alkyl, -a -COR,, group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRSO2R,a, group, where Rv is:
-a hydrogen, -a -CORX, where Rx is as defmed above, or -a C, to C6 alkyl, optionally substituted with:
-a halogen, -a -COR., group, where Rx is as defined above, -a -OCOR,s group, where Rx is as defined above, -a hydroxy, or -an alkoxy, and where R, is:
-a C, to C6 alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C, to C6 alkyl, -a 5 or 6 membered heterocycle, or - \ N
O
* N

-a , O
* N
~NH
-a , O

NH
*õ_-N

-a Ry N Ry -a O , optionally substituted with a Ct to C6 alkyl, where Ry is a CI to C6 alkyl or hydrogen, O
-a , = O O

.~
-a N
~Z
tI~
O S N
-a where RZ is hydrogen or a Ci to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SRX group, where R,, is as defined above, -a -SOZRaa group, where Ra is:
-a C, to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COOR. group, where RX is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -NHRbb group, where Rbb is:
N

N ~
-a -C(=S)NH2 group, or -a -PO(ORX)2 group, where Rx is as defined above;
-a ~ Rcc group, where is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a -a C6 to C$ aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a CI to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ct to C6 alkyls, -a -NHPORXRx, where RX is as defined above, -a -1VRCeCONRaRff group, where R, is a hydrogen or a CI to C6 alkyl, optionally substituted with a halogen, and Ra-is:
-a hydrogen, -a haloalkyl, -a haIoalkoxy, -a C, to C6 alkyl, or -a -CORx, where Rx is as defined above, -a -NRRggCORhh group, where Rhh is:
-a hydrogen, -a Cl to C6 alkyl optionally substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more Cl to C6 alkyls, ,-an amino optionally substituted with one or more Ci to C6 alkyls, where.
the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, andRgg is:
-a hydrogen, -a Ci to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR,e group, where R,t is as defmed above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more C1 to C6 alkyls, and/or -a -NRiiS02Rx group, where RX is as defined above, and R;; is:
-a hydrogen, -a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -CORX group, where Rx is as defined above;
Z is:
-a hydrogen;
-a Ct to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C$ aryl;
-a C2 to C6 alkylene;
-a C6 to Cg aryl optionally substituted with an alkoxy or one or more Cl to C6 alkyl(s);
-a -COORx group, where RX is as defined aboye; or q - .o--!
R is a hydrogen, a halogen or an alkoxy;

Ri is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR,. group, where R,e is as defined above;
-a C, to C6 alkyl optionally substituted with a dialkyl-arnino or a 5 or 6 membered heterocycle;
or R, joins together with R2 to form:
, O O :
r r ~ =
Q
= ~
R2 is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C, to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR,, group, where R,, is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group;
-a -COORx group, where R, is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to C8 aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR, group, where RX is as defined above;
-a -NHCORjj group, where Rij is:
-an alkoxy, or -an amino optionally substituted with one or more C, to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a -NHSO2Rx group, where Rx is as= defined above; or R2 joins together with R, to form:
O
~ ~.
. O
R3 is:
-a hydrogen; or -CH2OCORX, and RX is as defined above;
or a phannaceutically acceptable salt thereof.
In some embodiments of formula I, Xis:
-a nitro group;
-a cyano group;
-a -CORa group, where Ra is:
-a CI to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-atnino;
-a -COOR,, group, where Rx is a C, to C6 alkyl;
-a formyl group;
-a C6 to Cg aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:

-a C, to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more C, to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C, to C6 alkyl;
\

o C(N (CH2)n - Rb , where Rb is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;

{

( =
w ~ .

- , where is a hydrogen, a-CONFIR,, where R, is as defined above, or an -SO2Rx, where R,, is as defined above;

~~~
N/ %

- , where Rd is a C1 to C6 alkyl or a C6 to C8 aryl;
-a -NHCOR, group, where R. is:
-a C, to C6 alkyl;
-a C6 to C$ aryl optionally substituted with:
-a C t to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOORx group, where R. is as defined above;
-a -CHzO-Rfgroup, where Rfis a C6 to C$ aryl;
-a -NRgRh group, where Rg is a C, to C6 alkyl or a hydrogen and Rh is a C6 to C8'aryl optionally substituted with an alkoxy;
-a Ci to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a Cl to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a C6 to C$ aryl, optionally substituted with -COOR, where RX is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COORx group, where Rx is as defined above, or -a -NHCOORX group, where R. is as defined above;
-a C6 to Cg aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a C, to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more C, to C6 alkyl(s), -a NR;SOZR,, group, where R,t is as defined above and Ri is:
-a hydrogen, -a C, to C6 alkyl, -a -CORX group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:
-a C, to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more C1 to C6 alkyl(s), and Rj is:
-a hydrogen, -a C, to C6 alkyl, - a-COR, group, where R, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N~=N` group, or -a -CORi, where Rl is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more CI to C6 alkyl(s), -a Ct to C6 alkyl group, optionally substituted with:
-a -NHSO2R,, group, where R. is as defined above, or -a -NRxSO2RX group, where RX is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COORx group, where RX is as defined above, -a -CORm group, where Rm is:
-an amino optionally substituted with one or more C, to C6 alkyl(s), where the one or more CI to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more C, to C6 alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a dialkyl-amino, -a -NHRõ group, where Rõ is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halogen(s),.
-a nitro group, or -one or more alkoxy(s), 10. -a -N'RQCORP group, where RP is:
-a C, to C6 alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a C6 to Cg aryl, -a 5 or 6 membered heterocycle, -a C6 to C$ aryl, optionally substituted with a halogen, -a 5 or 6' membered heteroaryl optionally substituted with one or more C, to alkyl(s), -a hydrogen, N O
* 0 or N
- , and where Ro is:
-a hydrogen, -a Cl te C6 alkyl, -a -COR,t group, where RX is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRyCONRqRr group, where Rp is:
-a hydrogen, -a Cz to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where R,; is as defined above, and where Rr is:
-a C6 to C8 aryl optionally substituted with:
N
~ _ .

O~ =
-N
-a C, to C6 alkyl, -a haloalkyl, -a -ORs group, where Rs is a C6 to C8 aryl, or -a -COORX group, where R,, is as defined above, -a C, to C6 aIlcyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, -a C6 to C8 aryl, and/or -a -COORx group, where RX is as defined above, -a -COOR,, group, where RX is as defiried above, -a -NRcCOORõ group, where R. is:
-a Cl to C12 alkyl, optionally substituted with:
-a C6 to C$ aryl optionally substituted with a CL to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a CI to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a Ci to C6 alkyl, -a -CORX group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRõSOZR,,, group, where Rõ is:
-a hydrogen, -a -COR,, where R, is as defined above, or -a Cl to C6 alkyl, optionally substituted with:
-a halogen, -a -COR. group, where R,t is as defined above, -a -OCOR,, group, where RJe is as defined above, -a hydroxy, or -an alkoxy, and where Rw is:
-a C, to C6 alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Cl to C6 alkyl, -a 5 or 6 membered heterocycle, or ~ I

- ~ ~
- N
O

* N/

-a O

" N
[1,INH
a O

NH
-a -a o , .
Ry O

N Ry ~. ~..- N -a optionally substituted with a Cl to C6 alkyl, where Ry is a Ct to C6 alkyl or hydrogen, O

-a ___ N
D , O

-a N
RZ
O S

-a where RZ is hydrogen or a Ci to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SR, group, where R. is as defined above, -a -SOZRaa group, where R, is:
-a Cl to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COORx group, where R,, is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -NHRbb group, where Rbb is:
N
N
-a -C(=S)NH2 group, or -a -PO(OP.J2 group, where R., is as defined above;
-a R,o group, where R,,, is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a -a C6 to C$ aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a C I to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more C1 to C6 alkyl(s), -a NHPORRX, where RX is as defined above, -a -NReeCONRffRfr group, where Ree is a hydrogen or a CI to C6 alkyl, optionally substituted with a halogen, and Rff is:
-a hydrogen,.
-a haloalkyl, -a haloalkoxy, -a Ci to C6 alkyl, or -a -COR, where R,, is as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen, -a C, to C6 alkyl optionally substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more C, to C6 alkyl(s), -an amino optionally substituted with one or more Cl to C6 alkyl(s), where the one or more C, to C6 alkyl(s) is/are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is:
-a hydrogen, -a C, to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR, group, where R, is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more C1 to C6 alkyl(s), and/or -a -NRiSO2RX group, where RX is as defined above, and Ri; is:
-a hydrogen, -a C, to C6 aikyl, -a haloalkyl, -a haloalkoxy, -a -CORx group, where R,. is as defmed above;
Z is:
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C$ aryl;
-a C2 to C6 alkylene; _ -a C6 to C$ aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);
-a -COORK group, where RX is as defined above; or O

_ O___._J
R is a hydrogen, a halogen or an alkoxy;
R, is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -aC6toC8aryl,or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR,t group, where Rx is as defmed above;
-a Cl to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle; .
or Rl joins together with RZ to form:
O
. '~.
.
O
.~

R2is:
-a nitro group;
-a hydrogen;
-a halogen; =
-a hydroxy group;

-a C 1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCORx group, where R7e is as'defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group;
-a -COORX group, where R,, is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to Cs aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR,, group, where R,, is as defmed above;
-a -NHCORy group, where Ry is:
-an alkoxy, or -an amino optionally substituted with one or more C, to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a -NHSO2RX group, where R,, is as defined above; or R2 joins together with R, to form:

cii O
;and .
R3 is:
-a hydrogen; or -CH2OCOR, and Rx is as defined above;
provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, RI is a halogen, R2 is hydrogen, and R3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Rl is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:

-a C, to C6 alicyl substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to Cg aryl;
-a C2 to C6 alkylene;
-a C6 to C$ aryl optionally substituted with an alkoxy or one or more CI to C6 alkyl(s);
-a -COOR,, group, where R,, is as defined above; or Oo ;or or a phannaceutically acceptable salt thereof.
In some embodiments, X is a nitro group or a cyano group. In other embodiments, X is a cyano group.
In some embodiments, Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more C, to C6 alkyl(s), -a Cl to C6 alkyl group, optionally substituted with a-NHSO2R,, group, -a -NRoCORp group, where Rp is:
-a C, to C6 alkyl optionally substituted with:
-a halogen, or -aC6toC8aryl,or -a 5 or 6 membered heterocycle, and where Ro is a hydrogen, -a -NRqCONRyRT group, where RQ is:
-a hydrogen, or -a C1 to C6 alkyl, and where R, is a CI to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, or -a C6 to C8 aryl, -a -NR;COOR. group, where Rõ is:

-a Ci to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a Ct to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle, and where Rt is:
-a hydrogen, or -a C I to C6 alkyl, -a -NRõSO2R, group, where Rõ is a hydrogen, and where R,,, is a C, to C6 alkyl optionally substituted with a halogen;
O

* N
-a O
* N

- L'j NH
a , O

NH
N

-a O
-a *~ "~N

-a Rz N /
0 i~~
-a "'i N ( >
where RZ is a C, to C6 alkyl, and/or -a -NHRbb group, where Rbb is a-PO(ORX)a group.
In further embodiments, Y is a C6 to Cs aryl substituted with:
-a -NRCONRqRr group, -a -NR,COORõ group, -a -NRSO2RW group, or -a -NHRbb group, where Rbb is -a -PO(OR,,)2 group.
The C6 to C8 aryl may be substituted at the para, meta and/or ortho position(s). In some embodiments, the C6 to C$ aryl is phenyl. In other embodiments, the C6 to C$
aryl is phenyl substituted at the para position.
In some embodiments, Y is phenyl substituted with a-NRqCONRqRr group at the para position. In other embodiments, Y is phenyl substituted with a-NRtCOORõ group at the para position. In yet other embodiments, Y is phenyl substituted with a-NRSO2Rw group at the para position. In yet other embodiments, Y is phenyl substituted with a-NHI'O(ORX)2 group at the para position.
In some embodiments, Z is:
-a CI to C6 alkyl optionally substituted with -an alkoxy, or -one or more hatogen(s), or -a C2 to C6 alkylene.
In other embodiments, Z is a Ci to C6 alkyl. In yet other embodiments, Z is a a C2 to C5 alkyl. In yet other embodiments, Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl_ In some embodiments, R is hydrogen.
In some embodiments, Ri is:
-a hydrogen;

-an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl group, or -a 5 or 6 membered heterocycle; or Rt joins together with R2 to forrn:
O O
O
D O
In some embodiments, R2 is:
-a hydrogen;
-a halogen;
-a hydroxy group;
-a Cl to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCORX group, where R. is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to Cg aryl group;
-a -COORx group; or R2 joins together with Rl to form:
O
Q
In other embodiments, at least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl group, or -a 5 or 6 membered heterocycle group; or R2 is a-OCORX group, a-ORkk group, or an alkoxy group substituted with:

-an -OCORx group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group.
In yet other embodiments, R2 is a-ORkk group or an alkoxy group optionally substituted with:
-a dialkyl-amino. optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group.
In yet further embodiments, R2 is a Cl to C6 alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group.
In some embodiments, R3 is a hydrogen.
In some embodiments, X is a cyano group;
Y is a C6 to Cg aryl substituted with:
-a -NRqCONRqRr ggoup, -a -NRtCOORõ group, -a -NRSOZR, group, or -a -NHPO(OR,,)2 group;
Z is:
-a C1 to C6 alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or -a C2 to C6 alkylene; -R is hydrogen;
at least one of Ri and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl group, or -a 5 or 6 membered heterocycle group; or R2 is a-OCOR, group, a -ORkk group, or an alkoxy group substituted with:
-an -OCORX group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group; and R3 is hydrogen.
In some embodiments, Y is a phenyl substituted with a-NR,COORõ group. In further embodiments, Rt is a hydrogen, and Rõ is:
-a C, to C12 allcyl, optionally substituted with one or more_groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halogen, -an alcoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Cl to C6 alkyl, -halogen, or -a 5 or 6 membered heteroaryl, - a C2 to C6 alkylene, -a C6 to Cg aryl, optionally substituted with halogen.
In yet further embodiments, R. is a Ci to C6 alkyl_ In some embodiments, Y is a phenyl substituted with a-NRnCONRqRr group. In farther embodiments, Rq is a hydrogeri and Rr is:
-a Ci to C6 alkyl optionally substituted with one or more of the following:
-a hydroxy, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl optionally substituted with a halogen, -a C2 to C6 alkylene group, -a CI to C6 alkoxy group, -a 5 or 6 membered heterocycle group.
In yet fu.rther embodiments, Rr is a a Ct to C6 alkyl.
In some embodiments, Y is phenyl substituted with a-NRSO2R, group. In further embodiments, R, is a hydrogen, and where Ru, is -a C, to C6 alkyl.
In some embodiments, Y is phenyl substituted with a-NHPO(ORx)Z group.
In some embodiments, Y is a phenyl substituted at the para position with:
-a -NRqCONR.qR, group, -a -NRtCOORõ group, -a -NR,,SOyRW group, or -a -NHPO(ORX)2 group;
Z is a C1 to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group.
In some embodiments, the compound of formula I is not Compound 1.

In yet another embodiment, the present invention includes compounds of the following:
1. A compound of formula I
R x R, . ~ \
Y
N

z wherein:
X is:
-a nitro group;
-a cyano group;
-a -CORa group, where Ra is:
-a Cl to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where R. is a C, to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl, -a C6 to Cg aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;

-a halogen;
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl;
X O

O
O
(CH2)n N O
- Rb , where Rb is a hydrogen or a C, to C6 alkyl, and n is 0 or 1;
~
\\ O
I

õ I

- , where R, is a hydrogen, a-CONHRx, where RX is as defined above, or an -SO2RX, where RX is as defined above; or \Rd N

*lN
- , where Rd is a CI to C6 alkyl or a C6 to C8 aryl;
-a -NHCORe group, where Re is:
-a CI to C6 alkyl;

-a C6 to C$ aryl optionally substituted with:
-a Ct to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a NHCOOR,, group, where R,, is as defined above;
-a -CH2O-Rfgroup, where Rf is a C6 to C8 aryl;
-a -NRgRh group, where R. is hydrogen or a C1 to C6 alkyl and Rh is hydrogen or a C6 to C8 aryl optionally substituted with an alkoxy;
-a CI to C6 allcyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a Ci to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a C6 to Cg aryl, optionally.substituted with -COORx, where RX is as defined above, or -an arnino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR,, group, where R, is as defined above, or -a -NHCOORx group, where R. is as defined above;
-a C6 to C$ aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a Ct to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more C i to C6 alkyl(s), -a -NRiSO2Rx group, where R, is as defined above and Ri is:
-a hydrogen, -a Ci to C6 alkyl, -a -COR,, group, where R,t is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:

-a C1 to C6 alkyl, -a hydrogen, or --an amino optionally substituted with one or more C, to C6 alkyl(s), and Rj is:

-a hydrogen, -a C, to C6 alkyl, - a-CORX group, where R, is as defined above, -a haloalkyl, or --a haloalkoxy, -a -N=N=N" group, or -a -CORi, where R, is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Cl to C6 aIlcyl(s), .
-a C t to C6 alkyl group, optionally substituted with:
-a -NHSO2R, group, where RX is as defined above, or -a -NRXSO2RX group, where Rx is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COOR,, group, where RX is as defmed above, -a -COR,,, group, where Rm is:
-an amino optionally substituted with one or more Cl to C6 alkyl(s), where the one or more C 1- to C6 alkyl(s) is/are optionally substituted with:

-a hydroxy 25 -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more C, to C6 alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a dialkyl-amino, - 30 -a -NHRt, group, where Rõ is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NRaCORP group, where Rp is:
-a C, to C6 alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a C6 to C$ aryl, -a 5 or 6 membered heterocycle, -a C6 to C$ aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyl(s), -a hydrogen, ~ oriz 0 (IX> a - ~
and where Ro is:
-a hydrogen, -a C, to C6 alkyl, -a -COR,. group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR.qCONRqR, group, where Ra is:
-a hydrogen, -a C, to C6 alkyl, -a haloalkyl, -a haloalkoicy, or -a -COR. group, where R. is as defined above, and where Rr is:
-a C6 to C$ aryl optionally substituted with:

N

-N
-a Cl to C6 alkyl, -a haloalkyl, -a -OR, group, where R, is a C6 to C8 aryl, or -a -COOR, group, where R,, is as defined above, -a Ci to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, -a C6 to C$ aryl, and/or -a -COORX group, where R,, is as defined above, -a -COORx group, where RX is as defmed above, -a -NRtCOOR. group, where Rõ is:
-a CI to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C$ aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a C, to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a Ct to C6 alkyl, -a -COR, group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRSO2Rw group, where R,, is:
-a hydrogen, -a -CORx, where R,, is as defined above, or -a CI to C6 alkyl, optionally substituted with:
-a halogen, -a -CORX group, where RX is as defined above, -a -OCOR,, group, where R, is as defined above, -a hydroxy, or -an alkoxy, and where R,, is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ct to C6 alkyl, -a 5 or 6 membered heterocycle, or ~ f =
- N
O
1\~0 N

-a , O
` N
- NH
a O

NH
.~-'N

-a O , Ry N Ry ..~iN

-a optionally substituted with a C, to C6 alkyl, where Ry is a CI ta C6 alkyl or hydrogen, O
n "~N
-a "
O
O

'~~r -a N
i), RP
l, O S
I
-a where RZ is hydrogen or a Cl to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SRx group, where RX is as defined above, -a -SO2R88 group, where R,,, is:
-a C, to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COOR,. group, where R, is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -1VHRbb group, where Rbb is:

~

N

N _ ~ .

-a -C(=S)NH2 group, or a-PO(ORX)Z group, where RX is as defined above;
-a ' Roe group, where R,, is:
-a naphthalene, --a 5 or 6 membered heteroaryl, O
-a -a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a C, to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more CF to C6 alkyl(s), -a -NHPORRX, where R. is as defined above, -a -NRCeCONRffRff group, where R,,,,, is a hydrogen or a Cl to C6 alkyl, optionally substituted with a halogen, and Rff is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -aCl.toCfialkyl,or -a -CORX, where R,. is as defined above, -a -NRgsCORhh group, where Rhh is:
-a hydrogen, -a CI to C6 alkyl optionally substituted with:

-an alkoxy, -a halogen, or -an amino optionally substituted with one or more C, to C6 alkyl(s), -an amino optionally substituted with one or more Ci to C6 alkyl(s), where the one or more Cl to C6 alkyl(s) is/are optionally substituted with a halogen, -a 5 or 6 membered heterooycle, -a 5 or 6 membered heteroaryl, and RP., is:
-a hydrogen, -a CI to C 6 alkyl, .-a haloalkyl, -a haloalkoxy, or -a -CORx group, where R,, is as defmed above, -a haloalkyl, --5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more Ci to C6 alkyl(s), and/or -a -NR;SO2RX group, where Rx is as defined above, and Rii is:
-a hydrogen, -a C3 to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -COR,, group, where RX is as defined above;
Z is:
-a CI to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s); or -aCstoCgaryl;
-a C2 to C6 alkylene; -a C6 to C8 aryl optionally substituted with an alkoxy or one or more Ci to C6 alkyl(s);

-a -COOR,, group, where R,, is as defined above; or ~ .
O

- 0 --_/ ;
R is a hydrogen, a halogen or an alkoxy;
R, is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to Cg aryl, or -a 5 or 6 membered heterocycle;
-a C6 to Ca aryl optionally substituted with an alkoxy;
-a -CORx group, where RX is as defined above;
-a CI to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or Rl joins together with R2 to form:
O
O
=
R2 is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;

-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR,, group, where R,, is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group;
-a -COOR,, group, where Rx is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to Cs aryl;
-a 5 or 6 membered heteroaryl;
-a -OCORX group, where R,t is as defined above;
-a -NHCORy group, where Ry is:
-an alkoxy, or -an amino optionally substituted with one or more C} to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a NHSO2RJe group, where R,, is as defined above; or R2 joins together with R2 to form:
O

`=, O ' ` ~ -R3 is:
-a hydrogen; or -CH2OCOR,,, and R,, is as defined above;
provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, R, is a halogen, R2 is hydrogen, and R3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, Ri is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:
-a CI to C6 alkyl substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more Ci to C6 alkyl(s);
-a -COORx group, where R,, is as defined above; or ~ \.

f / 0 or or a pharmaceutically acceptable salt thereof.

2. The compound of embodiment 1, wherein X is a nitro group or a cyano group.
3. The compound of embodiment 1, wherein X is a cyano group.

4. The compound of embodiment 1, wherein:
Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-an amuto optionally substituted with one or more Ci to C6 allcyl(s), -a Cl to C6 alkyl group, optionally substituted with a-NHSO2R,. group, -a -NRoCORP group, where Rp is:
-a Ct to C6 alkyl optionally substituted with:
-a halogen, or -a C6 to Cg aryl, or -a 5 or 6 rnembered heterocycle, and where Rd is a hydrogen, -a -NRqCONRyR, group, where RQ is:
-a hydrogen, or -a CI to C6 alkyl, and where R, is a C, to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, or -a C6 to C$ aryl, -a -NRtCOORõ group, where R. is:
-a Cl to C12 alkyl, optionally substituted with:
,46 -a C6 to C$ aryl optionally substituted with a C, to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C$ aryl, optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle, and where Rt is:
-a hydrogen, or -a CI to C6 alkyl, -a -NRõSO2RW group, where Rõ is a hydrogen, and where RW is a C1 to C6 alkyl optionally substituted with a halogen;
O

" N
-a * N

Li NH
-a , NH
-a O
-a ~ N
O O

' -a N

0 % z I I, N
O S

*/N
-a where RZ is a Cl to C6 alkyl, and/or -a NHRbb group, where Rbb is a-PO(ORx)a group.

5. The compound of embodiment 4, wherein Y is a C6 to Cg aryl substituted with:
-a -NRqCONRaRr group, -a -NRtCOORõ group, -a -NRõSO2R,,, group, or -a -NHRbb group, where Rbb is -a -PO(ORX)2 group.

6. The compound of embodiment 5, wherein the C6 to C8 aryl is phenyl.

7. The compound of embodiment 6, wherein the phenyl is substituted at the para position.

8. The compound of embodiment 7, wherein Y is phenyl substituted with a -NR9CONRqR; group at the para position.

9. The compound of embodiment 7, wherein Y is phenyl substituted with a -NR{COORõ group at the para position.

10. The compound of embodiment 7, wherein Y is phenyl substituted with a -NRõSO2RW group at the para position.

11. The compound of embodiment 7, wherein Y is phenyl substituted with a -NHPO(ORX)Z group at the para position.

12. The compound of embodiment 1, wherein Z is:
-a C, to C6 alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or -a C2 to C6 alkylene.

13. The compound of embodiment 1, wherein Z is a CI to C6 alkyl.

14. The compound of embodiment 13, wherein Z is a -a C2 to C5 alkyl.

15. The compound of embodiment 14, wherein Z is cyclobutyl, cyclopropyl, cyclopropyhnethyl, ethyl or cyclopentyl.

16. The compound of embodiment 1, wherein R is hydrogen.

17. The compound of embodiment 1, wherein R1 is:
-a hydrogen;
-an alkoxy group optionally substituted with:
-one or more hatogen(s), -a C6 to Cg aryl group, or -a 5 or 6 membered heterocycle; or Ri joins together with R2 to form:
O O
O
. ~=
, c ) "
O

18. The compound of embodiment 1, wherein R2 is:
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C, to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR., group, where R, is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C$ aryl group;
-a -COORx group; or R2 joins together with Rl to form:
O

%
O

19. The compound of embodiment 1, wherein:

at least one of RI and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl group, or -a 5 or 6 membered heterocycle group; or R2 is a-OCOR,, group, a -ORkk group, or an alkoxy group substituted with:
-an -OCOR, group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

20. The compound of embodiment 19, wherein R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Cl to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

21. The compound of embodiment 20, wherein R2 is a Cl to C6 alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

22. The compound of embodiment 1, wherein R3 is a hydrogen.

23. The compound of embodiment 1, wherein:
X is a cyano group;
Y is a C6 to Cg aryl substituted with:
-a -NRqCOrIRyR, group, -a -NRtCOORõ group, -a -NRõSO2R,õ group, or -a -NHPO(ORX)z group;
Z is:
-a CI to C6 alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or -a C2 to C6 alkylene;

R is hydrogen;
at least one of R, and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to Cg aryl group, or -a 5 or 6 membered heterocycle group; or R2 is a-OCORx group, a -ORkk group, or an alkoxy group substituted with:
-an -OCOR,, group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group; and R3 is hydrogen.

24. The compound of embodiment 23, wherein Y is a phenyl substituted with a NRqCONRqR,- group.

25. The compound of embodiment 24, wherein:
Z is a Ct to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C, to Cb alkyl; or -a 5 or 6 membered heteroaryl group.

26. The compound of embodiment 23, wherein Y is a phenyl substituted with a -NRICOORõ group.

27. The compound of embodiment 26, wherein:
Z is a C, to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group_ 28. The compound of embodiment 23, wherein Y is a phenyl substituted with a-NRõSOZR,,, group_ 29. The compound of embodiment 28, wherein:
Z is a C1 to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

30. The compound of embodiment 23, wherein Y is -a -NHPO(OR,z)a group.

31. The compound of embodiment 30, wherein:
Z is a Ci to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

32. The compound of embodiment 1, wherein:
X is:
-a cyano group; or -a formyl group;
Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a C6 to C8 aryl, optionally substituted with -COORx, where R, is as defmed above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-a CI to C6 alkyl group;
-an amino optionally substituted with one or more Ci to C6 alkyl(s);
-a halogen;
-a hydroxy;
-a -CORm group, where Rm is:
-an amino optionally substituted with one or more C, to C6 alkyl(s);
-a -NRoCORP group, where Rp is:
-a C, to C6 alkyl optionally substituted with an alkoxy;
and where Ra is:
-a hydrogen;
-a -NRqCONRyR, group, where R. is hydrogen and where Rr is:
-a Cl to C6 alkyl;
-a -NRCOORõ group, where R, is hydrogen, and where Ru is:
-a Cl to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl;
-a halogen; or -a 5 or 6 membered heterocycle;
-a -NR-,SO2RW group, where Rõ is hydrogen and where Ru, is:
-a C, to C6 alkyl; or -an alkyl- or dialkyl-amino;
O
. ` O =
= N/

O
nN

RZ
L~N
O S

where Ra is hydrogen or a C, to C6 alkyl;
-a -SO2R,. group, where R. is:
-an amino group; or -an alkyl or dialkyl amino group;
-a -NHRbb group, where Rbb is:
-a -PO(ORX)2 group, where RX is as defined above;
Z is:
-a C, to C6 alky; or -a -COOR, group, where R,, is as defined above;
R is a hydrogen, Ri is:
-a hydrogen;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle;
R2 is:
-a hydrogen;
-a hydroxy group;
-a C, to C6 alkyl group, optionally substituted with one or more halogen(s);
-an alkoxy group optionally substituted with:

-one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl; or -a 5 or 6 membered heteroaryl group;
-a -COOR,, group, where R,t is as defined above;
-an amide group;
-a S or 6 membered heteroaryl; or -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is a hydrogen.

33. The compound of embodiment 32, wherein:
X is a cyano group;
Y is:
-a C6 to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more C, to C6 alkyl(s);
-a NRqCONRqRr group, where Rq is hydrogen and where Rr is:
-a C1 to C6 alkyl;
-a -NRtCOORõ group, where Rt is hydrogen, and where Rõ is:
-a Ct to C12 alkyl, optionally substituted with:
-a C6 to C$ aryl;
-a -NRSOZR,,, group, where Rõ is hydrogen and where RW is:
-a C 1 to C6 alkyl;
2isaC3toC6alky;
R is a hydrogen, RI is a hydrogen;
R2 is:
-an alkoxy group optionally substituted with:
-one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a Cl to C6 alkyl; or -a 5 or 6 membered heteroaryl group; or R3 is a hydrogen.

34. The compound of embodiment 32, wherein:
X is a cyano group;
Yis:

-a C6 to C8 aryl substituted with one or more of the following:
-a C1 to C6 alkyl group;
-an amino optionally substituted with one or more CI to C6 allcyl(s);
-a haiogen;
-a -NRtCOOR, group, where Rt is hydrogen, and where R. is:
-a Cl to C12 alkyl;
-a -NRSOZR,,, group, where Rõ is hydrogen and where R,,, is:
-a Cl to C6 alkyl; or -an alkyl- or dialkyl-amino;
ZisaCltoC6alky;
R is a hydrogen;
R, is -a hydrogen;
R2 is a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is a hydrogen.

35. The compound of embodiment 32, wherein:
X is:
-a cyano group;
Y is:
-a C6 to C$ aryl substituted with one or more of the following:
-a Cl to C6 alkyl;
-a halogen;
-a -NRcCOORõ group, where .R, is hydrogen, and where Rõ is:
-a CI to C12 alkyl;
-a -NRSOZRK, group, where R, is hydrogen and where RW is:
-a C, to C6 alkyl; or -an alkyl- or dialkyl-amino; or -a -NRqCONRqRr group, where Rq is hydrogen and where R, is:
-a C, to C6 alkyl;
Z is:
-a CI to C6 alkyl;
R is:
-a hydrogen, R, is:
-a hydrogen;

R2 is:
-an alkoxy group optionally substituted with:
-one or more halogen(s);
-an amide;
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl; or -a 5 or 6 membered heteroaryl;
R3 is:
-a hydrogen.

36. The compound of embodiment 35, wherein:
X is:
-a cyano group;
Y is:
-a C6 to C8 aryl substituted with one or more of the following:
-a halogen;
-a -NRCOORõ group, where R, is hydrogen, and where Rõ is:
-a C, to C12 alkyl; or -a -NRSOZRW group, where R,, is hydrogen and where R,, is:
-a Ci to C6 alkyl;
Z is:
-a Ci to C6 allcyl;
R is:
-a hydrogen, Ri is:
-a hydrogen;
R2 is:
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is:
-a hydrogen.

37_ The compound of embodiment 36, wherein the C6 to C8 aryl is phenyL

38. The compound of embodiment 37, wherein the phenyl is substituted at the para position.

39. The compound of embodiment 38, wherein:
Yis:

-a phenyl substituted with a-NR,COORõ group, where Rt is hydrogen, and where Rõ
is:a C, to C12 alkyl.

40. The compound of embodiment 38, wherein:
Y is:
-a phenyl substituted with a halogen and a-NRtCOORõ group, where Rt is hydrogen, and where Rõ is C, to C12 alkyl.

41. The compound of embodiment 38, wherein:
Y is:
-a phenyl substituted with a-NRSOZRW group, where Rõ is hydrogen and where Rw is CI to C6 alkyl.

42. The compound of embodiment 38, wherein:
Y is:
-a phenyl substituted with a CI to C6 alkyl and a-NRtCOORõ group, where Rt is hydrogen, and where Rõ is:a Ci to C12 alkyl_ 43. The compound of embodiment 35, wherein:
X is:
-a cyano group;
Y is:
-a C6 to C8 aryl substituted with -NRLCOORõ group, where R, is hydrogen, and where Rõ is a CI to CIZ alkyl.
Z is:
-a C I to C6 alkyl;
Ris:
-a hydrogen;
R, is:
-a hydrogen;
R2 is:
-an alkoxy group optionally substituted with:
-one or more halogen(s);
R3 is:
-a hydrogen.

44. The compound of embodiment 35, wherein R2 is: an alkoxy group substituted with one or more halogens.

45. The compound of embodiment 43, wherein the C6 to Cg aryl is phenyl.

46. The compound of embodiment 45, wherein the phenyl is substituted at the para position.

47. The compoi,ind of embodiment 35, wherein:
X is:
-a cyano group;
Y is:
-a C6 to Cg aryl substituted with one or more of the following:
-a -NRtCOORõ group, where Rt is hydrogen, and where Rõ is:
-a C, to C12 alkyl;
-a -NRqCONRgRr group, where Rq is hydrogen and where RT is:
-a C, to C6 alkyl;
Z is:
-a C1 to C6 alkyl;
Ris:
-a hydrogen, Ri is: .
-a hydrogen;
R2 is:
-a 5 or 6 membered heteroaryl;
R3is:
-a hydrogen.

48. The compound of embodiment 47, wherein the C6 to C8 aryl is phenyl.

49. The compound of embodiment 48, wherein the phenyl is substituted at the para position.

50. The compound of embodiment 49, wherein:
Y is:
-a phenyl substituted with a NRtCOORõ group, where Rt is hydrogen, and where R.
is:a Cl to C12 alkyl.

51. The compound of embodiment 49, wherein:
Y is:

-a C6 to C8 aryl substituted with -a NRqCONRqRr group, where RQ is hydrogen and where Rr is a CI to C6 alkyl.

52. The compound of embodiment 35, wherein:
X is:
-a cyano group;
Y is:
-a C6 to C8 aryl substituted with a-N&COORõ group, where R, is hydrogen, and where Rõ is a Cl to C12 alkyl;
Zis:
-a CI to C6 alkyl;
R is:
-a hydrogen, Rl is:
-a hydrogen;
R2 is:
-a amide;
R3 is:
-a hydrogen.

53. The compound of embodiment 52, wherein the C6 to C$ aryl is phenyl.

54. The compound of embodiment 53, wherein the phenyl is substituted at the para position.

55. The compound of embodiment 35, wherein R2 is: an alkoxy group substituted with one or more halogen(s).

56. The compound of embodiment 35, wherein R2 is: a-ORkk group, where Rkk is a 5 to 6 membered heteroaryl.

57. The compound of embodiment 32, wherein X is:
-a formyl group;
Y is:
-a C6 to Cg aryl substituted with one or more of the following:
-a -NRcCOORõ group, where Rt is hydrogen, and where R. is:
-a C, to C12 alkyl;

-a -NRqCONRR, group, where Rq is hydrogen and where R, is:
-a C1 to C6 alkyl;
Z is:
-a C, to C6 alky;
R is:
-a hydrogen;
R, is:
-a hydrogen;
R2 is:
-an alkoxy group;
R3 is:
-a hydrogen.

58. The compound of embodiment 32, wherein:
X is:
-a cyano group;
Y is:
-a C6 to C$ aryl substituted with one or more of the following:
-a Cl to C6 alkyl group;
-a halogen;
-a -NRtCOORõ group, where Rt is hydrogen, and where Rõ is:
-a Cl to C12 alkyl, optionally substituted with:
-a C6 to C$ aryl;
-a -NR SO2R,, group, where Rõ is hydrogen and where R, is:
-a Ct to C6 alkyl; or -an alkyl- or dialkyl-amino;
O
O

N
Z is:
-a C, to C6 alky;
R is:
-a hydrogen;

R, is:
-a hydrogen;
R2 is:
-an alkoxy group substituted with one or more halogen(s);
R3 is:
-a hydrogen.

59. The compound of embodiment 32, wherein:
X is:
-a cyano group;
Y is:
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-a -NRCORp group, where RP is:
-a C, to C6 alkyl optionally substituted with an alkoxy;
and where R. is:
-a hydrogen;
Z is:
-a C i to C6 alky;
R is:
-a hydrogen;
R, is:
-a hydrogen;
R2 is:
-an alkoxy group substituted with a 5 or 6 membered heteroaryl group;
R3 is:
-a hydrogen.

_ 60. The compound of embodiment 32, wherein:
X is:
-a cyano group;
Yis:
-a C6 to Cg aryl, optionally substituted with one or more of the following:
-a Ct to C6 alkyl group;
-an amino optionally substituted with one or more Cl to C6 allcyl(s);
-a halogen;
-a -1VRoCORp group, where Rp is:

-a C, to C6 alkyl;
and where Ro is:
-a hydrogen;
-a -NRqCONRqRr group, where Rq is hydrogen and where R, is:
-a Ct to C6 alkyl;
-a NRtCOORõ group, where Rt is hydrogen, and where Rõ is:
-a CI to C12 alkyl;
-a NR SOZR,, group, where Rõ is hydrogen and where Ru, is:
-a CI to C6 alkyl;
-a -NHRbb group, where Rbb is:
-a -PO(ORX)2 group, where R. is as defined above;
Z is:
-a C i to C6 alky;
R is:
-a hydrogen, R, is:
-a hydrogen;
R2is:
-a 5 or 6 membered heteroaryl;
R3 is:
-a hydrogen.

61. The compound of embodiment 32, wherein:
X is:
-a cyano group;
Y is:
-a C6 to Cg aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more CI to C6 alkyl(s);
-a -NRqCONRyRr group, where Rq is hydrogen and where R, is:
-a CI to C6 alkyl;
-a NR,COORõ group, where Rt is hydrogen, and where Rõ is:
-a CI to C}2 alkyl, optionally substituted with:
-a C6 to C$ aryl; or -a 5 or 6 membered heterocycle;
-a -NR SO2R,,, group, where Rõ is hydrogen and where R, is:

-a C1 to C6 alkyl;

1`
* N~

RZ
II__0 N
O S

N I

where R, is hydrogen or a Ct to C6 alkyl;
Z is:
-a C1 to C6 alky;
R is:
-a hydrogen, Rt is:
-a 5 or 6 membered heterocycle;
-an alkoxy substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle;
R-) is:
-a hydrogen;
R3 is:
-a hydrogen.

62. The compound of embodiment 61, wherein Ri is a 5 or 6 membered heterocycle.

63_ The compound of embodiment 61, wherein Rl is an alkoxy substitued with one or more halogen.

64. The compound of embodiment 61, wherein:
Y is:
-a C6 to CS aryl substituted with :
-a -NRtCOORõ group, where RI is hydrogen, and where R. is:
-a Cl to C12 alkyl, optionally substituted with:

-a C6 to Cg aryl; or -a 5 or 6 membered heterocycle;
RI is:
-an alkoxy substitued with one or more halogen.
65. A compound of formula IIIa R x R, ~ \ .
Y

N

Z
R3 IIIa wherein:
X is:
-hydrogen;
Y is:
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-a -NRyCONRqRr group, where Rq is hydrogen and where R, is:
-a Ci to C6 alkyl;
-a -NRtCOORõ group, where Rt is hydrogen, and where Rõ is:
-a C 1 to C 12 alkyl;
-a -NRõSO2RW group, where R. is hydrogen and where R, is:
-a CI to C6 alkyl;
Z is:
-a Ci to C6 alky;
R is:
-a hydrogen, R, is:
-a hydrogen;
R2 is:
-an alkoxy group optionally substituted with:
-one or more halogen(s); or -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is:

-a hydrogen.

66. The compound of embodiment 65, wherein:
X is:
-hydrogen;
Y is:
-a C6 to Cg aryl substituted with a-NRtCOORõ group, where Rt is hydrogen, and where Rõ is a Cl to C17 alkyl;
2 is:
-a C, to C6 alkyl;
R is:
-a hydrogen, R, is:
-a hydrogen;
R2 is:
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is:
-a hydrogen.

67. The compound of embodiment 65, wherein the C6 to C8 aryl is phenyl.

68. The compound of embodiment 65, wherein the phenyl is substituted at the para position.

69. A pharmaceutical composition comprising:
(i) a compound of formula I
R x R, ~ \ .
y I

N

Z

wherein:
X is:
-a nitro group;
-a cyano group;

-a -CO& group, where Ra is:
-a C, to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORX group, where R,, is a CI to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C, to C6 alkyl;
.
` O
o .
`\ o (CH2)n N O
- Rb , where Rb is a hydrogen or a Ci to C6 alkyl, and n is 0 or 1;
O

- / ;

. ( - , where R,, is a hydrogen, a-CONHRX, where R,{ is as defined above, or an -SO2R, where Rx is as defined above; or iRd *~~N
- , where Rd is a CI to C6 alkyl or a C6 to C8 aryl;
-a -NHCORe group, where Re is:
-a Cl to C6 alkyl;
-a C6 to C$ aryl optionally substituted with:
-a Ci to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOOR,, group, where R. is as defined above;
-a -CH2O-Rfgroup, where Rf is a C6 to C$ aryl;
-a -NRgRh group, where Rg is a C, to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
-a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a C, to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a C6 to C8 aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COORX group, where R,, is as defined above, or -a -NHCOORx group, where RX is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a CI to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more Cl to C6 alkyl(s), -a -NR;SOaRX group, where R, is as defined above and R; is:
-a hydrogen, -a C1 to C6 alkyl, -a -COR,. group, where RX is as defmed above, -a haloalkyl, or -a haloalkoxy, -a -NRCORk group, where Rk is:
-a Ct to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more C, to C6 alkyl(s), and Rj is:
-a hydrogen, -a C1 to C6 alkyl, - a-CORX group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N=N- group, or -a -CORI, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more C1 to C6 alkyl(s), -a nitro group, -a C1 to C6 alkyl group, optionally substitutedwith:
-a -NHSOzRX group, where RX is as defined above, or -a -NR,-SO2R,, group, where R, is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COOR, group, where R,, is as defined above, -a -CORm group, where Rm is:
-an amino optionally substituted with one or more C, to C6 alkyl(s), where the CI to C6 alkyls are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more C, to C6 alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a dialkyl-amino, -a -NHRn group, where Rn is:
-a -CH2CONH2, or -a C6 to Cg aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NRoCORp group, where Rp is:
-a C, to C6 alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a C6 to C$ aryl, -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyl(s), -a hydrogen, N o = 0 or N~ Z O
and where Ro is:
-a hydrogen, -a C, to C6 alkyl, -a -CORX gronp, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqR, group, where Rq is:
-a hydrogen, -a C, to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORX group, where R. is as defined above, and where Rr is:
-a C6 to C8 aryl optionally substituted with:
N
~ \ .

-N -a Cl to C6 alkyl, -a haloalkyl, -a -ORS group, where R, is a C6 to C8 aryl, or -a -COORX group, where R,, is as defined above, -a C1 to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, -a C6 to C8 aryl, and/or -a -COORX group, where R,e is as defined above, -a -COOR,, group, where R,, is as defined above, -a -NRtCOORõ group, where Rõ is:
-a Ct to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a Cl to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a C, to C6 alkyl, or -a 5 or 6 membered heterocycle, and R, is:
-a hydrogen, -a C1 to C6 alkyl, -a -CORX group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR,SO2RW group, where Rõ is:
-a hydrogen, -a -COR, where RX is as defined above, or -a CI to C6 alkyl, optionally substituted with:
-a halogen, -a -COR,, group, where RX is as defined above, -a -OCORX group, where RX is as defined above, -a hydroxy, or -an alkoxy, and where RW is:
-a C, to C6 alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C i to C6 alkyl, -a 5 or 6 membered heterocycle, or C~O
N
O

. N
-a O
- I NH
O

NH
.,-,- N

-a --<o , 0 Ry N I~z-Ry -a O , optionally substituted with a C1 to C6 alkyl, where RY is a Cl to C6 alicyl or hydrogen, O

n r~N
-a ".
O
-a RZ

O S
-a 'fN
where RZ is hydrogen or a CI to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SR,, group, where R,. is as defined above, -a -SO2Raa group, where R. is:
-a CI to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COORX group, where R, is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -NHRbb group, where Rbb is:
N

N

N
-a -C(=S)NH2 group, or -a -PO(OR,,)2 group, where R. is as defined above;
-a " Rcc group, where R.,,,, is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a -a C6 to Cg aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a CI to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more C, to C6 alkyl(s), -a -NHPORXR,,, where Rx is as defmed above, -a -NR~.CONRuRa group, where Rce is a hydrogen or a C, to C6 alkyl, optionally substituted with a halogen, and Rrr is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a C) to C6 alkyl, or -a -CORx, where RX is.as defined above, -a NRggCORhh group, where Rhh is:
-a hydrogen, -a Ci to C6 alkyl optionally substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more C, to C6 alkyl(s), -an amino optionally substituted with one or more Cl to C6 alkyl(s), where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and R., is:
-a hydrogen, -a Cl to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORX group, where R,, is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more Ci to C6 alkyl(s), and/or -a -NR;;SO2RX group, where RX is as defmed above, and Ri; is:
-a hydrogen, -a Cl to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -COR,, group, where R, is as defined above;
Z is:
-a Ci to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to Cg aryl;
-a C2 to C6 alkylene;
-a C6 to C$ aryl optionally substituted with an alkoxy or one or more Cl to C6 alkyl(s);
-a -COOR,s group, where R,, is as defined above; or R is a hydrogen, a halogen or an alkoxy;
Rl is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle;
-a C6 to Cg aryl optionally substituted with an alkoxy;
-a -CORX group, where R, is as defined above;
-a C, to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R, joins together with R2 to form:
O
O
R2 is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C, to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR, group, where RX is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C$ aryl group;
-a -COOR,, group, where R, is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to C8 aryl;
-a 5 or 6 membered heteroaryl;
-a -OCORX group, where R, is as defined above;
-a -NHCORjj group, where Rj; is:
-an alkoxy, or -an amino optionally substituted with one or more CF to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a -NHSO2RX group, where RX is as defined above; or R2 joins together with Ri to form:

O O

O
O
~. -R3 is:
-a hydrogen; or -CHZOCORx, and Rx is as defined above;
provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, R, is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:
-a Cl to C6 alkyl substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C$ aryl;
-a C2 to C6 alkylene;
-a C6 to Cs aryl optionally substituted with an alkoxy or one or more Cl to C6 allcyl(s);
-a -COORX group, where R,, is as defined above; or - 0; or or one or more pharmaceutically acceptable salt(s) thereof; and (ii) one or more pharmaceutically acceptable excipient(s).

70. A method for treating an infection by a virus in a subject in need thereof, wherein the virus contains an internal ribosome entry site (IRES), comprising adrninistering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more compound(s) of formula I

R x R, Y I
N

Z

wherein:
X is:
-a nitro group;
-a cyano group;
-a -CORa group, where Ra is:
-a C, to C6 alkyl, -a C6 to C$ aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORX group, where RX is a C, to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C 1 to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more C, to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a Cj to C6 alkyl;

O

O
O
( CHZ)n I
- Rb , where Rb is a hydrogen or a Ci to C6 alkyl, and n is 0 or 1;
O

- , where R, is a hydrogen, a-CONNHIZX, where RX is as defined above, or an -SO2R, where RX is as defined above; or Rc, N~ \\

*~-N
- , where Rd is a C1 to C6 alkyl or a C6 to Cg aryl;
-a -NHCORe group, where Re is:
-a C, to C6 alkyl;
-a C6 to C8 aryl optionally substituted with:
-a C I to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOORx group, where Rx is as defined above;
-a -CH2O-Rfgroup, where Rf is a C6 to C8 aryl;

-a -NRgRh group, where Rg is a Ci to C6 alkyl or a hydrogen and Rh is a C6 to Cg aryl optionally substituted with an alkoxy;
-a CI to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a CI to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a C6 to Cg aryl, optionally substituted with -COOR, where Rx is as defmed above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COORX group, where RX is as defined above, or -a -NHCOOR,. group, where R,, is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a C1 to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more C 1 to C6 alkyl(s), -a -NR;SO2R,, group, where R, is as defined above and Ri is:
-a hydrogen, -a CI to C6 alkyl, -a -COR. group, where R, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:
-a Cl to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Ct to C6 alkyl(s), and Rj is:
-a hydrogen, -a CI to C6 alkyl, - a-COR, group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N*=NN group, or -a -CORI, where R, is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more C 1 to C6 alkyl(s), -a nitro group, .
-a Cl to C6 alkyl group, optionally substituted with:
-a -NHSOzRX group, where R,, is as defined above, or -a -NRxSO2Rx group, where Rx is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COORX group, where R, is as defined above, -a -CORm group, where R. is:
-an amino optionally substituted with one or more C, to C6 alkyl(s), where the one or more CI to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more Ci to C6 alkyls, and/or -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a dialkyl-amino, -a -NHRõ group, where Rõ is:
-a -CH2CONH2, or -a C6 to Cg aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NRoCORp group, where Rp is:
-a Ct to C6 alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a C6 to C8 aryl, -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyl(s), -a hydrogen, N O
* O pr N~ 0 and where Ro is:
-a hydrogen, -a C2 to C6 alkyl, -a -CORX group, where Rx is as defmed above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqR, group, where Rq is:
-a hydrogen, -a C, to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where R,, is as defined above, and where Rr is:
-a C6 to C& aryl optionally substituted with:
N
. ~ `
O
. -N

-a Ct to C6 alkyl, -a haloalkyl, -a -ORs group, where RS is a C6 to C8 aryl, or -a -COORX group, where R,, is as defined above, -a C, to C6 alkyl optionally substituted with one or more of the following:

-a halogen, -an alkylene, -a C6 to C8 aryl, and/or -a -COORX group, where R,; is as defined above, -a -COOR,, group, where RX is as defined above, -a -NRtCOORõ group, where Rõ is:
-a CI to C,2 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C, to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to Cs aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a C, to C6 alkyl, or -a 5 or 6 membered heterocycle, and R, is:
-a hydrogen, -a C1 to C6 alkyl, -a -CORX group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR,SO2RW group, where Rõ is:
-a hydrogen, -a -CORX, where R., is as defined above, or -a C, to C6 alkyl, optionally substituted with:
-a halogen, -a -COR,, group, where RX is as defined above, -a -OCOR,t group, where Rx is as defined above, -a hydroxy, or -an alkoxy, and where R, is:

-a Ci to C6 alkyl optionally substituted with:
-a halogen, -a haloaikyl, -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl, -a 5 or 6 membered heterocycle, or AN>. O

* N
-a O
"` N

- L"; NH
a , NH
-a O Ry N Ry -a O , optionally substituted with a C, to C6 alkyl, where R. is a Ci to C6 alkyl or hydrogen, O
-a~N
>

-a *"~N

RZ
N
O S
-a *~N
where RZ is hydrogen or a CI to C6 alkyl, optionally substituted with a C6 to Cg aryl, -a -SRX group, where RX is as defined above, -a -SOZRaa group, where R., is:
-a C1 to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COORx group, where Rx is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -NHRbb group, where Rbb is:
*
N

N

-a -C(=S)NH2 group, or -a -PO(OR,,)2 group, where RX is as defined above;
-a " Rco group, where &C is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a O
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a Ci to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more C, to C6 alkyl(s), -a -NHPORXRX, where RX is as defined above, -a -NR-,CONRffRff group, where R,, is a hydrogen or a Ci to C6 alkyl, optionally substituted with a halogen, and Ra is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a C, to C6 alkyl, or -a -CORx, where RX is as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen, -a C1 to C6 alkyl optionally substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more Cl to C6 alkyl(s), -an amino optionally substituted with one or more C, to C6 alkyl(s), where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is:
-a hydrogen, -a CI to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR, group, where R,, is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more CI to C6 alkyl(s), and/or -a -NRiiSO2RX group, where RX is as defmed above, and Ri; is:
-a hydrogen, -a C I to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -COR,, group, where RX is as defined above;
Z is:
-a C, to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 ta Cs aryl;
-a C2 to C6 alkylene;
-a C6 to Cg aryl optionally substituted with an alkoxy or one or more Cl to C6 alkyl(s);
-a -COORX group, where R. is as defined above; or R is a hydrogen, a halogen or an alkoxy;
Ri is:

-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to Cg aryl, or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -CORx group, where Rx is as defined above;
-a Cl to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or Rt joins together with R2 to form:
O
~ ~.
O
R2 is:
-a nitro group; _ -a hydrogen;
-a halogen;
-a hydroxy group;
-a C, to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR, group, where R, is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Ci to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group;

-a -COORX group, where Rx is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to C$ aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR, group, where R,, is as defined above;
-a -NHCORjj group, where Rjj is:
-an alkoxy, or -an amino optionally substituted with one or more C, to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a -NHSO2RX group, where RX is as defined above; or R2 joins together with R1 to form:
0 ' . , ., ., R3 is:
-a hydrogen; or -CHZOCOR,,, and R,, is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.

71. A method for treating a Hepatitis C viral (HCV) infection in a subject in need thereof, comprising administering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more compound(s) of formula I
R
Ri Y I
N
RZ
z wherein:
X is:
-a nitro group;

-a cyano group;
-a -CORa group, where Ra is:
-a Ct to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COOR,; group, where R,t is a Cl to C6 alkyl;
-a formyl group;
-a C6 to Cs aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Cl to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more C, to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl;
\ O

O
*
O
(CH2)n N O
- Rb , where Rb is a hydrogen or a C, to C6 alkyl, and n is 0 or 1;

O

- , where R, is a hydrogen, a-CONHR,, where RX is as defined above, or an -SOZR, where RX is as defined above; or Rd N1-11 %
O
- , where Ra is a C, to C6 alkyl or a C6 to C8 aryl;
-a -NHCORe group, where R. is:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with:
-a Cl to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOOR,, group, where RX is as defined above;
-a -CH2O-R f group, where Rf is a C6 to C8 aryl;
-a -NRgRh group, where Rg is a C, to C6 alkyl or a hydrogen and Rb is a C6 to Cg aryl optionally substituted with an alkoxy;
-a CI to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a Cj to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a C6 to C$ aryl, optionally substituted with -COORx, where Rx is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR,, group, where Rx is as defined above, or -a -NHCOOR,, group, where RX is as defined above;

-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a Cl to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more CI to C6 alkyl(s), -a NRiSO2R,, group, where R,, is as defined above and R; is:
-a hydrogen, -a Ci to C6 alkyl, -a -COR, group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:
-a Ci to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more Ci to C6 allcyl(s), and Rj is:
-a hydrogen, -a C i to C6 alkyl, - a-CORX group, where RX is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N=N" group, or -a -CORl, where R, is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more CI to C6 alkyl(s), -a nitro group, -a C, to C6 alkyl group, optionally substituted with:
-a -NHSO2R, group, where R,, is as defined above, or -a -NRXSO2RX group, where Rx is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COORX group, where RX is as defined above, -a -COR,,, group, where RR, is:
-an amino optionally substituted with one or more CI to C6 alkyl(s), where the one or more C i to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more Cl to C6 alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a dialkyl-amino, -a -1VHR,, group, where Rn is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NRoCORP group, where Rp is:
-a Ci to C6 alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a C6 to Cg aryl, -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more Ct to C6 alkyl(s), -a hydrogen, N \ O
p or N
and where Ro is:

-a hydrogen, -a Ci to C6 alkyl, -a -COR,, group, where RX is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen, -a Cl to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR,, group, where R,, is as defmed above, and where Rr is:
-a C6 to Cg aryl optionally substituted with:
., ~
N

O
-N
-a Ci to C6 alkyl, -a haloalkyl, -a -OR, group, where RS is a C6 to C8 aryl, or -a -COORx group, where R, is as defined above, -a Ci to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, -a C6 to C8 aryl, andlor -a -COOR,. group, where R,, is as defined above, -a -COORX group, where R,, is as defined above, -a -NRtCOORõ group, where Rõ is:
-a C, to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to Cg aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a Ci to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a Ci to C6 alkyl, -a -COR,, group, where R, is as defined above, -a haloalkyl, or -a haloalkoxy, -a NRõSO2RW group, where Rõ is:
-a hydrogen, -a -CORX, where R,, is as defined above, or -a Ci to C6 alkyl, optionally substituted with:
-a halogen, -a -COR,, group, where R,, is as defined above, -a -OCOR, group, where R,, is as defined above, -a hydroxy, or -an alkoxy, and where RW is:
-a Cl to C6 alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a C6 to Cs aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a CI to C6 alkyl, -a 5 or 6 membered heterocycle, or * !

N

'` Ni~
-a O
" N

Li NH 0 NH
,._-N

-a O , Ry N Ry *~.N
-a optionally substituted with a CI to C6 alkyl, where Ry is a Ci to C6 alkyl or hydrogen, O
-a n O
-a ~

RZ
II,, N /
O S

-a where Rx is hydrogen or a Cl to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SRX group, where R. is as defined above, -a -SOzRaa group, where Rea is:
-a C 1 to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COORx group, where RX is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -NHRbb group, where Rbb is:
*
N

_ , .
N
- , .
-a -C(=S)NH2 group, or -a -PO(ORx)2 group, where RX is as defined above;
-a # Rcc group, where R,,,c is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a O
-a C6 to Cs aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a Cl to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ct to C6 alkyl(s), -a -NHPOR,,Rx, where R. is as defmed above, -a -NReeCONRffRff group, where Ree is a hydrogen or a Cl to C6 alkyl, optionally substituted with a halogen, and Rff is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a C, to C6 alkyl, or -a -CORX, where R,, is as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen, -a CI to C6 alkyl optionally substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more Ci to C6 alkyl(s), -an amino optionally substituted with one or more Cl to C6 allcyl(s), where the one or more CI to C6 alkyl(s) is/are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is:
-a hydrogen, -a Ct to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where RX is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more C1 to C6 alkyl(s), and/or -a NR;iSOZRX group, where R., is as defined above, and Ri; is:

-a hydrogen, -a C I to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -CORX group, where RX is as defined above;
Z is:
-a C, to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);
-a -COORX group, where R. is as defined above; or - O-- _! ;
R is a hydrogen, a halogen or an alkoxy;
Ri is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to Cs aryl, or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -CORx group, where R,, is as defined above;

-a CI to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R, joins together with R2 to form:
O O
O
.
~~ O
~~ = - -R2 is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCORX group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to Cg aryl group;
-a -COORX group, where R,, is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to Cg aryl;
-a 5 or 6 membered heteroaryl;
-a -OCORx group, where RX is as defined above;
-a -NHCORv group, where Rjj is:
-an alkoxy, or -an amino optionally substituted with one or more C] to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a -NHSO2RX group, where R, is as defined above; or R2 joins together with Ri to form:

O O

O
O
R3 is:
-a hydrogen; or -CH2OCORx, and RX is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.
72. A compound of formula IIIb R x R, y N

Z
R3 IIlb wherein:
X is:
-hydrogen;
Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a C6 to C8 aryl, optionally substituted with -COORX, where Rx is as defined above;
-a C6 to C$ aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more CI to C6 alkyl(s);
-a halogen;
-a hydroxy;
-a -CORm group, where Rm is:
-an amino optionally substituted with one or more Ci to C6 alkyl(s);
-a -NRoCORp group, where RP is:
-a C i to C6 alkyl optionally substituted with an alkoxy;
and where R. is:
-a hydrogen;
-a -NRqCONRyRr group, where Rq is hydrogen and where Rr is:

-a C, to C6 alkyl;
-a -NRtCOORõ group, where Rt is hydrogen, and where R,, is:
-a Cl to C12 alkyl, optionally substituted with:
-a C6 to Cg aryl;
-a halogen; or -a 5 or 6 membered heterocycle;
-a -NRSO2Rw group, where R,, is hydrogen and where RW is:
-a Cl to C6 alkyl; or -an alkyl- or dialkyl-amino;
O
O
* N

O
*li Nn_ RZ
1I,_,N /
O S
*~'N
where Rz is hydrogen or a C, to C6 alkyl;
-a -SO2R,, group, where R~a is:
-an amino group; or -an alkyl- or dialkyl-amino group;
-a -NHRbb group, where Rbb is:
-a -PO(ORX)2 group, where Rx is as defined above;
Z is:
-a C1 to C6 alky; or -a -COOR,, group, where RX is as defined above;
R is:
-a hydrogen, Rl is:
-a hydrogen;

-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle;
R2 is:
-a hydrogen;
-a hydroxy group;
-a Cl to C6 alkyl group, optionally substituted with one or more halogen(s);
-an alkoxy group optionally substituted with:
-one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl group; or -a -COORX group, where R. is as defined above;
-an amide group;
-a 5 or 6 membered heteroaryl; or -a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is:
-a hydrogen.

73. The compound of embodiment 72, wherein:
X is:
-hydrogen;
Y is:
-a C6 to C8 aryl, substituted with -NRjCOORõ group, where Ri is hydrogen, and where Ru is a Ct to C12 alkyl;
Z is:
-a C, to C6 alky;
R is:
-a hydrogen;
RI is:
-a hydrogen;
R2 is:
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
R3 is:

-a hydrogen.

74. A compound which is selected from the compound range: 866-1329, 1484-2127, 2129-2545.

75. The compound of embodiment 74 selected from:
N N
O >-< N
O
/f `\
NO I / N NH NH N O
b ~ No ~ H

N
~ o O ~N 6 ~ N ~ H I
INp N H

/N F /N
N cl o \ - H \ - H
~ ~o ~ N
F-/~o ( / N NFi O N ~0 0 N o O
NN N N

N N
N
N/- p .. F NH ~N - o, N~N 6 0 Fp N O~ ~ 0 N
b H
b N
// F
N \ N
)-- H
('0 NH\o No C N \/ NH o o N >==o ' N ...~~
\ ~ Q

N

I ~ F NH p~ -O !% p (7 ~ N N NH N I N NH
o N N b ~ ~ ...~~ N N

N

QN\/H
I\ // - NS.o O ~0 N~ i N H ! N 6 N o /

%
o Cz \ p p I / N ~ / N
H
';el As used herein, the term "alkyl" generally refers to saturated hydrocarbyl radicals of straight, branched or cyclic configuration, or combinations of cyclic and branched or straight, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclohexyl, n-heptyl, octyl, n-octyl, and the like. In some embodiments, alkyl substituents may be C, to C12, or Ct to C8 or Ci to C6 allcyl groups.
As used herein, "alkylene" generally refers to linear, branched or cyclic alkene radicals having one or more carbon-carbon double bonds, such as C2 to C6 alkylene groups including 3-propenyl.
As used herein, "aryl" refers to a carbocyclic aromatic ring structure.
Included in the scope of aryl groups are aromatic rings having from five to twenty carbon atoms. Aryl ring structures include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. Examples of aryl groups that include phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), and napthyl (i.e., napthalene) ring structures. In certain embodiments, the aryl group may be optionally substituted.

As used herein, "heteroaryl" refers to cyclic aromatic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon.
Heteroatoms are typically 0, S or N atoms. Included within the scope of heteroaryl, and independently selectable, are 0, N, and S heteroaryl ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds. In some embodiments, the heteroaryl groups may be selected from heteroaryl groups that contain two or more heteroatoms, three or more heteroatoms, or four or more heteroatoms. Heteroaryl ring structures may be selected from those that contain five or more atoms, six or more atoms, or eight or more atoms. Examples of heteroaryl ring structures include:
acridine, benzimidazole, benzoxazole, benzodioxole, benzofuran, 1,3-diazine, I,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoli.ne, quinoxaline, thiazole, thiophene, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.
As used herein, "heterocycle" refers to cyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon.
Heteroatoms are typically 0, S or N atoms. Included within the scope of heterocycle, and independently selectable, are 0, N, and S heterocycle ring structures. The ring structure may include compounds having one or more ring structures, such as mono-, bi-, or tricyclic compounds.
Example of heterocyclo groups include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl or tetrahydrothiopyranyl and the like. In certain embodiments, the heterocycle may optionally be substituted.
As used herein, "alkoxy" generally refers to a group with the structure -O-R, where R
is an alkyl group as defined above.
For the purposes of this invention, halo substituents may be independently selected from the halogens such as fluorine, chlorine, bromine, iodine, and astatine. A
haloalkyl is an alkyl group, as defmed above, substituted with one or more halogens. A
haloalkoxy is an alkoxy group, as defined above, substituted with one or more halogens.
For the purposes of this invention, where one or more functionalities encompassing X, Y, Z, R, Ri, R2, and R3, are incorporated into a molecule of formula I, each functionality appearing at any location within the disclosed compound may be independently selected, and as appropriate, independently substituted. Further, where a more generic substituent is set forth for any position in the molecules of the present invention, it is understood that the generic substituent may be replaced with more specific substituents, and the resulting molecules are within the scope of the molecules of the present invention.
By "substituted'.' or "optionally substituted" it is meant that the particular substituent may be substituted with a chemical group known to one of skill in the art to be appropriate for the referred-to substituent, unless a chemical group is specifically mentioned.

In some embodiments, X is selected from the X substituents of compounds 866-1329, 1484-2127,2129-2545.
Nonlimiting examples of X substituents include the following, where the *
indicates the bond of attachment of the scaffold molecule:

O
O O
~ ~

_ O
O~O F 0- N

O O
N"O // N N N N
O-O N
NN~
}--O jj * *
N
O~N
. ~ ~

N
S"
S N SN
YN Y N
C1 ~

Ci O
"-N O * }1 ~
S` ` -,N Pla *~ 107 In some embodiments, the X substituent is hydrogen; a cyano group; or a-COR,a group, where R.a is a Ci to C6 alkyl, or a dialkyl-amino.
In other embodiments, the X substituent is selected from the following:

~ Ifl --N` O * H
In yet other embodiments, the X substituent is selected from the following:
p In some embodiments, Y is selected from the Y substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of Y substituents include the following:
*
*-N
H
*-N
O //~O
O

* ~ ~ * Q j o O *-NH
O O H
*-N N
H ti O, * H N} O
-N Br H O
-N
H ~H O

FX H O
O F * / NH *-N
H
O-*

O * / ~ O
* -_ NH
%H /N-F ~/O
O N-~O
-~ / N
~H H O~ \-O, H H
N S O
g, O.

0 , _ 00 ~H NH * \ / ~H

F
p * _ ^ F
CI F

O
Br 'H
O O-~
H

* - /
CI

CI O
F
O O
F H

o O-H
O ~S 0 -N H
H

O \ j H H
O 0 N O\\ N-H
N`
* \ j , H ~H
H

O Br ~S
~ ``O
~
* - \ / N H
H

s y-N x \ I *~S
H

O

H N-H \N
H

* -_ p 0 qz- ;SlO
p-) N NH
O~--o OH H N~O
* \ / , H
- \ /

NJ -- O

F HN-S HN-FiN O

O H 0 H O N p - ~ - *-N%
H F
0 * ~~

H H *-N
'H

`N~ N_-~ N
O/
H
H~-CI O
H N p O
N~O zz< N~ ~ ~
* - \ / * - - ~
- \ / *--~~N I

H 'O' H O
N-P- * - ~ / N *
* - - 0~--~0 \ / O
O O
N * \ / N ~O-*
H
O
111 ~/

~-H
/ O.
S NS
-O
H
CI
Br . \ /

N-H
\ /N ~O * O
H Fi N-N_ \
o HO

" N
\ / S
* \ / O O * \ /
H -O
. H O
.
N-H O N-H - 'N-S
* ~ J ~ * O
- ~
\ / O

H H
. - * N
~
~ OS ~ NS'O
\> \-CI

O _ O
i n / N i ~J
0 * \ / ~

H O
H H ' O N
\ / S-N , ~/ N

*

Nj 0 S O / \
\ / -O

~0~ H

H O H
'N-S-/ O
O
*~ -N
N-S 0 ~ N I
H
O NH

O ~- O 0 -HN ~ ~ O 0 N~ HN--~ HN-~
_ 0 O
N' ` ~
~ O

HN-~ HN4 HN
O-~ O~_ O

HN- ~ HN4 HN4 CI

O O

. O O O ~ ~ CI
~ ~

HN ~ HN4 HN4 -O <:~ F O O ~ ~ Br 0 ~ ~ 0 O p * \ / NH * \ ./ NH * \ ~ NH
O ~CI

* \ / NH * \ / NH O

* G NH

CI F
F
0 /---/ / \
NN - ~O - ~-O
* \ / NH * \ ~ NH
Br / ~ . / \ *\ / - O i O 0 _ ~ -O -O N-H
* \ ~ NH * \ / NH H

0 NH H 0 jN
_ * ~\
CI \ /
~ ' \/
pvo .N ,N N
--N
* \ / / \ * ~ / ~ o o N SN-_ O
N
N-O * \ /
- H
s * \ / p C 00 * \ / O
I~! ~p N N-~
H H ~cl H 0 ~
* S
S

* * O -I \ O I \ \ / * ~ / N
~N O-~'-O
O
* N
H N

HN rj O
HN-~ Hf~-~ HN-~

O O-\ O
O O O
HN4 HN4 HN~
O-NH N~O HN-~O

* \ / ~
_ N~O ~ NH O * ~ / NH
O ~O
-O O
H
N
~
O _ O HN
- / ~
S-N ~ / S-N ~ ~ N
O H O H
N' O. /- O 0 O~ /
- õ S`
* \ / N O S-N O- N O
p H

H k \ /
Ol N-H ~ O N
`S\O * ~
- ~ / S-N N
O H \--\-N
O O O

as. ~=O ~ /
H H-N
'H CI
O O
* * / ~

CI \ / p N-H
CI

O
H, 0 O

N-H N-H
H-/ \ O

O O ~ N-H
N
d v --O-N+

N-H O HN--/*"
- N-H HN-~
O
N / \ * \ /
~- ~

* / \ O ~-CI ~
N-H HN HN
\ - HN-~ HN--~
O \ / 0 0 -O

HN- -H~(N~ HN~ HN
"O HN-~ HN-~
O O
CI

HN~ HN--/ HN
HN--~ HN-~ HN-~
O o O

HN--~ \ I HN HN O
O --~O -\ / NH

o HN-~ \ / O HN--~O O
NH

\/ N" \ / "H * / \ o NH
NH \ / ~ ~/o * \ 7/ - "~
\ / NH O
CI
* \ \ ~ H H
y I / / / \ \ * \ INo NI i ` I
O

NH C
~-NH N
HN O NS ~ N
CI O ~O
NH
NH * \ /
~NH ~NH H
o N

HN-~\ njH I
O~ OO
S~N~ * \ / N
O ~ O
H
0 NS` *--{~S
fõ~ O O

H ~
- O O~S~-O * \ / N _ N '-* - * O
H
H
* \ / N N H
HN -~ O~O
~N
-N \ / \ N H O
. \ /

O HN O
-~ \ / O
HN-\ 0 N
O
* \ / H 0 H
H
* Nu0 ~
II
O
0-0 0...!~~ H O-H
HN-~ O HN -,( 0~0 N-S ~
O \\O O
-/ F F O~-O
* \ / HN~( H - F HN-\
O N O
H N~O HO \ / * \ /

N-S-N N-S-N N
p 'O' ~-O O~-CI H O
* O N-O~
\ / \\ H^O HN-,( I \\ * \ /

O \ / O O,\ O-O o HN-<\
HN--\ 0 N
0 'H
* \ /

H 0 H .O O
N ~~
N-O-\~ * / \

H
~ / \ O 0 H ,Oi ~
N-S-N
N--\ H N O
Fi N H ~ \ /

N-~ N O
N-H ~
H H

/ \ O O O~
N N HN-~O
H ~ ~ *
0 N \ /
F

N-S-N~ ' O\
S
O `O
HH

~ 0--~ - H
HN-~O HN~$
O O H

H ~O
N F F
~
\ / O.S\\O F x \ / \

N
O H
\

NH H
-O
~
_ .S~ O- ~~ * N

;~ ,-S o o * - \ / N
H

N~ 0 CI 0 0 \f ~-'O N \
;S~O x \ / NH ~H
= \ ~ N~..~ .
O
* \ ~ ~ %O

N
O
\
H O O
N-S- * \ / ~ Y
x \ / p N -S
- \ / N H

S

x \ / H N N
\ / N H O.
x O
N

(\
(v N
/
\~N~', O~S~
. x \/ -S
x \ / \ O

OL/
x \ / 0 _ 0 ---\ N-S-0 _ S, ,Fi * \ / CI * - O * \ / N~
H O H /-- CI
_/ O
N-S- O\\ N

0 SO t \ / Nb * \ / * \ / N
H
- O`'S O-l~O-~ p * \ /Nv N~ ~O
~ H

I^O 0 O
~O - ~ -H * \ / ~ * \ / N `H
H H
O ~ 0 /- O O
N
* \ / NNH * \ / NH H \ / NH
H

C} /-- ~- p O
* \ / N * ~-N
N H N H * / \ N O
H ,H

O O,N O
I N
H ~ ~
-/ \ N * N Sr~N / \ N N-O
\ / H

O O ~NH
N O
-O
H H N
H
HN~ -H O~~g~- H 0 * - S O~
O O/J- H

H
H
* \ / N NH * \ / P\'O ~

~ ~ O O
-\ 440-* \ / N N N` * \ / N N
H

~
* \ / N'H *( )N~~ , "-N N O
O O// H ~j -iO

~
*
N N
e H H ~O
*-O t \ N ~O\ N ~O
0- ~-N
_ O ~ 0 * \ / F

- ~ O F
* \ / N -O ~
O%~ 0 \

~O
O-H
NO '-N N-S--a ~ O
F

H
N
~
* \ / 0 *- N-S I o O ~

/ \ II O HN
* ~N O N\O_ \\\o O . ~ ~

~C1 \\ HN
N

, HN / O..'9f0 S

F

o O `~O
~ ~ - o N
!ST~ H
~ "
o ~
. / \

~ ~ - o ~ ^ ~s *
- N~ ~!-H
\ / \ ~
o\\
/ '/ \S
* - N ~-'o NH \ H
F

H O` /- 0 'N-H S-O ~-O

NH NH
* \ / ~
F
Ct O~'/ 0 ~. ~ 0 S-O S-zz- O
* \ / N * \ / N O N
H H H
F F F

O\\ 0 H
N O . \ / N S~O
~'H O
H
F F ~
F

\\ F * N
~ O * \/ - NH2 >--O
* \ /
'H 0 F ~
H H O ~-* NS~O * \ / N'O NNH
O 'H
O H

O N
/ \ N ~
- 1 H 'H

O\\ O\\ f..~
I-N
I N
x \ / N H * \ / N H H
H H
F F
*~ H H O
\ / N N-S--< * - S~O
\ / N

O ~ * \ /

H

- ~N O
0- 0- * \ / N `H x \ / N H
H

O.1- O
'S`~O O
~
N ~p N
'H * \ / ~H 1 H
CI ~b ONS
O -~--0 - ~p $ \ / NH * \ / N
H
H 0 H p,/--* \ / ~-O NN--":'~H * \ / N O
O
H H

O ` H ,O
S\O - ,S\ N!\
` ~ O 'N
~ NN~ * - O
i i ~-- N ~ /
H I-i * / \ N H
H

F
N-r O 0 p H
N H
- NI O * \ / ~ * \ / ~
\ e //
'H 0 O~-O
O O

N _ O// .H \ / * N
H

p 0 \ /
~-O ~--0 * \ / NH ~ * \ / NH ~--N
N H
H
*
O \

I ~ N.H
~-N - y--NJ ~
"-NH
\ / * \ / NH O O

I I

O ~ O, S,O ^ O ~a ~O O
NH
H

_ 0 N O 0 \ / N `H * 0 N
H \ ~ N \ / N H
'H

O
p O ~ --( N-~
- -O

H NH
~ . O
P
O~N N~O~ O O
N H i I-H H * \ / NH

_ H
~"O O\l~ * \ / N) T-p H
H
O

O O
~--0 O ~\-O
T
H
N N
H

-ci O O ~
- ~--0 N~~ ~ ~ / NH * ~ / N>
- ~-O~ ~ 0 0 NH \\ p N O
~'H H
O r--1 0 O
- O - ~p N ~-p N
NH NH

\\
l-0 N l`\-p 0 \\
`H N, - 1'-O
*
H \ / NH
~
O p 0 ~H - -O O- N
Nf ~ * ~ / N ~ NH H
H

\\ - O j-~
j' o ~-t~ _ ~p N
'H ~ C~ NH H ~ NH
p /---\ O
N N
~! - N
'H H H *~ 'H 'H
O
~--0 O
~-p NH

In some embodiments, the Y substituent is selected from the following:

O
O
J *-N \ / `-N \ r O H H
F F H
p F * \ / NH
H
- -NH \ / ~ ~
H H
* \ r H O\\ S H
N O -N.\.O
H
* \ / NS'O _ \ / O~
O
O/~ f } \ / N
H

\ / Fi CI F
N F
* \ /
O
N~ N~
I H \ / H

O
_ N
\r N.
H
O_/- N 0 S- - %/ _ ~ .H
\ / N O _ \ / N
;s,.
NH O
\ / H-N vH
H

O lS
\ / "' - \ r O
aJ * - \ r \ o N-H
hl _ -~ NJ
N
- ` - N~
H O H O O
N N

NH F
* \\ ~ O Or-~ HN--//
NI~I *-N * - -H 'H - \ /

/, H N-~
N~( N _,\(\

* \ / = - \ / H -\ O

O CI

a -o o :S~o / * \ / NH * \ / NH
HO

NN - ~N-S
~ N H O
N O
* \ / p * \ / O * \ / O

H H

\ O N 'O s-NH
b o~ \-Ci o HN-~ -O HN
O
õ H HN
S-N O~ N
H * \ / N~
o 0 O~-HN--i HN4 HN-J<
O~- O--\O-~F
CI
O O O
HN~ HN4 - HN-~
* \ / O / \ O \ / CI O \ / Br /,-~F H
0 0 \ O ~S~O
- OT -* \ / NH * \ / NIH-HN~ HN~
OS \ O 0 O

/
O, O O- * N
O
O.
* NS O ;S-O N-H
NH
HN--J/ HN
HN~
HN-~ HN-~
0 0 HN-~
* \ / * \ / * \ / O
HN-/~ HN-J HN
HN-~ HN-~ HN--~

_ HN
_ o H
HN-~ HN \ / ~
0 \ / * \ / 0 OS-NH

* \ / NFi \ / NH ~ / " \ /N~

NH ~
~-N H O O\\
O HN-\~ T--- O
O * \ / N
H

0 ~-O * \ / N HN-~
\

. \ / N O N~
H H - O
H O H o~ H O
N ON HN~ 0 N O11 ~
O
r H to] 0 p~- / ~ N ,5 - `~~ NH
H ~ H H
.
O? Q~g\ ~N
O O O H
. / * ~
\ / . Nl OtV Oi ~O ~N- iS- H
O
O /\- 0 N
H * \/ N~ H O-/--õ \ / N O

- ~~ O, CN-) O.~ * \ / NSO * \ / NSO

* \ ~ N

H
11 N-S- N- OS~ H

* \ / O * \ / N\ * \ / N~
'H
- O0 `S~ 0 ~ \ / N\,j ~-p - ' NH * \ /N NH * \ / NH~NH
H

O 0 0 O,N
- ~-N - ~- ~
* \ / NI { " \ / NH " NH
H
H 'N-H
O N 0 ~N
N-~
* \ / N g-~N * / \ N O * - S
H ~ H

H O
*
* \ /N /~
.' * \ / N N, \ / IV~N
0 " 0 // H
o 0 o * \ ~ NN \ / N~ * \ / ~
H
~ ~

OS ~ \
N NHZ %Sf * \ / N- N/ O
H

HN O
\S

O\~__~\ 0 ~
* H , -_ NS=O
Fi 1 \ * ~

O, /-CI I / I
S ~ NH NH
N
. . ~ o I N O
F
H
O

O NH
HN O / NH INH
NH
.

CI / \ \ \
O ~--~ O
NH Q * / \ N NH
'H
O-:-~SN -1 O

O

kN
o NH
1 * ~
~
/ NO H
H

O
N
H
In other embodiments, the Y substituent is selected from the following:
O O
'H
J -N NH
O H

O NH Op /
NH O' ~- / -~~
H IH

. \\

/ p O, \ O r * ~ / N
'H
0 H OcS~- O. /

H
O
N p * N

O
O\\ OI-k_N~ - S
H F *-N O
H * ~ / NH
CI H

H
S1O S x / S \
N Fi \> p * p H HN--/< N ~O

O~S~
O H

HN-~ HN--~
O"\/" NH O
~ \O O O-*

~S 0 O ~
0, S _ * \ / N O \ / N `O N-H
\ ---( HN--J/
HN-<\ HN-~ HN
0 _ 0 HN-~
* \ / * \ / O
HN-/=- HN-/
HN- ~ HN- <\
HNO
O O HN--~ ~ /

- ~ .
* \ / NH ~

O
N-OS~ } - N~--~ - S\O
O

* \ / \ / H * \ / N
H
H O
ON
\ / N O, O~NH H * NScO
H 'U' 'N-S- O. ip 0 N
Q . N `S_ ~

- \~-O O ~ p /-~
* _ ~.
~H \ / N: NH * \ / ~' !-I
H H

- pI~` ~ - OT O `N
* ~ / NH H * ~ / NH H ~NH
H
O N O N
NP',O
x\/ NH S-N x/\ NH O J 0 * \ / N,~ * \ / N' H H NN , O O H
O -o o~
* \ ~ N\ N N * H
H _ _ 0 *-o x ~ / NS~O HN~
H Oi _ - O ~ ~ N~
x ~ ~ NH \ /

. / \
O` / p, l-CI

NH O x \ / ` s \ -\ * ~ O
. I / NH O
NH
o CI HN O
N
F NH
H ( { \ O NH H
O
f / NH ~ y NH O
O I

IH

~ NO
/
H
w y IIIIIN \ N N NH
H H I
H
O/ * \
/ *
iH
O`
`I~ O O
NH N js~0 I O ( I ~ CI

H
NH ~ N N~H N~

r~o ~ s /~ 0 o*1~

o .~ / ~ .
p V
In some embodiments, Z is selected from the Z substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonliniiting examples of Z substituents include the following:

~ ~ õ =
,O

H F
O\-'O

w x M

F
* *

~

In some embodiments, the Z substituent is a hydrogen; a Cl to C6 alkyl optionally substituted with an alkoxy, one or more halogens, or a C6 to C$ aryl; a C2 to C6 alkylene; or a C6 to C8 aryl optionally substituted with an alkoxy.
In other embodiments, the Z substituent is selected from the following:

= õ ,.
\ . ~

. ~ }
\\ ~
.. ~ k ~ *1 \
F /O~/
~

In yet other embodiments, the Z substituent is a hydrogen; a CI to C6 alkyl optionally substituted with: -a C6 to C8 aryl; -a C2 to C6 alkylene; and -a C6 to C8 aryl optionally substituted with an alkoxy.
In yet further embodiments, the Z substituent is selected from the following:

* * .
* .

*

C
In some embodiments, R is selected from the R substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of R substituents include the following:
cl H

In some embodiments, the R substituent is the following:
H

In some embodiments, Rl is selected from the Rt substituents of compounds 866-1329,.
1484-2127, 2129-2545.
Nonlimiting examples of RI substituents include the following:

O~*
N O . 11 _O,N \* O~

connects R1 and R2 ~=*
Fy F CO~ Br~ * C!~*
O"*
connects Rl and R2 F
S F
O
H,O
'*
1N,*
O
.

O (0) N " H ./o <\N, O O' I
N-N~N~,O,.
bo 140 o C\N' N ~0 N
iv `' S~ >- NH p ON~
i i --S

N^N N
\~O~*
In some embodiments, the RI substituent is a hydrogen; a halogen; a nitro group; a 5 or 6 membered heterocycle; an alkoxy optionally substituted with a C6 to Cg aryl;
or a C6 to Cs aryl optionally substituted with an alkoxy.
In other embodiments, the RI substituent is selected from the following:

N+
_0. -~*
OI~, ~N,* * H
~ * l In yet other embodiments, the R, substituent is selected from the following:
O
N+ CI~* /
_0, ',*

ON_. * H

In some embodiments, R2 is selected from the R2 substituents of compounds 866-1329, 1484-2127, 2129-2545_ Nonlimiting examples of R2 substituents include the following:

O, \0H `O/* N=
O~*

H p $0J F~ i C-Nl i* !\ N--( F
O p H O
* *

connects Rl and R2 connects Rl and R2 ~=
H,N` NA, N H, p~N N

* F
*
F/ / CI
F
O' N~N^/~p . CI ~* O
CI

Ll-,N,_~ pl,* pl, N --"N
N
~IV H/~ ~/
O" F pi * * *
O O' O1-~N , JN ? JN
. * v ~
pl,* pi* O pi ?
?
~N ~N N
N-N OJ
* ` *
* 0 O O~ N
H N

H O
~yp~\O-1 OS,N
O
H H

' -* `pN
-o F oSON~ S N
F H H H
O
~NN * H * Br H H
Br~, H.Ni H
* N *
N~ O ~N~\O/* ~N I O/ JN~ i p~ I O~* O~* ~0 \i-NJ \iN,/I co N\-j CNON 0i N 0 O
CNO' N~O N \\

H
N N 'O
p O~O
H *
O
I~ N N- N ~N~ O~~ p_*
N` N
H N
H
N~ ~ N N N pr~
N
O
0, < p N p`* -N O\*

N N <p`
N~ N ~~ N N.N
H H H H

N O~* N- N
O N,"'N

In some embodiments, the R2 substituent is a nitro group; a hydrogen; a halogen; a hydroxy group; a C, to C6 alkyl group, optionally substituted with one or more halogen(s); an alkoxy group optionally substituted with one or more halogen(s), a-OCORX
group, where Rx is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl, or -a 5 or 6 membered heteroaryl group; -an amide group; or a-NHSO2R,, group, where RX is as defined above.
In other embodiments, the R2 substituent is selected from the following:

O, +: *
H,O N
0_ H F
N * '`
H~ CI~ F' \
O F
* O~
N/r~N~~O/

CI

O~*
ON H F~/~Oi FO

N_ O' O'* O' *
O"
~ . .
r\/N C N-N
O *
O/ o NJ/
C

O
OS, N O ~Y

'O
\ F

H ON
N -o F
H F
F

'--O F
H

In yet other embodiments, the R2 substituent is a hydrogen; a C, to C6 alkyl group, optionally substituted with one or more halogens; or an alkoxy group optionally substituted with one or more halogens, a 5 or 6 membered heterocycle group optionally substituted with a Cl to C6 alkyl, or a 5 or 6 membered heteroaryl group.
In yet further embodiments, the R2 substituentis selected from the following:

F O, Oi F -V*
F
CI

F
CI ~ ~ .
\/\O ~ N N H~ O

O-- O'* Oll O' / N ~N

O
F
O --o F
r'N N F

F
* H '-o F
H

In some embodiments, R3 is selected from the R3 substituents of compounds 866-1329, 1484-2127, 2129-2545.
Nonlimiting examples of R3 substituents include the following:
0 .
H
In some embodiments, the R3 substituent is the following:
" H

Nonlimiting examples of compounds of formula I include the following:

'N-H
\ I O / -\ I N \ /

N
F - - H \ O / - H
H~p ~ i N \/ NS o Hx ~ N \/ N ao F ~ p% \J F p =S 1 /N /N
N
F H / C O `
HXp I N \ / 'H ~ N O I N "H
F ~ / NN I ~ F

// // /

~ -~ i H ~ ~-N 'H ~ ~ F H O ~ / N NH
F F

p o N
O
N N \\ ~
O \ o ~ \ 0 ~ - ~
r IO f F NH ~ F NH O
F
~\ NH

/N F
~-o rN F ii \ H
F o N\ NH N H F/~ i N Ns.
N 2 F ~ o=~

N N
- H H
F_~ ~ N 0-0 F~F NS, F-Cp NS
~ F/\ F o' !! 1 / Il F H

F~O N ~~o F~C c NH FX c N\~
p N ~p F ~ /-~
~ F O

\ >
g8'rJ - /

N
F H F ~ H H
F~o N o o F~o ~/ rv ~o 0 o S,o b F

g~~ F I) N NH NH F~ I NH H
N ry l~-N N o N F .Y H
FXO ~ N \ / ~NH ~ / \ N
N H H

/i o\\ N N ji jH

1 1% o / \ N

NN ^~ \ > ~ FXp I \ N NSJ
~ F ~" b N N N
I/ ll /I
F F F NF F I~ N~
N o;~ ~o N p' o F

i li N
p~o F F'~ N I\
O /~O , N N Q
N -S": O
"0 908 N
p O
`- _ \\-N ~~
~H p I / N NTH ~ N H
N H F ~I/
F F

/N % /N
~ p F \ - H
N \/ NH FX N F TO I/ N \/ N
"> F N

N N N
F H
F \ ` I
H F F I/ \ H
N
F NH

N N H O N H
u n \ O/ F{ \ O/ p p/ I p N-5-<
N NH

/N ~ N
/ I - N;S.O ~ ~ - pN `O 0 ^ ^p \ I \ /

= \UI R`1\ ~ ~ ~ O ~ `H

N N
p` r ~ ~
\ I p \ I N \ / NH p NH

N N
N _ O H
H yX-c0 o ~,o F ~o N o ,o `--~

N N AN

H H
H F - ~
H F ~~ \/ NH O
. ~O N ~ ~o N Ns,o N,o 1) ~ct F cil~ o N ,N N
H H' H
N NS. N

N N N
O
H ~ - H _ N o P~ ~o ~ / N ~P~ a I Nb ~ a~ 6 , ~~ a- ~O N

N
N N

\ - H \ H NH
N \~ NH H~ F I ~ F
F
!\O / N ~

N N N

\ - ~ ~ - H H
NP'o --O N 0 ~
/O

!N N
p\\ ,, N

N N N

i N N I i ~ H N O
O N li N N
N
0 / o N~ F\^O ~/ N ~/ NH NH F~\ ~/ ~/ N ~I
O H

o Z N o N

N N H F~n~ I / ~ NH ~ ~ - O
~ N NH 0 / N N
N
D
I ~ - NS ~a " !
o N\ H NH o O j i N NH

N
% 0 j 0 N O
I/ ~ ~O 0 I/ N NH O
~ O-C N NHO

N N
// C o N
\ TN \ ~LN O r O ~/ N NH H O I i N\ NH H 1-0 1 N HO

/N
~
F N NS I~ N \/ Nt~
F F ~~'0 b 6 /N ~ N N
p \\
\ 7~"O ~- - T~
/'p I/ N N" ^~ ~ N \/ NH O /~O I i N \/ NH .
b b b N 0- ci ~+ N ~\ N
~
/~p I ~ N F{ O
~-~p NH NH

\O H I/ O
- T-O1-< -// NH ~ ~ Nb ~0 N
N
'H

N N
O`\

NH N e_O H
o- b ~a 1 N

N N - N H - H
" o~ \o o~ ~ \D ~ ~ N

N N N
O
H ~ \ - H \ OI,S
O N S.O O ~ / N
~ O/ O/
\ \

N N N
H H ~ H
N 'O
N
O D.S~ O N ~~ N
D I / ~
O) D// O O

N -p N
H ~N H
N
~
~" o o ~o N N"o " os~
N "o H

-o -o sj /N -o N ~j N (/ os~ N \ d S
N- ~O N ~ < /
H H I H

-o -o ---//N /N - N

N p N 0 N 0 H
lk '-'," HH > I~ NN~H
H H
H H

lN N
N
O~
\ - S, F F N N F F N
F F F F F

N
N
O`
O~./-F ~~N NS~O FF ~,N N F OM
F S`O
F F F F N

-o -o /N %/N N
N ~ O N O
H NjLN~
H H H H

-o -o -o //N
% /
/ N
( 0 ( 0 !N \ 0 \ ~ Nill N'\ \ ( ~ NJ-N~ \ f ~ N
H H H H H H

N
O /-J F N O
`\
TNH ~\~ \ N NH ""0 N NH
O N H

N
p\\ N
O\\
\ ~ / \ H O
N )-I N
~`p \ N
H
H

/N H 0 H O N H~O
N~
~ p~_ N
~~O \ N

~ 1020 1021 N H 0 /~
N-/ N HN_l0 N
O
\ / \ `E.(N- \ N-H Of~ / \ ~-<
Nt ^p N N NH
/\

N N
p``Sp O
II
\ - \ - ' H ~
H F CI
NH

%~NH / \ i Ct~ NH
NH
O~O-N ~N N F{
p ~ II ~N4 G N
I\ ~ NH (\ ~ NH ~N O ) I

H o ~
-O
I N N 0~
N'H
~ I 1036 N N

O

N
O~

/N N p N
o~ ~--~ ~0 o ~ Fi N ,NSH N M Q ~ ~ NH
' N H O /N H O
/ N~Pp ,N~ -H
~ ~ N O`
N S`

H ~ 1042 1043 N
// tJ
~_ ~ - O~S

N p ~ i N / N HN-~ NH
y N
N

// O` N
~ p~o.
NF{ Br I/ N \ I NH \/

N O N N
.\
H, NS O N ~ H ~/ \ I Np J
O
H CIJr ~ CI

N N N
/
J~

1053 1054 ' l! p }_ li 0 N
O
~-O/- -O
NH

N p F N N N NH
H N NH ~ N \ / H

o ~ N
O F
O
N N

N 'H O ~O ~, N \/ NH ^O ~, N \/ NH

N N N HN O
\\ H

N N=H ^O I / N NH H
0 N~\O I / ~j \ / /\\

>
O N N N NJ F I\ - NH

N~\O ~/ N \/ ^w~~p ~ i N \ f O~-N

L/=N N
~-N N
O

` o p ~ p H

N o N o /N
- I~'o - N o - ~}LO
0 N NH ~ \O I / N H N \ / NH r b b O b N Q N IN
a N N~O \ ~O I / N N~ O~ ~0 I / N \ / NH O \ ~ -b b 6 N N

I\ - NH / O~ O O~N/
^0 / N \ / H ~ \ I / NP N \ / ~H
b b " b / N N

y \ -0 N ~ 0 N p NH

N 0 t GN J
</~-N ~N
NJ

/N O /N N
\ ~-O
Ho i ~ \ / NH c \ / NH
i L. o N

N
N
^ N \\_ NJ // N/
~ I N j ~ ~ N\^O ` ~1 =H

N
N // N Nl \ ~ O N !H N hl O ~ H

1093 1094 N /N p 0 N \\ `\

^ ~ I / \ ti NH N NH ~ ~ N }
NH ~~O \ N - H lo ~ y ti ~ c) WO 2007/084435 PCT/US2007/000996 N p N

p N NH / ~N
/~ \ / , N H ~ N `N
O
'H p ti \ N - =H

N
N
O N o, i ~-=N O \ - SQ
NH `H " \ N N \ / NH ~
!~ ,~ b N N
N
O. / Q` a , -S :So0 N
NJ \0 N N N

o\ N
o _ \\
-O Fv"O N 0 H
1108 }v`

~N
co, p -0 N
\ / \~ / ~\ NFI
Q N` ~ p ~

111o N.H 1112 o~o II

i ~
i l N~ \ N O N 0-~/ /

N H
N O I t'! \/ O5 `, / _0 1_ -N
~ I i ry \
J rJJ'N b /\ 'H

N `J
\\ ~ ~ ri // /j o ~ /
N /- ~
~ `H NH " _ NH-o N N H b N
p \ - H O

/) d\ ~ 1>

N
\\
( ~ - --Nõ ~ - N~-NH O~
~N~./~o H jH ~i I \ - N O

N
N
0 ~-- N
~--0 \ - ~ O
NH N F H
a b H FO N \/ O~ O

N
N
}i - H
F F~~ I/ N \/ O~0 F~p / N \/ o~O FFo - N \ I NH

N . N
F NH // ~ ~\ N /
~p p/-' p / N ~N
O H
O j N
H
F Fl-p I/ N NH ~ FlO N ~ ~ Fp N N
H ~ o~N `H

N N

- H ~ - H i o ~~ ~ N o S~o ^o / N o S~o \ ~
b N
- H ! N N
/
N O NH NH NH -O

N N
o`~-o N NH \ //
C C
~O / N NH /~p I / N/
NH

N i /~
p p p NH ~
N~O N Np N
/
\ - ~--0 r N N
0\\T
NH

N N O I\ N H \ - ~~?
~~O N H H
~ NH H

N /~ N O ~
\ _ Y
H O t~H
"
N
/ N.So H

N N
N /p "0 1 \ N 0 N I~ p N o ~
`~J ~ ~ b N N~SO H H
H^/ H
H

N
i0 io N
\ O I \ NxN~/\ N ' / N~N /\O ~ ~ N ~?H
H b H H

N N
p~ N
\ p ~\\
/\p / N H N ~H H 0 ~ i N p b b ~ .

/N O
- NS~`p I\ - N N~ ~N ~
=H N H - ~N
NH hi N
/% N
O\\ C ~ \ - p -Sa , N NTNH F~~~ I N \! NH O F\,p p N
=H
~a b Jv~ ' N
/I N o ~ N
\ N I\ p N p N p ~~// H H H b /O N O ~N O /N
N ~\ \ I \ o N
NO ~o~ N I N-'-O------ ~ / pS
H H ~ id 0 H

N
N N

N
I J N
~S~
N ~p l ~
H

i N
H
NH r/ F F I \ - NH
` Of/ F O i N \~ ` N
1> o~- 'H
N Jv~ OOr H

N

F \ - H
F NH'O F~O N S0 F NH
F O N OIS a O' > F~O H
b N
O p ~O N
I~ _ N NH !N O N, O~
- N
H ~ r ~
N O
N / b \ / H
b H

/N O\\ ~ /%, O !N O
TO ~O \ - 1 O \= O \ - ~ O~
NH NH N NH

O
- p`\ ~-N
~O
-,~0 N "
H =H

N
N
O\\
O`\ T-O !~ O,\
N
N \ / N \ - TO
H NH
H ~

O ~ N O N O\\
NH-O ~0 7-0 N \ J ~~O I N NH N NH

N N
H NH N
N NH

N /~ N
O\\ \[ 1 N o ~b J/ O\\

NH N=~ NH
b N
)~ p`\ /~ O ~- // O
N \ / N=H vH \ ~ ~ \ / N 'i N H
b O ~p` N
~
H "=H ~ N
b b b O
\ - ~Q % d ~-O \ Tp C N p N I s o I\ p I~ Nl \/ NH
N iN

!l O\\ b // p ~ N O \
- ~N
l N \-O O \ /
~ H ~ N \ NH
b '~ ~ H b r..~ /

/N N
p`\ ~ // O\\ b Q \ - 7~N
~ / N \ NH H / \ N
b b b IH

O ,P /N O

~p i \ f N NH Ft N \ I NH i N \ l NH
b b b -O
N ~ N N
"'o QSO / O~--o N H~Q N I~ OS \( N NH
N

N N
~
N
\\
To O, N
'H \ ~ N \ / NH C
N~O 0 H

\ N N
~N.n~p i ' s O7~'C ~ / - T ~ p~ / N
~ ~ N \ / NH ^C r N \ / N \ ` ~ ~ ~ ~-\
D IJ~~ M

N
/~ 1N
H 0 ~ 11 0 \ - \ - ~-o \ -N -o ~~O ( ~ N ~ ~ ~= I ~ N \ / NH ~p s N \ / NH

169.

N
p p p r-O
?\-~i~ N` \ / N" ~o ~ N \ / N

N ~

H // _ ~ - ~ - ~-O ~
L
N NH N" i / \ / NH

0\
N ~
O N WOJ
~N% p ~1 N H "' ( ~ ^p ~ i N \ f NH

N p /N N
_ 7 O
N
(O - NI ) ~ C N NH
N
O /;> \ \/

/N - ~ ` f~ _ p I Nr ~ ~ / \ /

~/ V v b /\ \ N - =H

/ N

N NH
ON,O

N
o /
\ - \\ -o I ~ p p ~ / A / NIN ~N~ v ~-p 6 -N O , ~/ N \/ NH l I/ N ~ I NH O
~`~, ~

N N
N
// - OTq \ / - p~--O
`o- p \ I / N \ / NH p N NH /\O I / N N
V

/" N
F ~ - H
N F H
F~Q I i N ~ ~, I ~\ N
p~ .H F O p~p F~\p N O
7) N
p \ /N - p _~ N T~ O

/N~ I/ N NH p p ~/ N NH
b J b `-~J b r~ \J'-= T-6 N NH
pI / N ~-o p \ - p~-=O
~N J ~ = g~ p I / N \ / NH O I / N \ / NH
~N~ b -N b /% N N
N N" p/~ N N p1/ N
N
vNJ H

N /N O - /%
-O ~N O`
p N \/ NH MO i N \/ NH O N NH`\O
J b L I ~ ~O \

N
O p I\ NTp I\ N p o ,H H ~-O
coy,-, rI O\\ N
-O p\\ O
N NH \
O ~ /~O I ~ N` NIi f~/~p ` \ / NH
~OI O ~pl p N N ~-N - p ~O ^ I N NH ~ N \ /
~ 1/O }~ H

~~ N~ ~ ~p \ lI - I-O --i0 S H
b N
O S~ 0 p ~p \ - p\\ O ~--0 N NH ~ ~, N \/ NHT N NH
b b b ~

N N
/N
_ /
\\ ~-H
T N -H O I~ N NH

O\\ /N \\
-O O-N NH NH i I~ N NH H
b b N
0 \\ N
\~ N
0\~ ~
~ i - 7-H !"N
~ N =H N NH H < I N NH H
b = b b N
~~ N
TN o N \ I NH H o N o I ~~~ N H ~N'~`o I ~~ 1+ ~
b ' -N ~~
N
~NV~O ~ =H O ~ ~ ~ ~ =N ~~Q ~ N \ I ) N \0 0~ o N
N \ / NH ^O N \ / NH ~ / \ / N
b b r b "

// N p\\ ,~... N
O
C~~0 I E. NH NH pi\\_N~~p N k ~ ~/ N \~ N ~ 1 " N O ~ =H
N

N /N O
~- N ' N
I/ N NH H --N
I/ NN /
N ~
O N =H iN~/~p I i N \~ NH H
b b b N N
\ a~'~ N " 11 p O N` H _ I / ~ NH H o N1D. I
O ~ H

N
O }-~ N N
H ~
0.
p N i NH N NH
=H

N~N~ 1/N - O ~ 11 - O
N
N
( \ ~O \ T
H 0 / N =H ~NN~ N NH

o ~\ - O
/=N NH
N~N I ~

N ~N /N
HN O\\ p O ~ -0 HNN O
H2N I e ~ / NH r O NH
" b b N N
\ - \\
o O
p I-~-O HN ~ N I NH
~ N NH
` NH "
~NH6 b b N=N

Z N N

\ 0 s ~-- N 0 I ~ NH ~ NH ~0 O N N~~ N NH
No b b ~-" b N
N /%~ O
p p O
~ ~ NH NH
r p N
~ /
N O N b II p "N v " ~N
NyN 16 H N-NH -N
p r NH }-- ~/ p! i N NH
N /-N O . OAIJ
N N

~N O\\
\ !-O}- N O
O ~ / N NH / \ - ~-o NH
~
O~O I / N. \ ~ NH N
N~
NH
~ ~NH
1s17 1518 1519 N
N
o ~-o NH O\\
)'o N NH
O N
~ ~-o N -NH
C ,,o~/ b/ \ !
~ CN
N-NH NH
N=N

N
O
-O
NH ~N o HN N \\TO O\\
N I N NH r ~/ "H
!=N O N
N.N
~o ~j "= J }) H p _ N
p N C Y~ - NH H I\ N~ o N ~/ r HZN N
o I i N or 0 / N \ ! J"~//
C b p ~

N N
HN o\\ /N O ~ z~ O\\
iN ~ TO HN p~N \ 7-O
~O I/ N NH O ~, \ NH ~p ( ~ N NH 1~7 N
p N
J-p N O O
O
p N\ NH NH O I/ N \/ NH
N'r 4 vv H N-NH

o !/ ~
o r N \ - ~-N
I` - NH ~1..- HZN NH
~ N \ / N H O

N N
!~ /N p / O
N J/ HN ~ N _ H~ I~ - NH NH ~p I N NH N pI/ N NH N/
O N ~
~ - NI-fb ~~// N-N

N
N // O\\
N / O\\ N `\ 7-NH
HN ~N TNH O sN ~ 7~'NH I \/ NH /}-p NH }-- ~O ~ ~ N NH - N

N 0 O`\ N O`\
S~ N NH ~ l-NH H
Yp ~ / C' NH ) _ N~O s N NH ^O N \ / H

/ NvTN

N

N ~-NH N
p NH O\\
~ ~-NH O N ~ - T-NH
N N O i N NH ~ NH
N-'N
. Kj N111 -NH N, v N~
H
v N
N O\\
T~NH N
NH
O

p~ \/ p N

N
N O
O\\ ~-NH N
O
NH NH ~-2N NH O O~/ N NH N
b N b .
N ~ NH N
~NH N-NH

o N
N
\ -NH 0 O ~/ N o ~NH
NH
~-N O N`
NH
; NH N~N

N
0 f O\\
\
\ ~/~ ~_/ NH ~
NH
~ -Cl N _ p NH
~ NH
O ~ N` NH NH
O N-NH

N
N N O
p`\ S ~-NH N
7~NH NH Z/ 0 NH r O N - ~H

N, O N'-O O N'NY
\ O I \ \ - O
f ~O OI N NH ~ \ \ - p~0 J N NH O ~ N \ / NH r b / b 0~
N NN "
N
N 0 O\\ C T`O NN ~ 7`O o N NH ~-J b / b N\N
~
nJ O O
O O ~ \ ~O N\ ' O
p N ~O O N Nhf ~ J/ N N
J H
J ~b NH 1734 1736 1738 N N
O O
HN N 7 O N~ N O`\
, \ \ - ~-O O i N \ - To J N \ / NH ,- O l NH ,--a N
N O
O
o SN N~ ~ ~N 11 0 I ~ N NH
O \ / - /~~
~ ( / N ~ / NH ~ ~ NyN
b O
N ~-O
// NH
N
N

O
~
~ ~
N N-, ~~ N NH N~ NOI / b N N OI/ N \/ NH ~
H

N

NH ~ N Q %
O \_.
O N
~o /N ~NiV`o % N \ / N~H o ~NJ~O N NH

-NH N b b N N O
HN M // N N
O OI- `
N NH ~ N N J N NH /Y-~

H
H N
N N~ N
N\/ N\
O\\ ~
O ~ \ I-Q 0 O N~ r J / NH `\
~ NH H
J I N ~ /

1 O~ N
~
N\ O '~ \ - O\, O O N O

O ~ N ~ / NH~ T--Q
J ~ N NH 0 N NH 1791 1793 1795 -'N
O -N O\\~ S
T~O -N
N NH
J N NH O N NH

N^O N O 4N
\ TO ~ / \ / NH o \ ~ o J / N NH ~ N O N Q 1~ N \ / NH
NJ~r~N`
N-NH
1807. 1809 1812 % NO N6\-S
o 0 O
~~ \0 -~-4 I\ \ - ~-0 !=N o ~ O N NH r O i N NH
N_ J b J b N- N
N NH O

O H 0\\
~\ \ NH
~--0 O N\ T-O
J N NH NH
b b \ \ _ ~~p 0 J N NH p N 1/ NH N\ N~{
b % b O//

N N

N'-O' \ N~ 0 p k N NH O 0 N NH ,--a I\ \ -J b ~--~ J b b N>; o O

O- / N\ I I /~

N N d \ \ - ~ O N H,--a O
J N O//~O/ J O~O O N\ NH

,o N N,. N
~ \
\\O

O N NH /-< \ \ - O O
NH p ~ N NH

H
N
N\ H
O N
\ 0 NI
I \ - ~-~ \ \ O ~ N NH \
J ~ N p ~ N N~
O
O

1 =
V N
N N~ ~
N\f I\ p~0 O~N
O ~ N NH O
J N N -p O ' - NH
~

F F
O ~ 1 F
N

J N 0H0~ N~O 0 N\ NH =)--~
// ~--S 1 S~ N~O
O
J,/ N \/ O~ p O N\ N~ O N\ N~~
b / b O b N/"-S
O N
\ \ O
O ' N~ ~ / NH O N NH ' \ - ~-O
p ~ N ~ / NH }-~

N'ZN H N
N~ NH A
N HN iN OS
( N ~ -O ONH
~NH ~ N NH
O

N
N
ZY p S lI OZ? o " ~ Ho To N \ / NH1o cc-QNH \ ~ 6 b O N b Oh -NH

o ~-N
O I \
O N\ NH P HN ' ~
N
J " NH Q J ~-NH NH
NH J b ~NH
o N
I~ N
O /N S N
~ NH Y I~ - NH O N ~NH N~NH
`p / N \/ ~--NH 0 I p p,/
b ~/ NJ1N b N-NH

N N 0.
~ N'-O' NH
~
NHNH N N p / N\ NH
NH o N N N~% O` NH
, JJ-N_ O~/
N Nx 0 N !I
N
\ O \ ~ - ~ X
N
~ \ ~ O ~ N NH ~ \ ~ - ~
p ~ ~y ~H NlllH~~~ ~\ O O ~ N O~-NH

O N \N I-N
X
O

N \ \ _ = ~ O

! \ / NH ' -NH ~ ~ O N N~NH
J b o /. b o//

N
O N
N\ ' \ O
~
I \ OI N\ , / N~NH ~ \ - fl J ~ N OH N~ h 0 Q / N ~/ O~NH
b // "`/// J b //
/

H
H ,N
N~ N
N
, ~ v N \l O ~ ~ N\ NH ~ O N NHN~ ~ \ \ IIDNH ~
J ` O-NH b 0// o N NH
o0//

N` O N
\ NH
J I~ N NH N~ ~ O~NH O N\ NH /
o/J- J \ /J-NH
o O

S
-N
N \ \ _ O<QNH N N~ N\/ ~NH

NO
O
--N NS
\ \ ._ \ \ - I / NH
J N N //~N~ O~NH O , N\ N '/~
~ O J \ NH
o 0 , ~S ~ N
N~N~ N~ N NH O
\ \ \ O'O~~ O~NH O I~ N
// \ O N~Np i N \/ NH
H
/t b J b 0 N

// O\\ N ~
N NH C'^'O _ I i \/ O
\ . ~ H
C N^~O ~ =H

N
N
.~ N
N~~~~~~ I~ N \/ NH N NH O~0 ~ N lo H NH

/N o N N

ON njH i0 / / \ NH
ccc1t N /-O \ I -/ N ~ ~
~

N p N 0 /N a ~o /

N - , " N
"

/%, /N N
pl s~- p p S/~p N 0 ," N NH N \ / NH
> ~ O

N
O\ ~ - = N \- \ N H O
d NH NH ~ \ I N ~-NH O
H
N

_ 2145 2146 N
N = N
/
N NH N NH ::C ~d ~p N H

p ~ 0 H
0 , - ~ - O- o ~ N
N / ~ / cc N
C-so 0 /N N
H H
N H ~ / N N~d N >=o N

H
\\

~,, C
N H N H
C
/" H-N N H H

N

I ~ NH O
/ ~
N NH " N~~O N \ I NH

N
N ~ ~~ - o\~ N - o N 0 ~p N N ~~p I / N }H OG'H
b } N 2163 2164 2165 \ )--0 `N N NuN N
N /=ry ~
~
N NH
N NH

N
N~N /N N /
O N
Q
~ \ - ~~ N~N N
0 I i N NH I~ N H
~/. N H
0 / N ~ ~ =H `
b 0 p ~ O N
\ ~ - I-p ~ ~ \ N NH 0\\ 0 N NH "p / N ~ ~ H NT-~~O 'H

j O
\ - ~o N N
p O~O i N \/ NH rr I\ - N O N~-O
~p co O N b ,H O pI \ i N H

N N C `\ -/
- T-O !l qJ~ // O
I
(~O N \/ H O NN O I/ N O
b b ~Y\p b H

F
N

O~p N O !N O\\
O yp \ - rr;
~O ~ .. H O~ ~ ~6 O / ~ \ / N H
~ O ~ H
O

O
// p \ / N p O~p 4/ N N-NH N NH
~p /~ ~r0 N tt O

N
N

n S-N 0 - ~
~\p N ~ N O NH 1 Q NH
.b b b N
N
N O N I \ _ O
lpt /\p N p H S-N S-N
\ ~~p = N p H N p H

N

N
olc/~ O O
S-N O N O H NH Fi b b /%t p\\
\ - T~N /N /N
N ~ H ~ ~ - ~ o Q
sN+N ~ i NH ` ~ NH
\N~ b // %-~ N 'H I i O Nu ~~ \/ NH p ~ i N \/ N ~
b b ~~ b N
N
~-o ~O
~O N \ / H 0 N
~ b ~J O N 'H

N
N N
N H ~ - N
~ p ~y b ~- b b N p\\ N p p N

I- \\ \\
N T-`
r Nl NH p N r1H
` />- b N
N
N
p~
0,// N~-a N - 7- \\-' ~~O NH O I / N ,H N

b b ~

N
// o N
p r - ~ / o\\
~ N - O
F{ N
~O ()N \/ H JN 1/1 ` N~O
O ` H

N N
// o` / o`
o ccx-o 14 cc ~ N \ / H 'H 2217 N
// ~ N N Z10 O~~ S. O p-N~O 1/ N \ ~ H O ~ ~ l / N O N O N ~H N O N
'H

N
N \ N

S-N F- p' JJ 0 D ` ~O N
H
\ 2224 / 2225 N
J/ ~ N N
Ol J/
I \ NS"O \ - O S. 0 ;SO
O~ 0 / N H O- I ~ N NH O O O I i N ~/ Nb ~~J7 b ``~t7 _ ~ ~ b N
o esO JN N
/ . ~
N~O NH C ~ ( r ~ / QN O C ~
N O N H N. O ~

N O.$~
~ N N \
N O N H ~ ~/
N O N H N ~/ NH
b b~==~

O
~ N H ~~i0 N rpiH p ~~p JN 00 o~o "H
A- b b O~ /N
N

I / N ~ / NH N - 5-/ N N,p N NFi NH
b b ` / //
N_ I\ - N

H NH
b b b N
N /N
O
~ - o N N~ N N-H /\O I / N N
b <\ ~ ~ b O

N
N
o / / o ~- -Q
o ~\0 ( / N N N N~
b b H

N
N
N
//
~ H p N-H p S
\ N O
H,O ~/ N NH .
N~p NH p ~/\p I~ N H
b b ~ 2255 N N
N //
~
/
0 ,~O ;S b - -S b NH N NH N NH

N /N N
O
~
- ~- _ o~o `~S
NH ~O
N /

~L0 \ NH
N NHb b~ ~ b O N N N
~
o~` 1 o , O
O ~ N
`~ v~ NHCIO 'N NH2 ~ N ~~ H N b b o~ N N
~N O
N \
N \ / NH N f / N NH ~ ~ / N NH~

b b 2265 2266 2267 N
N
p~ // ~ /N
N _ O~ O o O
~ 10~ ~ N ~ ~ NT
b b H b N
~O N ~ Oy O` ~O
O J O - O~ri \/\/O S
.~ ~/ N \ / NFIY N \ /
b b N N N Q
O-NH bN ~NH D O~-N
\/
N
\~ NH b ~ i N ~/ NH
H
b b b 2280 2281, 2282 N

~ O~ ~ QCo // N
~\ J

N~ N~b~-O o ~-o 0 NH
b b b N
N N
~C ~ ~ o~o 0\\-N
~0 7 O 0 I~ N OH O N NH
=b b VV ~

N N
J/ ll N
NvN~/~~ i N NSb N I\ - NH I N/, ~\ ~~ NH
~ `o `'N~o ~ N ~ / ^ ~N`i=o ` N ~-oACo N
O" 'N
Ff~F N
F S~~
N H

/=N
N N~N /N ~ 0' // O
0 \\
~ N N NH
'H

2299 = 2300 N' N
N N
O
"I-N~~ 4Q_N
O
H Nv NH N
H

/%!

Nz~ 0 o N b \ / NH NH
O I O N ~;.o b /O /N
O?S~Ni N
O .~ N ~'O/ - O

\/ NH N NH

% o p /N N
o p N~N~~O N NFi NH NvN~/~0I/ N \/ N~NH F-A-(, aN S:;.O
b "

N

- \\ N
NH o- \ N

~-O
0 N \ / ~~ ~ / N \ / NH NH
O\.OO O~O N
~

/N N N
~ / \\
~--0 O
\\
'r TN~õ~
~^^ NH \~~ I / N \ /. NH /-- ~ ~ / N \ / NHl\
/ o b \/
b N N N
p` 0 O` iN SN~ N
// - o~SO ~
N / N ~ N
~Q N H H ~~ ~/ N \` H H ~ N NH H
l N C N C &

2`/3\1~/9 2320 2321 N I I\ /N N~~ p rN O o' y_ N p ~/ N \/ ~O ~ H
b N~ ~ / N
y <~ N/-p //

N
/ p ~-< N
Tp ~ O
N N '\ N H
~N~\0 N \ f ~^N F,/, N NH ~ \ - rTp p ~H
U b N
//
F O~ O-o`
F~p N ~H F~p I/ N \/ T~ ^o ~/ N \ 1 NH
b b b N N
;
F 0~ F O`~ O
H NH O F~O N N~ NS``o b H H H o H

N N N
F
o~ H
F
S N
O ~o O N ~
O
F F I~ O O F~O N
H 0 N ~H H H
N'::~'N 0 ~

2334 2335.

N
N N
CI
o H
\
o, ~, F a, f/ /
I
FO N H Fp O N \/ Nb p O
~ N ~p NIJIIN
`\JI

N

rjH N \/ - H
/ O jO F

0 N p N
~ I N 0 )..,. F F ~ -~
NN ~

N N
\\ ~ ZN

\ H cccc-d- F~O N O~.o 'H ~ /
N O H
F b /-O / o /N
\\ N ~
~ ~ - P~ ~ - - F~O -O
NH O F NH
I/ N N

N F
F
H H \ H
F-p ,p p N "s,o ~ ~ ~ N
Fi ~S,o p~ \ N I N N~ N ^~
b ~ , N
// CI N

~Isl NO ~ N oF~o N -o ~N
NNI D o b ~ b , b 2352 = .

N N N
p 0 ~ H F O O/S~ F O O'S

F~ F I/ N ~ ~ S/ F I/ N \/ NH F N NH~
F ~ - ~
~

O N
F\ /O H
O g~ ccb-o- -F N NS~O N \/ S;O
~

!j o N
/ o NJ-O ~ / N \ / NH r-N'~o Sc0 \ ,O
N NH `NO I / N NH

N
= N N
f / O\~ p / 'N ~ - ~ ~cQ ~n1 \ - NS`O / N ~ - O S
~ ( N NH ~Ni`O N 'H I / N NH
N O ~ \ - N O

N ll 1/
;
;~ O;S cOx-c-H
/ NH NH O

N ~ /N N

ci-o-Z O S.~O \ - H \ H
N H F~O N NS=~O F\0 I / N ~'O
F O' F~F 6 Oel~l N N
N

F F \ H cOJf-oH O~~O N \ /r O
I / N N /p C ~ p0 2376 N N N
//
O-NS`O N N
O SaO
N O N H N. NSO N
~ ~ H b AN N N
/ 'N' \ g~ 0~ // _ O.
i~ O N S / N \

\N O / N NH ~~p N NH `Ni~O I/ N ~/ NH 2380 2381 2382 N
/ N
O
F O p(' O` /p - ~ N NH /\ c N NHF
N O ~ ` F O

N N N
V _ p O\~
F F ~ S FI N
F~p N NH F~ ~ / N NH~ F N I H

N
N zN
O
/ ~
F ~ \ ^ NS1~ CN ' ~ "S
F O ~ N \ / H O ~ N H N / N
H

lN F N

" H
rN ~~ // - N~ p f i N NH 0 N
~ i N H O Q
N~ N ~ N N 2392 v ~,>

N N
o p /Z p r~
~ i- ~ '"I ~ r F O I - p N O N NH i, I/ F N NH
~ N O 'H 6 N.
F O 0 ~ J% N 0 ~ O
F NH Ci~ ~ N - p N ~p N ~ /1 N N
/N O p // o =~Q
~-O
N NH a N N C N Nb N

N N
p // o /N

N~ c-c/ND o0c-c:
~ 0 b ~ b &

N N N
ll p IJ 0 \1/
\ p, ~ - o`S` - C -S
I ~ N ~ / Nr o I ~ N \ / N/ \/~0 I ~ N
/ ~ 1> f F /N F
\ H \ - H ~ - F
~ r N ~ IV N
\ / . ,O I
~ N O O 0 N ~~ p N O O
NN N~N . ~ ~

N F // N F N
\
.
N H N
O N ~0 p N / ~O p ~, N >=o ~ fV 0 Ni N p \ N ~ o \

N // O\\-o /N
y' O
N H N NH I\ N O
/ b ( iN
N

N
=-~ N N
O\\ o O O
!- O1` ji - - S
N` N \/ NH O \ ~ i N \/ Nb bp \ ~/ N
C'N b v" > >

N /N N
OI S N ` O~S o p I ~ N N N O ~ ~ N NH C l JD \ / N "o N O N ' N N N
O
` \ - O ;SO O-SO ` // - p`e ~p I / N Nb bO, O I / N \ / Nb ~O I / N N~
&

/~ N N
`~ ii O~ sO r p iO
~
S
FF\ ^ p ~, N Nb I N\ N NH \ N Nli F` bN b iN b N N
Sp N
O` O ; s o,sP
NH ~ / \ / Nb F NH
O \N
\~N b F p F

N N
N
O
\\
o O
N
ci~xcc/- N NH p N H CCN
H
N ~ . ~ .

N N N
// O p ~-p \ ~ ~
iN O S~ p \ f / N \ / NH \ ~ / N NH O I \ ( ~ N \ ~ NH
iN

.2437 2439 N O /N /N
N NH H \ ~ / N \ / NH H
\ I ~ N= \ ~ N
iN Jv~ N N

N
% O N CI H
\ _ 0 \ N
~
CE ~/N NH C H O N ~O
N 'N . J-, N N & 0 N
CI N
H
~ N aN NH N, o,5 N O C p C ~ J- N NH
N' IN 0- N" IN ~ N o 2448 .

N H N TJ
N H N
_ O` N~ ~ S. // O-F F ~S`~O F~j F O I\ NS
O / N \ / =H F \p N H /1O / N H

N

\ - H /N N
( - Oa' N
/ O 0 c0O0 N N N C1 O\\ ~-Q // CI O }- /l CI
\ - I~O \
0rc N N N
// o O` O , 0`
O0H FO F ^O I/ N\ NH F~O (/ N \/ NH

TF 6 TF /~ F ~

N
N O` O p\ N
p\ O
S~/\
NH NH I F\^0 ~/ N \/ NH~
F
'( V F

N N
N
O /
O'sP / ps~
F~p NH F\T ^O i N F~p I~ N NH
F b F
"

N
c0xx-o-0 H H
~ QQcc-o-// - o~~ N CN~Q N ~ NH N~o / N ~/ N Nao N NH
b b ~ b =2470 2471 2472 _ H H
/ N t \ ~ ~ O/- N of ~=7 p ~ N
~Nj~O / \ - N'ra ~p 1 ~ " \ / o~
Ni -\! ~I

/N p N p \ ~ N
\ - ~N \ - ~pJ"-"~ \ - Tp/-^O ~/ N ~/ NH H F~0 ~ i N \/ NH F~o I i N ~/ NH
F T b b F

N
CI I
~ - _ N H ~ H
0 N ~o N` N ~ ~ ~ N
a N N S~ -N ~ N >=O
NN j \/

N
H N
O.
N ~N}H I\ NS O i N i C~;
0 ~ N `H %L ~ ~ N \ / NH

N

N
/N
O ,-- N H
- NH \ / N O O` }.~n..~
N O N N 'H N O N N H ~' f N O
~ ~N O 'H

N H D N - ~~ p JN O
` \

/ NI (x0xc/
Ns`O \ No NH
H ` 6 N

N N 11 H o N ' p o O N O/J~,~ N\ O I ~ N NH cr0N

I
~

N

O
I \ ~ ~ }H~ ~ // - 0 ~ ~ F N
- ,N N O! O F I/ N \/ NH F~O ( \/ NH
N
,1i ~~~.
b %
F p FI p F~p 0 Fl"\, C NH F~
N NH F

N' `O
H

N N N

H H
o o,,.i.p N p N Q~S%~ o ~ N S~O
J ~l N~IN NN

N
N
O /N
\ H O ~
-~ / \ / ~ O ~ i N NH
N N
N a-tNu O H

F

N
N N
O, //
F NS~ \ - p N
~ N H F_ p ~, N \ I. N~ ~ N' N H
F
F 7` b b =2506 2507 2508 N N
// CI p` O /% / O
_ ~NH
F I/ ~ I NH O F p I/ N NH
Np N H O
F
F ~
~
~
lz~rl N

/ O p /~ O
-\I
- o F` 0 ~ i N
N \/ NH I/ ~/ NH 11 N H
T. ~ b N N
A o'S~ o ,sb bo o ;s o N F-N NH H
> b b N N
F N p\ p` ,O
O~ i \ ~ - S
F~O i i NH~ F\ ^0 ~/ N NH~ F\ ^~ ~ i N \/ NH~
N TF F.

N N
N
\ - Q ~- o CI - 0e0 F` ^0 I i N \ / NH
T ~N N H N o ~ H
F N~

N N
O //
O\\ `-a JN p\\~
\ - I-N \ - 7-o \ a N N NH H N~ / N NH F10 I~ N N
b b b N N
0 o N ~, \ -Q \ - ~T /l ~ ~1 F\ ~. ~ ~/ N ~ F~o I/ N NH F J~/ N O
TF F F Ci ~Q N =Fi ~O ~ ~ ~o F` ^p N F NH F~O / N ~ `N p O
F ~ F b c, N
H: p O` o ~ ~ ` \ \ ~ ~ ~O CIO O \ O
N N O N N H

N N N
~)0fc/sN'< ~
~~ N
O `N O N b O H NO N O H

N

c N \ I 1 \/ N~~\ i N i Jl F- p~ N N O}-~
N
O N ~/ N p~
b N O` H ~ 1~C1 b Nu v N
O
% /Y
_ ~o H

N \ \ O N I N CI\ / E{ ~ O 1 N \ / NH F~O , ~ N O/S~Q
/
\ b N~~ / IN ~C ~ b NJ H

N

~ O N~p I/ N N O

In some embodiments, the compound is selected from Compounds 866-1329, 1484-2127, 2129-2545.

B. Preparation of Comnounds of the Invention The compounds of the invention can be obtained via standard, well-known synthetic methodology. Many of the indole starting materials can be prepared using the routes described below or by those skilled in the art.
Compounds of formula I, represented by structure II can be prepared by the methodology depicted in Scheme A below:
An a-nitroketone derivative A2 can be derived from treatment of the anion of nitrornethane, obtained from the treatment of nitromethane with a base, such as, e.g., sodium or potassium t-butoxide or sodium hydride, with an activated carboxylic acid derivative, e.g., the acyl imidazolide AI. Reaction of the a-nitroketone A2 with amine derivative A3 can afford the nitro enamine A4 by mixing the components A3 and A4 and heating in a suitable solvent such as an alcohol or an aprotic solvent. Treatment of the nitro enamine A4 with quinone A5 in a polar protic solvent such as acetic acid at or near ambient temperature gives the compound of formula II.

I. Scheme A

p 0 R4Nh~2 NHR4 / s 2 ~ N0 ----N N R5 base R5 2 (A3) R5 \ N02 Al A2 A4 RS
HO N
(A5) ~4 HOAc Compounds of formula I, represented by structure III can be prepared as shown in Scheme B below:
Treatment of B 1 with a reactive alkyl or aryl group containing a leaving group L in a suitable solvent, with or without heat in the presence of a base, such an inorganic base, e.g., sodium or potassium carbonate or an organic base, e.g., triethylamine, can afford the compound of structure IIL Examples of leaving groups include but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates.
H. Scheme B

~ Rs Rs-L ~ \ R
N ~O ~ N
%
HO Q
R

BI
III
Compounds of formula I, represented by structure N can be prepared as shown in Scheme C below:
Compounds of structure IV can be obtained by nitrating an indole of structure C1, to give the 3-nitroindole C2. The nitration can be carried out by treatment of C1 with a nitrating agent, such as nitric acid or sodium nitrite in a solvent such as acetic acid, acetic anhydride, sulfuric acid or in a mixed solvent system containing an organic solvent such as dichioromethane. The reaction can be carried out a temperature of-30 C to +50 C. Treatment of C2 with a reactive functional group R9 containing a suitable leaving group L (C3) can give compounds of structure IV. Reactive functional groups can consist of but are not limited to alkyl and aralkyl. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. The reaction between C2 and C3 can be carried out in a suitable solvent in the presence of an inorganic base such as potassium carbonate or sodium hydride or an organic base such as a trialkylamine. Alternatively, the group R9 can represent an aryl or heteroaryl group and L can represent a halide, particularly chloro, bromo or iodo. The reaction can be ca.rried out in a polar or nonpolar solvent at a temperature from ambient to 200 C in the presence of a copper catalyst, e.g., Cul, a base such as CszCO3 or K3PC4, and optionally an amine ligand such as 1,2-bis(methylamino)ethane or 1,2-cyclohexanediamine.
An alternative pathway is to convert Cl into C4 in similar fashion as described above and then carry out the nitration reaction to afford compounds of structure IV_ III. Scheme C

I~ \ HN03 R, I~ \ Rs R, R5 ~ N ~ N
Rz RZ H

R9-L (C3) R9-L (C3) .

R~ I~ \ R5 HNO3 R~
~ ---- ~ R5 R3 R9 R3 Rg Compounds of formula 1, represented by structure V can be prepared as shown in Scheme D.
Treatment of 0-ketoesters of structure D1 with amines D2 gives the amino crotonate derivatives D3 by heating in a suitable solvent such as an alcohol or an aprotic solvent.
Reaction between D3 and quinone D4 in a polar protic solvent, such as acetic acid gives compounds of structure V.
W. Scheme D

C02-alkyl O R4NH2 NHR4 O~O
R5J~CO2 alkyl --- R~G02 alkyl R5 (D2) (134) HO ~ 4 HOAc v R
Compounds of the present invention, represented by structure VI compounds can be prepared by the chemistry described in scheme E below.
Indole-3-carboxylic esters El can be converted to indole-3-carboxylic acids E2 by treatment of compounds of structure El with, for example, either acid or base in aqueous or mixed aqueous-organic solvents at ambient or elevated temperature or by treatment with nucleophilic agents, for example, boron tribromide or tri.methylsilyl iodide, in a suitable solvent. Compounds of type E2 can then be activated and treated with amines of type E3 to give compounds E4. Activation of the carboxylic acid can be carried out, for example, by any of the standard methods. For example, the acid E2 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine E3, or alternatively the acid can be activated as the acid chloride by treatment of the acid with, e.g., thionyl chloride or oxalyl chloride or as the acyl imidazolide, obtained by treatment of the acid with carbonyl diimidazole, followed by treatment of the amine E3. Compounds E4 can be converted to compounds of structure VI by treatment of E4 with a reactive funetional group R9 containing a suitable leaving group L(E5) as described previously.
Alternatively, compounds of type El can be converted to compounds of structure E6 by treatment with E5.
Indole-3-carboxylic esters E6 can then be converted to indole-3-carboxylic acids E7 by the methods described above. Conversion of E7 to compounds of structure VI can be carried out by the activation and reaction with an amine E3 as described above.

V. Scheme E

R CO2-alkyl CH R CONR7R$
l :;$r025 activation I 2 R3 R3 H (0) R3 H

Rs L (E5) (E6) R C02-alkyl R
R~ \ :2025 CH R' CONR7RS
\ Rs hydrolysis 1. vation R 2. HNR7Ra R R5 Rs 9 dealkylation R3 R9 (E3) 2 R
Rg s Compounds of the present invention, represented by structure VII compounds can be prepared by the chemistry described in scheme F below.
Indoles F1 can be formylated with reagents such as phosphorous oxychloride in the presence of DMF to give the'indoie-3-carboxaldehydes F2. Conversion to compounds of structure VII can be accomplished by treatment of F2 with compounds F3 as described previously. Alternatively, compounds of type F 1 can first be converted to F4 and then be formylated to compounds of structure VII.

VI. Scheme F

R R CHO
R, I~ R POC13 R~ ~\ \ Rs ----Rz R3 H R3 H

1R9_L (F3) R9 L (F3) R, R CHO
XIL-F4 %
Vll 5 Compounds of formula G, represented by structure VIII can be prepared as shown in Scheme G.
Indole-3-carboxaldehydes of structure G1 can be converted to the indole-3-carboxylic acid derivatives by oxidation with reagents such as potassium permanganate under aqueous conditions.
VII. Scheme G

R, I R5 KMnO R1 a R5 GI VIII
Compounds of fonnula H, represented by structure IX can be prepared as shown in Scheme H.

Indole-3-carboxaldehydes of structure Hl can be converted to the indole-3-carbonitrile derivatives H2 by a variety of methods. Treatment of H1 with a nitroalkane, e.g., nitropropane, in the presence of an amine source, e.g., ammonium hydrogen phosphate gives the indole-3-carbonitriie H2 derivative. An alternative pathway to compound H2 is via the intermediate H3.
Conversion of Hl to the oxime derivative H3 can be followed by dehydration, e.g., treatment of the oxime with acetic anhydride and a base, or reaction of the oxime with thionyl chloride to give H2. The compound H2 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (H4) as described previously to afford compounds of structure IX.
Alternatively, Hl can be reacted with a reactive functional group R9 containing a suitable leaving group L(H4) to give the intermediate H5, which can be reacted with a nitroalkane as above to give the indole-3-carbonitrile IX compound. Compound IX can also be obtained by conversion to the oxime H6 followed by a dehydration reaction as described above.

VIII. Scheme H

R _NOH
RI

H2NOH Rz R3 Fi ~ H3 R CHO R
~NOz :Ir$NR5 H)zHP04 R3 3 H2 R9 L (H4) R9-L (H4) R CHO R CN
Ri ~ /~~NOZ Ri ~
R5 ~ ~ RS
N R ~ N
R2 R Rg (NH4)2HPO4 2 R3 R%
s H5 \ IX
H2NOH R NOH f [fHz01 R' Rs RZ N

Compounds of the present invention, represented by structure X can also be prepared as described in scheme I below.

Indoles 11 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (12) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g.

DMF, CH3CN or dioxane, to afford compounds of structure 13. The compound 13 can then be =' reacted with a reactive functional group R9 containing a suitable leaving group L(I4) as described previously afford the compound X.
Alternatively, compound I] can be reacted with a reactive functional group R9 S containing a suitable leaving group L to give compounds of structure 15 that can then be cyanated as above to give compounds of formula X.

IX. Scheme I

R R CN
R, CISO2NCO R, I ~ \ Rs ~-. I Re R2 ~ N (12) R2 H =

Ra-L (14) Rs"L (14) R R CN
R, CtSO2NCO R, \ R5 Rs R2 I~ N (12) RZ

Compounds of formula J, represented by structure XI can be prepared as shown in Scheme J.
Amino crotonates JI can be reacted with amines 12 to give.J3. Reaction of 73 with quinone in the presence of a polar, protic solvent, e.g., acetic acid, gives the compound of structure XI.

X. Scheme J

CN
NH2 RaNH2 NI-HR4 O~O ~~ \-- Rs CN /~iCN '% t~
R~ v (J2) Rs (J4) HO ~
HOAc R4 XI
Compounds of the present invention, represented by structure XII and XIII can be prepared as described in scheme K below.

Aldehydes of st.ructure K1 can be reacted with an alkyl azidoacetate K2 by heating the components together in a suitable organic solvent, e.g., a protic or non-protic solvent, in the presence of an organic or inorganic base, to give the a-azidoacrylate K3.
Heating K3 in the presence of a suitable non-reactive organic solvent, e.g., toluene or xylenes can give the 2-alkoxycarbonylindoles K4. Reduction of the ester functionality with a suitable reducing reagent, for example, lithium aluminum hydride, in a suitable solvent, e.g., ether or THF can give the intermediate K5. Reaction of K5 with a reactive functional group R9 containing a suitable leaving group L(K6) as described previously affords the compound K7.
Cyanation of K7 with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can give compound XII. Alternatively, cyanation of K5 with chlorosulfonyl isocyanate gives K8, which can be reacted with a reactive functional group R9 containing a suitable leaving group L(K6) as described previously, affords, the compound XII.
An alternative use of intermediate K4 is exemplified below. Hydrolysis of the alkoxycarbonyl group of the indole K4 either under acidic or basic conditions followed by decarboxylation can give the intermediate K9. Decarboxylation can be carried out thermally, i.e., heating in an appropriate solvent, e.g., toluene, xylenes, or quinoline.
Alternatively, a source of copper can be added, for example, copper bronze, to facilitate decarboxylation.
Reaction of K9 with a reactive fiznctional group R9 containing a suitable leaving group L(K6) as described above can afford the compounds K10. Cyanation of K10 with a cyanating agent, e.g., chlorosulfonyl isocyanate as described previously can give compound XIII. Alternatively, cyanation of K9 with chlorosulfonyl isocyanate gives Kl 1, which can be reacted with a reactive funetional group R9 containing a suitable leaving group L(K6) as described previously, affords the compound XIII.

XI. Scheme K

R N3~C02-alkyl R
R1 CHO R1 ~ ~. C02 alkyl ! (K2) N3 R2 Rz R3 base R3 a R R R
Hor OH
R, ~ It{l ::crco2a1 R~ ( R R2 H z H

R CN R CN
R9-L J (K6) R, I~ \ Ri I~ \ Rs L (KS) Kg \R9L K11 R R CN RCN R
R~ CISO2NCO R2 I~ Ri CISO2NCO R~ N
R2 R / N R N R2 f2 R3 ~3 R3 R9 2 R3 R9 Rs 9 Z
K7 XII Xlp K10 Compounds of formula L, represented by structure XIV can be prepared as shown in Scheme L.
Compounds of formula Ll can be halogenated on the 2-methyl group to give 2-bromomethyl or chioromethyl indoles L2. The halogenation reaction can be conducted with reagents, e.g., N-bromo- or chlorosuccinimide. The reaction can be conducted in a suitable solvent, such as chloroform, carbon tetrachloride, or THF and carried out in'a range between ambient temperature and 80 C. Optionally, a radical initiator may be added, e.g., benzoyl peroxide or AIBN. The compound L2 can then be reacted with a nucleophile R5-W
(L3) to give compounds of structure XIV. The reaction can be conducted in a suitable solvent, e.g., THF, CHZC12 or DMF, within a temperature range of 0 C to 120 C. A base, e.g., an inorganic base, such as potassium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction. The group W can refer to an N, 0 or S
atom.

XII. Scherne L

R X R x R X
Ri NBS R, Rs W R, I\ ~

}ZZ (~ or NS RZ I~ N Bror CI (L3) R2 ~ WR5 R3 R4 R3 t4 R3 L1 L2 Xlv Compounds of the present invention, represented by structure XV can be prepared as described in scheme M below.
Anilines of structure M1 can be diazotized and the resulting diazonium salt can be reduced to give the phenyl hydrazine compound M2. Reaction between the hydrazine M2 and a ketone M3 under acidic conditions can give the indole compound M4. The conditions for the cyclization reaction can be carried out under typical conditions utilized by one skilled in the art, for example, acidic conditions, utilizing acids such as a Bronstead acid, e.g., acetic acid, hydrochloric acid or polyphosphoric acid or a Lewis acid, e.g., zinc chloride.
The reaction can be carried out in the presence of a co-solvent, e.g., CH2C12 or THF typically within a temperature range of 0 C to 120 C. Reaction of M4 with a reactive functional group R9 containing a suitable leaving group L (M5) as described previously, can afford compounds M6. Cyanation of the indole M6 with a cyanating agent such as chlorosulfonyl isocyanate can give the compound of structure XV.
Alternatively, the indoles M4 can be cyanated to give compounds of structure M7.
Reaction of M7 with a reactive functional group R9 containing a suitable leaving group L (M5) as described above can give compounds of structure XV.

XIIL Scheme M

R R
R~ NaNO2 R1 R I NH2 SnG12 R2 NHNH2 O
.[H+] Rs"~' (M3) R R
Ri R9 L R, R2 #N R$ (M5) RZ I~ N Rs H R
R3 M4 R3 s R CN R CN
R~ R9-L R, R2 N R5 (M5) N
R3 H R3 Re MT Xv Compounds of formula I, represented by structure XVI can be prepared as shown in SchemeN.
Compounds of formula Nl can be reacted with a dialkylformamide dialkyl acetal, N2, e.g., dimethylformamide dimethyl acetal, optionally in the presence of a suitable solvent, e.g., DMF or dioxane, at a temperature range from ambient to 150 C to give the compound of structure N3. Reduction of the nitro group of compounds of type N3 under standard conditions can give the indole compounds of structure N4. The reduction can be carried out via hydrogenation, using a sub-stoichiometric amount 'of a hydrogenation catalyst, e.g., platinum or palladium, in the presence of a hydrogen source in a protic or aprotic solvent. The reduction can be carried out in a temperature range of ambient to 80 C. Alternatively, the reduction can be carried out via chemical reduction, e.g., in the presence of stoichiometric amounts of Fe or Sn compounds in a suitable solvent at a temperature range of ambient to 100 C.
The compound N4 can then be reacted with a reactive functional group R9 containing a suitable leaving group L (N5) as described previously to afford compounds of strncture N6. Cyanation of N6 with a cyanating agent such as chlorosulfonyl isocyanate in a suitable solvent can give the compounds of structure XVI.
Alternatively, compounds of structure N4 can be cyanated to give compounds of ' structure N7. Reaction of N7 with a reactive functional group R9 containing a suitable leaving group L (N5) as described above can give compounds of structure XVI.

XIV. Scheme N

R R11OXOR,, R

Rg R1 I~ N NR7R8 R1 #NO2 RZ ~ NO2 (N2) R2 -R3. R3 [~I
R R
R, ~ \ R9 L R, I~ \
R2 N (N5) R2 / N
R3 H R3 Rs R CN R CN
R, I R9 L R1 ~ \
R2 N (N5) R2 I N
H

NT X\/i Compounds of formula I, represented by structure XVII can be prepared as shown in Scheme O.
Compounds of structure 0 1 can be converted to 2-iodo- or bromoindoles 02.
Typically, a strong base, such as n-butyllithium or s-butyliithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with formation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of -78 C
to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not li.mited to iodine, bromine or N-bromosuccinimide to give compounds of structure 02. Reaction of 2-iodo- or bromoindoles 02 with a boronic acid (commonly referred to as a Suzuki reaction) or trialkyl stannane (commonly referred to as a Stille reaction) can give the compounds of structure XVII. The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DIVIF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150 C. For the Suzuld reaction, a base is usually added. The base can be in aqueous solution, e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride. For the Stille reaction a copper co-catalyst, e.g.; copper iodide, can be added.
Alternatively, indoles 01 can be converted to the indole-2-boronic acid or indole-2-trialkylstannane derivatives 03 by reacting the 2-indolyl anion described above with a trialkylborate or chlorotrialkyl stannane derivative, respectively. Compounds of type 03 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to forrn compounds of structure XVII.
XV. Scheme 0 R E R E
R N
, N 1. base R, I j I(or Br) 2 2. iodination R2 R3 R4 or bromination R3 R4 1.base R ~H
12-B()2 2.B(OR9)3 Pd or or Ri2-Sn(R11)3 ClSn(Rs)3 R E R E
R, R12-L R~
B(OH)2 or Sn(R )3 R12 R2 Pd R2 M

Compounds of formula I, represented by structure XVIII can be prepared as shown in Scheme P.
Compounds of structure Pl can be converted to compounds P3 by treatment of Pl with an aryl or heteroaryl halide (P2) in the presence of organometallic catalysis.
Such catalyst combinations can include palladium catalysts, e.g., palladium acetate and a source of copper, e.g., copper iodide. The reaction can be carried out in the presence of a base, e.g., cesium carbonate. The reaction can be carried out within a temperature range of ambient temperature to 150 C. Cyanation of the indole P3 with a cyanating agent such as chlorosulfonyl isocyanate can give the compound of structure XVIII.

XVI. Scheme P

Ri (P2) Rt ~ ~ CIS02NCO Ri I Rt2 -~ ~
Rt2 R2 N Pd(OAc)2 R2 ~ N DMF R2 N
R3 R4 CUI R3 R4 R3 ~+
P1 Cs2CO3 P3 XVtli Compounds of the present invention, represented by structure XIX can be prepared as described in scheme Q below.
Compounds of structure XIX can be prepared by protecting an indole compound of structure QI as e.g., the N-Boc derivative Q2. Alternatively, other protecting groups that can be utilized but not limited to include, e.g., benzyl, alkyl or aryl sulfonyl, or trialkyl silyl.
Treatment of Q2 with a strong base, e.g., lithium diisopropyl amide in an aprotic solvent, e.g., THF followed by quenching with a trialkylborate derivative can give the indolyl-2-boronic acid Q3. Reaction with an aryl or heteroaryl halide Q4 in the presence of palladium catalysis, e.g., tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand, can give the compound Q5.
Removal of the protecting group can give Q6. Reaction with Q6. with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure Q7. Cyanation of compound Q7 can give the compounds of structure XIX.

XVIL Scheme Q

R R R
Ri (Boc)20 Ri 1. base Ri \
N \
R2 I \
--~ N 2. B(ORii)3 ( N B(OH)2 R3 R3 BOO , R3 BOC
Q1 =
(Q2) 03 R R
L R12 R1 [H)+ Ri L-Ry (Q4) R2 I N R12 Rz I~ N R12 Pdo R3 Boc R3 H

F'` R CN
Rj) \ CIS02NCO Ri R2 NR12 DMF RZ I i N R12 R3 Rs R3 R9 XUf Compounds of formula I, represented by structure XX can be prepared as shown in Scheme R.
Compounds of structure R2 can be prepared by protecting an indole compound of structure RI as e_g., the N-Boc derivative R2 as above. Compounds of structure R2 can be converted to 2-iodo- or bromoindoles R3. Typically, a strong base, such as n-butyllithium or s-butyllithium or lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed, with fonnation of the 2-indolyl anion generated in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of-78 C to ambient temperature. The 2-indolyl anion can then be quenched with an electrophilic source of halogen, including but not limited to iodine, bromine or N-bromosuccinimide to give compounds of structure R3. After removal of the protecting group, compounds of R4 can be reacted with aryl or heteroaryl boronic acids or esters (R5) (commonly referred to as a Suzuki reaction) to give compounds of structure R6.
The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. Reaction of R6 with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XX.

XVIII. Scheme R

Rt (Boc)ZO ::' ;:;or Rt (H)N R2 ion R3 Boc R1 (R2) R E R12-Q(ORt1)a R E R E
:2c- (RS) LR9 N Pd Rz R2 R3 H Ra H Rs R
Compounds of the present invention, represented by structure XXI can be prepared as described in scheme S below.
2-iodo- or bromoindoles of structnre S 1 can be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXI. The coupling reactions can be carried out by methods known to those skilled in the art.
The choice of catalyst and solvents are similar to those described previously.
XTX. Scheme S

R E ~R1a R E
R1 ~ R1 R13 I N i(or Br) (S2) R2 I~ N
R3 R4 Pd R3 Ra S1 xxi Compounds of formula I, represented by structure XXII can be prepared as shown in Scheme T.
2-Iodo- or 2-bromoindoles of structure TI can be reacted with acetylenes in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XXII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure T1 with an acetylene compound T2 in the presence of a source of palladium, a copper co-catalyst and an amine source. The reaction is camed out in a suitably unreactive solvent and conducted within a temperature range from ambient to 150 C.

XX. Scheme T

E E
R, R13 R1 ~, N I(or Br) (T2) ~ i N R13 R2 , RZ , R3 R4 Pd R3 R4 TI XXII
Compounds of formuIa I, represented by structure XXIII can be prepared as shown in Scheme U_ Compounds of structure XXIII can be obtained from the reduction of compounds XXI
and XXII. Conditions for the reduction can include, but are not limited to catalytic reduction, e.g., hydrogenation over a source of platinum or palladium in a suitable solvent, e.g., CH2C12, ether, THF, methanol or solvent combinations.

XXI. Scheme U

R E R E R E
R, R13 [H2] :2cl-' \ ~ R13 [H2] R, \ R
~ 13 RZ N ~ N
R3 R4 R3 R4 R2 R3 Ra xxi XXIII XXII
Compounds of the present invention, represented by structure XXIV can be prepared as described in scheme V below.
Indoles of structure V 1 can be reacted with a suitable base, such as lithium diisopropylamide or potassium hexamethyldisilazide to generate the 2-indolyl anion in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically carried out in the range of -78 C to ambient temperature. The 2-indolyl anion can then be quenched with a source of zinc halide, e.g., zinc halide metal or solutions containing thenrn to give organozinc compounds of structure V2. Reaction of V2 with an arylhalide (V3) in the presence of a palladium catalyst (commonly referred to as the Negishi reaction) gives compounds of structure XXIV. Alternatively, 2-iodo or bromoindoles of structure V4, prepared from compounds V 1 as described previously, can be reacted with organozinc compounds of structure V5 in the presence of a suitable palladium catalyst to give compounds of structure XXIV. The organozinc compound V5 can be derived from, e.g., an alkyl or alkenyl halide after treatment with activated zinc or an aryl or heteroaryl lithium or magnesium compound after treatment with zinc halide. Furthennore, the reactions of V2 or V4 can be carried out in the presence of a palladium source, e.g., as tetrakis (triphenylphosphine) palladiurn (0) or bis (triphenylphosphine) palladium (II) dichloride in a suitable solvent and at a temperature range from ambient to 150 C.

XXII. Scheme V

R R E
E R
Ri (~ \ i. Base ~ I% \
ZnX
Rz N 2. Zinc halide R2 N

1. Base R13-i (V3) 2. lodination or bromination Pd R E Zn-R13 R E
l N I (or Br) (V5) R1 N R12 2 fRt Pd 2 R3 R3 Ra V4 xxiv Compounds of formula I, represented by structure XXV-XXVIII can be prepared as shown in Scheme W.
2-Iodo- or bromoindoles of structure W 1 can be reacted with acetylenes of structure W2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XX-V. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indoles of structure W 1 with an acetylene compound W2 in the presence of a source of palladium, an optional copper co-catalyst and an amine source. The reaction is carried out in a suitably unreactive solvent and conducted within a temperature range from ambient to150 C. Reaction with XXV with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XXVI. ' 2-iodo- or bromoindoles of structure W 1 can also be reacted with alkenes in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XXVII. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are siuiilar to those described previously. Reaction with XXVII with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XXVIII.
XXIII. Scheme W
R
E Rts R E R.ia_.- R E

:2(c13 (Vy3) ::ii- (or Br) R3 H Pd H Pd R2 H

XXVII
wi xocv R E
Ri R13 Rt R E
. ~ N R2 H R13 XXVIII R3 Ry XXVI
Corriponnds of formula I, represented by structure XXIX can be prepared as shown in Scheme X.
Indoles of structure XI and be acylated with acyl halides of structure X2 to give compounds of structure XXIX. The reaction can be promoted with a Lewis acid..The choice of' Lewis acid can be chosen from, but is not limited to aluminum chloride, ferric chloride, stannic.
chloride or diethyl aluminum. The reaction is typically carried out in a suitable non-reactive solvent including CH2Cl2, carbon disulfide or dichloroethane and is typically conducted within a temperature range of-20 C to 80 C.
XXIV. Scheme X

R, 1X21 Ri ~ i N R5 or AIC13 N RS
R

2 R3 ~ . EtzAICI 2 R3 R4 Compounds of formula I, represented by structure XXX can be prepared as shown in Scheme Y.
3-Cyanoindoles of structure Y1 can be converted to tetrazoles of structure Y2 by treatment with, e.g., sodium azide. Heating a mixture of Y2 and the reagent Y3 can give the 3-(1,2,4-oxadiazolyl)indole compound XXX. The reagent Y3 can be, e.g., an acyl halide or an acid derivative activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. The reaction can be carried out in a variety of solvents, including e.g., toluene, dioxane, pyridine and dichloroethane and can be carried out by heating Y2 and Y3 at a temperature range of 30 to 130 C.
XXV. Scheme Y

NN /,~ N~R1s R R13--'( RNH L R N~ O
:211cR5 NaN3 R2 N d N

R3 R4 3 . R4 Rg R4 Compounds of formula I, represented by structure XXXI can be prepared as shown in Scheme Z.
3-Cyanoindoles of structure Zl can be treated with hydroxyamine to give hydroxyamidine compounds of formula Z2. Reaction of hydroxyamidines of structure Z2 with compounds of structure Z3 can give O-acylhydroxyamidines Z4. Compounds Z3 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compounds of structure Z4 in a non-reactive organic solvent,,e.g., toluene, dichloroethane or dioxane in a temperature range of C to 150 C can give compounds of structure XXXI.

XXVI. Scheme Z

OH
R CN R HN NH
R, ~ NH2OH R
, I / N R5 ~ Rs R3 4 R3 Ra.

O
R13-/<
L
(Z3) O
~ R73 0 R N N R HN NHt3 R, R5 Ri I\ ~ R5 %

xxxi Z4 Compounds of the present invention, represented by structure XXXII can be prepared as described in scheme AA below.
Ketoindoles of type AAI can be converted to oximes of structure AA.2 by heating the ketoindoles with hydroxyamine (free base or acid salt) in a suitable solvent.
Bis-deprotonation of compounds of type AA2 with a strong organic base (e.g., n-butyllityium or sec-butyllithium or tert-butyllithium) followed by reaction with DMF can give compounds of formula XXXIL
XXVII. Scheme AA

OH ,O
O
R R N~ R N~
Ri NH2OH R, n-BuLi R, I N R5 ~ RS DMF R5 2 Rs R4 RZ R RZ R R%

Compounds of formula I, represented by structure XXXIII can be prepared as shown in Scheme AB.
3-Ketoindoles of structure AB 1 can be homologated to vinylogous amides of structure AB3 by reaction with dialkyl amide dialkyl acetals AB2. The dialkyl amides can include e.g., lower alkyl amides such as formamide, acetamide and propionamide. Examples would include dimethlformamide dimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction can be conducted by reacting AB 1 and AB2 with or without additional solvent at a temperature from ambient to 150 C. Treatrnent of AB3 with hydroxyamine (free base or acid salt) in a suitable solvent can give compounds of structure XXXIII. The reaction is typically conducted within a temperature range from ambient to 120 C.

XXVIII. Scheme AB

N
0 14R110 ORii O R14 R 0 Ri HxNR7Rg R NR7R8 NH2OH R R14 R2 N R5 (A82) 1 R5 R5 R3 4 Rg R4 Rg R4 ABI AB3 xXXtll Compounds of formula I, represented by structure XXXIV can be prepared as shown in Scheme AC.
Vinylogous amides of structure ACI (as prepared above) can be treated with hydrazines AC2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150 C to give compounds of structure XXXIV.
XXIX. Scheme AC

F?15 p RiN
R ::4NR7R8 NHNHR15 N (AC2) R5 R3 Ra ACI xxxiv Compounds of the present invention, represented by structure XXXV can be prepared as described in scheme AD below.
Indole-3-carboxaldehydes of structure ADI (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC) in the presence of a base to give compounds of structure XXXV. Bases can include potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene and the reaction can be carried out in a suitable organic solvent from ambient temperature to 150 C.

XXX. Scheme AD

oõo c SvNCO ~N
R CHO Me R O
R, =1 R5 (A D2) - Ri 2 N Base R5 AD1 xxXv Compounds of formula I, represented by structures 7CXXVI and XXXVII can be prepared as shown in Scheme AE.
3-Indolecarboxylic acids of structure AEI (from Scheme E) can be converted to amides of structure AE2. Compounds of structure AE2 can be activated by any of the standard methods. For example, the acid AEl can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of ammonia. Alternatively, the acid can be activated as the acid chloride or as the acyl imidazolide as described previously, followed by treatment of ammonia.
The indole-3-carboxamides of structure AE2 can be reacted with substituted aldehydes or ketones (AE3) containing a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 200 C. The reaction cain be performed with or without added base to afford oxazoles of structure XXXVI_ The indo(e-3-carboxamides of structure AE2 can also be converted to thioamides of structure AE4 by treating the primary'amides with Lawesson's reagent or phosphorous pentasulfide at or above ambient temperature in a suitable organic solvent.
The resulting thioamides AE4 can be reacted with substituted aldehydes orketones containing a suitable leaving group L (AE3), in a suitable solvent at temperatures above ambient and up to 150 C.
The reaction can be performed with or without added base to afford tlviazoles of structure XXXVII.

XXXI. Scheme AE

R1 ~~ R 1. :rt10 :uro2 Lawesson's . N p / N
2 2 I Rz O O

~ L-T-1- R13 (AE3) (AE3) R14 R1a R13 _ R13 R N R S N
I
R1 !/
Rz N R5 N R5 R.
. %

)UO(vl XXXVII
Compoundss of the present invention, represented by structure XXXVIII and XXXIX
can be prepared as described in scheme AF below.
3-Ketoindoles of structure AFI can be halogenated (e.g., brominated) to give compounds of structure AF3. Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AF2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.
Treatment of compounds AF3 with amides of type AF4 in a suitable solvent at temperatures above ambient and up to 200 C with or without added base cari give oxazoles of structure XXXVIII.
Treatment of compounds AF3 w-ith thioamides of type AF5 in a suitable solvent at temperatures above ambient and up to 150 C with or without added base can give thiazoles of st.cucture XXXIX.

XXXII. Scheme AF

R PhNMe3Br3 R
1 R1 Br R2 R5 (AF2) Rs 0 s R13~ NH2 (AF4) (AF5) R134 'NH2 = N~i `O N/r~S
:2rR514 R R ~ Rs xxxvm xxxix Compounds of formula I, represented by structure XL can be prepared as shown in Scheme A.G.
Indoles of structure AGl can be brominated or iodinated to give compounds of structure AG2. Brominating agents-may include but are not limited to bromine or N-bromosuccinimide and iodiinating reagents may include iodine monochloride or bis-trifluoroacetoxy iodobenzene. Reaction.of 3-iodo- or bromoindoles AG2 with a boronic acid AG3 (commonly referred to as a Suzuki reaction) can give the compounds of structure XL.
The coupling reactions are carried out by methods known to those skilled in the art and include conducting the reaction in the presence of a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in-a suitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150 C and typically in the presence of a base e.g., aqueous sodium carbonate or sodium bicarbonate, or the base can be employed under anhydrous conditions, e.g., cesium or potassium fluoride.
Alternatively, indole AG2 can be converted to the indole-3-boronic acid derivative AG5 by reacting the 3-haloindole AG2 with a strong organic base (alkyllithium or Grignard reagent) and reacting the resultant anion with a trialkylborate reagent AG4.
Compounds of type AG5 can be reacted with aryl and heteroaryl bromides and iodides under similar conditions to those described above to form compounds of structure XL.

XXXIII. Scheme AG
R
i R
Base Rl R B(OH)2 ~ ~ RS halogenation R R Bror!

R2 ~ N \= R2 I N R5 B(OR71)3 R2 N ~
R3 R4 R3 Ra (AG4) R3 R4 Pd Pd R12-B(OH)2 R12-L
(AG3) (AG6) R
RI, R, Rs XL
Compounds of the present invention, represented by structure XLI can be prepared as described in scheme AH below.
3-iodo- or bromoindoles of structure AH I can be reacted with alkenes AH2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of type XLI. The coupling reactions can be carried out by methods known to those skilled in the art. The choice of catalyst and solvents are similar to those described in Scheme AG.

xxxN. Scheme AH

Br or l R
RI Ri Rs -- ~ R s 2 N (AH2) 2 / N
C
R3 R4 Pd R3 R4 Compounds of formula I, represented by structure XLII can be prepared as shown in Scheme AI.
3-Iodo- or bromoindoles of structure All can be reacted with acetylenes A12 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type XLII. The coupling reactions can be carried out by methods known to those skilled in the art. A typical set of reaction conditions includes reacting the indole of structure All with an acetylene compound A12 in the presence of a source ofpalladium, a copper co-catalyst and an amine source and carrying out the reaction at a temperature range of ambient to 150 C.
XXXV. Scheme AI

R1s R BXI*N r ! R
(A!2) N
N
::
% R2 R3 R4 Pd R3 R4 All XLII

Compounds of the present invention, represented by structure XLIII and XLIV
can be prepared as described in scheme AJ below.
Nitroanilines of structure AJ 1 can be converted to indoles of structure XLIII
by condensation and cyclization with nitriles of structure AJ2. The reaction can be carried out in a suitable organic solvent, e.g., DMF or dioxane. Treatment of compounds of structure XLIII
with a base followed by reaction with a reactive functional group R9 containing a suitable leaving group L can give the compounds of formula XLIV.
XXXVI. Scheme AJ

E E
F ECN Base I/ (AJ2) N NH2 9L NH2 base H R9 Compounds of formula I, represented by structure XLV-XLVIII can be prepared as shown in Scheme AK.

2-aminoindoles of structure XLV can be alkylated with a reactive functional group Rts containing a suitable leaving group L in the presence of a base, e.g., sodium hydride or potassium carbonate in a suitable organic solvent to give compounds of structure XLVI. A
second alkylation utilizing a reactive functional group R'l 5 containing a suitable leaving group L similarly can give compounds of structure XLVII. ' Acylation of compounds of structure XLV with acyl chlorides of structure AK1 can give compounds of structure XLVIII. The reaction is typically carried out in the presence of an organic base, e.g., a trialkylamine or an inorganic base, e.g., potassium carbonate in a suitable organic solvent.
XXXVII. Scheme AK.

E O O E E
I~ \ ~ R5 Rg~CI
N ~ Base i N ~- ~ NHp NHR15 02N R (AK1) O2~J(`.~ N ~ N Ri5-~ 02N N
a XLVIII base Ra Ra XLV XLVI

Base R'15-L
E
~
NRi5R'15 02N ~ N\

XLVII
Compounds of the present invention, represented by structure XLIX can be prepared as described in scheme AL below.
Indole-3-carboxylic acids of structure AL1 can be activated to give compounds of structure AL2. Compounds of structure AL2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodi:imide. Reaction of compounds of structure AL2 with hydroxyamidines of structure AL3 can give 0-acylhydroxyamidines AL4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxyamine. Heating compounds of structure AL4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of30 C to 150 C can give compounds of structure XLIX.

XXXVIII. Scheme AL

R R O L NH
CH R13-/<
::.IIIiI::r02s ti ~ Ractivation R1 R HN-OH
~-~
N 2 N 5 (AL3) AL1 AL2 ti R p R13 R N~ O
RI
Re - R1. I~ R

R2)( Compounds of formula I, represented by structure XLX can be prepared as shown in Scheme AM.
Compounds of formula AM1 (in which R17, defined above, is 1-3 substituents placed on the indole) when treated with a base, copper (I) iodide and a substituted amine (Z-NH2 where Z is defined above) to provide compounds of structure AM2. Acylation with 2-chloroacetyl chloride and a base such as triethylamine in solvents such as but not limited to dichloromethane, tetrahydrofuran or toluene at temperatures from ambient to reflux provides intermediate AM3 which is subseqiiently cyclized to form compounds of structure AM4 employing palladium (II) acetate as catalyst, a phosphine ligand and a base such as triethylamine in solvents such as but not limited to tetrahydrofiuan, dimethylformannide or toluene at temperatures from ambient to reflux. Reduction and elimination with a hydride source such as DIBAL-H in solvents such as but not limited to dichloromethane, tetrahydrofuran or toluene at temperatures from 0 C to reflux provides intermediate AM5. The subsequentsteps leading to product XLX are described above.

XXXIX. Scheme AM

O I K3PO4/ Cul -_O NH base z i i Cf~ Pd , R3P X~
N O base NN
-_0 Z

~~ 1) B(OR11)3 / base `O ~ 2. BBr3 HO/-O Z 2) Pd , base R12L

/~~ _ HO base ~ N
R-ts0 Compounds of formula I, represented by structure XLXI can be prepared as shown in Scheme AN.
Compounds of formula AN1 can be treated with a triflate source, such as triflic anhydride, and a base, such as pyridine, in solvents such as but not limited to tetrahydrofuran, dichloromethane or toluene at temperatures from ambient to reflux to provide intermediate AN2. AN2 can either be directly reacted with palladium (0) and a R12 substituted trialkyl tin compound in the presence of cesium fluoride and copper (I) iodide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux to provide product XLXI or reacted in a two step sequence of coupling with a pinacol borane source, such as bis-pinacol diborane, in the presence of palladium (II) and a base, such as potassium acetate, in solvents such as but not limited to tetrahydrofuran, dioxane or toluene at temperatures from ambient to reflux to provide AN3 and then a second coupling with palladium (0), cesium fluoride and an appropriate R12L compound in solvents such as but not limited to tetrahydrofuran, dimethoxy ethane or toluene at temperatures from ambient to reflux would provide XLXI.

XL. Scheme AN

R17 E R17 E (R,10)3B-L R17 E
R5 Tf-L R5 N / N 5 /~ N
HO R4 base TfO R4 Pd (il) (R110)36 Ra Pdo R12SnBu3 R\7 E

Pdo R12 R4 XLXI
C. Methods of the Invention Another aspect of the invention relates to a method for treating Hepatitis C
viral (HCV) infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, as described above.
As used herein, the term "treating" refers to: (i) preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition,'i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
As used herein, the term "subject" refers to an animal or any living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Nonlimiting examples include members of the human, equine, porcine, bovine, murine, canine and feline species. In some embodiments, the subject is a mammal or a warm-blooded vertebrate animal. In other embodiments, the subject is a human.
As used herein, the term "patient" may be used interchangeably with "human".
Without being limited to any particular theory, it is believed that the compounds of the present invention inhibit IRES-mediated initiation, elongation and termination, i.e., translation by interfering with function of the IRES directly and/or with the interaction of the IRES and a cellular and/or viral factor. Thus, another aspect of the invention relates to a method for treating an infection by a wild type virus or a virus that is resistant to a currently available antiviral agent, in a subject in need thereof, wherein the wild type or resistant virus comprises an internal ribosome entry site (IRES), comprising administering to the subject an effective amount of one or more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of the invention or one or more pharmaceutically acceptable salt(s) thereof, as described above. Nonlimiting examples of such virus include viruses of the picornavirus genus, such as poliovirus, hepatitis A virus, coxsackievirus and rhinovirus;
viruses of the coronaviridae genus, such as SARS; viruses of the arbovirus genus; viruses of the flaviviras genus, such as yellow fever, dengue, and West Nile virus;
herpesviruses, such as herpes simplex virus and Kaposi's sarcoma-associated herpesvirus, and other viruses with a similar mode of replication; and HIV, human leukemia viruses (HTLV) and other viruses with a similar mode of translation.

Yet another aspect of the invention relates to a method for inhibiting HCV
IRES-mediated initiation, translation and/or replication in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, or a pharmaceutical composition comprising an effective amount of one of more compound(s) of formula I or one or more pharrnaceutically acceptable salt(s) thereof, as described above.
Some methods of the present invention comprise administering one or more compound(s) of formula I, or a pharmaceutical composition comprising one or more compound(s) of formula I wherein:
x is:
-a nitro group;
-a cyano group;
-a -CORa group, where Ra is:
-a C1 to C6 alkyl, -a C6 to Cg aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where R,, is a C, to C6 alkyl;
-a formyl group;
-a C6 to C$ aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
. -a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more Cl to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran; .
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C, to C6 alkyl; .
. *

. \ .
a ~ ~
(CH2)n e N
- Rb , where Rb is a hydrogen or a CI to C6 alkyl, and n is 0 or 1;
, x - - ~
1 .

* I

- , where R,, is a hydrogen, a-CONHR,,, where R,, is as defined above, or an -SO2R,., where R,e is as defined above; or O
iRd N~

.~-..-N
- , where Rd is a C1 to C6 alkyl or a C6 to C$ aryl;
-a -NHCORe group, where Re is:
-a C1 to Cg alkyl;
-a C6 to C8 aryl optionally substituted with:
-a C, to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOOR,, group, where RX is as defined above;
-a -CH2O-Rf group, where Rf is a C6 to Cg aryl;
-a -NRgRh group, where Rg is a Ci to C6 alkyl or a hydrogen and Rh is a C6 to Cg aryl optionally substituted with an alkoxy;
-a Ci to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a C1 to C6 allcyl, optionally substituted with a C6 to C8 aryl, -a C6 to C8 aryl, optionally substituted with -COORX, where RX is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR,, group, where R,, is as defined above, or -a -NHCOOR, group, where R,, is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
- -an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a C1 to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more Cl to C6 alkyl(s), -a -NR;SO2R,, group, where Rx is as defined above and Ri is:
-a hydrogen, -a C, to C6 alkyl, -a -COR,, group, where R,. is as defined above, -a halo alkyl, or -a halo alkoxy, -a -NRjCORk group, where Rk is:
-a C I to C6 alkyl, -a hydrogen, or -an amino optionally substituted witli one or more C, to C6 alkyl(s), and Rj is:
-a hydrogen, -a Ci to C6 alkyl, - a-CORX group, where Rx is as defiaed above, -a haloalkyl, or -a haloalkoxy, -a -N=N =N- group, or -a -CORI, where Ri is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more Ct to C6 alkyl(s), -a nitro group, -a C1 to C6 alkyl group, optionally substituted with:
-a -NHSOaR,t group, where RX is as defined above, or -a -NRxSOaR,, group, where R,, is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COORX group, where R,, is as defined above, -a -CORn, group, where R,T, is:
-an amino optionally substituted with one or more C, to C6 alkyl(s), where the one or more C 1 to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more C, to C6 alkyls, and/or -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a dialkyl-amino, -a -NHRõ group, where Rn is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NRoCORP group, where Rp is:
-a Ct to C6 alkyl optionally substituted with:
' -a halogen, -an alkoxy, or -a C6 to C8 aryl, -a 5 or 6 membered heterocycle, -a C6 to Ca aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more CI to C6 alkyl(s), -a hydrogen, i 0 ~ p or N~ 0 - ., -and where R. is:
-a hydrogen, -a C i to C6 alkyl, -a -CORx group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen, -a C I to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORX group, where R,, is as defined above, 10, and where R,= is:
-a C6 to C8 aryl optionally substituted with:
N
-N
-a CI to C6 alkyl, -a haloalkyl, -a -ORS group, where RS is a C6 to C$ ,aryl,. or -a -COORX group, where Rx is as defined above, -a Cl to C6 alkyl optionally substituted with oiie or more of the following:
-a halogen, -an alkylene, -a C6 to C8 aryl, andlor -a -COOR., group, where RX is as defined above, -a -COOR,, group, where R,, is as defined above, -a -NRiCOORõ group, where Rõ is:
-a C, to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C, to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C8 ar.yl, optionally substituted with:
-an alkoxy, -a halogen, or -a C I to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, =a Cl to C6 alkyl, --a -CORx group, where R, is as defined above, -a haloalkyl, or -a haloalkoxy, -a NR.,SO2R,,, group, where Rõ is:
-a hydrogen, -a -COR,,, where Rx is as defined above, or -a CI to , C6 alkyl, optionally substituted with:
-a halogen, -a -CORx group, where RX is as defined above, -a -OCOR, group, where R,, is as defined above, -a hydroxy, or -an alkoxy, and where RW is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a C6 to C$ aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, =
-an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C, to C6 alkyl, -a 5 or 6 membered heterocycle, or ~ ~ .

N/
O

. N/ =
-a O
LI,,,NH
O

NH
õ__--N

-a --<o , . .
Ry N Ry ./N =
-a O , optionally substituted with a Ci to C6 alkyl, where Ry is a CI to C6 alkyl or hydrogen, O
-a N
O O

-a N

0 / Rz O S
-a where RZ is hydrogen or a CI to C6 alkyl, optionally substituted with a C6 to Cg aryl, -a -SR,, group, where R,, is as defined above, -a -SO2R... group, where Ra. is: --a Cl to C6 alkyl, -an amino groiup, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COORX group, where R,t is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C$ aryl, and/or -a -NHRbb group, where Rbb is:
N
aN
_ , .
N

-a -C(=S)NH2 group, or -a -PO(ORX)2 group,.where R,e is as defined above;
-a Rcc group, where R,,, is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a O
-a C6 to Cs aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a Ci to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with oiie or more Ci to C6 alkyl(s), 5 -a 1VHPOR,,R,,, where Rx is as defined above, -a -NR,,,rCONRffRff group, where R,., is a hydrogen or a C, to C6 alkyl, optionally substituted with a halogen, and Rff is:
-a hydrogen, -a haloalkyl, 10. -a haloalkoxy, -a Cl to C6 alkyl, or ' -a -COR,,, where R,, is as defined above, -a -NRggCORht, group, where Rhh is:
-a hydrogen, 15 -a Ct to C6 alkyl optionally.substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more Ci to C6 alkyl(s), 20 -an amino optionally substituted with one or more CI to C6 alkyl(s), where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is:
25 -a hydrogen, -a Cl to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where Rx is as defined above, 30 -a haloalkyl, -5 or 6 membered heterocycle groups, _ -an amino optionally substituted with one or more C, to C6 alkyl(s), and/or -a -NRiiSO2RX group, where R, is as defined above, and R;i is:
-a hydrogen, -a C z to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -CORX group, where RX is as defmed above;
Z is:
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -aC6toC$aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more Ct to C6 alkyl(s);
-a -COORX group, where RX is as defined above; or o - o-/

R is a hydrogen, a halogen or an alkoxy;
R, is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to Cg aryl, or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR,, group, where RX is as defined above;
-a CI to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R, joins together with R2 to form:
O
O
.~ .

Rz is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a CI to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCORJe group, where Rx is as defined above, -a dialkyl-amino optionally substitated with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group;
-a -COORx group, where Rx is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to Ca aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR,, group, where RX is as defined above;
-a NHCORi; group, where'Ri; is:
-an alkoxy, or -an amino optionally substituted with one or more C, to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a -NHSO2R, group, where Rx is as defined above; or R2 joins together with Rl to form:

0 ::1.
R3 is:
-a hydrogen; or -CH2OCORX, and R,.is as defined above.
As used herein, the term "effective amount" refers to the amount required to produce a desired effect. For example, the effective amount may be the amount required to treat a Hepatitis C viral (HCV) infection, the amount required to treat an infection by a virus which comprises an internal ribosome entry site (IRES), the amount required to inhibit HCV IRES-mediated initiation and/or translation, or the amount required to inhibit viral replication or infectivity, in a subject or, more specifically, in a human. In some instances, the desired effect can be determined by analyzing (1) the presence of HCVRNA; (2) the presence of anti-HCV
antibodies; (3) the level of serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) (ALT and AST are elevated in patients chronically infected with HCV); (4) hepatocellular damage resulting from HCV infection, including steatosis, fibrosis and cirrhosis; (5) hepatocellular carcinoma as a result of chronic HCV
infection; and (5) extrahepatic sequelae (non-limiting examples include pruritis, encephalopathies, mental disorders such as anxiety or depression) of infection with HCV or other viruses which contain an IRES element. The effective amount for a subject will depend upon various factors, including the subject's body weight, size and health. Effective amounts. for a given patient can be determined by routine experimentation that is within the skill and judgment of the clinician.
For any compound, the effective amount can be estimated initially either in cell culture assays or in relevant animal models, such as chimpanzees, marmosets and tamarins. The animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., EDSo (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50. In some embodiments, the effective amount is such that a large therapeutic index is achieved. In further embodiments, the dosage is within a range of circulating concentrations that include an EDso with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
More specifically, the concentration-biological effect relationships observed with regard to the compound(s) of the present invention indicate an initial target plasma concentration ranging from approximately 0.1 g/mL to approximately 100 g/mL, from approximately I p,g/mL to approximately 50 gg/mL, from approximately 5 g/mL
to approximately 50 g/mL, or from approximately 10 g/mL to approximately 25 g/mL. To achieve such plasma concentrations, the compounds of the invention may be administered at doses that vary from 0.1 g to 100,000 mg, depending upon the route of administration.
Guidance as to particular dosages and methods of delivery is provided in the literature and is generally available to practitioners in the art. In general, the dose will be in the range of about 1mg/day to about lOg/day, or about 0_lg to about 3g/day, or about 0.3g to about 3g/day, or about 0.5g to about 2g/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).
The exact dosage will be determined by the practitioner, in light of factors related to the subject. Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the' severity of the disease state, general health of the subject, ethinicity, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, experience with other HCV therapies, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
The compounds and compositions of the present invention may be administered to the subject via any drug delivery route known in the art. Nonlimiting examples include oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary routes of administration.

D. Metabolites of the Compounds of the Invention Also falling within the scope of the present invention are the in vivo metabolic products of the compounds described herein. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radio-labeled (e.g. C14 or 113) compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating its conversion products from urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites may be done in the same way as conventional drug metabolism studies well-known to those skilled in the art_ The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no biological activity of their own.

E. Pharmaceutical Compositions of the Invention Yet another aspect of the invention relates to a pharmaceutical composition comprising:
(i) an effective amount of one or more compound(s) of formula I or one or more pharmaceutically acceptable salt(s) thereof, as described above; and (ii) one or more pharmaceutically acceptable excipient(s).
- In some embodiments, the pharmaceutical composition comprises one or more compound(s) of formula I wherein:
X is:
-a nitro group;
-a cyano group;
-a -CORa group, where R. is:
-a C, to C6 alkyl, -a C6 to C$ aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COORx group, where R, is a C, to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a Ci to C6 alkyl, -a C6 to Cs aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Yis:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more CI to C6 alkyl(s);
-a benzofnran;
-a benzothiophene;
-a dibenzofitran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally-substituted on the nitrogen with a C, to C6 alkyl;

O
*
~ -(CH2)n . I - =
N O
- Rb , where Rb is a hydrogen or a CI to C6 alkyl, and n is 0 or 1;
* . .

I . = .
- / ;

~ I

where is a hydrogen, a-CONIIRx, where R,, is as defmed above, or an -SO2R,,, where R,, is as defined above; or \\ iRd N~
*~-N
- , where Rd is a C1 to C6 alkyl or a C6 to CS aryl;
-a -NHCORe group, where Re is:
-a CI to C6 alkyl;
-a C6 to Cs aryl optionally substituted with:
-a CI to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOOR,, group, where R,, is as defined above;
-a -CH2O-R group, where Rf is a C6 to C$ aryl;
-a -NRgRh group, where R. is a Ci to C6 alkyl or a hydrogen and Rh is a C6 to C8 aryl optionally substituted with an alkoxy;
-a C i to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a CI to C6 alkyl, optionally substituted with a C6 to C$ aryl, -a C6 to C8 aryl, optionally substituted with -COOR,, where RX is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COORX group, where RX is as defined above, or -a -NHCOOR., group, where R. is as defined above;
-a C6 to C$ aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a Ct to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more Ct to C6 alkyl(s), -a NR;SOzR,, group, where R, is as defined above and Ri is:
-a hydrogen, -a Ci to C6 alkyl, -a -COR,, group, where R,. is as defmed above, -a haloalkyl, or -a haloalkoxy, -a -NRjCORk group, where Rk is:
-a Ci to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more C, to C6 alkyl(s), and Rj is:
-a hydrogen, -a Cl to C6 alkyl, - a-COR, group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N+=N- group, or -a -CORI, where R, is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more C1 to C6 altcyl(s), -a nitro group, -a C, to C6 alkyl &oup, optionally substituted with:
-a -NHSO2R. group, where Rx is as defined above, or -a -NRXSO2RX group, where RX is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COOR,s group, where R,. is as defined above, -a -CORn, group, where Rr,, is:
-an amino optionally substituted with one or more C, to C6 alkyl(s), where the CI to C6 alkyls are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more Cl to C6 alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a dialkyl-amino, -a -NHR,, group, where Rj is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NRoCORP group, where R. is:
-a Cl to C6 alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a C6 to Cg aryl, -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more CL to C6 alkyl(s), -a hydrogen, N ~ O
* ~ Or `
N "e ~ 0 and where Ro is:
-a hydrogen, -a C1 to C6 alkyl, -a -COR,, group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqRr group, where Rq is:
-a hydrogen, -a Ci to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where RX is as defined above, and where Rr is:
-a C6 to C8 aryl optionally substituted with:

. ~ ' N

O
-N
-a C, to C6 alkyl, -a haloalkyl, -a -ORs group, where RS is a C6 to C8 aryl, or -a -COOR, group, where R,, is as defined above, -a Ct to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, -a C6 to C8 aryl, and/or -a -COOR. group, where R,, is as defined above, -a -COORX group, where R,, is as defined above, -a -NRtCOORõ group, where Rõ is:
-a Ci to C12 alkyl, optionally substituted with:
-a C6 to Cg aryl optionally substituted with a Cl to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C$ aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a Cl to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:

-a hydrogen, -a Cl to C6 alkyl, -a -COR, group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRySOZRW group, where R,, is:
-a hydrogen, -a -CORx, where R. is as defined above, or -a C, to C6 alkyl, optionally substituted with:
-a halogen, -a -CORx group, where R,, is as defmed above, =a -OCOR. group, where R,, is as defined above, -a hydroxy, or -an alkoxy, and where Rw is:
-a CI to C6 alkyl optionally substituted with:
-a halogen, -a haloalkyl, -a C6 to C$ aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C t to C6 alkyl, -a 5 or 6 membered heterocycle, or - N
O

= N/

-a , " N
[,,,NH
-a , O

NH
~..N -_,,X<

-a O
Ry N Ry x~N

-a 0 , optionally substituted with a Ci to C6 alkyl, where RY is a C1 to C6 alkyl or hydrogen, O
-a N

-a N ::)2 RZ
o O S
-a where R. is hydrogen or a C, to C6 alkyl, optionally substituted with a C6 to Cg aryl, -a -SR,, group, where R7e is as defined above, -a -SO2R,, group, where R., is:
-a CI to C6 alkyl, -an anai_no-groups -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COORX group, where RX is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a NHRbb group, where Rbb is:

N~'N\ /
, N
-a -C(=S)NHZ group, or -a -PO(ORX)Z group, where R,, is as defined above;
-a * Rco group, where is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a O
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a Ct to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Cl to C6 alkyl(s), -a -NHPORxRx, where Rx is as defined above, -a -NReeCONRffRff group, where R,, is a hydrogen or a CI to C6 alkyl, optionally substituted with a halogen, and Ra is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a CI to C6 alkyl, or -a -CORx, where Rx is as defined above, -a -NRggCORhh group, where Rhh is:
-a hydrogen, -a CI to C6 alkyl optionally substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more Ci to C6 alkyl(s), -an amino optionally substituted with one or more C, to C6 alkyl(s), where the alkyls are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and R., is:
-a hydrogen, -a Cl to C 6 allcyl, -a haloalkyl, -a haloalkoxy, or -a -CORx group, where R,, is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more C, to C6 alkyl(s), and/or -a -NRiiSO2R,, group, where R. is as defined above, and R;; is:
-a hydrogen, -a C i to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -CORX group, where R,; is as defined above;
Z is:
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to Cg aryl;
-a C2 to C6 alkylene;
-a C6 to Cg aryl optionally substituted with an alkoxy or one or more Ct to C6 alkyl(s);

-a -COOR, group, where Rx is as defined above; or (?"_;
- o-_./
R is a hydrogen, a halogen or an.alkoxy;
Rl is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to Cg aryl, or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted.with an alkoxy;
-a -COR, group, where R. is as defined above;
-a C, to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or Ri joins together with R2 to form:
. ,.
O
=
= 0 =
= ;
R2 is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C, to C6 alkyl group, optionally substituted with one or more halogen(s);
266 =

-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR,, group, where R,, is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a Cl to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to Cg aryl group;
-a -COOR, group, where R,, is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to C$ aryl;
-a 5 or 6 membered heteroaryl;
-a -OCORX group, where RX is as defined above;
-a -NHCORj group, where Rij is:
-an alkoxy, or -an amino optionally substituted with one or more Ct to C6 alkyl(s);
-a -ORkk group, where Rkk is a 5 to 6 membered heteroaryl;
-a -NHSO2RX group, where R, is as defined above; or R2 joins together with Rt to form:
O O
O
O
~ - , R3 is:
-a hydrogen; or -CH2OCORX, and RX is as defined above;
provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, RI is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is;
-a Ci to C6 alkyl substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C$ aryl;
-a C2 to C6 alkylene;
-a C6 to C$ aryl optionally substituted with an alkoxy or one or more CI to C6 alkyl(s);
-a -COORx group, where RX is as defmed above; or 1 \
*

or or one or more pharmaceutically acceptable salt(s) thereof.

The pharrnaceutical composition may be formulated to achieve a physiologically compatible pH, ranging from a pH of about 3 to a pH of about 11. In some embodiments, the pharmaceutical composition is formulated to achieve a pH of about 3 to a pH of about 7. In other embodiments, the pharrnaceutical composition is formulated to achieve a pH of about 5 to a pH of about 8.
The pharmaceutical composition may compiise a combination of compounds of the present invention, or may include a second active ingredient useful in the treatment of viral infections, such as anti-viral agents that include, but are not limited to:
pegylated interferon, including by way of non-limiting example pegylated a-interferon; un-pegylated interferon, including by way of non-limiting example, un-pegylated a-interferon; ribavirin or prodrugs or derivatives thereof; protease inhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors, including fusion inhibitors such as FuzeonTM. (Trimeris); helicase inhibitors;
a Toll-like receptor agonist, a caspase inhibitor, anti-fibrotics; drugs that target IMPDH
(inosine monophosphate dehydrogenase inhibitors), such as Merimepadiv"' (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha I(ZADAXINTM, SciClone Pharmaceuticals Inc.); a glycosidase inhibitor; a glucosidase inhibitor;
therapeutic viral vaccines, such as those produced by Chiron and Immunogenics; and immunomodulators, such as histamine, antibodies against HCV, such as XTL-6865 and XTL-002 (XTL
Biopharmaceuticals), antisense RNA, ribozymes, RNAi, and anti-HCV agents with unknown mechanism of action.
The term "pharmaceutically acceptable excipient" refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention. The term refers to any pharnaceutical excipient that may be administered without undue toxicity.
Pharmaceutically acceptable excipients may be determined in part by the particnlar composition being administered, as well as by the particular mode of administration and/or dosage fonn. Nonlimiting examples of pharmaceutically acceptable excipients include carriers, solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions of the present invention (see, e.g., Remington's Pharmaceutical Sciences).
Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
Other exemplary excipients in.clude antioxidants such as ascorbic acid; chelating agents such as EDTA;
carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or eiriulsifying agents; pH
buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
The pharmaceutical compositions of the invention may be formulated in any form suitable for the intended method of administration. Suitable fonnulations for oral administration include solids, liquid solutions, emulsions and suspensions, while suitable inhaleable formulations for pulmonary administration include liquids and powders.
Alternative formulations include syrups, creams, ointments, tablets, and lyophilized solids which can be reconstituted with a physiologically compatible solvent prior to administration.
When intended for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of phannaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
Pharmaceutically acceptable excipients suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For- example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil_ In other embodiments, pharmaceutical compositions of the invention may be formulated as suspensions comprising one or more compound(s) of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet other embodiments, pharmaceuticaI compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of one or more excipient(s).
Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these_ Suitable emulsifying agents include naturally-occun-ing gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain .
sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a-demulcent, a preservative, a.fIavoring or a coloring agent.
Additionally, the pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous emulsion or oleaginous suspension. Such emulsion or suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension.
in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,2-propane-diol.
The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils may be employed as a solvent or suspending medium_ For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The compounds of the invention may be substantially insoluble in water and sparingly soluble in most pharmaceutically acceptable protic solvents and vegetable oils, 'but generally soluble in medium-chain fatty acids (e.g., caprylic and capric acids) or triglycerides and in propylene glycol esters of medium-chain fatty acids. Thus, contemplated in the invention are compounds which have been modified by substitutions or additions of chemical or biochemical moieties which make them more suitable for delivery (e.g., increase solubility, bioactivity, palatability, decrease adverse reactions, etc.), for example by esterification, glycosylation, PEGylation, etc.
In some embodiments, the compound of the invention is formulated for oral administration in a lipid-based composition suitable for low solubility compounds. Lipid-based formulations can generally enhance the oral bioavailability of such compounds. As such, pharmaceutical compositions of the invention may comprise a effective amount of one or more compound(s) of the invention, together with at least one pharmaceutically acceptable excipient selected from medium chain fatty acids or propylene glycol esters thereof (e.g., propylene glycol esters of edible fatty acids such as caprylic and capric fatty acids) and pharrnaceutically acceptable surfactants, such as polyoxyl4Q hydrogenated castor oil.
In alternative embodiments, the pharmaceutical composition may further comprise one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimiting examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of a-, ¾-, and y-cyclodextrin, and hydroxypropyl-o-cyclodextrin (HI'BC). In some embodiments, the pharmaceutical composition fiuther comprises about 0.1 % to about 20%
hydroxypropyl-(3-cyclodextrin, about 1% to about 15% hydroxypropyl-(3-cyclodextri_n, or about 2.5% to about 10% hydroxypropyl-(3-cyclodextrin. The amount of solubility enhancer employed may depend on the amount of the compound of the present invention in the composition.

F. Combination Therapy It is also possible to combine any compound of the present invention with one or more other active ingredients usefnl in the treatment of HCV infection, including compounds, in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment. When administered sequentially, the combination may be administered in two or more administrations. In an alternative embodiment, it is possible to administer one or more compounds of the present invention and one or more additional active ingredients by different routes.
The skilled artisan will recognize that a variety of active ingredients may be administered in combination with the compounds of the present invention that may act to augment or synergistically enhance the viral inhibiting activity of the compounds of the invention. Such active ingredients include anti-HCV agents. Anti-HCV agents include agents that target the virus as well as agents that have an imrnunomodulatory effect.
For example, anti-HCV agents include, but are not limited to, interferon, including, for example without limitation, IFN-a, ribavirin or prodrugs or derivatives thereof; protease inhibitors, polymerase inhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspase inhibitor and a glycosidase inhibitor, antibodies against HCV, such as XTL-6865 and XTL-002 (XTL
Biophatrmaceuticals), antisense RNA, ribozymes, RNAi, and anti-HCV agents with unknown mechanism of action.. Furthennore, the compounds of the invention may also be administered in combination with other compounds that affect IRES activity.
According to the methods of the invention, the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art. When delivered in alternation therapy, the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together. Various sequences of intermittent combination therapy may also be used.
To assist in understanding the present invention, the following Examples are included.
The experiments relating to this invention should not, of course, be construed as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the purview of one skilled in the art are considered to fall within the scope of the invention as described herein and hereinafter claimed.
It will be apparent to those skilled in the art that specific embodiments of the present invention may be directed to one, some or all of the above-indicated aspects as well as other aspects, and may encompass one, some or all of the above- and below- indicated embodiments, as well as other embodiments.
Other than in the working examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified by the term "about".
Accordingly, unless indicated to the contrary, such numbers are approximations that may vary depending upon the-desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding techniques.
While the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

EXAMPLES

The present invention is described in more detail with reference to the following non-limiting examples, which are offered to more fully illustrate the invention, but are not to be construed as limiting the scope thereof. The examples illustrate the preparation of certain compounds of the invention, and the testing of these compounds in vitro and/or in vivo.
Those of skill in the art will understand that the techniques described in these examples represent techniques described by the inventors to function well in the practice of the invention, and as such constitute preferred modes for the practice thereof. However, it should be appreciated that those of skill in the art should in light of the present disclosure, appreciate that many changes can be made in the specific methods that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1: Preparation of Compounds of the Invention Example lA: Preparation of 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (compound 5).
CN CN
wl!~N\ CtS02NC0 I ~ ~ NaH
D ~
Me0 DMF MeO ~ N Etl MeO N
H H DMF ) Step A: A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) is cooled to 0 C and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture is stirred at this temperature for 1 h. The dark solution is poured into ice water (600 mL) and the light brown solid is collected by filtration, washed with additional H20 and dried to afford 9_9 g (85%) of 6-methoxy-lH-indole-3-carbonitrile as a light brown solid.
Step B: To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 nunol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H20 and extracted with EtOAc (2X). The organic phases are washed with H20 (3X) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2CI2/hexanes (50-100%) as eluent to yield 6-methoxy- 1 -ethyl- 1H-indole-3-carbonitrile as a tan solid.
Utilizing steps A and B above and substituting different indoles and alkyl halides gives, the following compounds: Compounds 43, 45, 51, 52, 108, 109, 115, 118, 120, 123, 126, 179 and 714.

Example 1B: Preparation of 6-ethoxy-l-ethyl-lH-indole-3-carbonitrile (compound 9).
CN CN CN
I BBf3 I K2CO3 0 N CH2CI2 HO N Ett ~p o C MEK
Step A: To a solution of 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (2.85 g, 14.2 mmol), prepared by example lA, step B, in CH2C12 (40 mL) is added a 1M
solution of BBr3 in CH2C12 (28.5 mL, 28.5 mmol) at 0 C. The mixture is allowed to warm to room temperature and kept for 2.5h. The dark reaction mixture is then poured onto ice and sufficient 1 M NaOH
is added until the pH is 8-9. The product is extracted with CHZC12 (3X) and the combined organic phases are washed with saturated NaHCO3, H20 and saturated NaCl. After drying over MgSO4i the solution is concentrated and the product is purified by chromatography (EtOAc/CH2C12, 0-10%) to afford 2.15 g (82%) of 6-hydoxy-l-ethyl-lH-indole-3-carbonitrile as a yellow solid.
Step B: To a solution 6-hydoxy-1-ethyl-lH-indole-3-carbonitrile (80 mg, 0.43 mmol) in mL of inethyl ethyl ketone is added anhydrous K2C03 (71 mg, 0.52 nunol) and iodoethane (0.05 mL, 0.60 mmol). After stirring overnight at reflux, the reaction mixture is cooled, diluted with H20 and extracted with EtOAc (3X). The combined organic phases are dried and concentrated. Flash chromatography (CHZC12) gives 94 mg (100%) of 6-ethoxy-l-ethyl-1H-indole-3-carbonitrile as a white wax.
In similar fashion, following steps A and B, above, the following compounds are also prepared: Compounds 6, 10, 11, 12 and 24 Example 1C_ Preparation of 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (compound 44).

CN
CN

\ K3P04 /C ~ n1 NH I~ \O -Me0' v ~ ~
Cul, tigand toluene, reflux A mixture of p-iodoanisole (85 mg, 0.36 inmol), anhydrous K3POA (102 mg, 0.48 mmol), Cul (4.6 mg, 0.024 mmol) and N,N'-Dimethyl cyclohexane-1,2-diamine (14 mg, 0.096 mmol) is added to 5H-[1,3]dioxolo[4,5-t]indole-7-caxbonitrile (45 rng, 0.24 mmol), prepared as described by the method of example 1A, step A, in anhydrous toluene (0.4 mL).
After heating.
at reflux for 24h, the solvent is evaporated under vacuum. The residue is dissolved with CH2C12 (5 mL) and the mixture-is filtered. The filtrate is concentrated to afford crude product, which is purified by silica ge1 chromatography using EtOAc/petroleum ether (1:4) as eluent to yield 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-fJindole-7-carbonitrile.

Utilizing the procedure above and substituting different aryl iodides gives the following compounds: Compounds 4, 8, 102, 103, 111, 112, 117, 119, 124, 125, 127, 154.

Example 113: Preparation of 1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile (compound 13).

CN CN
K2C03 CN ~
NO IN NO I/ N
`NI CI
DMF, 110 C

To a solution of 1-ethyl-6-hydroxy-lH-indole-3-carbonitrile (60 mg, 0.32 mmol) prepared as described in example lA, step A, in DMF (5 mL) is added K2C03 (55 mg, 0.40 mmol) and 2-chloropyridazine (45 mg, 0.40 mmol). The mixture is heated at 110 C for 18h.
After cooling to room temperature, the reaction mixture is diluted with H20 and extracted with EtOAc (3X). The combined organic phases are washed with H20 and saturated NaCl, dried and concentrated. The product is isolated by chromatography (EtOAc/CHZCIZ, 1-3%) over silica gel to afford 76 mg (96%) of the title compound, 1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile, as an off-white solid.

Example 1E: Preparation of 3-cyano-l-ethyl-1H-indole-6-carboxylic acid phenylamide (compound 15).

CN CN
IN NaOH
I ~ \ (COC1)2 MeO i N THF HO / N DMF
O ~ reflux O CH2CI2 CN I ~ CN
~ NH2 H

CI I i N THF ~~ N N 14 O O
Step A: A solution of methyl 3-cyano-l-ethyl-lFl-indole-6-carboxylate (1.60g, 7.02 mmol), prepared by the method described in example 1 A from methyl 1H-indole-6-carboxylate, in THF (35 mL) is treated with 1N NaOH (7.7 mL, 7.7 mmol) and heated at reflux for 2.5h. After cooling to room temperature, most of the THF is removed and the soluiion is diluted with H20 and extracted with ether (2X). The ether extracts are discarded. The aqueous phase is then acidified with 6N HCI to pH 2 and then extracted with EtOAc (3X). The EtOAc layers are combined, washed with saturated NaCl and then dried and concentrated to afford 1.43 g (95%) of 3-cyano-l-ethyl-lFl-indole-6-carboxylic acid as a white solid.
Step B: A suspension of 3-cyano-l-ethyl-1H-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CHZC12 (15 mL) is cooled to 0 C. The suspension is treated with DMF
(2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) is added via syringe during 2 minutes after which the ice bath is removed and the reaction mixture is allowed to warm to ambient temperature during 1.5h during which time the reaction becomes a yellow solution. The solution is then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-l-ethyl-lH-indole-6-carbonyl chloride as a yellow solid.
Step C: A suspension of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride (70 mg, 0.30 mmol) in THF (5 mL) is cooled to 0 C and treated with aniline (0.08 mL, 0.90 mmol). After the addition, the reaction is warmed to ambient temperature and after stirring for an additional 16 hours, the reaction mixture is diluted with H20 and extracted with EtOAc (2X). The combined organic phases are washed with saturated NaCI and then dried and concentrated to afford the product. Chromatography (EtOAc/CH2CI2, 2/98) over silica gel gives 44 mg (51 %) of 3-cyano-l-ethyl-lH-indole-6-carboxylic acid phenylamide.
Utilizing essentially the procedure above gives the following compound:
Compound 89.
Example 1F: Preparation of t-butyl (3-cyano-1-ethyl-1HHindol-6-yl)-carba.mate (compound 16).

CN CN
I \ ~ DPPA J j\
.`~~%'~N HN N
H02C Et3N
t-BuOH
A solution of 3-cyano-l-ethyl-lH-indole-6-carboxylic acid (0.60 g, 2.80 mmol) from Example IE, step A, in t-butanol (20 mL) is treated with Et3N (0.46 mL, 3.36 mmol) and diphenylphosphoryl azide (0.73 mL, 3.36mmol) and then heated at reflux for 4h.
After cooling to room temperature, most of the t-butanol is removed in vacuo to give an oil, which is then dissolved in EtOAc. After washing with H20, the organic phase is back-extracted with EtOAc and the organic layers are combined and washed sequentially with additional H20, saturated NaHCO3 and saturated NaCI. The organic phase is dried, concentrated and the resulting crude product is purified by chromatography over silica gel using EtOAc/CH2Cla (0-1%) to afford 0.52 g (65%) of t-butyl (3-cyano-l-ethyl-lH-indol-6-yl)-carbamate as a white solid.
The following compound is made in similar fashion: Compound 90.

Example 1Ga: Preparation of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile via Suzuki route (compound 55).

~ NHZ
CN CN 0 ~ ~
CN
f j \ LDA ~~ \ o \ _ Meo ~ 12 MeO ~ N PdClz(PPh3o)2 Me0 N ~~ NHZ
THF CsF
'700C - rt DME
reflux Step A: A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7.8 nunol) is diluted with THF (5 mL) in a flame-dried flask. After cooling the reaction to -30 C, a solution of 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10 mL) is added dropwise during 10 min, maintaining the temperature at -30 C.
After stirring for an additiona130 min at this temperature, a solution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) is added during 10 min. After the addition, the reaction is warmed to ambient temperature during lh. The reaction is then diluted with ice-H20 and extracted with EtOAc (2X). The combined organic phases are washed withlM sodium thiosulfate and saturated NaCI and then concentrated to a brown solid. Chromatography (CH2CI2/hexanes, 1/1) over silica gel gives 1.31 g(62%) of 1-ethyl-2-iodo-6-methoxy-lH-indole-3-carbonitrile as an off-white solid.
Step B: A mixture of 1-ethyl-2-iodo-6-methoxy-lH-indale-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetramethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90 mmol), CsF
(1.46 g, 9.58 mmol) and Pd(PPh3)2C12 (110 mg, 0.15 mmol) in DME (20 mL) is added to a flask and altematively evacuated and flushed with N2. The reaction is then heated at reflux for 24h and then cooled to room temperature. The reaction mixture is diluted with H20 and extracted with EtOAc (2X). The combined organic phases are washed with H20 and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix is purified by flash chromatography on silica gel using EtOAc/CH2C12 (5/95) as eluent to afford 765 mg (69%) of 2-(4-aminophenyl)-i-ethyl-6-methoxy-lH-indole-3-carbonitrile as a yellow solid.
Utilizing essentially the same procedure described above and substituting different boronic acids gives the following compounds: Compounds 19, 20, 21, 22, 53, 63, 70, 71, 74, 76, 77, 79, 80, 100, 110, 229, 239, 240, 247, 250, 254, 255, 256, 257, 258, 259, 260, 281, 282, 283, 284, 286, 335, 336, 337, 338, 339, 347, 348, 426, 427, 428, 429, 476, 543, 578, 758.
Example 1Gb: Preparation of 2-(4-aminophenyl)-1-butyl-6-methoxy-lH-indole-3-carbonitrile via alternative Suzuki route.

CN 1. iPr2NH, n-BuLi, THF CN
2. B(OMe)3 l ~ I ~ ~ / NH2 Me0 M 3. K3PO4 (3M, aq.) Me0 `N

I~ PdCl2dppf, DMF

To a solution of (i-Pr)2NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to -78 C
is added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in one portion. The acetone/dry ice bath .
is exchanged for ice/water bath and the solution is stirred further for 40 miri. The solution is cooled to -78 C and solution of 1-butyl-6-methoxy-lH-indole-3-carbonitrile, prepared as in example lA (2.0 g, 8.77 mmol) in THF (10 mL) is added dropwise. This solution is stirred for 15 min at -78 C, following by 20 min at -20 C. Trimethyl borate (1.0 mL, 8.77 mmol) is added, the reaction mixture is stirred for 15 min at -20 C after which the cooling bath is removed and this solution is stirred further at room temperature for lh. A
solution of K3PO4 is added (11.7 mL, 3M aqueous solution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g, 11.40 mmol) and PdCl2dppf catalyst (640 mg, 0.88 mmol) in DMF (40 m.L, plus a 5 mL
rinse). The reaction mixture is stirred overnight (ca. 18h) and then water (80 mL) is added and the product is extracted with EtOAc (3X50 mL). The combined organic fractions are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified via flush chromatography on silica gel (5--a60% EtOAc/Hexanes as eluant) to afford the desired 2-(4-aminophenyl)-1-butyl-6-methoxy-lH-indole-3-carbonitrile as a tan solid (2.4 g, 86% yield).
The following compounds are prepared in similar fashion utilizing other indole and aryl and hereroaryl bromides and iodides: Compounds 656, 659, 660, 661, 682, 683, 712, 731, 732, 733, 806, 807, 808, 809, 810, 811, 812, 813, 814, 827.

Example 1Gc: Preparation of 2-(4-aminophenyl)-6-methoxy-l-propyl-lH-indole-3-carbonitrile via Negishi route.

= CN 1_ LOA, ZnCi2 CN
I \ ~ THF I \ ~ - HZ
N 2. Jl _ NHz C i Pd2dba3 r~\/ ro ~
PPhg THF
A
A nitrogen-purged flask fitted with a septum and a nitrogen needle is charged with dry THF (all additions performed by syringe) (20 mL). Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) is added, and the solution is cooled to 0 C. n-Butyllithium (8.50 mL of 1.6 M
solution in hexane, 13.6 mmol) is added slowly. The flask is allowed to warm to room temperature briefly, and then is cooled to -78 C. A concentrated THF solution of 6-methoxy-1-propyl-lH-indole-3-carbonitrile (2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A) is added slowly, and the resulting solution is maintained at -78 C
for 30 min.
The flask is then transferred to a water-ice bath and allowed to come to 0 C
for about 15 minutes. The solution is once again cooled to -78 C, and ZnC12 (0.5 M solution in THF, 27.0 mL, 13.5 mmol) is slowly added. A precipitate is observed at this point, which may be the bis(indole)zinc compound, but the solution becomes homogeneous when the entire volume of zinc chloride solution is added. After about 10 minutes, the solution is allowed to come to room temperature, and a THF solution (5 mL) of 4-iodoaniline (3.47 g, 15.8 mmol) and triphenylphosphine (338 mg, 1.29 mmol) is- added. The septum is removed, and solid Pd2(dba)3 (295 mg, 0.322 mmol) is added. A reflux condenser is fitted to the flask, and the solution is degassed by three successive cycles of vacuum pumping/N2 purging.
The solution is then heated to reflux overnight. After cooling to room temperature, the solution is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The resulting mixture is vigorously stirred for 30 minutes, then filtered through celite (with ethyl acetate washing) to remove solid Zn- and Pd-containing material. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed in sequence with saturated brine, combined, dried over anhydrous sodium sulfate, filtered and evaporated.
A solid precipitate forms at this point, -which is sufficiently pure product and is collected by trituration with ether and filtration. The remaining material is purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica ge160). Total yield of the product, 2-(4-amino-phenyl)-6-methoxy-l-propyl-lH-indole-3-carbonitrile, is 2.75 g (8.99 mmol, 70%).

The following compounds are made using essentially the same procedure and substituting other aryl or heteroaryl iodides or bromides: Compounds 393, 408, 430, 431, 436, 437, 438, 459, 460, 461, 462, 483, 484, 632, 633, 634, 635, 636, 650, 651.

Example lGd: Preparation of 1-ethyl-2-(3-hydroxyphenyl)-6-methoxy-lH-indole-3-carbonitrile (Compound 288).

OH
CN CN
I~ 1. LOA, THF \ \ ~/' \ CN OH
Me0 ) N 2. Bu3Snl Me0 N SnBu3 --- I/ \ \/
> 1 Pd(PPh3)2C12, Meo / CuI,THF Step A: A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol) is cooled to -78 C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2 mmol) is added dropwise over 5 minutes. The LDA mixture is stirred at -78 C for 10 minutes, and then at 0 C
for 20 minutes.
The solution is re-cooled to -78 C. 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (5.0 g, 25 mmol), prepared as in example lA, is taken up in THF (30 mL) and added dropwise to the LDA mixture over 15 minutes. The reaction is stirred at -78 C for 10 minutes, and at 0 C for 30 minutes. Once again, the reaction mixture is cooled to -78 C. Tributyltin iodide (10 mL, 35 mmol) is added dropwise. This is stirred at -78 C for 15 minutes, and then at 0 C for 30 minutes. The reaction mixture is absorbed onto silica gel and concentrated.
Purification by i chromatography (CH2CI2) yields 1-ethyl-6-methoxy-2-tributylstannanyl-lH-indole-carbonitrile (12.05 g, 98%).
Step B: 1-Ethyl-6-methoxy-2-tributylstannanyl-lH-indole-3-carbonitrile (1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh3)ZC12 (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This mixture is heated at 65 C overnight. The reaction mixture is diluted in EtOAc, and is filtered through celite. The filtrate is concentrated and the residue is purified by silica gel chromatography (4: l, CH2C12/EtOAc) to yield crude product. Ether trituration yields 1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-lH-indole-3-carbonitrile (430 mg, 72%) as a yellow-white solid.
The following compounds are prepared similarly as above, using other commercially available iodides and bromides, or using iodides derived from a one step amidation of p-iodophenylsulfonyl chloride: Compounds 275, 276, 277, 278, 331, 363, 364, 373, 374, 375, 474, 475, 678.

Example 1Ge: Preparation of ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-l-ethyl-lH-indol-2-yl)-phenyl]-amide via Heck route (compound 519).

i () _s~
F H _ F - S~O
~ N ~ ~ NH
F O PPh3, Cs2CO3, Pd(OAc)2 F
DMF, 135 C

N
O.
CISO2NCO F ~ ~ - 'S--O
NH
DMF, r.t. FO N

Step A. A solution of 6-difluoromethoxy-l-ethyl-lH-indole (402.8 mg, 2.04 mmol), ethanesulfonic acid (4-iodo-phenyl)-amide (712.1 mg, 2.29 mmol), cesium carbonate (733.2 mg, 3.82 mmol), triphenylphosphine (33.1 mg, 0.13 mmol) and palladium acetate (5.7 mg, 0.025 mmol) in DMF (5 ml) is heated to 135 C for 48h. The reaction mixture is diluted with water and extracted with EtOAc (2 X 10 mL). The combined organic phases are washed with brine, dried over MgSO4, and then concentrated. The residue is purified via column chromatogrphy on sitica gel (25 g) using EtOAc/Hexanes (10-20%) as eluent to afford 298.2 mg (37.1 lo yield) of ethanesulfonic acid [4-(6-difluoromethoxy-l-ethyl-1 H-iodo-2-yl)-phenyl]-amide, compound 516, as a light brown solid.
Step B: Following the procedure lA, step A, ethanesulfonic acid [4-(6-difluoromethoxy-1-ethyl-lH-iodo-2-yl)-phenylj-amide is converted to ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-l-ethyl-lhT-indol-2-yl)-phenyl]-amide, compound 519.
Following steps A and B above, the following compounds are prepared in similar fashion: Compounds 343, 344, 345, 346, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 515, 517, 518, 520, 521, 522, 523, 524, 575, 577, 579, 580, 611, 612, 613, 614 Example 1H: Preparation of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-lH-indole-3-carbonitrile (compound 67).

CN F CN
~ F
Me0 (~ NPdCI2(PPh3)2 MeG N
Cul DMF Et3N

A mixture of 1-ethyl-2-iodo-6-methoxy-lH-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example 1Ga, step A, 4-fluorophenylacetylene (80 mg, 0Ø69 mmol), bis(triphenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and Cul (4 mg, 0.018 mmol) is added to a sealable tube and alternatety evacuated and flushed with N2. To the tube is then added DMF (4 mL) and Et3N (0.25 mL, 1.84 mmol) and the reaction is heated at 80 C for 20h and then cooled to room temperature. The reaction mixture is diluted with H20 and extracted with EtOAc (2X). The combined organic phases are washed with H20 (3X) and saturated NaCI and then dried over MgSO4 and concentrated. The crude reaction mix is absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%) of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-lH-indole-3-carbonitrile as a yellow solid.
Utilizing essentially the same procedure described above and substituting different acetylene derivatives gives the following compounds: Compounds 64, 65, 66, 68, 69, 91, 92, 93, 94, 95, 96, 133, 134, 135, 136, 137, 143, 144, 145, 146, 147, 148, 149,150, 151, 158, 159, 160, 161, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 184, 185, 186, 187, 188, 196, 197, 198, 199, 200, 201, 202, 223, 230, 231, 232, 233, 234, 235, 236, 237, 238.

Example 11: Preparation of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-lH-indole (compound 28).

N HN NH
H
NH2OH EtCOCI IN

Me0 I~ N H20/MeOH Me0 D N ~\
N~ Me0 N

Step A: A solution of 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (1.00 g, 5.00 mmol) in MeOH (10 mL) is treated with a 50% aqueous solution of hydroxyamine (0.38 mL, 6.25 mmol) and heated at reflux for 18h. After cooling to room temperature, the heterogeneous mixture is filtered to afford 525 mg of desired product as a tan solid. The filtrate is concentrated to an oil, which is then dissolved in CH2C12 and chromatographed over silica gel using EtOAc/CH2C12 (15-50%) to afford an additional 295 mg of product as a tan solid. Total yield of 1-ethyl-N-hydroxy-6-methoxy-lH-indole-3-carboxamidine is 820 mg (70%).
Step B: The N-hydroxycarboxamidine above (50 mg, 0.21 mmol), polystyrene-diisopropylethylamine 165 mg, 3.90 minol/g loading) and propionyl chloride (0.03 mL, 0.32 mmol) in CH2C12 (10 mL) are placed in a tube and rotated for 22h at room temperature. After this time, trisamine resin (77mg, 2.71 mmol/g loading) is then added and the tube rotated for an additional 30 min at room temperature. Solids are filtered and then the filtrate is concentrated and diluted with toluene (5 mL) and heated at 110 C overnight. The crude reaction mixture is concentrated and purified by chromatography (EtOAc/CH2C12, 2/98) to afford 27 mg (46%) of.
1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole as a white solid.
The following compound is prepared utilizing the above procedure with substitution of the appropriate acyl halide: Compound 29.

Example 1J: Preparation of 1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-indole (compound 54).

N-N N~
/N N N N
H O
NaN3 EtCOCI I ~
MeD N Et3N HCI Meo N DCE Meo ~
toluene d Step A: A mixture of 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (1.00 g, 5.00 mmol) in toluene (30 mL) is treated with triethylamine hydrochloride (1.03 g, 7.50 mmol) and sodiurn azide (0.49 g, 7.50 mmol) and is heated at reflux for 16h. After cooling to room temperature, the reaction mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is then washed with additional NaHCO3 (2X). The combined aqueous phases are acidified to pH 2 with 6N HCI. The resultant thick precipitate is extracted with hot EtOAc (3X) and the combined organic phases are washed with saturated NaCl and dried and concentrated to give 0.55 g (45%) of 1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.
Step B: A suspension of the tetrazole above (50 mg, 0.21 rnmol) and propionyl chloride (0.03 mL, 0.31 mmol) in dichloroethane (5 mL) is heated at reflux for 21h.
After cooling the reaction mixture to room temperature, polystyrene trisamine resin (70 mg, 3.4 meq/g) is added and the reaction is rotated for 4h at room temperature. After filtering off the resin, and removal of the solvent, the crude product is absorbed on silica gel and the product is isolated by silica gel chromatography (EtOAc/CHaClZ, 5-10%) to afford 30 mg (53%) of 1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole as a tan solid.

Example 1K: Preparation of ethyl5-difluoromethoxy-l-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (compound 49).

CO2Et CO2Et N CMZCI2 F Jl N

~ NaOH ~ ~
~OMe 0 C
OMe Freon-22 (HCFZCI) gas is bubbled into a solution of ethyl 5-hydroxy-1-(4-methoxyphenyl)-2-methyl-lH-indole-3-carboxylate (250 mg, 0.77 rnmol) in CH2C12 (5 mL) at 0 C containing a small amount of tetrabutylammonium bromide as a phase transfer catalyst. A
50% solution of NaOH is added dropwise at 0 C. After the addition, the mixture is stirred at 0 C for 2h. After the addition of H20, the organic phase is separated and washed with brine and dried over Na2SO4- The solvent is then concentrated and the residue is purified by column chromatography over silica gel using EtOAc/petroleum ether (1/2) as eluent to yield the desired product in 40% yield.
The following compounds are prepared utilizing the above procedure with substitution of the appropriate hydroxyindole: Compounds 18, 46, and 50.

Example 1L: Preparation of 1-[5-methoxy-l-(4-methoxyphenyl)-1-H-indol-3-yl]-ethanone (compound 42).

O
~ I \ Et2AICl _-10 CH3COCI N

5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared by the method of example IC, is dissolved in I mL of CH2C12 at 0 C. Et2AIC1(300 L, IM
in hexanes, 0.3 nunol) is then added. After stirring at 0 C for 30 rnin, a solution of acetyl chloride (22 L, 0.3 mmol) in 1 mL of CH2CI2 ;s added dropwise. This is stirred at 0 C
for a further 90 min. The reaction mixture is quenched with H20 and is extracted with CH2C12 and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CHZC12 (5/95) yields the title compound as a white solid (42 mg, 71%).
Utilizing essentially the same procedure described above and substituting different acyl chlorides, the following compounds are prepared: Compounds 32, 33, 34, 37, 38, 39, 47, 48.
Example 1M: Preparation of 1-ethyl-3-isoxazol-3-yl-6-methoxy-1 H indole (compound 57).

OH O
~ N~
k~ NHzOH HCI ~ \ n-Bui, THF
Me0 N NaOAc Me0 I~ N DMF,THF Meo N
EtOH
A

Step A: A mixture of 1-(1-ethyl-6-methoxy-l-H-indole-3-yl)ethanone (200 mg, 0.92 mmol), prepared from 1-ethyl-6-methoxy-1.i3 indole by the procedure described in example 1L, hydroxyamine hydrochloride (128 rng, 1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH
(7mL) is heated at 85 C for 4h. The reaction mixture is then partitioned between H20 and EtOAc. The organic phase is dried and concentrated in vacuo. Purification by colunm chromatographyusingEtOAc/CH2C12 (1/9) yields 1-(1-ethyl-6-methoxy-l-H-indole-3-yl)ethanone oxime as a white solid (189 mg, 92%).
Step B: 1-(1-Ethyl-6-methoxy-l-H-indole-3-yl)ethanone oxime (100 mg, 0.43 mmol) is dissolved in THF (900 L) at 0 C. n-BuLi (450 L, 2.5 M in hexanes, 1.12 mol) is added dropwise, resulting in instant precipitation of solids. DMF (70 L, 0.9 mol) in 260 L of THF
is then added dropwise. This is stirred at 0 C for lh, then at room temperature for lh. The reaction mixture is pipetted into a mixture containing 1 mL of H20, 1 mL of THF, and 100 L
of concentrated H2S04. This mixture is heated at 75 C for 1h and then is partitioned between H20 and EtOAc. The organic phase is dried and concentrated. Purification by column chromatography (CH2Clz) yields 1-ethyl-3-isoxazol-3-yl-6-rnethoxy-l-H-indole product as a white solid (13 mg, 12%).

Example 1N: Preparation of 1-ethyl-3-isoxazol-5-yl-6-rnethoxy-lH-indole (compound 58).

N
O p `
1. DMF DMA

j/ 2. NH20H HCI
Me0 ~ MeO N
1-(1-Ethyl-6-methoxy-lH-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from ethyl-6-methoxy-lFi=indole by the procedure described in example 1L, is heated with 1.5 mLof dimethylformamide dimethylacetal and 100 L of pyrrolidine at 110 C overnight.
The dimethylformamide dimethylacetal is then concentrated in vacuo. The residue is redissolved in 1.25 mL of EtOH and 250 L of H20, and is treated with hydroxyamine hydrochloride (66 mg, 0.95 mmol) and heated at 80 C for 2h. Partitioning between H20 and EtOAc and drying and concentration of the organic phase followed by purification by silica gel chromatography (EtOAc/CH2C12, 5195) gives 1-ethyl-3-isoxazol-5-yl-6-methoxy-lH-indole as a white solid (72 mg, 66%).
Utilizing essentially the same procedure described above, the following compound is prepared: Compound 60.

Example 10: Preparation of 1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (compound 59).

N
~ HN
1. DMF DMA
~ ~ - ~ ~
MeO I~ N 2. NH2NH2 H2O Me0 N
1-(1-Ethyl-6-methoxy-lH-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL
of dimethylformamide dimethyl acetal and 100 L pyrrolidine at 110 C
overnight. The DMF
dimethyl acetal is removed in vacuo. The residue is redissolved in 3 mL of acetic acid, hydrazine hydrate (70 L, 1.38 mmol) is added, and the mixture is heated to 100 C for 2h. The acetic acid is removed in vacuo, and the residue is partitioned between EtOAc and saturated NaHCO3. The organic phase is dried and concentrated and the product purified by silica gel chromatography (EtOAc/Hex, 1/1) to give 59 mg of 1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (54%) as a colorless semisolid. Trituration in Et20 gives a white crystalline powder.
The following compound is prepared utilizing the above procedure: Compound 61.
Example 1P: Preparation of methyl 1-ethyl-3-oxazol-5-yl-lH-indole-6-carboxylate (compound 72).

CHO N
POCI3 I j ~ T05MIC
--" \
MeO2C N OMF MeO2C N K2CO3 '\_ MeOH Me02C N
Step A: 1-Ethyl-lH-indole-6-carboxylic acid methyl ester (900 mg, 4.45 nunol) is dissolved in DMF (3.3 mL). This is added dropwise to an ice-cold solution of POC13 (430 L, 4.5 mmol) in DMF (1.5 mL). The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is then treated with 6N NaOH (3.5 ml). The mixture is then partitioned between H20 and ethyl acetate. Purification by silica gel chromatography (5-10%
EtOAc/CHaCIZ) yields l-ethyl-3-formyl-IH-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
Step B: I-Ethyl-3-formyl-lH-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mrnol), TOSMIC (100 mg, 0.52 mmol), K2C03 (178 mg, 1.29 mmol), and MeOH (800 gL) are heated at 80 C overnight. The reaction mixture is then partitioned between H20 and ether.
After drying and- concentrating the organic phase, the product is purified by silica gel chromatography (EtOAc/CH2C12, 10/90) to give methyl 1-ethyl-3-oxazol-5-yl-IH-indole-6-carboxylate (26 mg, 23%) as an off-white solid.

Example IQ: Preparation of methyl 1-ethyl-3-oxazol-2-yl-1Fl-indole-6-carboxylate (compound 75).

~ ~ KMnO4 ^ ~( 1_(COCI~DMF
MeO2C I~ N acetone MeO2C)(I~ ~N 2. NH4OH

OMe -N
B, OMe \ ~
Me02C ~~ N diglyme N
MeO2C

Step A: 1-Ethyl-3-formyl-lH-indole-6-carboxylic acid methyl ester (800 mg, 3.5 mmol), prepared as shown in example 1P, step A, is dissolved in acetone (98 mL). A solution of KNInO4 (655 mg, 4.15 mmol) in H20 (31 mL) is added. The reaction mixture is stirred at room temperature for 90 minutes. Another addition of KMnO4 (108 mg) in H20 (6 mL), followed by stirring for another 45 minutes is required to drive the reaction to completion. The reaction mixture is then quenched with 10% H202 (1.5 mL). The mixture is filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume. The residue is acidified with 6N HCI, and is extracted into ethyl acetate. The solids isolated from the ethyl acetate layer are triturated with acetone to yield 1-ethyl-lH-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) as a light orange solid.
Step B: 1-Ethyl-lH-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) is suspended in a solution of CH2C12 (27 ml) and DMF (20 L). Oxalyl chloride (470 gL, 5.38 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (10 mL).
This is then partitioned in H20 and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 6-methoxycarbonyl-1-ethyl-lH-indole-3-carboxamide (511 mg, 85%) as a white solid.
Step C: A mixture of 150 mg (0.61 mmol) of 6-methoxycarbonyl-l-ethyl-lH-indole-carboxamide in diglyme (3.6 mL), and bromoacetaldehyde dimethyl acetal (430 L, 3.7 mmol) is heated at 125 C for 2h. The reaction mixture is cooled and partitioned in H20 and EtOAc.
The organic phase is dried and concentrated and the product is purified by silica gel chromatography (EtOAc/CH2Cl2 5-10%). The product containing fractions are combined and concentrated and the solid is triturated with hexanes to yield methyl 1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (75 mg, 46%) as a yellow solid.

Example 1R: Preparation of 1-ethyl-6-methoxy-3-thiazol-2-yl-lH-indole (compound 73).

CHO COZH
~ POCI3 I ~ ~ KMnO4 1. (COCI)Z DMF
/ -~
Me0 N DMF Me0 ~ . a H2oe M80 2. NHyOH
~
CONHZ L awesson's CSNH2 OMe ~N
I ~ reag ent I ~ ~ BrOM.
~
Me0 / toluene Ma0 / N diglyme MeO I~ N

Step A: 1-Ethyl-6-methoxy=lH-indole (900 mg, 5.14 mmol) is dissolved in DMF
(1.5 mL). This is added dropwise to an ice-cold solution of POC13 (500 }a.L, 5.2 mmol) in DMF
(1.75 ml). After stirring at room temperature for 90 minutes, the reaction mixture is re-cooled in an ice bath and is slowly quenched with 6N NaOH (4 mL). The reaction mixture is partitioned between EtOAc and HZO_ Purification by silica gel chromatography (EtOAc/CHzClz, 5/95) yields 1-ethyl-6-methoxy-IH-indole-3-carbaldehyde (849 mg, 81%) as a yellow solid.
Step B: I-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol) is dissolved in acetone (85 mL). A solution of KIvInO4 (450 mg, 2.85 nimol) in H20 (28 mL) is added. This is stirred at room temperature for 5 hours. Another solution of KMnO4 (450 mg, 2.85 mmol) in H20 (25 mL) is then added. After stirring for another hour at room temperature, the reaction is complete_ The reaction mixture is quenched with 10% H202 (1.5 mL), and is then filtered through celite. The filtrate is stripped down under vacuum to roughly 1/3 of the volume. The residue is acidified with 6N HCI, and is extracted into ethyl acetate. Purification by silica gel column (hexanes/acetone/acetic acid, 70/30/1) yields crude product. Trituration with ether yields pure 1-ethyl-6-methoxy-lH-indole-3-carboxylic acid (365 mg, 56%) as a yellow solid.
Step C: 1-Ethyl-6-methoxy-lH-indole-3-carboxylic acid (250 mg, 1.14 mmol) is suspended in a solution of CHZCI2 (12.5 mL) and DMF (10 L). Oxalyl chloride (230 L, 2.64 mmoI) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH40H (5 mL).
This is then partitioned in H20 and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 1-ethyl-6-methoxy-lH-indole-3-carboxamide (134 mg, 54%) as a white solid.
Step D: 1-Ethyl-6-methoxy-lH-indole-3-carboxamide (120 mg, 0.55 mmol), Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) are heated at 90 C
for 90 min.
The reaction mixture is concentrated and purified by silica gel chromatography (EtOAc/CH2C12, 1/9) to yield 1-ethyl-6-methoxy-lH-indole-3-thiocarboxamide as a yellow solid (92 mg, 71 %).
Step E: 1-Ethyl-6-methoxy-lH-indole-3-tluocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 gL, 1.86 mmol) are heated at 80 C for 16h. More bromoacetaldehyde dimethyl acetal (250 L.) is added. This is heated at 80 C for 2h. Addition of 250 L more bromoacetaldehyde dirnethyl acetal is followed by heating for another 2 hours. The reaction mixture is cooled to room temperature, absorbed onto silica and purified by silica gel chromatography (hexanes/EtOAc, 7/3) to afford 1-ethyl-6-methoxy-3-thiazol-2-yl-LH-i.ndole as a brown oil (44 mg, 47%).
The following compounds are prepared following the procedure described above:
Compounds 78, 101, 104, 105 and 106.

Example 1S: Preparation of 1-ethyl-6-methoxy-2-phenoxymethyl-lH-indole-3-carbonitrile (compound 99).

CN
LiAIH4 CISOZNCO I ~ ~
Me0 I ~ N C02Me dioxane MeO N pMF MeC ~ N
H OoC H H
CN CN
NaH NaH
benzoyl peroxide DMF Me0 I~ N NBS Me0 N Br OH
Etl > benzene / DMF
CN

Me0 O 0 Step A: To a suspension of LiAIHa (7.6 g, 0.2 mol) in dioxane (100 mL) is added dropwise a solution of inethyl6-rnethoxy-lH-indole-2-carboxylate (8.2 g, 0.04 mol) in dioxane (50 mL) at 0 C. After the addition, the mixture is stirred at room temperature for lh and then heated at reflux for 5h. After cooling to 0 C, the reaction is quenched by water (dropwise) and then 15% aqueous NaOH. After stirring at room temperature for lh, the mixture is filtered through Celite. The solid is washed with a large amount of EtOAc. The solvent is washed with brine, dried over Na2SO4 and evaporated under vacuum. The residue is purified by flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 61%
of 6-methoxy-2-methyl-lH-indole.
Step B: To a solution of 6-methoxy-2-methyl-lH-indole (3.9 g, 24 mmol) in acetonitrile (200 mL) and DMF (20 mL) is added dropwise a solution of C1SO2NCO (4 mL, 1.3eq.) in acetonitrile (31 mL) at 0 C. After the addition, the mixture is stirred at room temperature for 3h. Then it is poured into ice water and saturated NaHCO3 is added to it until it becomes basic.
The aqueous phase is extracted with CH2C12 and then evaporated. The residue is purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of 6-methoxy-2-methyl-lH-indole-3-carbonitrile.

Step C: To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) is added a solution of 6-methoxy-2-methyl-lH-indole-3-carbonitrile (1.3 g, 7.0 mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0 C. After stirring for lh, the mixture is poured into ice water and then extracted with CH2Cl2. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (1/5) as eluent to yield 92% of 1-ethyl-6-methoxy-2-methyl-lH-indole-3-carbonitrile_ Step D: To a solution of 1-ethyl-6-methoxy-2-methyl-lH-indole-3-carbonitrile (1.38 g, 6.45 mmol) in benzene (130 mL) is added benzoyl peroxide (226 mg) and NBS
(1.21g, 1.05eq.). Then the mixture is heated to reflux for 3h. After cooling and filtering, the filtrate is concentrated under vacuum. The crude 2-bromomethyl-l-ethyl-6-methoxy-lH-indole-carbonitrile (1.6 g, 86%) is used without further purification.
Step E: To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) is added 2-bromomethyl-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (80 mg, 0.274 mmol) and phenol (2 eq.). After stirring for 20h, the mixture is poured into ice water and ex[racted with CH2C12. The organic layer is washed with brine and dried with Na2SO4. The solvent is evaporated under vacuum and purified with flash column chromatography on silica gel using EtOAc/petroleum ether (115) as eluent to yield 1-ethyl-6-methoxy-2-phenoxymethyl-lH-indole-3-carbonitrile, compound 99.

Example 1T: Preparation of 6-nitro-2-pyrrol-l-yl-lH-indole-3-carbonitrile (compound =
7).

CN CN
F KZC03 Me0 p OMe ~ ~ \
p2N NH2 NC~CN 0 N ~/ N NH2 AcOH 02N I N N~
DMF Z
A
Step A: A solution of 2-fluoro-5-nitroaniline (11.7 g, 74.9 mmol) in dimethylformarnide (120 mL) is treated with malononitrile (5.28 g, 80.0 mmol) and potassium carbonate (11.05 g, 80.0 mmol) (Modification of Chem. Heterocyclic Cpd. Engl Trans., 9, 37 (2001)). The resulting heterogeneous mixture is heated to gentle reflux for 3h, then cooled and poured into water (500 mL). The resulting precipitate is collected by filtration and taken up into ethyl acetate (300 mL). This solution is dried over Na2SO4, filtered and partially evaporated to give a precipitate, which is collected by filtration. Further evaporation and filtration give a second crop. The two crops are combined and dried under vacuum to give 2-amino-l-ethyi-6-nitro-1H-indole-3-carbonitrile (7.90 g, 52%) as an orange powder.
Step B: A solution of 2-amino-6-nitro-lH-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) is treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution is heated to reflux for 14h. After cooling to ambient temperature, the solution is poured into water (100 mL), and solid sodium bicarbonate is added until CO2 evolution ceased.
The mixture is extracted with EtOAc (2 X 100 mL), and the extracts are washed with saturated brine, combined, dried over MgSO4, filtered and concentrated. The residual material is separated by silica gel chromatography (EtOAc/hexanes, 114) to afford 6-nitro-2-pyrrol-l-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51 %).

Example lU: Preparation ofN-(3-cyano-l-ethyl-6-nitro-lFl-indol-2-yl)acetamide (compound 25).

CN CN CN O\
NaH NaH ~ I-\ ~ X \ NH
OZN N NH2 DMSO NHz aceiyl chloride O2N ~ N
H Ett O2N dioxane ~

Step A: Sodium hydride (42 mg, 1.05 mmol, 60% w/w suspension in mineral oil) is washed with hexane and taken up in dimethylsulfoxide (1 mL). A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (prepared in procedure IT) in dimethylsulfoxide (1 mL) is added by, syringe, and the resulting mixture is stirred for 20 min. Then, iodoethane (77 L, 0.96 mmol) is added by syringe, and the mixture is stirred for 14h_ The reaction is then poured into EtOAc (50 mL), and this solution is washed with water (3 X 50 mL) and saturated brine (40 mL). The aqueous phases are back-extracted with EtOAc, and the organic extracts are combined, dried over Na2SO4, filtered and evaporated. The residual material is separated by column chromatography over silica gel (EtOAc/hexanes, 1/1) to afford first a small amount of a dialkylated analog, then the desired compound, 2-amino-l-ethyl-6-nitro-lH-indole-3-carbonitrile (114 mg, 52%), and finally unreacted starting material. The desired product is isolated as an orange powder.
Step B: Sodium hydride (44 mg, 1.10 mmol, 60% w/w in mineral oil) is washed with hexanes and suspended in 1,4-dioxane (3 mL). A solution of 2-amino-l-ethyl-6-nitro-lH-indole-3-carbonitrile (120 mg, 0.521 mmol), prepared in step B, above, in dioxane (2 mL) is added, and the resulting mixture is allowed to stir for 30 min. Then, acetyl chloride (45 L, 0.63 mmol) is added by syringe, and the solution is stirred for an additional 12h. The reaction is partitioned between water and EtOAc (20 mL each), and the organic phase is washed with brine. The aqueous phases are back-extracted in sequence with ethyl acetate, and the organic extracts are combined, dried over MgSO4, filtered and evaporated. The resulting solid is triturated with Et20, collected by filtration and dried under vacuum to afford 1V-(3-cyano-l-ethyl-6-nitro-lH-indol-2-yl)-acetamide (100 mg, 71%), compound 25, as an off-white powder.
Using this procedure and substituting the appropriate acid chlorides or chloroformates gives the following compounds: Compounds 23, 26, 35, 36, 203, 204, 214, 215, 216.
Example 1 V: Preparation of N-ethyl-3-phenyl-5-nitroindole (compound 41).

pyridinium bromide Br ~% B(OH)2 OZN \ I perbromide O2N \
H pyridine H Pd(OAc)2 PPh3 DME
NaZCO3 02N NaH OZ N
JrNi J
DMF H Etl Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine (200 mL) at -4 C

is added a solution of pyridinium bromide perbromide (10.99 g, 34.3 mrnol) in pyridine (200 mL) dropwise under nitrogen with stirring. After complete addition, the reaction mixture is stirred for 5 min at 0 C. The reaction mixture is diluted in 0 C water (200 mL) and extracted with 200 mL of Et20. The organic layer is washed with 6 M HCI (300 mL), 5%
NaHCO3 (300 mL), and brine (300 mL). The organic phase is dried over MgSO4 and solvent is removed to give 3-bromo-5-nitroindole as a yellow powder, 80% pure with 20% 5-nitroindole (6.80 g, 74%yield).
Step B: A solution of 3-bromo-5-nitroindole from above (625 mg, 2.1 mmol), phenylboronic acid (381 mg, 3.13 mmol), triphenylphosphine (109.3 mg, 0.417 mmol) in dimethoxyethane (4.16 mL) is degassed. To this mixture 2N sodium carbonate (6.25 mL) is added, and the reaction mixture is degassed again. To the reaction is added palladium (II) acetate (23.4mg, 0.104 mmol), and the reaction is refluxed under dry nitrogen with stirring for 8 hours. The reaction mixture is then diluted with I M HCI (100 mL), and extracted with ethyl acetate (100 mL). The organic phase is washed with water (100 mL), and brine (100 mL). The organic phase is dried over MgSO4 and concentrated in vacuo. The crude product is purif'ied by chromatography over silica gel (EtOAc/hexanes, 10/90) to afford 3-phenyl-5-nitroindole as an orange powder (45 mg, 9% yield).
Step C: To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) and DMF
(1.0 mL) is added dropwise a solution of 3-phenyl-5-nitroindole (40.0 mg, 2.1 mmol) in DMF (0.75 rnL)- The reaction mixture is stirred for 20 min at 0 C under N2. Ethyl iodide (14.8 L, 0.185 mmol) is added dropwise and the reaction mixture is stirred for an additional 3 hours. The reaction mixture is diluted with water (250 mL), and extracted with EtOAc (30 mL). The organic phase is washed with water (250 mL) and is then dried over MgSO4 and the solvent is removed in vacuo. The desired N-ethyl-3-phenyl-5-nitroindole is obtained as a yellow powder (40.0 mg, 89.5% yield).
In similar fashion the following compound is prepared: Compound 40.

Example 1W: Preparation of [3-Cyano-l-(4-methoxyphenyl)-1H-indol-6-yl]-carbamic acid propyl ester (compound 97).

/N /
I ~ ^~OCOCI 0 ( ~
H2N ~ N t v~O~N ~ N

EtOH 0 so /-0 6-Amino-l-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), is suspended in EtOH (300 L). Propyl chioroformate (168 L, 1.5 mmol) is added, and this mixture is stirred at room temperature overnight. The addition of triethyla.mine (300 L), followed by another hour of stirring at room temperature, completes the reaction. This reaction mixture is loaded directly onto a silica column, and is eluted with CH2C12.
Another silica column (3/2, ether/hexanes) is needed to fully purify the product, [3-cyano-l-(4-methoxy-phenyl)-IFl-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.

Example 1X: Preparation ofN-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-methanesulfonamide (compound 130).

/N // N
.
O
MeS02Cl ~ - - NW
I - NH2 ~ - ~ /
~10 pyridine ~O N
j; rt 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (50 mg, 0.16 mmol), prepared as described by the method of Example 1H, is dissolved in pyridine (550 L) at room temperature. Methanesulfonyl chloride (17 pL, 0.21 mmol) is added dropwise. This is stirred overnight at room temperature. The reaction mixture is then diluted in ethyl acetate and is washed with aqueous HCI, followed by brine. The organic layer is dried and concentrated.
Purification by silica gel chromatography (9/1, CHZCIz/EtOAc) yields N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-methanesulfonamide (58 mg, 92%) as an off-white solid.
The following compounds are made using the procedure shown above, by substituting the appropriate aminophenylethynyl indoles and sulfonyl chlorides: Compounds 131, 132, 208, 209, and 210.

Example lY: Preparation of N-[4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-methanesulfonamide (compound 129).

!N /N
O~- /
- MeSOaCI ~ - S~O
I \ -_ ~ / NH
O N NHZ EtsN O / f > THF
rt A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0 C and treated with triethylamine (0.04 mL, 0.31 mmol) and methanesulfonylchloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H20 and extracted with ethyl acetate (3X). The organic phase is washed with Ha0 and saturated NaCI, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%) ofN-[4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-methanesulfonamide as a tan solid.
Using essentially the same procedure as above and substituting the appropriate aminophenylindole and sulfonyl chloride or carrying out the reaction in pyridine as both base and solvent gives the following compounds: Compounds 83, 85, 86, 87, 88, 243, 251, 252, 272, 273, 287, 289, 365, 366, 367, 368, 369, 370, 371, 394, 439, 440, 448, 449, 451, 452, 477, 487, 488, 495, 505, 510, 548, 549, 550, 551, 552, 562, 563, 598, 599, 601, 602, 608, 609, 610, 615, 616, 617, 621, 622, 623, 629, 630, 631, 639, 655, 657, 658, 662, 669, 670, 671, 674, 675, 701, 702, 703, 706, 707, 708, 709, 710, 711, 713, 715, 720, 789, 790, 791, 850, 851, 867, 868, 890, 891, 912, 919, 920, 921, 922, 923, 924, 932, 933, 934, 935, 941, 953, 968, 982, 988, 990, 995, 996, 997, 998, 1035, 1038, 1041, 1103, 1105, 1115, 1116, 1117, 1123, 1140, 1141, 1155, 1160,1161,1170,1175,1181,1182,1188,1189,1228,1229,1230,1231,1280.

Example 1Za: Preparation ofN-[4-(3-cyano-I-ethyl-6-methoxy-lH-indol-2-ytethynyl)-phenyl]-acetamide (compound 138).

N O
Acetyl chioride Me0 N NHy Et3N MeO N \/ NH
THF

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-lFl-indole-3-carbonitrile (95 mg, 0.29 mmol), prepared as described in Example I H, is dissolved in THF (1.4 mL).
Triethylamine (84 gL, 0.6 mmol) is added, followed by dropwise addition of acetyl chloride (44 L, 0.5 mmol).
This is stirred at room temperature for lh. The reaction naixture is partitioned between H20 and EtOAc. The organic layer is dried and concentrated. Purification by silica chromatography (9/1, CH2CI2/EtOAc) yields N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-acetamide (103 mg, 96%) as a yellow solid.
The following compounds are prepared by the procedure shown above, substituting the appropriate aminophenylethynyl indoles and acid chlorides: Compounds 82, 139, 152, 153, 162, 163, 165, 167, 205, 206, 207, 211, 212, 213, 219, 224, 225, 228.

Example lZb: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-formamide (compound 241).

CN CN
~ i I` \ NH Ac20, HCOOH I% \ _ ~~ NHCHO

Me0 N THF Me0 N

Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) are heated at 65 C for 1 hour.
This is cooled to 0 C. 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as in example 1H, is taken up in THF (1.2 mL) and added to the formic acetic anhydride mixture. This is stirred at 0 C for 30 minutes.
The reaction mixture is then partitioned between H20 and EtOAc. The EtOAc layer is washed with saturated NaHCO3, followed by saturated brine. The organic layer is dried and concentrated.
Purification by silica gel chromatography (4/1, CH2Cl2/EtOAc) yields of N-[4-(3-cyano-1-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-formamide (105 mg, 96%) as a yellow solid.
The following compound is prepared similarly as described above: Compound 218.
Example lAA: Preparation of N-[4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-acetamide (compound 128).

N N
~ _ 0j~-\ ~ NH AcCt_~ I ~ \ NH
p i ~ N \ ~ 2 EtsN
THF
A solution of 2-(4-aminophenyl)-1-ethyl-6-rnethoxy-lFl-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL) is cooled to 0 C and treated with triethylamine (0.04 mL, 0.31 mmol) and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to room temperature overnight. The reaction mixture is then diluted with H20 and extracted with ethyl acetate (3X). The organic phase is washed with H20 and saturated NaCI, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 57 mg (71%) ofN-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]acetamide as a tan solid.
Using essentially the same procedure as above and substituting appropriate aminophenyl indoles and the acid chlorides, the following compounds are prepared:
Compounds 81, 242, 244, 324, 325, 326, 327, 328, 329, 330, 383, 420, 421, 422, 423, 424, 425, 544, 558, 559, 560, 561, 565, 566 567, 644, 645, 646, 755, 756, 757, 759, 760, 761, 762, 763, 764, 765, 766, 798, 799, 801, 802, 803, 804, 854, 855, 856, 857, 858, 859, 895, 896, 897, 898, 899, 900, 901, 913, 914, 915, 916, 983.

Example IAB: Preparation of 1-[3-(3-cyano-I-ethyl-6-methoxy-IH-indol-2-ylethynyl)phenyl]-3-ethyl urea (compound 220).

/N N
/
::: _ N
NH2 ~ HN
MV-\
2-(3.-Arninophenylethynyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is dissolved in pyridine (670 L).
Ethyl isocyanate (62 L, 0.75 mmol) is added. The reaction mixture is then heated at 100 C for 2h.
The mixture is then diluted in EtOAc, and is washed with aqueous HCl, followed by brine.
The organic layer is dried and concentrated. Purification by silica chromatography (4/1, CH2CI2/EtOAc), followed by trituration with hexanes/acetone (1/1), yields 1-[3-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.

Example 1AC: Preparation of 1-(2-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-lH-indoi-2-ylethynyl)-phenyl] urea (compound 156).

N A ~ci N - ~/ NHZ toluene N - ~~ NH
A

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mrnol), prepared as described in Example 1H, is suspended in toluene (60011L).
2-Chloroethyl isocyanate (32 p.L, 0.37 mmol) is added, and the mixture is heated at 100 C
for 5h. The reaction mixture is then cooled, diluted in acetone, and absorbed onto silica.
Purification by column chromatography (5-10% EtOAc in CHaCI2) yields 1-(2-chloro-ethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl] urea (73 mg, 54%) as a yellow solid_ The following compound is prepared using the procedure above: Compound 221.

Example lAD: Preparation of Ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyljmethyl amide (compound 157).

N N
O. K2C03 O-.
NH O Mel ~ DMF ) N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)phenyl] ethanesulfonamide (70 mg, 0.17 mmol), prepared as in Example 1X, is combined with K2CO3 (49 mg, 0.35 rnmol), and DMF (1.0 mL). lodomethane (16 L, 0.26mrnol) is added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is then diluted in EtOAc, and is washed with H20 and then brine. The organic layer is dried and concentrated.
Purification by silica chromatography (95/5, CH2C12/EtOAc) yields a light tan solid. Trituration gives ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]methyl amide (61 mg, 85%) as an orange-white solid.
The following compounds are prepared using the procedure above, substituting the appropriate sulfonamide: Compound 182, 652, 840.

Example 1AE: Preparation of 1-ethyl-5-methoxy-2-[4-(morphoiine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (compound 245).

MeO ~ \ ^ NaOH Me0 N C02Me H2OJTHF COZH
N
1. (COCI)2/DMF Me0 ~ O

2. morpholine f~ N N
~) Step A: Methyl 4-(3-cyano-l-ethyl-5-methoxy-lH-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example i Ga step B, is combined with NaOH (40 mg, 1 mmol), H~O (0.8 rnL), and THF (3.4 mL) and is heated at 80 C for 1 hour. The reaction mixture is diluted in H20 and is then ether-washed. The aqueous layer is acidified with aqueous HCl, and is extracted into EtOAc. The organic layer is dried and concentrated to yield 4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-benzoic acid (311 mg, 92%) as a pure white solid.
Step B: 4-(3-cyano- 1 -ethyl-6-methoxy- IH-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) is suspended in CH2Cl7- (2.2 mL) and catalytic DMF (2 L). Oxalyl chloride (22 L, 0.25 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour, at which time full dissolution occurred. This reaction mixture is pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CH2C12 (5m1). After addition is complete, the reaction mixture is washed with aqueous HCl solution. The organic layer is dried and concentrated.
Purification by silica column (1:1 CHZC12/EtOAc) yields 1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 90%) as a white solid.
The following compounds are prepared similarly as described above: Compounds 113, 114, 246, 270, 271 290, 291, 292, 323, 377, 378, 379, 380, 381, 382, 384, 385, 386, 387, 388, 389, 390, 391, 392, 432, 433, 564, 568, 569, 570, 571, 572, 573, 647, 648, 853, 860, 861, 862.

Example lAF: Preparation of cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-ylethynyl)-phenyl] amide (compound 194).

o\\ o\\
BBfg \
MeO CLN H CH2CI2 HO ~ 'H

Cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-methoxy-IH-indol-2-ylethynyl)-phenyl]-amide (60 mg, 0.16 mmol), prepared as described in Example 1Za, is stirred in BBr3 (800 L, 1M in CH2C12, 0.8 mmol) at room temperature for 1 hour. The reaction mixture is quenched with H20, aind is extracted with CH2C12. The organic layer is dried and concentrated.
Purification by silica chromatography (EtOAC) gives impure product. This crude product is triturated with 1/1 hexanes/acetone to yield cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-ylethynyl)-phenyl]-amide (32 mg, 54%) as an off-white solid.
The following compounds.are prepared using the procedure above, substituting the appropriate sulfonamides (from Example 1X) or amides (from Example 12):
Compounds 164, 168, 183, 193, 195.

Example lAG: Preparation of 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (compound 166).

N
N ci ~~
O H
~-NH I \
NH ~~ o N \ / ~J
K2COs N
p ~ DMF ~

1-(2-Chloroethyl)-3-[4-(3 -cyano-l-ethyl-6-methoxy-1 H-indol-2-yl ethynyl)-phenyl]
urea (55 mg, 0.13 mmol), prepared as in Example 1AC, is combined with K2C03 (50 mg, 0.36 nunol) and DMF (550 L). This mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted in EtOAc, and is washed with H20, and then with brine. The organic layer is dried and concentrated. Purification by silica chromatography (10-50%, EtOAc/CH7-Cl2) yields 2-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile (47 mg, 94%) as a white solid.
The following compound is prepared using the above procedure, substituting the appropriate urea: Compound 222_, Example 1AH: Preparation ofN-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (compound 227).

N N
NH2 HN-~P-I ~ ~ - - Me2P(O)CI
N Pyridine '-O N
THF
rt 2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is dissolved in pyridine (300 L) at 0 C.
Dimethylphosphinic chloride (60 mg, 0.53 mmol) in THF (300 L) is added. _ The reaction is stirred at room temperature for 2 hours. The reaction mixture is diluted in EtOAc, and is washed with aqueous HCI followed by brine. The organic layer is dried and concentrated.
Purification by silica chromatography (acetone) yields N-[4-(3-cyano-I-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-dimethylphosphinic amide (65 mg, 52%), compound 227, as a pure white solid. The silica column is then flushed with 9/1 CH2C12/MeOH to yield 9 mg of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-bis-(dirnethylphosphinic) amide as a by-product.

Example 1AI: Preparation of 1-ethyl-6-methoxy-3-[5-(4-methoxyphenyl)-isoxazol-yl]-1H-indole (compound 116).

OH OH
N\ N OMe H NCS ~ \ Ci I~ OMe rj O J ~ I
( \ --- \
Me0 pyridine MeO ~ N Et3N

rt Me0 N

Step A: A mixture of 1-ethyl-6-methoxy-lFl-indole-3-carbaldehyde oxime (0.20 g, 0.92 mmol), prepared from the aldehyde precursor in example 1R, in dichloroethane (3 mL) is treated with N-chlorosuccinimide (0.12 g, 0.92 mmol) and pyridine (0.04 mL, 0.46 mmol) and stirred at room temperature for lh. The reaction mixture is then poured into H2O and acidified with 1 N HCl until the pH is 2_ The mixture is extracted with EtOAc and the organic phases are washed with H20 and saturated NaCt and dried and concentrated to a mixture of chlorooximes, which are used in the next step without fiuther purification.
Step B: The mixture of chlorooximes prepared above is dissolved in CH2CI2 (5 mL) and to this is added 4-methoxyphenylacetylene (0.24 g, 1.84 mmol) and triethylamine (0.25 mL, 1.84 mmol) at 0 C and the reaction is then stirred overnight warming to room temperature. The reaction is then diluted with H20 and extracted with EtOAc (3X). The organic phases are washed with HZO and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/hexanes, 10-20%) gives 76 mg (24%) of 1-ethyl-6-methoxy-3-[5-(4-methoxy-phenyl)-isoxazol-3-yl]-1H-indol.e as a tan solid.

Example lAJ: Preparation of [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-carbarnic acid ethyl ester (compound 121).

CN CN O ~--_ CICOOEt -_ Me0 f~ N NH2 NH
NaHC03 Me0 N
~ EtOAc ~

A biphasic mixture of 2-(4-amino-phenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (70 mg, 0.24 mmol), prepared as described in example 1Ga step B, and ethyl chioroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHC03 (3 mL) is prepared at 0 C and then allowed to warm to room temperature and stirred for 24h. The reaction is then diluted with Ha0 and extracted with EtOAc (2X). The organic phases are washed with H20 and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 20-40%) gives 48 mg (55%) of [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-carbamic acid ethyl ester as an off-white solid.
The following compounds are prepared in similar fashion: Compound 122, 293, 294, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 372, 434, 435, 450, 453, 454, 455, 457, 485, 486, 489, 490, 500, 501, 502, 503, 506, 507, 508, 509, 545, 546, 547, 553, 554, 555, 556, 557, 581, 582, 583, 584, 585, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 603, 604, 605, 606, 607, 618, 619, 624, 625, 637, 640, 641, 664, 665, 676, 677, 721, 722, 723, 734, 735, 736, 737, 738, 739, 744, 745, 746, 747, 787, 788, 792, 793, 794, 795, 796, 797, 819, 822, 823, 824, 825, 826, 849, 925, 926, 945, 946, 947, 948, 949, 950, 951, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 981, 984, 985, 986, 991, 992, 993, 1015, 1020, 1021, 1022, 1029, 1030, 1031, 1032, 1033, 1034, 1037, 1040, 1042;
1044, 1055, 1056, 1057, 1058, 1059, 1062, 1063, 1064, 1065. 1071, 1073, 1074, 1075, 1077, 1078, 10791107, 1109, 1111, 1112, 1113, 1114, 1122, 1127, 1128, 1129, 1145, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1169, 1174, 1176, 1177, 1178, 1179, 1180, 1186, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1211, 1222, 1232, 1233, 1300, 1302.

Example 1AK: Preparation of 1-ethyl-5-thiophen-3-yl-lH-indole-3-carbonitrile (compound 141).

B(OH)2 CN
CN S aWN
Br PdCta(PPh3)2 CsF

DME
A tube is charged with a mixture of 5-bromo-1-ethyl-1HHindole-3-carbonitrile (100 mg, 0.40 mmol), thiophene-3-boronic acid (72 mg, 0.56 mmol), PdCI2(PPh3)2 (11 mg, 0.016 mmol) and CsF (152 mg, 1 mmol) and then alternately evacuated and filled with nitrogen (3X) and diluted with dimethoxyethane (3 mL) and then heated to 90 C for 19h. After cooling, the crude reaction mixture is diluted with saturated NaHCO3 and extracted with EtOAc (2X). The combined organic phases are washed with saturated NaCl and dried and concentrated. Flash chromatography over silica gel (CH2C12/hexanes, 40/60) gives 25 mg (25%) of 1-ethyl-5-thiophen-3-yl-lH-indole-3-carbonitrile as a white solid.
The following compounds are prepared in similar fashion: Compounds 140 and 142.
Example IAL: Preparation of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-N-methyl methanesulfonamide (compound 180).

N
!
!
X ~'S NaH ~ - O O
O I N NH O Mel O I ~ N ~/ N
1) DMF

A solution of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]
methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) is treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min.
lodomethane (0.03 mL, 0.53 mmol) is added, and the mixture is stirred at room temperature for 18h. The reaction mixture is then diluted with H20, and extracted with EtOAc (2X). The organic phases are washed with H20 and saturated NaCI and then dried and concentrated.
Purification by flash chromatography over silica gel (EtOAc/CH2C12, 0-1 %) gives 60 mg (45%) ofN-[4-(3-cyano-l-ethyl-6-methoxy-lFl-indol-2-yl)-phenyl]-N-mthyl methanesulfonamide as a white solid.
In similar fashion the following compounds are prepared: Compounds 181, 642, 643, 672, 673, 816, 852, 1002, 1003, 1004, 1005, 1006, 1007.

Example lAM: Preparation of N-[4-(3-cyano-l-ethyl-6-hydroxy-IFl-indol-2-yl)-phenyl]-methanesulfonamide (compound 189).

N
/%~ &N' / O ,S O BBr3 ~O
N NH CH2CI2 HO Me0 A solution of N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]
methanesulfonamide (85 mg, 0.23 mmol) in CH2C12 (2 mL) is cooled to -5 C. A
solution of boron tribromide (1.15 mL, 1.15 mmol, 1M solution in CH2C22) is added and the reaction mixture is allowed to warm to 10 C over 4h. The reaction mixture is poured into H20 and extracted with EtOAc (3X). The combined organic phases are washed with H20 and saturated NaCl and dried and concentrated. Chromatography over silica gel (EtOAc/CHaC12, 5-10%) gives 18 mg (22%) of N-[4-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-yl)-phenyl]
methanesulfonamide as a tan solid.
The following compounds are made similarly: Compounds 190, 191, 192.
Example 1AN: Preparation of inethyl3-[5-(3-cyano-6-methoxy-lH-indol-2-yl)-[1,2,4]oxadiazol-3-yljbenzoate (compound 226).

CN CN CN
(Boo)20 LDA ~
COzH
N DMAP ~O I ~ N CO2 (9) I/ N
H CH2CI2 Boc O Boc HO-N O CN
1. HZN ~ \ O~ \ O
N N
DCE H O
HOBt 2.A
Step A: To a mixture of 6-rnethoxy-lH-indole-3-carbonitrile (5.88 g, 40 mmol), prepared as described in the previous examples, and (Boc)20 (9.59 g, 44.0 mmol) in DCM (50 mL) is added DMAP (0.10 g, 0.8 mmol). The mixture is stirred at room temperature for 48h, then treated with water (30 mL) and dried over anhydrous Na2SO4. The crude product is chromatographed over silica gel (hexanes/EtOAc, 7/1) to fizrnish the desired intermediate, 3-cyano-6-methoxyindole-l-carboxylic acid tert-butyl ester (8.48 g, 86%).
Step B: The above intermediate (2.72 g, 10.0 mmol) is dissolved in anhydrous THF (20 mL), and cooled at -78 C, followed by the addition of LDA (1.5 M monoTHF in cyclohexane, 10.0 mL, 15 mmol). After stirring for 45 min, CO2 gas is introduced for 2h.
The mixture is then brought to room temperature and the solvent is removed in vacuo, and the residue is treated with water and acidified to pH = 2 with 6 N HC1. The precipitate is collected and washed with water and dried to provide the acid intermediate, 3-cyano-6-methoxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester (2.40 g, 73%).
Step C: To a solution of 3-cyano-6-rnethoxyindole-l,2-dicarboxylic acid 1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg, 1.5 mmol) in DCE/DMF (10 mL/1 mL), is added DCC (310 mg, 1.5 mmol), followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg, 1.5 mmol). The mixture is stirred at room temperature for 2h and filtered. The filtrate is collected and the solvent is replaced with chlorobenzene, followed by the heating at 150 C for 48h. After cooling to room temperature, the solvent is removed in vacuo and the residue is chromatographed (silica gel, CH2CI2/EtOAc, 8/2) to furnish the intermediate, 3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-l-carboxylic acid tert-butyl ester, which is treated with 50% TFA in DCM (10.0 mL) at room temperature for lh.
After removal of the volatiles in vacuo, the.residue is suspended in water and neutralized with K2C03 to provide the desired product, methyl3-[5-(3-cyano-6-methoxy-lH-indol-2-yl-)[
1,2,4]oxadiazol=
3-yl]benzoate, compound 226 (350 mg, 62%).

Example lAO: Preparation of 1-ethyl-2-(4-methanesulfonylphenyl)-6-methoxy-lH-indole-3-carbonitrile (compound 265).

CN CN
m-CPBA -sMe \ S02Me Me0 N CHaCf2 MeO N ~~
~ rt ~
A solution of 1-ethyl-6-niethoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitriie (0.12 g, 0.37 mmol) in CH2CI2 (5 mL) is treated with m-chloroperbenzoic acid (Aldrich, <
77%, 0.26 g) in one portion and the reaction is stirred for I Oh at room temperature. The reaction is then diluted with HZO and saturated NaHCO3 and extracted twice with EtOAc. The organic phases are washed with NaHCO3 (2X) and saturated NaCl and dried and concentrated to a dark semi-solid. The crude product is purified by flash chromatography (EtOAc/CH2C12i 0-3%) through a 5 gram silica cartridge topped with 1 gram of basic alumina to give 72 mg (55%) of 1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile as an off-white solid.

Example IAP: Preparation of N-{4-[3-cyano-l-ethyl-6-(2-morpholin-4-yl-ethoxy)-indol-2-yl]-phenyl} methanesulfonamide (compound 478).

CN o, 5p ~N OIPEA H CN 0'10 \
CI~~O N / N NH
N
> Nat I>

A

A solution of N-{4-[6-(2-chloroethoxy)-3-cyano-l-ethyl-1H-indol-2-yl]-phenyl}
methanesulfonamide (90 mg, 0.21 mmol), morpholine (0.06 mL, 0.65 mmol), NaI
(32 mg, 0.21 mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol) in CH3CN (2 mL) is heated in a sealed tube at 100 C for 25h. The reaction mixture is cooled to room temperature, diluted with H20 and extracted with EtOAc (3X). The combined organic phases are washed with saturated NaCl, dried and concentrated. The crude solid is triturated with EtOAc and filtered to give 41 mg (41%) ofN-{4-[3-cyano-l-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}
methanesulfonamide as a tan solid.
The following compounds are made similarly: Compounds 479, 480, 481, 482, 496, 497 and 498.

Example lAQ: Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] amide (compound 653).

CN 00 CN `
NHz ,HcO
Me0 N pyridine Meo N \/

N
~..NH CN

Me0 e Step A: A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile, prepared by example 1 Ga step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) is treated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 rnmol) at room temperature. After stirring for 4h, the reaction mixture is quenched with ice-water and enough 6N
HCl is added until the pH is lowered to 2. The suspension is extracted with hot EtOAc (3X).
The organic phases are then washed sequentially with 1N HCI, H20 and saturated NaCI and dried and concentrated to give ethenesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] amide as a pale orange solid which is used directly in the next step without further purification_ Step B: A suspension of ethenesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-1HHindol-2-yl)-phenyl] amide, prepared above, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH3CN (1.5 mL) is heated at reflux for 1.5h. After cooling to room temperature, the reaction is concentrated and the residue is purified by flash chromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg (100%) of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] amide as a tan foam.
The following compound is made similarly: Compound 654.

Example lAR: Preparation of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] methyl amide (compound 668).

`N_ 3 N
CN 0`~ K2C03 CN
S,O ~
NH Met ~ / \ \ ~ N S
meo I ~ N N
DMF Me0 r.t.

A solution of 2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-~
indol-2-yl)-phenyl] amide, prepared in example 1AQ (60 mg, 0.13 mmol) in DMF
(3 mL) is treated with K2C03 (35 mg, 0.26 mmol) and methyl iodide (0.02 mL, 0.26 mmol).
After stirring at room temperature for 1.5h, the reaction mixture is diluted with H20 and extracted with EtOAc (2X). The organic phases are then washed with H20 (3X) and saturated NaC1, and then dried and concentrated to afford a residue. Flash chromatography over silica gel (acetone/EtOAc, 0-2%) gives 31 mg (50%) of2-morpholin-4-yl-ethanesulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] methyl amide as an off white solid.
The following compounds are made similarly: Compounds 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698.

Example lAS: Preparation of2-[4-(1,1-dioxo-11 6-isothiazolidin-2-yl)phenyl]-l-ethyl-6-methoxy-lH-indole-3-carbonitrile (compound 84).

CI
CN pSp CI CN
I~ \ NH2 C1' I\ \ NH ~
meo ~ N pyridine meo ~ N
~ r.t.
K2CO3 cN a\o DMF N
7o C meo N

Step A: A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile, prepared by example 1Ga step B, (2.78 g, 9.55 mmol) in pyridine (40 mL) is treated dropwise with 3-chloropropanesulfonyl chloride (1.45 mL, 11.9 mmol) and the reaction is stirred for 4h at room temperature. The reaction is diluted with water and enough 6N HCl to lower the pH to 2. The reaction mixture is extracted with EtOAc (3X) and the combined organic layers are washed sequentially with IN HCI, water and saturated NaCI and then dried and concentrated to give 3.9 g (95%), of 3-chloropropane-l-sulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] amide as a brown foam which is used directly in the next step.
Step B: A solution of 3-chloropropane-l-sulfonic acid [4-(3-cyano-l-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide, prepared above (3_65 g, 2.33 mmol) in DMF (100 mL) is treated with K2C03 and heated at 70 C for 2h. After cooling to room temperature, the reaction mixture is diluted with H20 and extracted 3X with hot EtOAc. The hot organic layers are washed with warm H20 (3X) and saturated NaCI and dried and concentrated to a solid.
Trituration (CH2C12/hexanes) gives 2.27g (68%) of 2-[4-(1,1-dioxo-lX6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile as a light brown solid.
The following compounds are made in similar fashion: Compound 649, 775, 809, 969, 980.

Example 1AT: Preparation of 2-[4-(1,1-dioxo-lX6-isothiazolidin-2-y1)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (compound 666).

ON O`S~ O CN O` CN O"SP
BBr3 NS1 K2C03 l N
~ O
Me0 \~N \ ` ~ CH2CI2 HO' v ~N \ / V ~
-15 C , !
MEK

Step A: Following the procedure in examplelB step A, 2-[4-(l,1-dioxo-lX,6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile is treated with 1M
BBr3 solution in CH2C12 at -15 C for 1.5h and then poured into ice-water and filtered and dried to afford 2-[4-(1,1-dioxo-1%6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-lH-indole-3-carbonitrile in nearly quantitative yield.
Step B: Following the procedure in examplelB step B, 2-[4-(1,1-dioxo-la.6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-lH-indole-3-carbonitrile, K2C03, 2-iodopropane and methyl ethyl ketone are heated at reflux to give, after flash chromatography (EtOAc/CH2C12, 0-2%), 61% of 2-[4-(1,1-dioxo-1X6-isothiazolidin-2-yl)phenyl]-1-ethyl-6-isopropoxy-lH-indole-3-carbonitrile as an off-white solid.

The following compounds are made similarly: Compounds 667, 699.

Example 1AU: Preparation of2-[4-(1,1-dioxo-lX6-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile (compound 729).

CN O` ~O KZC03 CN 0\ 0 S O~ ~\ \ N
HO CN O^N-\- N
~ - CI HCl >
MEK/DMF /
1~0 C

A mixture of 2-[4-(1,1-dioxo-17t.b-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-ll-I-indole-3-carbonitrile, prepared in example 1AT above (70mg, 0"25 mmol), K2C03 (75 mg, 0.51 mmol), sodium iodide (27 mg, 0.18rnmo1), 4-(2-chloroethyl) morpholine hydrochloride (42 mg, 0.25 mmol) in methyl ethyl ketone (3 mL) is heated in a sealed tube at 100 C. After 13 hours, DMF (3 mL) is added and the reaction is heated for an additional 6h.
After this time, an additiona142 mg of 4-(2-chloroethyl) morpholine hydrochloride and 135 mg of K2CO3 is added and the reaction is heated for an additional 6h to complete the reaction. The reaction mixture is cooled to room temperature, diluted with water, and extracted with EtOAc (3X).
The combined organic phases are washed with water (2X) and saturated NaC1 and dried and concentrated. Pure 2-[4-(1,1-dioxo-lX6-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile is obtained by flash chromatography (MeOH/CH2C12, 0-6%) to give 29 mg (34%) of a tan solid.
The following compounds are made similarly: Compounds 728 and 730.

Example IAV: Preparation of 2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-l-ethyl-l.H-indole-3-carbonitrile (compound 779).

CN CN O
OCNVC02Et ~H 0 NH2 --- I i \ H
O N dioxane ff) e CN O
t-Bu0"K' NI-d THF/t-BuOH
Q f O

Step A: A solution of 2-(4-aminophenyl)-6-ethoxy-l-ethyl-lH-indole-3-carbonitrile (585 mg, 1.92 mmol) in 10 mL of 1,4-dioxane is treated with ethyl isocyanatoacetate (0.25 mL, 2.12 mmol), and the resulting solution is heated to reflux overnight. The solution is allowed to cool, and the solvent is removed by rotary evaporation. The residual material is triturated with ether, and the resulting precipitate is collected by filtration and dried under vacuum to afford compound 773 (587 mg, 1.35 mmol, 70%).
A similar procedure is used to prepare methyl 2-{3-[4-(3-cyano-6-ethoxy-1-ethyl-lH-indol-2-yl)-phenyl]-ureido}-3-phenyl-propionate (compound 777).
Step B: A solution of ethyl {3-[4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-phenyl]-ureido}-acetate (compound 773, 101 mg, 0.23 2 nunol) in THF (10 mL) is treated with a solution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M, 0.30 mmol), and the resulting mixture is allowed to stir overnight. The reaction mixture is partitioned between water and ethyl acetate (50 mL each), and the organic phase is washed with saturated brine.
The aqueous phases are extracted with more ethyl acetate, and the extracts are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatography (eluting 2/1 ethyl acetate/hexane on silica ge160) to afford 2-[4-(2,5-dioxo-imidazolidin-l-yl)-phenyl]-6-ethoxy-l-ethyl-lH-indole-3-carbonitrile, compound 779, which is purified further by tritu.ration with ether, collection by filtration and drying under high vacuum (76 mg, 0.196 mmol, 84%).

Example lAVV: Preparation of 2-[4-(2,4-dioxo-imidazolidin-1-yl)phenyl]-6-ethoxy-l-ethyl.-lH-indole-3-carbonitrile (compound 776).

CN NCO
IOI CN

NH
N dioxane N e 60 C o 2. DBU

A solution of 2-(4-aminophenyl)-6-ethoxy-l-ethyl-lH-indole-3-carbonitrile (319 mg, 1.04 mmol) in 1,4-dioxane (3 mL) is treated with chloroacetyl isocyanate (0.10 mL, 1. 17 mmol), and the resulting solution is warmed to 60 C overnight. The solution is cooled, and DBU (0.20 mL, 1.31 mmol) is added. This mixture is stirred at ambient temperature overnight, and then is partitioned between water and ethyl acetate (50 mL each). The organic layer is washed with saturated brine, and then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is triturated with ether, and the resulting solid is collected by filtration and dried under high vacuum to afford the title product (319 mg, 0.821 mmol, 79%).

Exarnple 1 AX: Preparation of N,N-Dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carboxamide (compound 780) and N,N-Dimethyl-6-ethoxy-l-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidin-l-yl)-phenyl]-1H-indole-3-carboxamide (compound 781).

N O
02Et 6N HC
CN HXN~
I
N NH acetone NH
O O
.--N
O
O
NaH ~
+ ~
MeI 110/ N )-N_ DMF p O

Step A. A solution of ethyl {3-[4-(3-cyano-6-ethoxy-l-ethyl-1HHindol-2-yl)-phenyl]-ureido} acetate (compound 773, 325 mg, 0.748 mmol), prepared in procedure lAV, step A, in acetone (5 mL) is treated with HC1(3 mL, 6 N), and the resulting solution is heated to reflux overnight. The reaction mixture is cooled, and the resulting precipitate is collected by filtration, washed with ether and dried under high vacuum to afford the product, 6-ethoxy-l-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (264 mg, 0.650 mmol, 87 l0).
Step B. Sodium hydride dispersion in mineral oil (75 mg) is washed with a small portion of hexane, and the hexane layer is decanted off. A solution of 6-ethoxy-l-ethyl-2-[4-(2,5-dioxo-imidazolidin-l-yl)-phenyl]-1H-indole-3-carboxamide (190 mg, 0.468 mmol) in dimethylformamide (2 mL) is added, and the mixture is stirred for 1 hour.
Then, methyl iodide (0.10 mL, 1.61 mmol) is added by syringe. The resulting mixture is allowed to stir at ambient temperature overnight and then is poured into 50 mL of ethyl acetate. The organic phase is washed with water (3 X 50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by coluxnn chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica ge160) to afford the title products, compounds 780 and 781.

Example lAY: Preparation ofN-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)-methanesulfonarnide (compound 828).

CN O CN o.
NaH
MeO I~ N \/ B~~OCOCH3 MeO N
H
DMF O
CN O~
LiOH ~ \ . 0 THFlHzO Me0 N
60 C "-~OH

Step A: Sodium hydride dispersion in mineral oil (108 mg) is washed with a small portion of hexane, and the hexane layer is decanted off. A solution of1V-[4-(3-cyano-l-ethyl-6-rnethoxy-lH-indol-2-yl)-phenyl] methanesulfonamide (compound 129, 500 mg, 1.35 mmol) in DMF (5 mL) is slowly added. After gas evolution is complete, 2-bromoethyl acetate (0.30 mL, 2.64 mmol) and sodium iodide (20 mg) are added. The mixture is stirred at ambient temperature overnight, and then is poured into 50 mL of ethyl acetate. This is washed with water (3 X 50 mL) and saturated brine (20 mL), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by column chromatogaphy (1/1 ethyl acetate/hexane, eluting on silica ge160) to afford compound 815 (364 mg, 0.799 mmol, 59%).
Step B: A mixture ofN-(2-acetoxyethyl) 1V-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl] methanesulfonamide (compound 815, 164 mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg, 1.07 mmol) in 5 mL THF/1 mL water is warmed to 60 C overnight.
The mixture is cooled and poured into ethyl acetate (50 mL). This is washed with water (50 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered and evaporated to afford a solid. The solid is triturated with ether, collected by filtration and dried under high vacuum to afford N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-N-(2-hydroxyethyl) methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).

Example 1AZ: Preparation of 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-indole-3-carbonitrile (compound 248).

CN Br/~OMe CN O-\ ` OH I \ ~ 0 Me0 N) ICZC03, DMF Me0 N

1-Ethyl-2-(4-hydroxy-phenyl)-6-rnethoxy-lH-indole-3-carbonitrile (40 mg, 0.14 rnxnol), prepared as in example IGa step B, is combined with K2C03 (77 mg, 0.56 mmol), bromoethyl methyl ether (26 gL, 0.28 mmol), and DMF (450 L). This is stirred at room temperature for 1 hour, and then at 75 C for 3 hours. The reaction mixture is then partitioned between H20 and EtOAc. The organic layer is dried and concentrated.
Purification by silica gel chromatography (CH?Cl2, 0-5% EtOAc) yields 1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-IH-indole-3-carbonitrile (44 mg, 90%) as a white solid.
The following compound is prepared similarly as above: Compound 249.
Example 1BA: Preparation of 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (compound 261).

CN H PPh CN Br \ 3 NBS
MeO N O CHZCIZ O
a\
Morpholine CN NJ
Acetonitrile \ ~
Q
85 C Me0 Step A: 1-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-1H-indole-3-carbonitrile (450 mg, 1.34 mmol), prepared as in example 1A2;, is combined with PPh3 (878 mg, 3.35 mmol) in CH2C12 (32 mL) at 0 C. N-bromosuccinimide (600 mg, 3.37 mmol) is added in one portion. The reaction mixture is stirred at room temperature for 30 minutes.
The reaction mixture is washed with aqueous NaHCO3_ The organic layer is dried and concentrated, and purified by silica gel chromatography (CH2C12) to yield 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (506 mg, 95%), compound 253 as a white solid.
Step B: 2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (40 mg, 0.1 mmol), prepared as in step A above, is combined with morpholine (50 L, 0.58 mmol) and acetonitrile (1.0 mL). This is heated at 85 C for 2h. The reaction mixture is then partitioned between CH2C12 and H20. The organic layer is dried and concentrated.
Purification by silica gel chromatography (6/4, acetone/hexanes) yields 1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile (39 mg, 96%) as a white solid.

The following compounds are prepared similarly as above, using different amines:
Compounds 262, 263, 264.

Example 1BB: Preparation of N-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-ethyl) methanesulfonamide (compound 268).

CN Br CN N3 ~ \ O NaN3 ~O H2, Pd/C
Meo N \~ MeOH Me0 N
75 C >

CN NH2 CN NHSO2Me ~ MeSO2Cl I ~ \ ~O~

Me0 N Pyridine Me0 ~ N

Step A: 2-[4-(2-Bromoethoxy)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (258 mg, 0.65 mmol), prepared in example IBA, step A, is combined with NaN3 (144 mg, 2.2 mmol), and MeOH (3.2 mL). This is heated overnight at 75 C. The reaction mixture is then partitioned between CH2C12 and H20. The organic layer is dried and concentrated.
Purification by silica gel chromatography (CHZCIZ) yields 2-[4-(2-azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg, 80%), compound 266 as a white solid.
Step B: 2-[4-(2-Azidoethoxy)phenyl]-1-ethyl-6-rnethoxy-lH-indole-3-carbonitrile (410 ' mg, 1.14 mmol), prepared as in step A, above, is suspended in a solution of MeOH (20 mL) and concentrated HCl (500 l.d.). Pd/C (150 mg, 10%) is added, and this mixture is hydrogenated at 30 p.s.i. for lh. This is filtered and the filtrate is concentrated. The filtrate residue is partitioned between EtOAc and 0.5N NaOH. The organic layer is dried and concentrated. Purification by silica gel chromatography (10-30%, MeOH/CH2Cl2) yields 2-[4-(2-aminoethoxy)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (298 mg, 78%), compound 267, as a white solid.
Step C: 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared in step B, above, is dissolved in pyridine (300 L).
Methanesulfonyl chloride (8 L, 0.1 mmol) is added. This is stirred at room temperature for 45 minutes. More methansulfonyl chloride (4 .L, 0.05 mmol) is added. Stirring continues for another hour. The reaction mixture is partitioned between EtOAc and aqueous HCI. The organic layer is dried and concentrated. Purification by silica gel chromatography (1/1 CH2ClZ/EtOAc) yields N-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)phenoxy]ethyl} methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.
The following compound is prepared similarly as above: Compound 269.

Example 1BC: Preparation of N-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-ethyl} acetamide (compound 274).

CN NHZ CN iVHAc I~ \ - O AaCI, Et3N C \ - O
Me0 N THF Me0 N \/

2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, step B, is dissolved in THF (400 L), and Et3N (24 u.L, 0.17 mmol). Acetyl chloride (10 L, 0.14 mmol) is added, and the reaction mixture is stirred at room temperature for 2h. The reaction mixture is partitioned between EtOAc and H20. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-lH-indol-2-yl)phenoxy]ethyl}
acetamide (33 mg, 97%) as a white solid.

Example IBD: Preparation of 1-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy] ethyl} -3 -ethyl-urea (Compound 279).

CN NH2 EtNCO CN - HN-~
~ O H
Me0 I ~ \ c / O ~ pyridine M~ / ~ \ ~
~
2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (30 mg, 0.09 mmol), prepared as in example 1BB, is combined with ethyl isocyanate (18 L, 0.21 mmol) and pyridine (300 L). This mixture is stirred at room temperattue for 90 minutes, and is then partitioned between EtOAc and aqueous HCI. The organic layer is dried and concentrated. Purification by silica gel chromatography (EtOAc) yields 1-{2-[4-(3-cyano-1-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea (34 mg, 93%) as a white solid.

Example 1BE: Preparation ofN-{2-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]ethyl}formamide (compound 280).

Ac.zO. HCOOH, r' Me0 N O THF N O
~ Me0 ~

Acetic anhydride (700 L) and 98% formic acid (280 L) are heated at 65 C for lh.
This is cooled to 0 C. 2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-lH-indole-carbonitrile (30 mg, 0.09 mmol), prepared as in example IBB, is taken up in THF (400 L), and added to the mixed anhydride. This is stirred at 0 C for 45 minutes. The mixture is then portioned between EtOAc and aqueous NaHCO3. The organic layer is dried and concentrated.
Purification by silica gel chromatography (4/1, CHaC12/acetone) yields N-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]-ethyl} formamide (28 mg, 86%) as a white solid.

Example 1BF: Preparation of 1-ethyl-2-{4-[2-(3-hydroxypyrrolidin-1-yl)-2-oxo-ethoxy]phenyl}-6-methoxy-lH-indole-3-carbonitrile (compound 285).

CN CN
Br_'_'COOtBU O COOt-Bu TFA, CH2CI2 Me0 N OH DMF, Me0 I~ N \/
KzC03 ~

CN CN O
-COOH L (COC1h, DMF
O \ \ ~ /
Me0 N 2. S-3-hydroxy- Me0 N N
1 pyrrolidine ~ OH

Step A: 1-Ethyl-2-(4-hydroxyphenyl)-6-methoxy-lH-indole-3-carbonitrile (559 mg, 1.91 mmol), is used to prepare [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (780 mg, 100%) utilizing essentially the same procedure as example lAZ.
Step B: [4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-acetic acid tert-butyl ester (745 mg, 1.83 mmol) is stirred in 20% TFA in CHaC12 at room temperature for 3 hours.
This is concentrated and the residue is partitioried between H20 and EtOAc.
The organic layer is dried and concentrated. The residue is triturated with CHaCl2 to yield [4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-acetic acid (634 mg, 99%) as a white solid.
Step C: [4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenoxy]-acetic acid (40 mg, 0.12 mmol) is suspended in CH2C12 (1.65 mmol) and DMF (2 L). Oxalyl chloride (17 L, 0.19 mmol) is added. This is stirred at room temperature for 30 minutes. The resulting solution is then pipetted into a stirring solution of S-3-hydroxypyrrolidine (150 L) and CHaC12 (3.0 mL). The mixture is washed with aqueous HCI. The organic layer is dried and concentrated. Purification by silica gel chromatography (3/2 CH2CI2/acetone) yields 1-ethyl-2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-phenyl} -6-methoxy-lH-indole-3-carbonitrile (40 mg, 79%), compound 285 as a white solid.

Example 1BG: Preparation of 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-yl)-1H-indole-3-carbonitrile (Compound 332).

CN CN
OH H2, Pd/C ~ j OH
Mep (/N Me0 > NO2 NH2 CN
CDI. THF

Me0 I ~ N \ / O
H
Step A: 1-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-IH-indole-3-carbonitrile (369 mg, 1.1 mmol), prepared as in example 1Gd, is combined with EtOAc (20 mL) and Pd/C (150 mg, 10%). This mixture is hydrogenated at 30 p.s.i. for lh. This is filtered through celite. The filtrate is concentrated and triturated with ether to yield 2-(3-amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (307 mg, 91 %), compound 322, as a white solid.
Step B: 2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.33 nnnol), prepared as in step A, is combined with CDI (83 mg, 0.51 mmol), and THF (1.1 mL). This is heated at 65 C for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HCI. The organic layer is dried and concentrated.
Purification by silica gel chromatography (9/1, CH2CI2/EtOAc) yields 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile (89 mg, 81%) as a white solid.

Example 1BH: Preparation of 1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[ 1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (compound 334).

CN CN
Me0 I~ \ 4\/ OH BrCHzCOOH. ~ N OH CI
EDCI-HCI, ACN Me0I~
NH2 HN--~
O
CN
K2C03, DMF I~ \ I O
Me0 ~ N
HN
O
Step A: Bromoacetic acid (52 mg, 0.37 mmol) is combined with EDCI
hydrochloride (62 mg, 0.4 mmol) and acetonitrile (900 .L) to form a homogeneous solution. 2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.33 mmol), prepared as in example 1 BG, step B, is added to the solution. A thick paste soon forms.
Another 1.1 mL
of acetonitrile is added and the mixture is then stirred at room temperature for 2 hours. The reaction niixture is then partitioned between H2O and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (4/1, CH2C12/EtOAc) yields_2-chloro-N-[5-(3-cyano-l-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxyphenyl] acetamide (82 mg, 60%), compound 333, as a white solid.
Step B: 2-Chloro-N-[5-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-2-hydroxy-phenyl]
acetamide (57 mg, 0.13 mmol), prepared in step A, is combined with K2C03 (55 mg, 0.4 mmol), and DMF (400 L). This is heated at 80 C for 1 hour. The reaction mixture is then partitioned between H20 and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2C12/EtOAc) yields 1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (45 mg, 90%) as a white solid.

Example 1BI: Preparation of 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-yl)-11Y-indole-3-carbonitrile (Compound 340).

COOH COOH HN
OH 1. NaNOZ, HZSOq, H2O ~ OH OPPA, Et3N, O
I~ 2. KI I~ THF I/
NH2 Pd(PPh3)2CI2, Cul, THF CN

~
CN ~ NH
Me0I~
~ SnBu3 ~ O O
MeO N

Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) is suspended in H2SO4 (26 mL, 2.7M) at -5 C. Sodium nitrite (1.8 g, 26.1 mmol) in H20 (6.5 mL) is cooled to ice bath temperature and is added dropwise to the aminosalicylic acid mixture over 5 minutes. The resulting suspension is stirred at -5 C for 15 minutes. A solution of KI (6.8 g, 41 mmol) in H2SO4 (13 mL, 1M) is added dropwise to the diazonium salt, with considerable evolution of N2. The reaction mixture is heated at 70 C for 20 minutes. The reaction mixture is then partitioned between H20 and EtOAc. The organic layer is dried and concentrated.
Purification by silica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yields 4-iodosalicylic acid (5.33g, 85-90% pure).
Step B: Crude 4-lodosalicylic acid (1.0 g, 3.8 mmol) is dissolved in THF (28 mL) and Et3N (1.15 mL, 8.2 mmol). DPPA (1.7 mL, 7.8 mmol) is added. This is heated at overnight. The reaction mixture is then partitioned between H20 and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (9/1, CH2CI2/EtOAc) yields 472 mg crude intermediate. Trituration with ether yields 6-iodo-3H-benzooxazol-2-one (369 mg, 37%) as a white solid.
Step C: 6-Iodo-3.Fl-benzooxazol-2-one (118 mg, 0.45 mmol) is used to prepare 1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile, compound 340 (75 mg, 55%), utilizing essentially the same procedure as in example 1 Gd.

Example 1BJ: Preparation of 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (compound 339).

CN CN
p NaH, Mel, THF ~
Me0 Me0 I~ N 4\/ O
HN
-~ p N~

1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[ I,4]oxazin-6-yl)-1H-indole-3-carbonitrile (20 mg, 0.058 mmol), prepared as in example 1BH, is combined with NaH (14 mg, 60% suspension in oil, 0.35 mmol). THF (300 L) is added. This is stirred at room temperature for 5 minutes. A solution of methyl iodide (4.4 L) in THF (100 L) is added.
This is stirred at room temperature for 1 hour. The reaction mixture is partitioned between EtOAc and aqueous HC1. The organic layer is dried and concentrated.
Purification by silica gel chromatography (9/1, CH2C12/EtOAc) yields 1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2H-benzo[1,4]oxazin-6-yl)-1.H-indole-3-carbonitrile (16 mg, 76%) as a white solid.
The following compound is prepared similarly: Compound 341.

Example IBK: Preparation of 1-ethyl-2-iodo-6-methoxy-5-nitro-lH-indole-3-carbonitrile (compound 499).

CN CN
~ HNO3, HOAc 02N
I ~ ) Me0 ~ ~` Me0 1-Ethyl-2-iodo-6-methoxy-lH-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1Ga, Step A, is suspended in acetic acid (620 gL) at 0 C. Nitric acid (4.25M in AcOH) is added. This is stirred at room temperature for 2 hours. The reaction mixture is then partitioned between CH2C12 and H20. The organic layer is washed with aqueous NaHCO3, and then is dried and concentrated. Purification by silica gel chromatography (6/4, CH2C12/hexanes), followed by ether trituration, yields 1-ethyl-2-iodo-6-methoxy-5--nitro-lH-indole-3-carbonitrile (16 mg, 29%) as a yellow solid.

Example 1BL: Preparation of 1'-ethanesulfonyl-l-ethyl-6-methoxy-2',3'-dihydro-1H,1H'-[2,6']biindolyl-3-carbonitrile (compound 753).

O2N I~ N AcHF Et3N I i Hz. Pd/C I~ N
H O2N N EtOAc /
Ac Ac 1. NaNOa, HZSOq, H20 I ~ NaOH, EtOH, ~
i ~r 2. KI I Ac HO 1 / H
Pd(PPh3)zClz, Cul, CN
THF
EtSOzCi CN
CN N
~ M~ N Pyridine I i N \~
~ ~ SnBu3 H Me0 Me0 ~
N EtOzS
Step A: 6-Nitroindoline (3.0 g, 18.3 mmol) is dissolved in THF (45 mL) and Et3N (3.4 mL, 24.4 mmol) at 0 C. Acetyl chloride (1.5 mL, 21 mmol) is added dropwise.
The mixture is stirred at room teniperature for 30 minutes. The mixture is partitioned between EtOAc and aqueous HCI. The organic layer is dried and concentrated to yield 1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.
Step B: 1-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) is suspended in EtOAc (200 mL).
Pd/C (650 mg, 10%) is added, and the mixture is hydrogenated at 40-55 p.si.i.
for 2 hours. The mixture is then filtered through celite. The filtrate is concentrated, and the residue is triturated with ether to yield 1-acetyl-6-aminoindoline (3.18 g, 99%) as an orange solid.
Step C: 1 -Acetyl-6-aminoindoline (1.5 g, 8.5 mmol) is used to prepare 1-acetyl-6-iodoindoline (1.06 g, 43%), utilizing essentially the same procedure in example 1BI, Step A.
Step D: 1-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16g, 29 mmol), EtOH (8 mL), and H20 (6 mL) are heated at 90 C overnight. The reaction mixture is then partitioned between H20 and EtOAc. The organic layer is extracted into aqueous HC1. The aqueous layer is in turn basified with NaOH, and is extracted with EtOAc. The organic layer is dried and concentrated. Hexane trituration yields 6-iodoindoline (57.7mg, 64%) as a brown solid.
Step E: 1-Iodoindoline (600 mg, 2.45 mmol) is used to prepare 1-ethyl-6-methoxy-2',3'-dihydro-1H,1H =[2,6']biindolyi-3-carbonitrile (535 mg, 67%), utilizing essentially the same procedure as in example lGd, Step B.

Step F: 1-Ethyl-6-methoxy-2',3'-dihydro-1H,1H'-[2,6']biindolyl-3-carbonitrile (30 mg, 0.095 mmol) is used to prepare 1'-Ethanesulfonyl-l-Ethyl-6-methoxy-2',3'-dihydro-1H,1H'-[2,6']biindolyl-3-carbonitrile (24 mg, 62%), utilizing the procedure in example lY.
The following compounds are prepared similarly as above: Compounds 752 and 754.
Example IBM: Preparation of 5-acetyl-l-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (compound 844).

CN
CN
N NO2 AcCI, AICI3, DCE Ac I~ N02 Me0 MeO~N
> ]

1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc is suspended in 1,2-dichloroethane (500 L) at 0 C.
Acetyl chloride (50 L, 0.69 mrnol) is added, followed by A1C13 (55 mg, 0.4 mmol) in one portion. This is stirred at 0 C for 1 hour, at room temperature for 4 hours, and at 45 C
overnight. The reaction mixture is then partitioned between CH2CI2 and HaO.
The organic layer is dried and concentrated. Purification by silica gel chromatography (195:5 CH2C12/EtOAc) yields 5-acetyl-l-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (33 mg, 29%) as an orange solid.

Example 1BN: Preparation of 1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (compound 845).

CN ~ ~ Br CN
_ ~

Me0 ~ HBr. Me0 ~
HOAc C~~
morpholine CN
-~ ~
DCE G / `\ NOp Me0 N

Step A: 1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg, 0.3 mmol), prepared by the method of example 1Gc, is combined with 1,3,5-trioxane (64 mg, 0.71 mmol) and acetic acid (2.0 mL). 33% HBr in acetic acid (2.0 mL) is added. This is stirred at room temperature for 4 hours. The reaction mixture is then partitioned between CH2C12 and H20. The organic layer is washed with aqueous NaHCO3, and is subsequently dried and ~
concentrated. The crude material is carried through to the next step.
Step B: Crude 6-bromomethyl-l-ethyl-6-mthoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile (0.3 mmol) is heated with morpholine (150 L, 1.75 mmol) and DCE
(1.0 mL) at 90 C overnight. The reaction mixture is then partitioned between H20 and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography (50-100%, EtOAc/CH2C12), followed by trituration with 1/1 hexane/acetone yields 1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitrophenyl)-1Fl-indole-3-carbonitrile (57 mg, 44%
overall yield) as a yellow solid.

Example 1BO: 2-[4-(1,1-dioxidoisothiazolidin-2-y1)phenyl]-1-cyclopropylmethyl-methoxy-lH-indole-3-carbonitrile (compound 716).

I~ \ (Boc)201 cat. DMAP I~ \ 13(O~Pr)3/LDA I~ N B(OHh N TH F/ 0 C - r.t. Me0 Me0 H DCMl40 C Me0 O` -- O
/~-- ~
O~ ~p O'/, s S ~ \ ' ' \ ~Nj Me0 ' ~ N \ / N 1). 60% TFA-DCM
PdCI2(dppf)/KZCO3/DMF O
r.t. ~

O` ~O CN 0`
~ \ NSl CISO2NC0/DMF \ \ - NSl Meo I ~ N O C - r.t. Me0 N
H H

S
K2C03 Me0 , N ~O J
`

50'C Izil Step A: To a solution of 6-methoxyindole (5.88 g, 40.0 mmol) and di-tert-butyl dicarbonate (9.59 g, 44.0 mmol) in DCM (50 mL) is added, at 40 C while stirring, DMAP

(0.10 g). After stirring overnight, the mixture is washed sequentially with 0.1 N HCI, water and brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is chromatographed (silica gel, EtOAc/hexanes, 1/7) to provide tert-butyl 6-methoxy-lH-indole-1-carboxylate (8.48 g, 86%).
Step B: The above Boc-indole (3.08 g, 12.5 mmol) and isopropylborate (4.83 mL, 21.9 mmol) are dissolved in anhydrous THF (20 mL) and the solution is cooled at 0 C. While stirring, LDA (12.5 mL, 1.5 M mono-THF complex in cyclohexane, 18.7 mmol) is added dropwise. The mixture is stirred at 0 C for 15 min and then room temperature for 0.Sh, followed by the addition of HCl (6 N, 3_0 mL, 18 mmol) in an ice-water bath.
The organic solvent is removed in vacuo and the residue is suspended in H20 (100 mL) and acidified with HCl (6 N) to pH 4-5. The precipitate is collected via filtration and washed with water and hexanes and dried in air to provide 1-Boc-6-mehoxyindole-2-boronic acid (3.38 g, 93%).
Step C: To a solution of 4-iodoanilline (3.18 g, 14.5 mmol) in pyridine (15 mL) at 0 C, is added 3-chloropropanesulfonyl chloride (2.3 mL, 18.9 mmol). After the addition, the mixture is stirred for 2h at room temperature, and poured into ice-water (200 mL). The organic is separated and the aqueous layer is extracted with DCM (2 X 50 mL). The combined organics are washed with HCl (2 N, 2 X 15 mL), water (2 X 50 mL) and brine (20 mL) consecutively and dried over anhydrous Na2SO4. The solvent is then evaporated and the residue is chromatographed to furnish 3-chloro-N-(4-iodophenyl)propane-l-sulfonanzide (4.68 g, 90%). The chlorosulfonamide obtained (3.47 g, 9.6 mmol) is then treated with K2CO3 (3.33 g, 24.1 mmol) in DMF (50 mL) at 50 C for 2h. The mixture is poured into ice-water (300 mL)., and the precipitate is collected and dried in air to provide essentially pure 2-(4-iodophenyl)isothiazolidine-l,1-dioxide (3.11 g, 100%).
Step D: To a mixture of 1-Boc-6=mehoxyindole-2-boronic acid prepared in step B
above (0.36 g, 1.25 mmol), 2-(4-iodophenyl)isothiazolidine-1, 1 -dioxide (0.32 g, 1.0 mmol) and PdC12(dppf) (0.037 g, 0.05 mmol) in DMF (4.0 mL), is added aqueous K2C03 solution (1.5 mL, 2.0 M, 3.0 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM /EtOAc, 9/1) to furnish 1- Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1Ff indole (0.43 g, 98%).
The following compound is made similarly: Compound 768 Step D: 1- Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-lH-indole (1.63 g, 3.7 mmol) is treated with TFA (25 mL) in DCM (25 mL) at room temperature for 4h.
After the removal of the volatiles, the residue is carefully stirred with saturated NaHCO3 for 0.5h. The precipitate is collected via filtration and washed with water thoroughly and dried to provide essentially pure 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (1.17 g, 92%).
Step E: At 0 C, 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (0.95 g, 2.8 mmol) is dissolved in DMF (10 mL) and treated with chlorosulfonyl isocyanate (0.36 mL, 4.2 mmol). The mixture is then stirred at room temperature overnight and poured into ice-water (150 mL) then stirred for 0.5h. The precipitate is collected via filtration and washed thoroughly with water and dried in air to furnish 1-H-2-[4-(1,1.-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile (0.89 g, 87%).
The following compound is prepared in the same fashion as described above:
Compound 829 Step F: To a solution of 1-H-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile (73 mg, 0.2 mmol) and K2C03 (69 mg, 0.5 mmol) in DMF (3.0 mL) is added cyclopropylmethyl iodide (0_029 mL, 0.3 mmol). The mixture is stirred at 50 C
overnight and poured into ice-water (10 mL). The precipitate is collected via filtration, washed with water and purified by column chromatography to provide 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-l-cyclopropylmethylindole-3-carbonitrile, compound 716 (73 mg, 87%).
The following compounds are prepared in the same fashion as described above:
Compounds 717, 718, 719, 782, 783, 784.

Example 1BP: Preparation of 2-[4-(1,1'-dioxo-1 T.6-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-l-propyl-lH-indole (compound 805).

n-Prl, NaH,DMF OO
Me0 I~ N Me0 CI-~ N
H e /--N
1. POCI3, DMF O
SO
2. TOSMIC. MeOH.
K2CO3 Me0 N

Step A: 2-[4-(1,1'-Dioxo-1%6-isothiazolidin-2-yl)-6-methoxy-indole (900 mg, 2.62 mmol), prepared in example 1BO, step D is used to prepare 2-[4-(1,1'-dioxo-1a,6-isothiazolidin-2-yl)-6-methoxy-l-propyl-lH-indole (608 mg, 60%), utilizing essentially the same procedure as example lA, Step B. , Step B: 2-[4-(1,1'-Dioxo-I X6-isothiazolidin-2-yl)-6-methoxy-1-propyl-lH-indole (50 mg, 0.13 mmol) is used to prepare 2-[4-(1,1'-dioxo-1?,6-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-l-propyl-IH-indole (9 mg, 15% overall yield) according to the protocol in example 1P. -Example BQ: Preparation of 2-[4-(cyclopropylsulfonyI)piperazin-l-yl]-1-ethyl-6-(trifluoromethyl)-IH-indole-3-carbonitrile (compound 842).

CN CN HN N-Boc CN
~ 1) LDA ~ ~\
~ \ ~ \ N N-Boc F3C ~ N 2) C2CI6 F3C N K2CO3/DMF F3C / N ~--~
/ TIlF.-78 C-rt / ~
CN CN
TFA/DCM NNH ~-\

F3C PYridineF3C N

Step A: To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile (2.54 g, 10.0 mmol), prepared by the method of procedure 1A, in anhydrous THF (20.0 mL), at -78 C is added LDA (8.3 mL, 1.5 M mono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture is continued for 0.5h after the addition, followed by the addition of hexachloroethane and the mixture is then brought to room temperature slowly and stirred for 0.5h. The solvent is then evaporated and the residue is treated with water. The organics are extracted with dichloromethane, washed with water and brine and dried over anhydrous Na2SO4.
The crude product obtained after the removal of the solvent is chromatographed (silica gel, dichloromethane/hexanes, 3 /2) to provide 2-chloro-l-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g, 64%).
Step B: The chloroindole obtained above (0.27 g, 1.0 mmol), K2C03 (0.35 g, 2.5 mmol) and N-Boc-piperazine (0.28 g, 1.5 mmol) are stirred at 70 C in DMF (5.0 mL) for 3 days and then poured into water (50 mL). The precipitate is collected via filtration and washed with water. Chromatography of this crude product (silica.gel, dichloromethane/ethyl acetate, 9/1) provides 4-(3-cyano-l-ethyl-6-trifluoromethyl-lH-indol-2-yl)-piperazine-l-carboxylic acid tert-butyl ester, compound 785 (0.30 g, 71%).
The following compounds are prepared in the same fashion as described above, by using other amines: Compounds 514, 785, 786.

Step C: 4-(3-cyano-l-ethyl-6-trifluorometb.yl-lH-indol-2-yl)-piperazine-l-carboxylic acid tert-butyl ester (0.26 g, 6.1 mmol) is treated with TFA (5 mL) in dichloromethane (5 mL) for lh at room temperature. After the removal of the volatiles, the residue is treated with saturated NaHCO3 and the precipitate is collected via filtration, washed with water thoroughly and dried in air to furnish essentially pure 1-ethyl-2-piperazin-l-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (0.20 g, 100%).
Step D: To a solution of 1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) is added cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixture is stirred at room temperature overnight. This is then diluted with dichloromethane (5 mL), washed with HCI (2 N, 2 X 2 mL), water (2 X S mL) and brine (5 mL) and chromatographed over silica gel (dichloromethane/ethyl acetate, 9/1) to provide 2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile, compound 842 (30 mg, 70%).
The following compounds are prepared in the same fashion as described above, using corresponding sulfonyl chlorides: Compounds 841, 843.

Example 1BR: Ethanesulfonic acid [3-cyano-2-(4-cthoxyphenyl)-1-ethyl-lFl-indol-yl]-amide (compound 835).

CN CN
HZN-Boc _ ~ - O
Br O K2 O3l o uene BocHN I~ N

CN CN
TFAJDCM ~ - ~- E#S02CI
N I/ N \~ O
HZN ~ ~ õ O PYridine Eto2S, v H d Step A: 6-Bromo-2-(4-ethoxyphenyl)-l-ethyl-lH-indole-3-carbonitrile (0.74 g, 2.0 mmol), compound 831, prepared from 6-bromoindole as described in example 1Gb, is mixed with K2C03 (0.55 g, 4.0 mmol), CuI (0.02 g, 0.1 mmol), tert-butyl carbamate (0.35 g, 3.0 mmol), N, N'-dimethylcyclohexane-l,2-diamine ligand (0.028 g, 0.2 mniol) and anhydrous toluene (5.0 mL) in a sealed tube. The reaction system is flushed with nitrogen and then stirred at 110 C overnight. After cooling, the solvent is replaced with dichloromethane and chromatographed (silica gel, dichloromethane) to provide [3-cyano-2-(4-ethox)i-phenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid tert-butyl ester (0.68 g, 84%), compound 832.

Step B: Compound 832 prepared in step A above (0.63 g, 1.56 mmol) is treated with TFA./DCM (7.5 mL/7.5 mL) at room temperature for 2h, and the volatiles are removed in vacuum. The residue is treated with saturated NaHCO3 and the precipitate is collected via filtration and washed thoroughly with water, dried in air to provide 6-amino-2-(4-ethoxyphenyl)-l-ethyl-lH-indole-3-carbonitrile (0.45 g, 96%), compound 833.
Step C: The above amine (31 mg, 0.1 mmol) is treated with ethanesulfonyl chloride (19 mg, 0_15 mrnol) in pyridine (1.0 mL) at room temperature overnight to provide, after purification using column chromatography, ethanesulfonic acid [3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-i.ndol-6-yl]-amide (83%), compound 835.
The following compounds are prepared in the same fashion as described above:
Compounds 830, 834, 836 aind 837.

Example 1BS: Preparation of [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-lH-indol-6-yl]-carbamic acid ethyl ester (compound 838) CN CN
1- EtOCOCI
~ p O
\ O
H N I~ N pyridine ~ \/

6-Amino-2-(4-ethoxyphenyl)-7-ethyl-lH-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example 1BR, step B is treated with ethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to furnish, after purification using column chromatography [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-lH-indol-6-yl]-carbamic acid ethyl ester (30 mg, 79%).

Example IBT: Preparation of 1-[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-lH-indol-6-yl]-3-ethyl-urea (compound 839).

CN CN
~ - l- EtNCO O C-X'~
~ N \/ O PYridine ~N~N O
H N I

6-Amino-2-(4-ethoxyphenyl)-i-ethyl-lH-indole-3-carbonitrile (31 mg, 0.1 mmol) is treated with ethyl isocyanate (14 mg, 0.2 nunol) in dichloromethane (1.0 mL) at 40 C
overnight. The precipitate is collected via filtration, washed with dichloromethane an dried in air to fiuuish, 1-[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-lH-indol-6-yl]-3-ethyl-urea (36 mg, 95%).

Example 1BU: Preparation of 1-(2-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-urea (compound 442).

CN CN O
CICHZCHZNCO /~~. \ -- NH
II ~-NH ) `
Me0 N THF Me0 N C~
e To a solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (50 mg, 0.172 mmol) in THF (2 mL) is added 2-chloroethyl isocyanate (22 uL, 0.258 mmol) at room temperature. After stirrming overnight at reflux, the reaction mixture is concentrated in vacuo and the residue is diluted with ethyl acetate. The resulting semi-solid is triturated with hexane and the precipitate collected is collected by filiration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford (62 mg, 91%) of 1-(2-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-urea.
Utilizing essentially the same procedure, the following compounds are prepared:
Compounds 295, 362, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 443, 444, 445, 446, 511, 512, 513, 600, 620, 626, 627, 628, 679, 680, 681, 740, 741, 742, 743, 748, 749, 750, 751, 774, 817, 818, 846, 847, 848, 954, 955, 956, 957, 958, 987, 999, 1000, 1001, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1016, 1017, 1018, 1019, 1023, 1024, 1027,1036,1039, 1043, 1045, 1060,1061, 1066, 1067,1070, 1080, 1092, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1106, 1108, 1118, 1120, 1124, 1125, 1126, 1136, 1137, 1138, 1139, 1143, 1144, 1156, 1157, 1162, 1163, 1164, 1165, 1171, 1172, 1173, 1197,1190, 1214,1221, 1223, 1224, 1225, 1225, 1227, 1256, 1279, 1301, 1303, 1304, 1305, Example 1BV: Preparation of 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-l-yl)-phenyl]-IH-indole-3-carbonitrile (compound 771).

CN O CN O
\_~ \ - NH NH KOH I \ N~NH
MeO I ~ N ~ / ~ MeOH Me0 N ~
] CI ~

To a solution of 1-(2-chloroethyl)-3-[4-(3-cyano-l-ethyl-6-rnethoxy-lH-indol-2-yl)-phenyl]-urea (100 mg, 0.252 mmol) in MeOH (10 mL) is added aqueous 1M KOH (504 uL) and then stirred at 49 C for 24h. The solvents are removed under reduced pressure. The residue is diluted with ethyl acetate and then washed with water. The organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (56 mg, 62%).
Using essentially the same procedure, the following compounds are prepared:
Compounds 770, 778 Example 1BW: Preparation of 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile (compound 638).

CN O\~ CN O
/ O K2C03 \ - l~Q
NH DMF N
~ CI ) To a solution of [4-(3-cyano-l-ethyl-6-isopropoxy-lH-indol-2-yl)-phenyl]-carbamic acid 2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) is added aqueous K2C03 (10 mg) and then stirred at 50 C for 18h. The reaction mixture is poured into cold water and the precipitate collected by filtration and washed with hexane and dried in vacuo to afford the title compound (21 mg, 81%).
The following compounds are made in sirnilar fashion: Compounds 820, 821, 863, 864_ Example 1BX: Preparation of [3-[3-cyano-l-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-indol-2-yl]-phenyl}-carbarnic acid ethyl ester (compound 530).

o~ 0 --\ 0 0 -\
CN NH CN NH
C \ BBC3 K2C03 Me0 N 0,-/ CH2Ch HO I~ N \/ Br'-----CI
DMF

pq~ O=< O--\
CN NH CN NH
CNH
N Naf O N

DIPEA J( CI e ~N

Step A: To a solution of [3-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.65 g, 4.37 mmol) in DCM (20 mL) is added 1M BBr3 in DCM
(13.12 mL) over a period of 20 min. The reaction mixture is stirred furt.her lh at room temperature and then the solvents are removed under reduced pressure. The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [3-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbarnic acid ethyl ester (1.5 g, 98%).
Step B: To a solution of [3-(3-cyano-l-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethyl ester (1.2 g, 2.91 mmol) in DMF (10 mL) is added K2C03 (538 mg, 3.9mmol) and 3-bromo-l-chloropropane (383 uL, 3.9 mmol) and the reaction is stirred for overnight at 50 C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.1 g, 89% of the desired product.
Step C: To a solution of {3-[3-cyano-l-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yI]-phenyl}-carbamic acid ethyl ester (50 mg, 0.12 mmol) in CH3CN (2 mL) is added DIPEA
(31 uL, 0.18 mmol), sodium iodide (20 mg, 0.132 mmol) and pyrrolidine (30 uL, 0.36 mmol).
The resulting mixture is stirred at reflux temperature for overnight. The solvent is evaporated and the residue is diluted with ethyl acetate and then triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford 1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile, compound 638 (46 mg, 85%).
The following compounds are made in similar fashion following steps A-C, above:
Compounds 441, 447, 491, 492, 493, 504, 525, 526, 527, 528, 529, 531, 532, 533, 534, 535, 536, 537, 538, 539.

Example 1BY: Preparation of [3-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-thiourea (Compound 767).

CN NH2 NCS CN HN--? O
HN
~ ~ - ~ ~ - =
Meo I~ acetone Me0 `~ ~_~

s NaOH CN HN--~
~
MeOH/Hz0 N NH2 50oC Me0l~

Step A: The starting material2-(3-amino-phenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitril.e (187 mg, 0.642 mmol) is dissolved in anhydrous acetone (3.0 mL).
Benzoyl isothiocyanate (107 mg, 0.656 mmol) is added to the solution at room temperature and the mixture is stirred for 17h during which time a precipitate forms. The precipitate is filtered, washed with acetone and dried to give 264 mg of 1-benzoyl-3-[3-(3-cyano-l-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (90% yield) as a light yellow solid.
Step B: A suspension of 1-benzoyl-3-[3-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-thiourea (241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) is stirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) is added.
The reaction mixture is heated to 50 C for 17h. The reaction mixture is concentrated to remove methyl alcohol. Water is added to the mixture and the solid is filtered, washed with water and dried to give 179 mg of [3-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-thiourea, compound 767 (96% yield) as a white solid.

Example 1BZ: Preparation of 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (Compound 458) \ CN - ~J-N CN
~--Me0 I~ N ~~ NHZ EtOH MeO N N
-> DIPEA N

A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.343 mrnol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL) is heated to reflux overnight.
The solution is cooled and evaporated, and the residue taken up in ethyl acetate (50 mL). This is washed with water and saturated brine (50 mL each), then dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid is triturated with ether, collected by filtration and dried under vacuum to afford 1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile (139 mg, 0.280 mmol, 82%).

Example 1CA: Preparation of diethyl [4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-phenyl]-phosphoramidate (compound 772).

CN CN
CIP(O)(OEt)2 N NHz DIPEA /-O I/ N C/ P
> dioxane - O~

A solution of 2-(4-aminophenyl)-6-ethoxy-1 -ethyl- 1H-indole-3-carbonitrile (148 mg, 0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) and diisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) is stirred at ambient temperature for 12 hours, then heated to 80 C for an additiona124 hours. The solution is cooled and poured into 50 mL of ethyl acetate. This is washed with water and saturated brine (50 mL each), then dried over anhydrous magnesium sulfate, filtered and evaporated. The residual material is separated by flash chromatography (eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl [4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-phenyl]-phosphoramidate (108 mg, 0.245 mmol, 51%) as a white powder after evaporation.
The following examples are made in similar fashion: Compounds 936, 937, 942, 943, 944, 1081.

Example 1CB: Preparation of 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-lX6-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile (compound 726).

o N ~ H
~ ~ Ct-S-N N
I ~ _ . NH K2CO3 ~
i ~ ~ ~- N DMF
O N Pyridine C N-H
!!) CH2CI2 CI
lJt N
o p N

DMF ~

Step A: To a solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-lFl-indole-3-carbonitrile (202 mg, 0.693 mmol) in pyridine (2.0 mL) is added the N-(i-(chloroethylamino)sulfonyl chloride (222 mg, 1.39 mmol). The mixture is stirred at room temperature for 17h then water (12.0 mL) is added and the mixture is extracted with ethyl acetate (3 X 2 mL). The extract is washed with 10% aqueous HCI (2 X 2 mL), water (2 X 2 mL), dried over MgSO4i filtered and concentrated on a rotary evaporator. The crude product is purified by flash chromatography (0-5%, ethyl acetate/methylene chloride) to give 217 mg of N-(2-chloro-ethyl),N'-[4-(3-cyano-l-ethyl-6-methoxy-LH-indol-2-yl)phenyl]
sulfamide, compound 724, as a tan solid (75% yield).
In similar fashion the following compounds are prepared: Compounds 540, 541, 542, 574, 576, 704.
Step B: To a solution ofN-(2-chloro-ethyl)-N'-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-yl)phenyl] sulfamide (100 mg, 0.241mmol) in anhydrous DMF (1.25 mL), is added potassium carbonate (71.0 mg, 0.514 mmol). The mixture is stirred at room temperature for 17h, then diluted with water (7.5 mL). The reaction mixture is extracted with ethyl acetate (3 X 2 mL) and the extract is washed with water (2 X 2 mL), dried over MgSO4 and concentrated to give 2-[4-(1,1-dioxo-1 X6-[ 1,2, 5] thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1 FI-indole-3 -carbonitrile, compound 725, as a white solid (84 mg, 88% yield).
In similar fashion the following compound is prepared: Compound 705.
Step C: To a solution of 2-[4-(1,1-dioxo-1 k6-[ 1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (34 mg, 0.086mmo1) in anhydrous DMF (1.0 mL) is added potassium carbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol).
The mixture is stirred at room temperature for 2h and then diluted with water (6.0 mL) to give a precipitate. The precipitate is filtered, washed with water and dried to give 1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-l~.6-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile, compound 726, as a white solid (35 mg, 98% yield).
In similar fashion the following compounds are prepared: Compounds 727, 1110.
Example 1CC: Preparation of [4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester (compound 877).

~-- ~
~
CI O
~ C ~ - NHZ
Map I~ N NaHC03 Me0 N NH
, EtOAc , F

A biphasic mixture of 2-(4-arnino-3-fluorophenyl)-1-ethyl-6-methoxy-IH-indole-carbonitrile (74 mg, 0.24 mmol), prepared as described in example IGb, and propyl chloroformate (0.033 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO3 (3 mL) is prepared at 0 C and then allowed to warm to room temperature and stirred for 24h. The reaction is then diluted with H20 and extracted with EtOAc (2X). The organic phases are washed with H20 and saturated NaCl and then dried and concentrated. Flash chromatography (EtOAc/hexanes 10-40%) gives 60 mg (63%) of [4-(3-cyano-l-ethyl-6-methoxy-IH-indol-2-yl)-2-fluorophenyl]-carbamic acid propyl ester as an off-white solid.
The following compounds are prepared in a similar fashion: Compounds 875, 876, 878, 879. By utilizing 2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile the following compounds are prepared: Compounds: 963, 964, 965.
Utilizing the same starting material and procedures described in examples lY, the following compounds are prepared: Compounds 871, 872, 873, 874. In similar fashion, utilizing 2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile, the following compounds are prepared: Compounds 959, 960, 961, 962.
Utilizing the same starting material and procedures described in examples 1BU, the following compounds are prepared: 909, 910, 911. In a similar fashion, utilizing 2-(4-amino-3-methylphenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile, the following compounds are prepared: Compound: 966, 967..

Example CD: Preparation of cyclopropanecarboxylic acid {4-[3-cyano-l-ethyl-6-(2-imidazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-amide (compound 1183).

CN CN O
N D--COCI \ ~a BBr3 Et3N, THF Et0 N) DCM, -10 oC
Et0 `~ ) \/ NH2 N

CN O\\ ~~ CN O\\ ~
NH CICHZCHZBr I ~ \ NH
HO N K2CO3, MEK, reflux N

CN O
imidazole N_~ I ~ \ NH
CH3CN, (\\~NO

Nal, 90 C

Step A: To a solution of compound 2-(4-aminophenyl)-6-ethoxy-l-ethyl-lH-indole-carbonitrile (3.66 g, 12 mmol), prepared as described in example 1Gb, in 20 mL
of THF is added Et3N (3.37 ml) and cyclopropanecarbonyl chloride (1.6 mL, 18rnmo1). The mixture is stirred for 3h at room temperature. Then water and ethyl acetate are added to the reaction mixture. The organic layer is separated, washed with brine (2X), dried over anhydrous NaaSO4, filtered and concentrated. The residue is recrystallized with ethyl acetate and hexane to yield 99% of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-phenyl]-amide.
Step B: To a solution of cyclopropanecarboxylic acid [4-(3-cyano-6-ethoxy-l-ethyl-lH-indol-2-yl)-phenyl]-amide (4.4 g, 11.8 mmol) in 60 mL of DCM is added BBr3 (6.65 mL, 70 mmol) at -10 C. After the addition, the mixture is stirred for 3h at 0 C. Then aqueous NaHCO3 is added to the mixture carefully until it became basic. The crude solid is collected by filtration to give 91% of cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-hydroxy-lH-indol-2-yl)-phenyl]-amide and is used for the next step without farther purification.
Step C: To a solution of cyclopropanecarboxylic acid [4-(3-cyano-l-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-amide (4 g, 11.6 mmol) in 15 mL of MEK is added K2C03 (8 g, 58 mmol) and 1-bromo-2-chloro-ethane (6.7 mL, 70 mmol). Then the mixture is heated at reflux overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2X), dried over anhydrous Na2SO4, filtered and concentrated to yield 81% of the crude cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1 H-indo l-2-yl] -phenyl } -amide.
Step D: To a solution of cyclopropanecarboxylic acid {4-[6-(2-chloroethoxy)-3-cyano-I-ethyl-1H-indol-2-yl]-phenyl}-amide (102 mg, 0.25 mmol) in 1.5 mL of acetonitrile are added NaI (46 mg, 0.275 mmol), K2C03 (138 mg, 1 mmol) and imidazole (51 mg, 0.75 n-mol) in a sealed tube. Then the mixture is heated to 90 C and stirred overnight. After it is cooled to room temperature, water and ethyl acetate are added. The organic layer is separated, washed with brine (2X), dried over anhydrous Na2SO4, filtered and concentrated. The crude compound is purified by preparative HPLC to give 71% of cyclopropanecarboxylic acid {4-[3-cyano-l-ethyl-6-(2-imidazol-l-yl-ethoxy)-1H-indol-2-yl]-phenyl}-amide.
Using the same procedure and substituting the appropriate nucleophilic reagents gives the following compounds: Compounds 952, 1025, 1054, 1090, 1091, 1092, 1093, 1184.
Example CE: Preparation of ethanesulfonic acid [4-(3-cyano-l-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]arn.ide (compound 881).

i O~ CN
NH ci \ 2 CuCh/t BuONO
F3CO i~ NOZ CH3CN/61 C/3 h F3CO NO2 K2C03/DMF/45 C
H2(50 psi), 5% Pd/C CISO2NCO
IO
I CN EtOH/CH3CO2H/H20 F3CO DMF

CN CN
I ~ EtI/K2C03 1). B(Oi-Pr)3/LDAlTHF/-78 C
F CO N DMF/50 C/overnlght F3CO 2}.PdCl2(dppf)/K2C03/
3 H 4-iodoaniline CN O CN O, ~ - CI `S
~ - ~
L NHZ a - ~ \ ",\/ NH O
F3C0 I~ N pYridine F3CO / N

Step A: To a suspension of t-BuONO (8.01 mL, 67.5 mmol) and CuC12 (7.26 g, 54 nimol) in acetonitrile (50 mL), at 61 C with gentle stirring, is added 2-nitro-trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise. The mixture is stirred at this temperature for 2h after the addition. The solvent is removed on a rotorvap and the residue is treated with HC1(6 N, 200 mL), and extracted with dichloromethane (3 x 100 mL). The extracts are combined, dried over anhydrous Na2SO4, and passed through a short silica gel pad.
The solvent is removed and the residue is added to a suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K2C03 (12.42 g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 45 C overnight and poured into ice-water (700 mL), and extracted with dichlorornethane (3 x 100 mL). The organics are dried over anhydrous Na2SO4 and again passed through a short silica gel pad, eluting with ethyl acetate. The solvent is then replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL), and the reaction mixture is hydrogenated over 5% Pd/C
(2.80 g) at 50 psi overnight. The mixture is filtered over Celite and the volatiles are removed in vacuo. The residue is dissolved in dichloromethane (200 mL), washed withNaZCO3 (2 M, 2 x 50 mL), water (2 x 50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/
Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70 g, 63% based on 2-nitro-4-tri fluoromethox yaniline).
Step B: To a solution of 6-trifluoromethoxyindole (2.68 g, 13.3 mmol) in dry DMF (10 mL) at 0 C, is added chlorosulfonylisocyanate (2.35 g, 1.44 mL, 16.6 mmol).
The mixture is then brought to room temperature slowly and stirred for lh. The mixture is poured into ice (100 mL) and stirred for lh. The precipitate is collected by filtration and washed thoroughly with water and dried in vacuo, which is then dissolved in DMF (15 mL). To the solution is added K2C03 and EtI (2.59 g, 1.34 mL, 16.6 mmol), and the mixture is stirred at 50 C
overnight. It is then poured into ice-water (200 mL). The precipitate is collected by filtration and washed with water, dried in air and purified by chromatography (silica gel, DCM) to furnish 1-ethyl-6-trifluoromethoxyindole-3-carbonitrile (2.90 g, 86%).
Step C: To a solution of the intermediate (2.03 g, 8.0 mmol) obtained above, triisopropylborate (2.16 g, 2.65 mL, 12.0 mmol) in dry THF (15 mL) at -78 C is added LDA
(6.7 mL, 1.5 M, 10.0 mmol). The mixture is stirred at -78 C for 15 min after the addition, then slowly brought to room temperature and stirred for 30 min. It is then cooled at -78 C and followed by the addition of 4-iodoaniline (2.10 g, 9.6 mmol), PdCIZ(dppf) (0.29 g, 0.4 mmol), DMF (30 mL) and K2CO3 (12.0 mL, 2.0 M, 24.0 mmol). The mixture is brought to room temperature slowly and stirred overnight and poured into ice-water (400 mL).
The precipitate is collected and washed with water, chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to furnish 2-(4-aminophenyl)-1-ethyl-6-trifluoromethoxyindole-3-carbonitrile (1.99 g, 72%).

Step D: To a solution of the compound obtained in step C(31 mg, 0.1 mmol) in dry pyridine (1.0 mL) is added ethanesulfonyl chloride (14 L, 0.15 mmol). The mixture is stirred at room temperature overnight and diluted with water (5 mL). The organic is extracted with DCM (5 mL) and washed with HCl (2N, 2 x 3 mL), water (2 x 4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, ethanesulfonic acid [4-(3-cyano-l-ethyl-6-trifluoromethoxyindol-2-yl)phenyl]amide (33 mg, 83%).
Compounds 882, 883, 884, 885, 886, 887, 888, 889 are prepared utilizing the above route using either the appropriate alkylsulfonyl chlorides (procedure 1Y) or chloroformates (procedure 1 AJ).

Example 1CF: Preparation of 2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-ethyl-6-(trifluoromethoxy)indole-3-carbonitrile (compound 903).

1 ~ (Boc)ZO/DMAP ! ~ B(O'"Pr)3/LDA 2N HCI

H Boc O,/[
01' \ B(OH)2 \ S
F3CO' g c PdCl2(dppf)/K2CO3/DMFF3C0 I N ~~ N
RT, overnight Boc Ol 0 1). 50% TFA-DCM, RT/2hr N S CISO2NCO/DMF
2). NaHCO3 F3CO ~ \/ J 0 C - RT, 3hr CN QSO CN O
Etl/K2C03JDMF ~ - O
F3CO H 50 C I ovemight F3CO I~ ~\' ~~

Step A: To a solution of 6-trifluoromethoxyindole (3.01 g, 15.0 mmol) and di-tert-butyl dicarbonate (3.59 g, 16.5 mmol) in DCM (30 mL) at 40 C is added DMAP (0.04 g) while stirring. After stirring ovemight, the mixture is washed sequentially with 0.1 N HCI, water and brine and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is chromatographed (silica gel, EtOAc(Hexanes, 1/9) to provide tert-butyl6-trifluoromethoxy-1H-indole-l-carboxylate.
Step B: The above Boc-indole and triisopropylborate (4.73 g, 5.8 mL, 26.3 mmol) are dissolved in anhydrous THF (20 mL) and the solution is cooled to 0 C. While stirring, LDA

(15.0 mL, 1.5 M mono-THF complex in cyclohexane, 22.5 mmol) is added dropwise.
The mixture is stirred at 0 C for 15 min and then room temperature for 0.5h, followed by the addition of HCI (6 N, 3.75 mL, 22.5 mmol) in an ice-water bath. The organic solvent is removed in vacuo and the residue is suspended in H20 (100 mL) and acidified with HCl (6 N) to pH 4-5. The precipitate is collected via filtration and washed with water and hexanes and dried in air to provide 1-Boc-6-trifluoromehoxyindole-2-boronic acid (2.56 g, 49%).
Step C: To a mixture of 1-Boc-6-trifluoromehoxyindole-2-boronic acid prepared above (0.74 g, 2.1 mmol), 2-(4-iodophenyl)isothiazolidine- 1, 1 -dioxide (0.76 g, 2.4 mmol), and PdC12(dppf) (0.08 g, 0.1 mmol) in DMF (6.0 mL), is added K2C03 solution (3.2 mL, 2.0 M, 6.4 mmol). The mixture is stirred at room temperature overnight and then poured into ice-water (100 mL). The precipitate is collected and washed with water and purified by flash column chromatography (silica gel, DCM/EtOAc, 9/1) to fiu-nish 1- Boc-2-[4-(1,l-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole, which is treated with 50%
TFA in DCM
(15 mL) at room temperature for lh. After the removal of the volatiles, the residue is carefully stixred with saturated NaHCO3 for 0.5h. The precipitate is collected via filtration and washed thoroughly with water and dried to provide essentially pure 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole.
Step D: At 0 C, a solution of the intermediate obtained above in dry DMF (10 mL) is treated with chlorosulfonyl isocyanate (0.38 g, 0.23 mL, 2.68 mmol). The mixture is then stirred at room temperature overnight and poured into ice-water (150 mL) then stirred for 0.5h.
The precipitate is collected via filtration and washed thoroughly with water and dried in air to furnish 1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole-3-carbonitrile (0.81 g, 90%).
Step E: To a solution of 1-H-2-[4-(l,l-dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxyindole-3-carbonitrile (63 mg, 0.15 rnmol) and K2C03 (62 mg, 0.45 mmol) in DMF (2.0 mL) is added ethyl iodide (36 L, 0.45 mmol). The mixture is stirred at 50 C
overnight and poured into ice-water (10 mL). The precipitate is collected via filtration, washed with water and purified by colunm chromatography to provide 2-[4-(1, 1 -dioxidoisothiazolidin-2-yl)phenyl]-6-trifluoromethoxy-l-ethylindole-3-carbonitrile (59 mg, 88%).
The following compounds are prepared in the same fashion as described above:
Compounds 902, 904, 905, 906.

Example ICG: Preparation of [4-(3-cyano-l-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acid isopropyl ester (compound 1234).

H -NHiN-OH DCC/HOBU >-NH2 N -V K2COg/Cul/
O Br0 DCM-DMF/RT/4hr -O Br0 toluene/110 C/48h CN
O DIBAL-H ~~ \ CISO2NCO
O / N DCM/O C - RT -O / N DMF/ O C -RT
~O I/ N
4h &

CN O d CN O
1). S(Of-Pr)3/LDAITHF/-780C CI ~ - y C
2).PdCI2(dPPfYK2C0'3 -O N NHZ pyr ~O I/ N \/. NH
4-iodoaniline Step A: To a suspension of 2-bromo-4-methoxyphenylacetic acid (24.5 g, 100 mmol) in DCM (100 mL), while stirring, is added DMF (-10 mL) until all the solid disappears, which is followed by the addition of DCC (22.66 g, 110 mmol) and HOBt (14.85 g, 110 mmol). After stirring at RT for 10 min, cyclopropylamine (8.55g, 10.4 mL, 150 mmol) is added to the mixture, and the resulting mixture is stirred at room temperature for 4h. The solid is filtered and washed thoroughly with DCM (300 mL). The filtrate is cooled to -10 C and gently stirred for lh and filtered again to remove additional urea by-product. The filtrate is passed through a silica gel pad and eluted with DCM/EtOAc, 8/2). After the removal of the solvent, the cyclopropyl amide intermediate is obtained as white solid (28.34 g, 100%).
Step B: A mixture of above am.ide (14.2 g, 50.0 mrnol), K2C03 (13.8 g, 100 mmol), CuI
(0.74 g, 5.0 mmol) and N,N' dimethylcyclohexanediamine (1.42 g, 1.57 mL, 10.0 mmol) in toluene (150 mL) is stirred at 110 C under N2 atmosphere for 48h. After cooling to room temperature, the mixture is filtered over Celite and washed thoroughly with DCM. The filtrate is evaporated under reduced pressure to dryness and the residue is chromatographed (DCM/EtOAc, 9.5/0.5) to provide the product, 1-cyclopropyl-6-methoxyoxindole as pale yellow solid (4.30 g, 42%).
Step C: To a solution of the oxindole obtained above (5.0 g, 24.6 mmol) in dry DCM
(25 mL), at 0 C, is added DIBAL-H (1.0 M in DCM, 35.0 mL, 35.0 mmol). After the addition, the mixture is stirred at room temperature for 4h and re-cooled to 0 C, followed by the addition of HCl (2 N) dropwise. The DCM layer is washed with HCl (2 N, 10 mL) water and brine and dried over anhydrous Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (hexanes/EtOAc, 9.5/0.5) to provide the 1-cyclopropyl-6-methoxyindole as a colorless oil (4_52 g, 98%).
Step D: To a solution of 1-cyclopropyl-6-methoxylindole (3.29 g, 17.6 mmol) in dry DMF (30 mL), at 0 C, is added chlorosulfonyl isocyanate (3.11 g, 1.91 mL, 22.0 mmol). After the addition, the mixture is stirred at room temperature for 2h, followed by aqueous work-up.
Chromatography (silica gel, hexanes/EtOAc, 9/1) furnishes 3-cyano-l-cyclopropyl-6-methoxyindole (3.05 g, 82%).
Step E: To a solution of the intermediate (2.65 g, 12.5 mmol) obtained above and triisopropyl borate (3.38 g, 4.14 mL, 18.8 mmol) in dry THF (18 mL) at-78 C is added LDA
(10 mL, 1.5 M, 15.0 mmol). The mixture is stirred at -78 C for 15 min after the addition, then slowly brought to room temperature and stirred for 30 min. It is then cooled at -78 C and followed by the addition of 4-iodoaniline (3.29 g, 15.0 mmol), PdCI2(dppf) (0.46 g, 0.6 mmol), DMF (40 mL) and K2C03 (18.8 mL, 2.0 M, 37_6 mmol). The mixture is brought to room temperature slowly and stirred overnight and then poured into ice-water (400 mL). The precipitate is collected and washed with water, and after drying, is chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to furnish 2-(4-aminophenyl)-1-cyclopropyl-6-methoxyindole-carbonitrile (2.84 g, 75%).
Step F: To a solution of the compound obtained in step E (61 mg, 0.2 mmol) in dry pyridine (2.0 mL) is added isopropylchloroformate (0.3 mL, 1.0 M, 0.3 mmol) in toluene. The mixture is stirred at room temperature overnight and diluted with water (10 mL). The organic layer is extracted with DCM (10 mL) and washed with HCl (2N, 2 x 3 mL), water (2 x 4 mL) and brine (3 mL) and chromatographed (silica gel, EtOAc/DCM, 0.5/9.5) to provide the product, [4-(3-cyano-1-cyclopropyl-6-methoxyindol-2-yl)phenyl]carbamic acid isopropyl ester (66 mg, 85%).
Compounds 1235 and 1236 are prepared by utilizing the above chemistry.

Example 1CH: Preparation of 1-allyl-6-methoxy-2-[4-(2-oxopyrrolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile (compound 938) CN
CN i, iPr2NH, n-BuLi, THF
2, B(OMe)3 N
~ , N - Me0 N
Me0 3. K3PO4 (3M, aq.) 0 PdCl2dppf, DMF

C`
O
Utilizing the proeedure described in Example 1Gb, substituting 1-allyl-6-methoxy-lH-indole-3-carbonitrile (92.3 mg, 0.43 mmol) and 1-(4-iodophenyl)-pyrrolidin-2-one gives 99.0 mg (61.3% yield) of compounds 938.

Example I CI: Preparation of 6-cyclopropoxy-2-[4-(1,1-dioxo-1 X6-isothiazolidin-2-yl)-phenyl]-1-ethyl-lH-indole-3-carbonitrile (compound 1046) CN CN CN
I~ \ BBrg K2C03, DMF, 80PC
O
O ~ CHDCl2 HO ~ 2) K(OtBu), 80 C ~01( N
CN 1. LDA, THF, -7&C CN
2. B(O'Pr)3 CICH21, Et2Zn _ 'L' O 3. K2C03(3M, aq.) O O-SO
(CH2)2C12 -1QuC-RT ~ ~
4.
N I PdCl2dppf, DMF
~S=O
u O
Step A: Utilizing the procedure described in Example 1B (Step A) gives 6-hydoxy-l-ethyl-1 H-indo le-3 -carbonitrile.
Step B: To a solution of 6-hydoxy-l-ethyl-lH-indole-3-carbonitrile (503.9 mg, 2.70 mmol) in 5 mL of DMF is added anhydrous K2CO3 (1.12 g, 8.12 mmol) and 1-bromo fluoroethane (413.7 mg, 3.29 mmol). The resulting mixture is stirred at 80 C
until complete consumption of the starting material as determined by TLC. The reaction mixture is cooled, potassiurn tert-butoxide (1M solution in THF, 5.5 ml, 5.43 rnmol) is added, and stirring continued at 80 C overnight. The mixture is partitioned between EtOAc (30 mL) and IN HC1 (20 mL). The organic phase is washed with saturated NaHCO3, satt.irated NaCI
and dried and concentrated. The product is isolated by chromatography (EtOAc/hexanes, 10-25%) over silica gel to afford 430.2 mg (74.9%) 1-ethyl-6-vinyloxy-IH-indole-3-carbonitrile as a white solid.
Step C: Via a syringe, diethyl zinc is added to a mixture of 1-ethyl-6-vinyloxy-lH-indole-3-carbonitrile (288.1 mg, 1.36 nunol), chl.oroiodomethane (268.9 mg, 1.53 nunol) and 5 ml of 1,2-dichloroethane over a period of 10 rnin, maintaining the temperature at -10 C. The mixture is warmed to 20-25 C for 20 min., and then cooled back to 0 C.
Saturated NH4C1(15 mL), concentrated ammonium hydroxide (15 mL), and ethyl acetate (15 mL) are added in sequence at this temperature, and stirred for 10 min. After the phases are separated, the aqueous phase is back-extracted with ethyl acetate (10 mL). The combined organic phases are washed with saturated NH4CI (10 mL), dried over MgSO4 and then the solution is concentrated.
and the product is purified by chromatography, eluting with 15-30% ethyl acetate / hexanes to afford 140.5 mg (45.7% yield) of 6-cyclopropoxy-l-ethyl-lH-indole-3-carbonitrile as a yellow solid.
Step D: Utilizing the same procedure described in Example 1Gb substituting 4-iodoaniline with 2-(4-iodo-phenyl)-isothiazolidine 1,1-dioxide gives the title compound.
In similar fashion, following steps A to D, above, compound 1047 is also prepared.
Example CJ: Propane-l-sulfonic acid [4-(3-cyano-6-difluoromethoxy-l-ethyl-lH-indoel-2-yl)-phenyl]-amide (compound 928).

N
1. B(O'Pr)3, THF %
F I~ 2. LDA, THF, -78 C F ~ \ -l- / N ~ I/ ~ NHZ
F O /I ~ DMF F O 1 4. K2CO3 (3M, aq.) PdClZdppf N
n-PrSO2C! 0S
F ~
pyridine F~O I/ N NH-\
rt ) Step A: A solution of6-difluoromethoxy-l-ethyl-iH-indole-3-carbonitrile (316.3 mg, 1.34 mmol) and triisopropyl borate (402.9 mg, 2.14 mmol) in THF (15 mL) is cooled to -78 C
and treated with LDA (1.5 M mono-THF in cyclohexane, 1.07 mL, 1.61 mmol).
After the addition, the acetone/dry ice bath is exchanged for an ice water bath and the solution is stirred ~ further for 30 min. The solution is cooled to -78 C and a solution of 4-iodoaniline (299.5 mg, 1.37 mmol) in DMF (8 mL), K2CO3 (2M, 2.01 mL, 6.02 mmol) and PdCl2dppf (51.3 mg, 0.07 mmol) are added in sequence. The mixture is degassed by three successive cycles of vacuum purnping/N2 purging and is stirred overnight (ca. 16h.). The reaction mixture is poured into 4 volumes of water, and 4 volumes of ethyl acetate are added. The phases are separated, and the aqueous phase is extracted with more ethyl acetate. The organic phases are washed by water, saturated NaCI and then dried over anhydrous MgSO4, filtered and evaporated.
The remaining material is purified by column chromatography, eluting with 5-15% ethyl acetate/hexanes on silica gel to yield 304.5 mg (70%) of the aniline intermediate as a white solid.
Step B: Utilizing the same procedure described in Example 1Y and substituting n-propylsulfonyl chloride gives the title compound.
The following compounds are made using essentially the same procedure and substituting other sulfonyl chlorides: Compounds 929, 930, 931.

Example 1CK: [4-(3-cyano-6-difluoromethoxy-l-ethyl-lH-indol-2-yl)-phenyll-carbamic acid methyl ester (compound 1130).

rN 0 N
F
N H
F ~ N EtoAc F 0 N O~ O
aq. K2CO3 A solution of 2-(4-aminophenyl)-6-difluoromethoxy-l-ethyl-lH-indole-3-carbonitrile (200 mg, 0.611 mmol) and methyl chloroformate (95 L, 1.23 mmol) in ethyl acetate (2 mL) is treated with 2 M aqueous potassium carbonate solution (0.370 mL, 0.74 mmol), and the resulting mixture is stirred vigorously overnight. Saturated brine solution (1 mL) is added, and the mixture is stirred for 10 minutes. The organic layer is removed, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting solid is triturated with 1/1 ether-hexane, collected by filtration and dried under vacuum to afford the title product as a white solid.
Similarly prepared from appropriate reagents are: Compounds 1131, 1132, 1133, 1134, 1135.

Example 1 CL: 1-[4-(3-cyano-6-difluoromethoxy-1-ethyl-lH-indol-2-yl)-phenyll-3-propyl-urea (Compound 893)_ N ~N
~ - ~iNCO F ~ -F~O ~ i N \/ NH2 Et N F~O ~ i N \/ N~NH
~ 3 CHZCIZ

A solution of 2-(4-aminophenyl)-6-difluoromethoxy-1-ethyl-lH-indole-3-carbonitrile (200 mg, 0.611 mmol) in 1,2-dichloroethane (2 mL) is treated with n-propylisocyanate (115 mL, 1.23 mmol) and triethylamine (170 mL, 1.22 mmol). The resulting solution is stirred at ambient temperature for 12 hours, and then concentrated. The residual material is separated by silica gel chromatography (1/2 ethyl acetate-hexane) to afford the title product as a solid.
Similarly prepared from appropriate reagents are: Compounds 892, 894.

Example 1CM: Preparation ofmorpholine-4-carboxylic acid [4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-amide (compound 1166).

1. iPr2NH, n-Buli, THF
CN CN 2. B(OiPr)3 ~ ~ \ Br 1 \
EtO ~ N Et0 N 3. K3PO4 (3M, aq.) H Cs2CO3, DMF, 4 NH2 80 C PdCl2dppf, DMF
CN Ciy A ~--\
O ONH

Et0 N
CH2CI2, Pyridine CN O
N
N NH
Et0 6 Step A: 6-Ethoxy-lH-indole-3-carbonitrile (2.8 g, 15 mmol), prepared as shown in example lA, step A, is combined with Cs2CO3 (11.6 g, 35.6 mmol), DMF (21 mL), and cyclobutyl bromide (1.73 mL, 17.9 mmol) in a capped tube. The reaction mixture is heated at 80 C for 8h. This is then quenched with H20 (200 mL) and is extracted with EtOAc. The EtOAc layer is backwashed with H20, and then with brine. The organic phase is dried and concentrated. Purification by silica gel chromatography (hexanes/CH2C12, 50-100%) yields I-cyclobutyl-6-ethoxy-lH-indole-3-carbonitrile (3.00 g, 83%) as a white solid.
Step B: Following essentially the procedure in example 1Gb, 1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (3.0 g, 12.4 mmol) is converted via Suzuki coupling to yield 2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-lH-indole-3-carbonitrile (2.60 g, 68%) as an off-white solid_ Step C: 2-(4-aminophenyl)-1-cyclobutyl-6-ethoxy-lH-indole-3-carbonitrile (40 mg, 0.12 mmol), 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), CHa.Cl2 (400 p.L), and pyridine (25 L, 0.31 mmol) are stirred at room temperature for 1 hour. Morpholine (60 L, 0.70 mnnol) is added. After stirring at room temperature for an additional 30 minutes, the reaction mixture is diluted in CH2C12 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct. The organic layer is dried and concentrated.
Purification by silica gel chromatography (CH2C12/EtOAc, 7/3) yields morpholine-4-carboxylic acid [4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-amide (53 mg, 100%) as a white solid.
The following compounds are prepared in a similar fashion, using the appropriate amine in the final step: compounds 1087, 1088, 1089, 1119, 1159, 1168, 1191, 1266, 1288, 1324, 1325, 1326.

Example 1CN: Preparation of rac-[4-(3-cyano-l-cyclobutyl-6-ethoxy-IH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 1147).

CN CI O
N~ ~ I ~ U
EtO N NO2 - OH -6 DCE, Pyridine 80 C

CN p~ )--a Et0 ~ N ~ / NH
2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-lH-indole-3-carbonitrile (50 mg, 0.15 mmol), prepared as in example 1CM, step B, ias combined with 4-nitrophenyl chloroformate (76 mg, 0.38 mmol), DCE (0.5 mL), and pyridine (30 L, 0.37 mmol). This suspension is stirred at room temperature for lh. Rac-cyclopropyl methyl carbinol (100 L, 0.98 mmol) is added. This mixture is heated at 75 C overnight. The reaction mixture is then diluted in CH2CI2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol byproduct.
The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2C12) yields rac-[4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (40 mg, 60%) as a white solid.
The following compounds are prepared in a similar fashion, using the appropriate alcohols: Compounds 1146, 1158, 1167, 1192, 1208, 1209, 1210, 1215, 1216, 1240, 1241, 1242, 1243, 1244, 1246, 1247, 1248, 1249, 1250, 1264, 1265, 1267, 1268, 1281, 1282, 1283, 1286, 1287, 1289, 1290, 1291, 1292, 1294, 1295,1296, 1297,1298, 1299, 1312, 1313.

Example 1CO: Preparation of 1-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (compound 1239).

CN CN O
~ \ NH2 TFAA, Et3N, ~'CFg NH
Et0 I~ N
CH2C12 Et0 N
b CN p CN
Etl, DMF, ~ \ - ~-CF3 \ NH
NaH Et0 N NEt + Et0 N Et CN
NaOH, H20, H
\ ~ O N
MeOH, 80 C EtO '~ I N Et b Step A: 2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-lH-indole-3-carbonitrile (600 mg, 1.81 mmol), prepared as in example 1 CM, step B, is suspended in CH2Cl2 (18 mL), and Et3N
(390 L, 2.7 mmol). Trifluoroacetic anhydride (310 L, 2.2 mmol) is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes, after which time dissolution is complete. The reaction mixture is then washed with saturated NaHCO3 solution.
The organic layer is dried and concentrated to yield 1V [4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (802 mg, 100%) as a yellow solid.
Step B: N-[4-(3-Cyano-l-cyclobutyl-6-ethoxy-1H=indol-2-yl)-phenyl]-2,2,2-trifluoro-acetamide (800 mg, 1.8 mmol) is dissolved in DMF (10 mL). NaH (140 mg, 60% oil suspension, 3.5 mmol) is added. This is stirred at room temperature for a few minutes, after which ethyl iodide (176 L, 2.2 rnmol) is added. This is stirred at room temperature overnight, and then at 75 C for 6h. Additional portions of NaH (200mg, 5.0 mmol) and iodoethane (200 L, 2.5 mmol) are necessary to push the reaction further. This is heated overnight at 75 C.
Additional ethyl iodide (200 L, 2.5 mmol) is added. This is heated for another 2h. The reaction mixture is then diluted in H20 and is extracted into EtOAc. The EtOAc layer is dried and concentrated. Silica gel chromatography (CH2Cla) yields 384 mg of an inseparable mixture of expected N-[4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-N-ethyl-2,2,2-trifluoro-acetamide and hydrolyzed 1-cyclobutyl-6-ethoxy-2-(4-ethylamino-phenyl)-1H-indole-3-carbonitrile.
Step C: The crude mixture from the previous step is dissolved in methanol (5 mL). 6N
NaOH (1.0 mL, 6 mmol) is added, and the mixture is heated at 80 C for lh. The reaction mixture is then dil.uted in H20 and is extracted into CH2C12. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2C12) yields pure 1-cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (343 mg, 53% over two steps) as a white solid.
1-Cyclobutyl-2-(4-diethylamino-phenyl)-6-ethoxy-lH-indole-3-carbonitrile (compound 1217, 77 mg, 11%) is isolated as a byproduct of the reaction described in example 1CO, step B.
Example 1CP: Preparation of [4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-ethyl-carbamic acid cyclopentyl ester (compound 1251).
Ci o cN ~
Et cN ~
I i \ ~ / NH ~ \ - O
Et0 N N
pyridine Et0 ~ N \ / 'Et 1-Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (35 mg, 0.10 mmol), prepared as in example 1CO, step C, is dissolved in pyridine (300 }tL).
Cyclopentyl chloroformate (25 pL, 0.17 mmol) is added. The reaction mixture is stirred at room temperature for 2.5h. More chloroformate (101.t.L, 0.07 nunol) is added to drive the reaction to completion_ After an additiona190 min of stirring, the reaction mixture is partitioned between aqueous HCI and EtOAc. The organic layer is dried and concentrated.
Purification by silica gel chromatography yields [4-(3-cyano-l-cyclobutyl-6-ethoxy-lH-indol-2-yl)-phenyl]-ethyl-carbamic acid cyclopentyl ester (41 mg, 87%) as a white solid.
Compound 1252 is prepared similarly using the appropriate chloroformate.

Example 1CQ: Preparation of {4-[3-cyano- 1 -cyclobutyl -6-(3-[1,2,4]triazol-l-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1255).

CN O CN O~
~ NH O BBr3 I~ O
I / \ ~ ~ b HO' v N \ / NH ~

b CN O
K2CO3 \ ~--0 1) Nal. CH3CN
NH
Br~~CI ci O ~ N 2) DMF
DMF ~ NNNa CN O
O
N I NH

Step A: To a solution [4-(3-cyano-l-cyclobutyl-6-methoxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (950 mg, 2.35 mmol) in DCM (10 mL) is added BBr3 (556 uL, 5.9 mmol) over a period of 20 min. The reaction mixture is stirred further for lh at room temperature and then water (lmL) is added. The solvents are removed under reduced pressure.
The residue is dissolved in MeOH and then poured into cold water. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cyano-1-cyclobutyl -6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (650 mg, 71%).
Step B: To a solution of [4-(3-cyano-l-cyclobutyl -6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (340 mg, 0.87 mmol) in DMF (2 mL) is added K2CO3 (132 mg, 0.96 rnmol) and 3-bromo-l-chloroproane (172 uL, 1.75 mmol) and the reaction is stirred for 5h at 60 C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 370 mg (92%) of the desired product.
Step C: To a solution of {4-[6-(3-chloro-propoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (37 mg, 0.08 mmol) in CH3CN (1 mL) is added sodium iodide (71 m.g, 0_48 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is then evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.16 mmol) at room temperature overnight. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and then washed with water. The organic layer is concentrated and triturated with hexane and the precipitate is collected by filtration and washed well with 50%
ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-l-cyclobutyl -6-(3-[1,2,4]triazol-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1255 (31 mg, 78%).
The following compounds are made in similar fashion following steps A-C, above:
Compounds 1253, 1254, 1260, 1261, 1262.

Example 1CR: Preparation of {4-[3-cyano-l-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (compound 1276).

CN O CN O~
NH
8 ~KZC03 i I \ \ /
N -HO I N
iC~ ~J
O ~ ~
CH3CN CIv CN D
1) Nal, AnN \>--0 2) DMF ~ NH
/-N O N
N~/NNa N~Nv Step A: To a solution of [4-(3-cyano-l-cyclobutyl -6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (390 mg, 1.0 mmol) in CH3CN (5 mL) is added K2CO3 (414 mg, 3.0 mmol) and 3-bromo-l-chloroetahne (250 uL, 3.0 mmol) and the reaction is stirred for 18h at 80 C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 420 mg, 93% of the desired product.
Step B: To a solution of {4-[6-(3-chloroethoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (42 mg, 0.09 mmol) in CH3CN (1 mL) is added sodium iodide (56 mg, 0.37 mmol). The resulting mixture is stirred at reflux temperature overnight.
The solvent is evaporated and the residue is diluted with anhydrous DMF (1 mL) and then treated with the sodium salt of 1,2,4-triazole (0.18 mmol) at room temperature for overnight.
The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and.
then washed with water. The organic layer is concentrated and triturated with hexane. The precipitate is collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-l-cyclobutyl -6-(3-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1276 (28 mg, 64%).

The following compounds are made in similar fashion following steps A and B, above:
Compounds 1269, 1270, 1271, 1272, 1273, 1274, 1275, 1276, 1277, 1278.

Example 1CS: Preparation of {4-[3-cyano-l-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (compound 1329).
CN CN O
~ ~ - 1) 4Nitropheny1 chloroformate ~ - O
HO I N NHZ 2) HO N NH
HO

CN O
ICZCOg I~ ~N~O 1) Nal. AcN
Br~~CI O / N ~/ 2) QMF
CH3CN Cf J N
NNa CN p O
N O I / N -NH

Step A: To a solution of 2-(4-aminophenyl)-1-cyclobutyl-6-hydroxy-lH-indole-3-carbonitrile (909 mg, 3 mmol) in pyridine (5 mL) is added 4-nitrophenyl chloroformate (6 mmol) at room temperature and then stirred for 2h at room temperature. To the reaction is added cyclopropyl methyl carbinol and then stirred for 8h at 80 C. The reaction mixture is diluted with 1N HCl and then extracted with ethyl acetate. The organic layer is concentrated and the residue is dissolved in EtOAc and triturated with hexane. The precipitate is collected by filtration and washed with hexane and dried in vacuo to afford [4-(3-cya.no-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (996 mg, 80%)_ Step B: To a solution of [4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (1.5 g, 3.61 mmol) in CH3CN (8 rnL) is added K2CO3 (1.5 g, 10.8 mmol) and 2-bromo-l-chloroethane (895 uL, 10.8 mmol) and the reaction is stirred for 18h at 80 C. The reaction mixture is then poured into cold water and the precipitate is collected by filtration and washed with hexane and dried in vacuo to afford 1.46 g, 84% of the desired product.
Step C: To a solution of {4-[6-(2-chloroethoxy)-3-cyano-1-cyclobutyl-lH-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in. CH3CN
(10 mL) is added sodium iodide (1.84 g, 12.22 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (20 mL) and then used without further purification. To 1 mL of the DMF
solution containing the iodoethyl intermediate (0.153 mmol) is added the sodium salt of 1,2,4-triazole (0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with 0.5 mL DMF and the desired product is purified by preparative LC
to give {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).
The following compounds are made in similar fashion following steps A-C, above:
Compounds 1327, 1328.

Example 1CT: Preparation of 1-{4-[3-cyano-l-cyclobutyl-6-(3-[1,2,4]triazol-l-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314).

N N
O O
H NH BBr3 NH N
~O N CH2CI2 Hp N
N o Nal Br^^CI _ ~ ~ \ N H
K CO CI------O ~\ H CH3CN/DMF (411) N _ Na+ o ~\ I/ N \/ N }{ N~N ~'N.N^/~O N N
H
[ O H DMF N--J

Step A: To a solution of 1-[4-(3-cyano-l-cyclobutyl-6-methoxy-lH-indol-2-yl)-phenyl]-3-isopropyl-urea (2.21 g, 5.49 mmol in CH2C12 (30 mL) is added a 1M
solution of BBr3 in CH2C12 (16.5 mL, 16.5 mmol) at 0 C. The mixture is allowed to warm to room temperature and kept for lh. The reaction mixture is then poured onto ice and aqeouslM
NaHCO3 is added until the pH is 7-8. The product is extracted with 100 mL of ethyl acetate (3X) and the organic phases are washed with 100 mL of saturated NaCI. The organic phases are combined and dried over MgSO4. Solvent is removed to recover 1.95 g (92%) of 1-[4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-3-isopropyl-urea, as a tan solid.
Step B: To a solution of 1-[4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-3-isopropyl-urea (750 mg, 1.93 mmol) in 10 mL of acetonitrile is added anhydrous K2C03 (800 mg, 5.79 mmol) and 1-bromo-3-chloropropane (382 pL, 3.86 mmol). After stirring overnight at 80 C, the reaction mixture is cooled and solvent is removed. The reaction is re-suspended in 100 mL of ethyl acetate. The organic phase is washed with 200 mL of H20, and the aqueous phase is re-extracted 2X with 100 mL of ethyl acetate. The organic phases are combined, dried over MgSO4 and the solvent is removed to afford 769 mg (86%) of 1-{4-[6-(3-chloropropoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]-phenyl}-3-isopropyl-urea as a tan powder.
Step C: To a solution of 1-{4-[6-(3-chloropropoxy)-3-cyano-l-cyclobutyl-lH-indol-2-yl]-phenyl}-3-isopropyl-urea (400 mg, 0.860 mmol) in 8 mL of acetonitrile/DMF, (4/1) is added anhydrous NaI (258 mg, 1.72 mmol). After stirring overnight at 60 C, the reaction shows conversion to product by LCMS-iN_ The reaction mixture is cooled, the solvent is removed and redissolved in DMF to 14.0 mL total volume:
Step D: To I mL of the DMF solution above, 1-{4-[3-cyano-l-cyclobutyl-6-(3-iodopropoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (34 mg, 0.062 mmol) is added anhydrous 1,2,4-triazole, sodium salt (10.0 mg, 0.110 mmol). After stirring overnight at rt, the reaction mixture is filtered and purified by preparatory LC/[TV purification.
The solvent is removed to obtain 12.3 mg (40%) of 1-{4-[3-cyano-l-cyclobutyl-6-(3-[1,2,4]triazol-l-yl-propoxy)-1H-indol-2-yl]-phenyl}-3-isopropyl-urea (compound 1314), as a white powder.
The following compounds are prepared following the above procedure: Compounds 1306, 1307, 1308, 1309, 1315, 1316, 1317, 1318, 1319, 1320, 1321, 1323 and 1324.

Example 1CU. Preparation of [4-(3-cyano-l-cyclobutyl-6-pyrimidin-2-yl-1 H-indol-2-yi)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 2419).

CN O ~-a CN Q~ O/ OB O
~ - ~O Tf20, Pyridine ~ ~'--HO I~ N ~ I NH CH2CI2 Tf0 I~ N NH -~r-~ Pd(dPACI2. dppf KOAc, dioxane CN NH ~a ~N CI ` CN NH
p O N Pd(PPh3)4, N= I~ N
CsF, DME N
1oooC

Step A. Into a solution of [4-(3-Cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (1.8 g, 4.3 mmol) in CH2C12 (20 mL) at 0 C was added pyridine (2.74 g, 34.6 nunol), followed by the slow addition of a solution of TfZO (3.67 g, 13.0 mmol) in CH2C12 while maintaining the temperature below 10 C. Upon completion the reaction mixture was washed with dilute HCl, water and brine, and then dried over MgSO4, concentrated and triturated with hexanes to provide the product as a solid (1.8 g, 96%).
Step B. A mixture of trifluoro-methanesulfonic acid 3-cyano-l-cyclobutyl-2-[4-(1-cyclopropyl-ethoxycarbonylamino)-phenyl]-1H-indol-6-yl ester (1.1 g, 2.0 mmol), bis(pinacolato)diboron (0.56 g, 2.2 mmol), Pd(dppf)C12 (49 mg, 0.06 mmol), dppf (24 mg, 0.06 mmol) and potassium acetate (0.59 g, 6.0 nunol) in dioxane (12 mL) was stirred at 80 C
overnight. The reaction mixture was diluted with EtOAc, washed with H20 and brine, dried over Na2SO4, concentrated and purified on silica gel (CH2Cla/EtOAc) to provide the product as a solid (0.96 g, 91%).
Step C_ A mixture of {4-[3-cyano-l-cyclobutyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (0.2 g, 0.38 mmol), 2-chloropyrimidine (39 mg, 0.34 mg), Pd(PPh3)4 (22 mg, 0.095 nunol) and cesium fluoride (0.116 g, 0.76 mmol) in DME (2.0 mL) was stirred at 100 C for 16 h. The mixture was then diluted with EtOAc (20 mL), washed with water and brine, dried over Na2SO4, concentrated and purified on silica gel (CHZC12/EtOAc) to provide [4-(3-cyano-l-cyclobutyl-6-pyrimidin-2-yl-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (0.15 g, 82%).

Example 1CV. Preparation of [4-(3-cyano-l-cyclobutyl-6-pyridin-2-yl-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (compound 2417).

N - ~-O~Rl ~ NSnBu3 \ \N - DO~R/
Tfo I ~ N ~ / NH N NH
Pd(PPh3)4 Cul, CsF
DMF, 800C

To a solution of of trifluoro-methanesulfonic acid 3-cyano-l-cyclobutyl-2-[4-(1-cyclopropyl-ethoxycarbonylamino)-phenyl]-1H-indol-6-yl ester prepared as in Example 1CU
Step A (200 mg, 0.37 mmol) in DMF (2.0 mL) was added 2-(tributylstannyl)pyridine (160 mg, 0.44 mmol), Pd(PPh3)4 (21 mg, 0.018 mmol), Cul (7 mg, 0.037 mmol) and CsF (111 mg, 0.73 mmol). The mixture was stirred at 80 C for 2 h, treated with ether (20 mL) and potassium fluoride (0.5 g). The mixture was stirred for another hour and filtered. The-filtrate was washed with water and brine, dried over Na2SO4i concentrated and purified on silica gel (CH2CI2/EtOAc) to provide [4-(3-cyano-l-cyclobutyl-6-pyridin-2-yl-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (82 mg, 47%).

Example 1CW: Preparation of (R)-{4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester (compound 2210).

\ õ ~N
CN LDA, -78 C- rt CN O
` \ ~OiPr)s. THF: NH O`-V CI NH
N DMF. 8q. KZC03 (2M), HO N Cs2C03, HO ' N
Ptl(tlppf)Cly, rt 0~~ DMF.70 C

1 aNH

,OH
CHZCIZ

NCO

Step A: To a suspension of 4-iodophenylisocyanate (0.84 g, 3.5 mmol) in CH2C12 (6 mL) was added (R)-1-cyclopropylethanol (0.67 mL, 6.9 mmol). The solution was then directly subjected to silica gel chromatography (CH2Cl2) to provide (R)- (4-iodo-phenyl)carbamic acid 1-cyclopropyl-ethyl ester (1.05 g, 93%).
Step B: To a solution of (R)-1-cyclobutyl-6-hydroxy-lH-indole-3-carbonitrile (0.53 g, 2.5 mmol), triisopropylborate (0.86 mL, 3.75 mmol) in THF (7.5 mL) at =78 C
was added LDA (1.5M monoTHF in cyclohexane, 3.83 mL, 5.75 mmol). The mixture was stirred at -78 C
for 10 minutes and then at room temperature for 30 minutes, followed by the addition of (4-iodo-phenyl)-carbamic acid 1 -cyclopropylethyl ester (0.83 g, 2.5 mmol) and PdCh,(dppf) (0.055 g, 0.075 mmol). The reaction mixture was cooled to -78 C and flushed with nitrogen before the addition of DMF (15 mL) and aq. K2C03 (2.OM, 3.75 mL, 7.5 mmol).
The cooling bath was removed and the mixture was stirred ovemight, poured into ice water (100 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in air and dissolved in CH2CI2, purified on silica gel (CH2CI2/EtOAc, 9: 1) to provide (R)-[4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (0.58 g, 56%).
Step C: A mixture of (R)-[4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.083 g, 0.2 mmol), Cs2CO3 (0.163 g, 0.5 mmol), 2-chloropyrimidine (0.046 g, 0.4 rnmol) in DMF (2.0 mL) was stirred at 70 C for 2 h. After cooling to room temperature, the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water, purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester (0.073 g, 74%).

Example 1CX: Preparation of (R)-{4-[3-cyano-l-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropylethyl ester (compound 2217).

D--NHZ
I~ K3PO4, Cul CICOCH2CI CI
~O / I HO(CH2)2OH O NH CH2CI2, KOH ~O
i-PrOH, 80 C A EOAc/ HZO

~ Px 1) DIBAL-H
CHaCI2 CN

Pd(OAc)2, Et3N, N 2) CSI
toluene / 80 C DMF, 0 C

CN LDA, -78OC- rt CN 0 \--a BBr3, CH2CI2 B(OiPr)3, THF; C \ /\ NH
78 C ' 0 C N DMF, aq. K2C03 (2M), HO N
HOI Pd(dppt)CIy rt I ~ ~ NH

N CN O ~--Q
N"-CI ~/ 1NI ~ N N'H O
Cs2CO3, DMF \NO I ~ N

Step A: A mixture of 3-iodoaniso (2.3 8 mL, 20.0 mmol), cyclopropylamine (2.10 mL, 30.0 mmol), K3P04 (8.48 g, 40.0 nunol), Cul (0.19 g, 1.0 mmol), ethylene glycol (2.23 mL, 40.0 mmol) and isopropanol (20 mL) was stirred at 80 C overnight. The reaction mixture was concentrated and suspended in CH2Cla (100 mL) and water (100 mL). This mixture was then treated with 28% aq. ammonia hydroxide until the solids dissolved_ The organic layer was separated, dried over Na2SO4 and purified on silica gel (CH2C12/hexane, 6:4) to provide cyclopropyl(3-methoxyphenyl)amine as colorless oil (1.52 g, 47%).
Step B: To a mixture of cyclopropyl(3-methoxyphenyl)amine (1.52 g, 9.3 mmol), KOH
(1.57 g dissolved in 8 mL H20) and EtOAc (15 mL) at 0 C was added dropwise, with vigorous stirring, chioroacetyl chloride (1.12 mL, 14.0 mmol). The mixture was stirred for additional 30.

minutes, washed with water (3X350 mL), concentrated and purified on silica gel (CH2C12/hexane, 1: 1) to provide 2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)acetamide as a solid (1.80 g, 81%).
Step C: A mixture of 2-chloro-N-cyclopropyl-N-(3-methoxy-phenyl)-acetamide (1.25 g, 5.2 mmol), Pd(OAc)Z (0.06 g, 0.26 mmol), Et3N (0.79 g, 1.10 mL, 7.8 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (0.155 g, 0.52 mmol) in toluene, (6.0 mL) was stirred at 80 C
overnight. After cooling to room temperature the mixture was purified on silica gel (CHZC12/
EtOAc, 9.5:0.5) to provide 1-cyclopropyl-6-methoxy-1,3-dihydro-indol-2-one as a solid (0.89 g, 84%).
Step D: To a solution of 1-cyclopropyl-6-methoxy-1,3-dihydro-indol-2-one (5_0 g, 24.6 mmol) in CH,_,CL) (25.0 mL), at 0 C was added DIBAL-H (1.0 M in CH2C12 33.3 mL, 33.3 mmol). The mixture was then stirred at room temperature for 4h and treated with HCI (1.0 N).
The organic layer was separated, washed with water and purified on silica gel (CH2Cl2) to provide the indole intermediate, which was then dissolved in dry DMF (40.0 mL) and cooled at 0 C. The solution was treated with chlorosulfonyl isocyanate (5.09 g, 3.13 mL, 36.0 mmol), and stirred at 0 C for 2h and poured into ice-water (300 mL). The precipitate was collected by filtration and washed with water and purified on silica gel (hexane/EtOAc, 9:1) to provide 1-cyclopropyl-6-methoxy-lH-indole-3-carbonitrile as a solid (3.60 g, 69%).
Step E: A solution of 1-cyclopropyl-6-methoxy-1H-indole-3-carbonitrile (3.60 g, 17.0 mmol) in CH2CI2 (50.0 mL) was cooled to -78 C and treated with BBr3 (21.27 g, 8.03 mL, 84.9 mmol), stirred for 10 min and then brought to room temperature and stirred for additional 30 minutes. The reaction mixture was poured into ice-water (150 mL), neutralized with NaHCO3 and the precipitate was collected by filtration, washed with water and purified on silica gel (CH2Ci2/EtOAc, 9:1) to provide 1-cyclopropyl-6-hydroxy-lH-indole-3-carbonitrile as a solid (3.02 g, 90%).
Step F: To a solution of 1-cyclopropyl-6-hydroxy-lH-indole-3-carbonitrile (0.59 g, 3.0 mmol) and triisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at -78 C was added LDA
(1.5M mono THF in cyclohexane, 4.60 mL, 6.9 mmol) with stirring. The mixture was stirred at -78 C for 10 min and at room temperature for 30 min followed by the addition of (R)-(4-iodo-phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6mmo1) and PdC12 (dppf) (0.11 g, 0.15 mmol). The reaction mixture was cooled to -78 C and flushed with nitrogen whereupon DMF (30 mL) and aq. K2C03 (2.OM, 4.5 mL, 9.0 mmol) was added. The cooling bath was removed and the mixture was stirred overnight, poured into ice water-(100 mL) and neutralized with acetic acid. The precipitate was filtered, washed with water, dried in air and purified on silica gel (CH2C12/EtOAc, 9:1) to give (R)-[4-(3-cyano-l-cyclopropyl-6-hydroxy-lH-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester as a solid (1.16 g, 97%).
Step G: A mixture of (R)-[4-(3-cyano-l-cyclopropyl-6-hydroxy-lH-indol-2-yl)-phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (0.060 g, 0.15 mmol), CsaCO3 (0.122 g, 0.375 mmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (1-5 mL) was stirred at 70 C for 2h.
After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration, washed with water, and purified on silica gel (CH2CiZ/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-l-cyclopropyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester as a solid (72 mg, 100%).

Example ICY: Preparation of 1-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-indol-2-yl]-phenyl}-3-isopropylsulfonylurea (compound 2263).

CSI, CH CI 1) NPrOH, DIAD, 2 2, O`` ~O PPh3, CH2CI2, 0 C: \/N S, 0 ~C .-rt H NHBoc OH I 0~NH2 2) TFA, CHzCI2 0 C-rt CN
HO I N
CN
N O LDA, -78OC- rt O,S' ~ I B(OiPr)s, THF; NH ~
~ H HO N
I DMF, aq. K2C03 (2M), Pd(dppf)CI2, rt N
`~ Sp N C{ O' \ IN I~ \ N N{õ{
Cs2CO3, DMF

Step A: To a solution of tert-butanol (10.5 mL, 110.0 mmol) in CH2C12 (100 mL) at 0 C was added chlorosulfonyl chloride (9.55 mL, 110.0 mmol). The mixture was stirred for 5 min and added to a stirred cold (0 C) mixture of 4-iodoaniline (21.9 g, 100.0 mmol), Et3N
(15.43 mL, 110.0 mmol) in CHZCla (100 mL). The reaction mixture was stirred at 0 C for 30 minutes and at room temperature for 4.5h. The reaction mixture was concentrated, treated with water (1000 mL) and stirred overnight- The precipitate was filtered, washed thoroughly with water and dried in vacuum to provide N-Boc-N'-4'-iodophenyl sulfonylurea (36.11 g, 91 l0).
Step B: To a'solution of PPh3 (7.32 g, 30.0 mmol) in CH2C12 (20 mL), at 0 C, was added DLAD (5.94 mL, 30.0 mmol), and stirred for 0.5 h, then added to a mixture of N-Boc-N'-4'-iodophenyl sulfonylurea (7.96 g, 20.0 mmol), and isopropanol (2.29 mL, 30.0 mmol) in DCM (20 mL) at 0 C while stirring. The resulting mixture was stirred at 0 C
for 1 h and then room temperature for 4 h, and chromatographed (silica gel, CH2C12). The crude product obtained was suspended in hexanes, stirred for 20 min, filtered and washed with hexanes and dried in air. This was then suspended in CH2Cla (40 mL) and treated with TFA
(10 mL) for 4 h at room temperature. The mixture was carefully neutralized with NaHCO3 and the layer was purified on silica gel (CH2C12/EtOAc, 9:1) to provide N-isopropyl-N'-4'-iodophenylsulfonylurea as a solid (4.89 g, 72%).
Step C: To a solution of 1-cyclopropyl-6-hydroxy-lH-indole-3-carbonitrile (0.42 g, 2.0 mmol), triisopropylborate (0.80 mL, 3.5 rnmol) in THF (6 mL), at -78 C, was added LDA
(1.5M monoTHF in cyclohexane, 3.33 rnL, 5.0 mmol) with stirring. The mixture was stirred at -78 C for 10 min and at room temperature for 30 min, followed by the addition of N-isopropyl-N'-4'-iodophenylsulfonylurea (0.96 g, 2.4 mmol) and PdC12 (dppf) (0.07 g, 0.1 mmol). The reaction mixture was cooled at -78 C and flushed with nitrogen before the addition of DMF
(12 mL) and aq. K2C03 (2.OM, 3.0 mL, 6.0 mmol). The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid.
The precipitate was filtered and washed with water, dried in air and purified on silica gel (CH2Clz/EtOAc, 8:2) to give 1-[4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-3-isopropylsulfonylurea as a solid (0.45 g, 74%).
Step D: A mixture of 1-[4-(3-cyano-l-cyclobutyl-6-hydroxy-lH-indol-2-yl)-phenyl]-3-isopropylsulfonylurea (0.085 g, 0.2 mmol), Cs2CO3 (0.163 g, 0.5 xnmol), 2-chloropyrimidine (0.034 g, 0.3 mmol) in DMF (2.0 mL) was stirred at 70 C overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate collected via filtration, washed with water and purified on silica gel (CH2C12/EtOAc, 8.5:1.5) to provide 1-{4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-1 H-indol-2-yl]-phenyl } -3-isopropylsulfonylurea (0.061 g, 61%).

Example 1CZ: Preparation of 1-cyclopropyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (compound 2434).

CN
HOI~

LDA, -78PC- rt B(OiPr)3, THF:
I ~ ~ NH2 -~- I ~ ~ NH `
Cs2CO3, DMF, aq. K2CO3 (2M), DMF, 90 C Pd(dppf)CI2, rt CN N CN
~ ~ CI aNOID \ ~ \ N'H
HO N Cs2CO3, DMF N
~ 70 C

Step A: A mixture of 4-iodoaniline (4.38 g, 20.0 mmol), Cs2CO3 (16.3 g, 50.0 mmol), isopropyliodide (3.0 mL, 30.0 mmol) in DMF (20 mL) was stirred in a sealed tube at 70 C for 24h. The mixture was cooled to room temperature and poured into water (200 mL). The organic layer was separated and washed with water and brine and purified on silica gel (CH2ClZ/hexanes, 1:1) to provide (4-iodophenyl)-isopropylamine (3.26 g, 63%).
Step B: To a solution of 1-cyclopropyl-6-hydroxy-lH-indole-3-carbonitrile (0.59 g, 3.0 mmol), triisopropylborate (1.03 mL, 4.5 mmol) in THF (15 mL) at-78 C was added LDA
(1.5M mono THp' in cyclohexane, 4.60 mL, 6.9 mmol) with stirring. The mixture was stirred at -78 C for 10 min and at room temperature for 30 min, followed by the addition of (R)-(4-iodo-phenyl)-carbamic acid 1-cyclopropyl-ethyl ester (1.19 g, 3.6mmol) and PdC12 (dppf) (0.11 g, 0.15 mmol). The reaction mixture was cooled to -78 C, flushed with nitrogen and DMF (30 mL) and aq. K2C03 (2.OM, 4.5 mL, 9.0 mxnol) added. The cooling bath was removed and the mixture was stirred overnight, poured into ice water (100 mL) and neutralized with acetic acid.
The precipitate was filtered, washed with water and CH2C12 and dried in air to provide 1-cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-1H-indole-3-carbonitritleas a solid (0.85 g, 86).
Step C: A mixture of (1 -cyclopropyl- 6-hydroxy-2-(4-isopropylamino-phenyl)- 1 H-indole-3-carbonitrile (0.099 g, 0.3 mmol), Cs2CO3 (0.244g, 0.75 mmol), 2-chloropyrimidine (0.069 g, 0.6 mmol) in DMF (2.0 mL) was stirred at 70 C overnight. After cooling to room temperature the rnixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water and purified on silica gel (CH2CI2/EtOAc, 9:1) to provide 1-cyclopropyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile as a solid (0.104 g, 85%).

Example 1DA: Preparation of [4-(3-cyano-l-cyclobutyl-6-cyclopropyl-lH-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (compound 2513).
-B(OH )z CN B(O'Pr)3, THF, CN 0 >~
f D~N LDA -T8 C- rt; O KF, TH F NH
PdCI2(dppf), DMF, N
Br aq. K2C03(2M) Br t-Bu3PHBF4, Pd2(dba)3, 60 C
I F~\ NHO

CN C~~--~ O
NH

Step A: To a solution of 6-bromo-l-cyclobutyl-lH-indole-3-carbonitrile (1.38 g, 5.0 mmol), and triisopropylborate (1.37 mL, 6.0 mmol) in THF (15.0 mL) at-78 C was added LDA (1.5M mono THF in cyclohexane, 3.83 mL, 5.75 mmol) with stirring. The mixture was stirred at -78 C for 10 min and at room temperature for 30 min followed by addition of (4-iodophenyl)-carbamic acid tert-butyl ester (1.75 g, 5.5 mmol) and PdC12(dppf) (0.37 g, 0.5 mmol). The reaction mixture was cooled to -78 C, flushed with nitrogen and DMF
(30 mL) and aq. KZCO3 (2.OM, 7.5 mL, 15.0 mmol) added. The mixture was stirred at -78 C for 20 min, room temperature overnight and poured into ice water (200 mL). The precipitate was filtered, washed with water and purified on silica gel (hexanes/EtOAc, 9:1 to 8:2) to give [4-(6-bromo-3-cyano-l-cyelobutyl-lH-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester as a solid (1.23 g, 53%).
Step B: A mixture of [4-(6-bromo-3-cyano-l-cyclobutyl-lH-indol-2-yl)-phenylJ-carbamic acid tert-butyl ester (0.17 g, 0.4 mmol), cyclopropylboronic acid (0.047 g, 0.55 mmol), (tert-butyl)3PHBF4 (0.014 g, 0.048 mmol), KF (0_093 g,1_6 nunol), and Pd2(dba)3-CHC13, 0.021 g, 0.02 mmol) in THF (2.0 mL) was stirred at 60 C overnight. The mixture was concentrated, taken up in CH2C12 and filtered through Celite. The solid was washed with CHZC12 and the filtrate was purified on silica gel (CHZC12) to provide [4-(3-cyano-1-cyclobutyl-6-cyclopropyl-lH-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester as a solid (0.10 g, 59%).

Example 1DB: {2-chloro-4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-yl]-phenyl}-carbamic acid isopropyl ester (compound 2339):

CN B(O'Pr)3, LDA, CN CI ^N
I~ \ THF, 0 C - rt; N2 `N_~Cl (2M), N
/ PdCI2(dffp), K2C03 HO
HO N CsCO3, DMF
DMF, 0 C - rt 700 C
CI

cLOXXcc/CINH2 Ci opyridine O N ~
// Q
6 toluene, CH2CI2 O /j--Step A: To a solution of 1-cyclobutyl-6-hydroxy-lH-indole-3-carbonitrile (3.0 g, 14.1 mmol) and isopropylborate (5 mL, 21.1 mmol) in anhydrous THF (40 mL) at 0 C
was added LDA (16_2 mL, 2.0 M in heptane/THF/ethylbenzene, 32.4 mmol) dropwise. The mixture was stirred at 0 C for 15 min and then at room temperature for lh. After cooling the reaction niixture to 0 C a solution of 2-chloro-4-iodo-phenylamine (3.9 g, 15.5 mmol) in DMF (40 mL) was added followed by addition of PdC12(dppf) (0.3 g, 0.4 mmol) and aq. K2C03 (14 mL, 2.0 M). The mixture was warmed to room temperature and continued to stir overnight. The reaction was diluted with water and then extracted with ethyl acetate. The organic layers was dried, concentrated and triturated with chloroform to provide 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-lH-indole-3-carbonitrile (3.1 g, 64%) as an off-white solid.
Step B: 2-(4-Amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-lH-indole-3-carbonit.rile (0.67 g, 2 rnmol), prepared in step ZA, was dissolved in DMF (7 mL), followed by the addition of 2-chloro-pyrimidine (0.34 g, 3 mmol) and cesium carbonate (1.3 g, 4 mmol).
The mixture was brought to 70 C and stirred for I h. After cooling, the solid was filtered and washed with EtOAc. The filtrate was washed with water and brine, dried, concentrated and triturated with ether to provide 2-(4-amino-3-chloro-phenyl)-l-cyclobutyl-6-(pyrimidin-2-yloxy)-IH-indole-3-carbonitrile (0.76 g, 91%) as a white solid.
Step C: To 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (0.26 g, 0.6 mmol) in CH2C12 (0.5 mL) and pyridine (0.5 mL) was added a solution of isopropyl chloroformate in toluene (1.OM, 0.8 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with aq. HCI (IN) and extracted with CH2C12. The organic layer was washed with water and brine, dried, concentrated and purified on silica gel (40% EtOAc/hexane) to provide {2-chloro-4-[3-cyano-l-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester (0.29 g, 93%) as a white solid.
Example 2: Screening of low molecular weight compounds using a cell-based HCV
IRES
monocistronic translation assay Chemical libraries are screened using a cell-based monocistronic HCV IRES-regulated translation assay designed to closely mimic natural HCV mRNA translation and then compound analogs are made based on hits in the chemical libraries and screened as well. A
DNA construct is prepared, termed pHCVIRESmono, in which HCV IRES sequences (HCV
2b, nucleotides 18-347) are inserted between a promoter and the firefly luciferase (Flue) reporter gene. A stably transfected HepG2 (hepatoblastoma) cell line (termed HepG mono-4) or a Huh7 cell line (termed Huhmono 7), or a Helacell line (ternied Helamono), are established by tr-ansfection with the pHCVIRESmono DNA by selecting for resistance to hygromycin.
Example 3: Determination of selectivity for HCV IRES-reaulated translation using the cell-based cara-denendent translation assays Since translation assays are used to screen HCV IRES inhibitors, the selected hits may specifically act on HCV IRES-driven translation or may modulate general protein synthesis in mammalian cells. The compounds that act on general translation will most likely have significant toxicity. To address this possibility, various cell-based cap-dependent translation assays are established for the further evaluation of all selected compounds.
Plasmid DNAs containing 130 nucleotides of vector sequence 5' to Fluc are constructed. This construct is referred to herein as pLuc. A stable cell line is established in cap-dependent translation assays using 293T cells (a human embryonic kidney cell line). HepGmono-4 and pLuc are treated with compound for 20 hours and activity is determined by quantifying the Fluc signal. A five- ' fold selectivity between the HCV IRES and cap-dependent translation is considered to be desirable. For example, using these cell-based cap-dependent translation assays, Applicants identified compounds that showed IC50 values that were at least 5-fold greater in the cap-dependent translation assays than in the HCV IRES translation assay. Fig. 1 shows an example of a hit that was selective against HCV IRES-regulated translation over cap-dependent pLuc translation. Importantly, the compound had the same level of activity in an HCV IRES
monocistronic 293T cell line as in HepGmono-4 (data not shown). It is thus unlikely that the selectivity of the compounds between HepGmono-4 (HepG 2) and the cap-dependent translations (293T) is due to the different cell types used.
Additionally, western blotting assays are used to further demonstrate that the compounds selectively inhibit HCV IRES-driven translation. Both HepGmono-4 and pLuc cells are treated with the compounds as described above, following treatment with the test compounds for 20 hours, cells are collected and lysed in Laemmli buffer containing 0.5% SDS.
Proteins are separated on a 10% SDS-PAGE, then transferred onto a nitrocellulose membrane, and blotted using antibodies against Fluc (RDI) and P-actin (Oncogene). For example, some of the compounds of the present invention were tested in this manner and as expected, the compounds that selectively inhibited HCV IRES-driven translation in assays using Flue signal as an end point showed comparable reductions of the luciferase reporter protein levels in HepGmono-4 cells and were relatively inactive against pLuc in the Western blot (data not shown). Importantly, these compounds did not inhibit the expression of endogenous 0-actin, the translation of which is cap-dependent in both cell lines. Consistently, compounds that did not show selectivity in the translation assays inhibited protein accumulation in both the HCV
IRES and cap-dependent translation assays (data not shown). As expected, the general protein translation inhibitor puromycin also inhibited both the HCV IRES-driven and cap-dependent protein production (data not shown). Therefore, the Western blot results confirm that the compounds of the present invention selectively inhibit HCV IRES-driven translation.
Testing conditions for these cell lines are optimized and the effects of rnRNA
level on activity of the compounds are controlled by quantitating Fluc mRNA levels by RT real-time PCR. For example, some of the compounds of the present invention were tested in this manner, and no significant differences in Fluc mRNA levels were observed between the HepGmono-4, or the Helamono cells, or the Huhmono cells, and cap-dependent translation cell lines used (data not shown).

Example 4: Evaluation of the selectivity for HCV IRES-driven translation using cellular IRES-mediated translation assays A number of human mRNAs have been shown to harbor IRES elements (18, 19, 39, 44, 45, 91, 126, 130). Although the primary sequences and secondary structures of the HCV IItES
are different from those of cellular IRES, an important test for selectivity is to determine whether the selected compounds are active against cellular IRES. The VEGF IRES
has poor initiation activity in in vitro assays, but demonstrates substantial activity in cell-based translation assays (45). For example, some of the compounds of the present invention were tested and all of the compounds that had good selectivity with respect to cap-dependent translation exhibited at least 5-fold higher IC50 values against the VEGF IRES
than against the HCV IRES (data not shown). These data indicate that the selected compounds have selectivity against viral IRES. In addition to having different structures, the VEGF IRES
also have different interactions with non-canonical cellular translation factors. These differences may contribute to the selectivity of the HCV IRES inhibitors that we have identified.

Example 5: Evaluation of cytotoxicity Effects on cell proliferation are a critical issue for any drug discovery effort. Therefore, a cell proliferation/cytotoxicity assay is used to eliminate any compounds that affect mammalian cell growth. The effects of the selected hits on cell proliferation are tested in human cell lines 293 T and Huh7 (a human hepatoblastoma cell line). Cells are grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, L-glutarnine, penicillin, and streptomycin. Cells in log phase are treated with test compounds for three days, with 250 M being the highest concentration of test compound used.
The effect of the compounds on cell proliferation is assessed by using the CeliTiter 96 AQueous One Solution Cell Proliferation Assay (Promega, Madison, WI). Compounds that have at least 5-fold higher CC50 values relative to IC50 values in HepGmono-4 are considered to have a sufficient window between activity and cytotoxicity and, hence, are selected for ftuther evaluation. For example, some of the compounds of the present invention were tested in this manner, and importantly, all compounds that had good selectivity with respect to cap-dependent translation also demonstrated a greater than 5-fold ratio of CC50 to IC50 values.
Examnle 6: Evaluation of the efficacy of the compounds in the HCV replicon system The lack of reliable and readily accessible cell-culture and small animal models permissive for HCV replication has limited the development of new anti-HCV
agents. Self-replicating subgenomic HCV systems, termed HCV replicons, have been described and have been widely used to assess the efficacy of anti-HCV inhibitors (8, 9, 46, 70, 103, 104).
Interferon (IFN) cc and inhibitors of the HCV protease and polymerase have been reported to be active in the HCV replicon system (8, 17, 32, 68, 69, 117).
HCV replicons that include bicistronic and monocistronic systems are available and can.
be used for testing the HCV inhibitors. In the bicistronic replicons, the HCV
IRES directs the expression of the selective marker (Neo and/or a Fluc reporter), and the EMCV
IRES mediates the expression of viral non-structural proteins. In the monocistronic replicon, the HCV IRES

directly mediates viral protein synthesis. The HCV IRES inhibitors are analyzed in the bicistronic replicon by quantitating the Fluc reporter signal. Replicon-containing cells are cultured with the compounds of the invention for 2 days or for 3 days.
Interferon (IFN) a is used as a positive control_ For example, the compounds of the present invention were tested in this manner, and the experiments showed that compounds that selectively inhibited HCV
IRES-mediated translation inlubited Flue expression in the bicistronic replicon.
In the following table (Table 1), * = replicon or HCV-PV IC50 > 2NM
** = replicon orHCV-PV ICjo between 0.5 uM and 2pM
*** = replicon or HCV-PV ICSo < 0.5 uM

Replicon IC50 values are determined by firefly luciferase signal.
HCV-PV IC50 values are determined by viral RNA reduction_ Table 1 Mass Replicon Replicon Compound Melting Number Point ( C) Spec !C$o NM IC50 NM 'H NMR Data [M+H} 2-day 3-day 866 143-145 382.5 867 198-200 448.26 868 188-190 446.23 **' ***
869 205-206 354.3 870 328.28 871 158-161 402.24 *
872 176-179 416.28 "
873 183-187 414.27 874 182-186 448.26 875 136-140 368.15 **
876 = 382.18 **
877 396.19 878 396.19 879 400.14 **
880 310.26 881 194-195 438.2 *** ***
882 181-183 452.3 ***
883 198-200 450.2 *** **`
884 195-196 452.3 *** ***

Mass Replicon Replicon Compound Melting Spec ICS pM IC50 NM 'H NMR Data Number Point ( C} [M+Hj 2-day 3-day 885 148-150 466.3 ***
886 173-175 404.2 **
687 181-183 418.2 **
888 187-189 436.3 889 160-162 432.2 **
890 158-160 450.3 **
891 144-146 452.3 **
892 225-226 417.2 893 191-193 431.3 894 180-182 445.3 **
'H NMR (DMSO-de, 300MHz), 6 10.17 (s, 1 H), 7.73 (d, J=7.2Hz, 2H), 7.48-7.43 (m, 3H), 7.17 (s, 895 225-226.7 348.4 1 H), 6.61 (d, J=7.5 Hz, 1 H), 4.13-4.05 (m, 4H), 2.03 (s, 3H), 1.31 (t, J=6.6 Hz, 3H), 1.12 (t, J= 7.5Hz, 3H).
'H NMR (DMSC}-d6, 300MHz), b 10.13 (s, 1H), 7.77 (d, J=8.7Hz, 2H), 7_51-7.45 (m, 3H), 7.20 (s, 896 245.9-247 362.1 ** 1 H), 6.88 (dd, J=6.9Hz and 2.1 Hz, 1H), 4.16-4.05 (m, 41-1), 2.34 (q, J=7.5Hz, 2H), 1.33 (t, J=6.9Hz, 3H), 1.19-1.04 (m, 6H).
'H NMR (DMSO-ds, 300MHz), 6 10.45 (s, 1 H), 7.78 (d, J=8.7Hz, 21-1), 7.51-7.45 (m, 3H), 7.20 (d, 897 254.4-256.3 374.1 ** J=1 =8Hz 1 H), 6.88 (dd, J=6.6Hz and 2.1 Hz, 1 H), 4.16-4.05 (m, 4H), 1.81-1.75 (m, 1H), 1.34 (t, J=6.9Hz, 3H), 1.14 (t, J=6.9Hz, 3H), 0.81-0.79 (m, 4H).
'H NMR (DMSO-d i 300MHz), 6 >300 C 10.09 (s, 1 H), 7.80 (d, J=8.7Hz, 374.5 2H), 7.62-7.45 (m, 3H), 7.20 (d, 898 decompose J=1.5Hz, 1 H), 6.88 (dd, J=8.7Hz d and 2.4Hz, 1 H), 4.18-4.05 (m, 4H), 2.62-2.56 (m, 1 H), 1.33 (t, J=6.9Hz, 3H), 1.19-1.04 (m, 9H).
`H NMR (DMSO-d6, 300MHz), 6 9.99 (s, 1 H), 7.80 (d, J=8.4Hz, 2H), 7.51-7.45 (m, 3H), 7.20 (s, 899 246.8-249.7 386.5 ** 1H), 6.89 (dd, J=8.7Hz and 2.4Hz, 1H), 4.16-4.05 (m, 41-1), 2.25-2.02 (m, 4H), 2.01-1 B6 (m, 1 H), 1.84-1.76 (m, 1 H), 1.34 (t, J=6.9Hz, 3H), 1.17 (t, J=7.8Hz, 3H).
900 185.7 422.4 ** 'H NMR (DMSO-d6, 300MHz), E.

Compound Melting Mass Replicon Replicon Number Point ( C) Spec ICsa pM IC50 NM
'H NMR Data [M+H] 2-day 3-day 10.44 (s, 1 H), 7.79 (d, J=8.7Hz, 2H), 7.52-7.48 (m, 3H), 7.32-7.19 (m, 6H), 6.88 (dd, J=8.7Hz and 2.1 Hz, 1 H), 4.16-4.05 (m, 4H), 3.66 (s, 2H), 1.35 (t, J=7.2Hz, 3H), 1.14 (t, J=7.2Hz, 31H).
'HNMR(DMSO-ds, 300MHz), 5 10.18 (s, 1 H), 7_76 (d, J=8.7Hz, 2H), 7.52-7.45 (m, 3H), 7.26-7.13 901 160.4 436.5 ** (m, 6H), 6.B9 (dd, J=8.7Hz and 1.8Hz, 1H), 4.16-4.05 (m, 4H), 2.92 (t, J=2.7Hz, 2H), 2.68-2.62 (m, 2H), 1.33 (t, J=6.9Hz, 3H), 1.14 (t, J=6.9Hz, 3H).
902 233-235 436.1 903 230-232 450.2 ***
904 193-195 464.1 **
905 171-173 468.2 *** ***
906 246-247 480.1 **
'H NMR (300 MHz, CDCI3)_ b 7.63 (1 H, d, J = 8.8 Hz), 7.53 (1 H, td, J
= 7.7, 1.1 Hz), 7.41-7.32 (2H, m), 6.96 (1H, dd, J = 8.5, 2_0 Hz), 907 224-225 410.17 ** 6.89 (1 H, d, J = 2.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 4.12 (2H, q, J = 7.0 Hz), 3.86 (2H, t, J = 6.6 Hz). 3.42 (2H, t, J = 7.4 Hz), 2.58 (2H, p, J
= 7.0 Hz), 1.48 (3H, t, J = 7.0 Hz), 1.38 (3H, t, J 7.0 Hz).
908 186-189 476.2 **
909 180-182 381.24 **
910 195-198 409.26 **
911 228-230 395.24 **
912 217-221 428.2 [M H]-913 200-202 388.2 **
914 212-214 402.2 **
915 200-202 430.2 **
916 183-185 478.2 **
917 207-209 266.2 **
918 219-221 277.4 **
919 181-183 474.2 920 182-183 453.3 **
921 237-238 460.2 **

Compound Melting Mass Replicon Replicon ' Number Point( C) Spec lC5o pM IC50 NM H NMR Data [M+H] 2-day 3-day 922 246-248 474.2 **
923 225-229 488.2 924 221-223 486.2 925 190-192 440.2 926 195-196 454.3 **
927 204-206 306.25 928 206-208 432.14 *** *"*
(M-H+) 929 177-178 432.09 *** ***
930 183-184 468.02 *** ***
931 196-197 432.15 *** ***
(M-H+) 932 184-185 438.22 *** ***
933 156-157 438.21 934 192-193 436.15 *** ***
935 152-153 472.14 *** **
'H NMR (300 MHz, CDC13): 6 7.62 (1 H, d, J= 9.1 Hz), 7.38 (2H, d, J = 8.3 Hz), 7.23 (1 H, d, J = 2.3 Hz), 7.12 (2H, d, J = 8.3 Hz), 6.95 936 191-192 468.23 *** =** (1H, dd, J = 8.8, J = 2.2 Hz), 6.12 (1 H, d, J = 9.0 Hz), 4.93 (1 H, m), 4.20 (6H, m), 2.85 (2H, m), 2.35 (2H, m), 1.96 (2H, m), 1.48 (3H, t, J=6.9Hz),1.37(6H,t,J=6.3 Hz) 937 204-205 440.17 *=*
938 147-148 372.21 **
939 253-255 332.29 **
940 58-59 263.20 **
941 460.19 '** ***
'H NMR (300 MHz, DMSO-ds): b 8.48(1H,d,J=9.0Hz),7.48(1H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.21 (1 H, obscurred), 7.20 942 209-210 412.18 ** (2H, d, J = 8.5 Hz), 6.90 (1H, dd, (M-H+) J = 8.8, 2.2 Hz). 4.16 (2H, q, J=
7.3 Hz), 4.10 (2H, q, J = 7.0 Hz), 3.69 (6H, d, J = 11.4 Hz), 1.36 (3H, t, J=7.0Hz), 1.18(3H,t,J
7.0 Hz).
iH NMR (300 MHz, DMSO-de): 6 943 219-220 428.25 ** 8.40 (1 H, d, J = 9.0 Hz). 7.49 (1 H, d,J=8.8Hz,7.45 2H,d,J=8.5 Mass Replicon Replicon Compound Melting Spec IC50 NM ICSO M 'H NMR Data Number Point ( C} [M+H] 2-day 3-day Hz), 7.23 (1H, obscurred), 7.21 (2H, d, J = 8.5 Hz), 6.91 (1H, dd, J=8.8,2.0 Hz), 4.17 (2H, q, J =
7.0 Hz), 4.13-3.97 (4H, m), 3.84 (3H, s), 1.24 (6H, td, J= 7_0, 0.6 Hz), 1.15(3H,t,J=7.0 Hz).
'H NMR (300 MHz, DMSO-dfi): b 8.48 (1 H, d, J = 9.0 Hz), 7.49 (1 H, d, J = 8.8 Hz), 7.46 (2H, d, J = 8.5 Hz), 7.22 (1 H, d, J = 2.0 Hz), 7.20 944 223-224 400.20 ** (2H, d, J = 8.5 Hz), 6.91 (1 H, dd, J = 8.8, 2.0 Hz), 4.17 (2H, q, J =
7.0 Hz), 3.84 (3H, s), 3.68 (6H, d, J= 11.1 Hz), 1.19(3H,t, J=7.0 Hz).
945 190-193 414.2 946 163-172 410.2 *** ***
947 146-148 424.3 *** ***
948 166-167 458.2 "** ***
'H NMR (DMSO-dg, 300MHz), b 9.94 (s, 1 H), 7.66 (d, J=8.7Hz, 2H), 7.51-7.45 (m, 3H), 7.20 (s, 949 decompose 392.2 1 H), 6.88 (d, J=8.7Hz, 1 H), 4.16-d >300 4.02 (m, 6H), 1.64-1.61 (m, 2H),1.34 (t, J=6.9Hz, 3H), 1.15 (t, J=6.9Hz, 3H), 0.92 (t, J=7.5Hz, 3H).
'H NMR (DMSO--de, 300MHz), b 10.13 (s, 1H), 7.67 (d, J=8.4Hz, 2H), 7.52-7.46 (m, 3H), 7.20 (s, 950 decompose 396.3 ** 1H), 6.89 (d, J=8.7Hz, 1H), 4.73 d >300 (br, 1 H), 4.57 (br, 1 H), 4.40 (br, 1H), 4.30 (br, 1H), 4.16-4.05 (m, 4H), 1.33 (t, J=7.2Hz, 3H), 1.15 (t, J=7.2Hz, 3H).
'H NMR (CD3CI, 300MHz), 6 7.62 (d. J=8.4Hz, 1 H), 7.52-7.42 (m, 4H), 6.96 (dd, J=1.8Hz and 8.4Hz, 951 decompose 405.1 ** 1 H), 6.88 (d, J=1.8Hz, 1 H), 6.71 d >300 (s, 1 H), 4.86-4.82 (m, 1 H), 4.12 (q, J=6.9Hz, 4H), 3.29 (q, J=6.3Hz, 2H), 1.52-1.31 (m, 10H), 0.95 (t, J=7.5Hz, 3H).
'H NMR (CD3CN, 300MHz), b 9.01 (s, 1 H), 7.79 (d, J=8.7Hz, 2H), 7.58-7.49 (m, 3H), 7.11 (d, J=1.5Hz, 1 H), 6.96 (d, J=8.4Hz, not 952 detected 472.3 ** 1 H), 4.31 (t, J=4.2Hz, 2H), 4.16 (q, J=6.9Hz, 2H), 3.34-3.19 (m, IOH), 2.77 (s, 3H), 2.35-2.30 (m, 1 H), 1.25 (t, J=6.9Hz, 3H), 0.92-0.82 (m, 4H).

Mass Replicon Replicon Compound Melting Spec IC50 }iM IC50 NM 'H NMR Data Number Point ( C) [M+H] 2-day 3-day 184-186 442.2 **
[MH]-954 232-234 395.2 **
955 203-206 409.2 ** *
956 217-220 409.2 *** **
957 192-195 423.3 *' ***
958 210-212 407.2 ** *
959 169-171 384.19 **
960 178-180 398.25 **
961 174-177 412.24 962 172-174 410.24 ** .
963 203-206 364.24 964 153-155 378.28 *
965 156-157 392.27 **
966 212-215 377.25 **
967 218-221 391.27 **
968 241-244 412.18 *** **
969 264-266 434.15 *** ***
970 206-208 390.22 *** ***
971 213-215 404.27 *** ***
972 195-196 418.27 *** * *
'H NMR (300 MHz, CDCI3): b 7.63 (1 H, d, J = 8.5 Hz), 7.54 (2H, d, J
=8.5Hz),7.43(2H,d,J=8.5 Hz), 7.21 (1H, d, J = 2.2 Hz), 6.95 973 190-192 418.27 *** ** (1 H, dd, J = 8.8, J = 2.2 Hz), 6.70 (1 H, s), 5_05 (1 H, m), 4.94 (1 H, m), 4.14 (2H, q, 6.9 Hz), 2_82 (2H, m), 2.33 (2H, m), 1.87 (2H, m), 1.51 (3 H, t, J = 4.6 Hz), 1.33 (6H, d, J = 6.1 Hz).
974 215-217 422.22 *** *
975 140-141 434.27 **
976 158-159 428.25 **
977 181-182 452.22 ***
978 185-186 482.28 **
979 179-180 432.26 *** ***
980 236-238 436.24 *
981 201-203 416.26 *** ***
982 169-171 422.22 * 'H NMR (300 MHz, DMSO-d6): b Mass Replicon Replicon Compound Melting Spec IC50 NM IC50 NM 'H NMR Data Number Point ( C) [M+H] 2-day 3-day 10.16(1H,br),7.57(2H,d,J
8.5 Hz), 7.52 (1 H, d, J = 8.5 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.33 (1 H, d, J= 2.0 Hz), 6.93 (1 H, dd, J =
8.5, 2.0 Hz), 4.13 (2H, d, J = 7.0 Hz), 3.85 (3H, s), 2.77 (1 H. p, J=
6.3 Hz), 0.98 (6H, d, J = 6.3 Hz), 0.96-0.88 (1H, m), 0.34-0.27 (2H, m), 0.05-0.00 (2H, m).
'H NMR (300 MHz, DMSO-d6): 6 10.48 (1 H, s), 7.80 (21-1, d, J = 8.8 Hz), 7.53 (2H, d, J = 8.8 Hz), 7.52 (1H,d,J=8.6Hz),7.32(1H,d,J
983 217-219 386.22 ** = 2.0 Hz), 6.92 (1 H, dd, J= 8.6, 2.0 Hz), 4.13 (2H, d, J = 6.8 Hz), 3.84 (3H, s), 1.82 (1 H, p, J= 6.0 Hz), 0.99-0.90 (1 H, m), 0.89-0.75 (4H, m), 0.33-0.27 (2H, m), 0.05-0.00 (2H, m).
'H NMR (300 MHz, DMSO-de): 6 9.95 (1H, s), 7.67 (2H, d, J = 8.4 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.51 (1H,d,J=8.8Hz),7.32(1H,d,J
984 179-180 390.25 ** = 2.3 Hz), 6.91 (1 H, dd, J = 8.8, 2_3 Hz), 4-15 (2H, q, J = 7.0 Hz), 4.12 (2H, d, J = 7.0 Hz). 3.84 (3H, s), 1.26 (3H, t, J = 7.0 Hz), 1.00-0.90 (1 H, m), 0.33-0.25 (2H, m), 0.05-0.00 (2H, m).
'H NMR (300 MHz, DMSO-d6): 6 9.96 (1H, s), 7_67 (2H, d, J = 8.5 Hz), 7.52 (2H, d, J= 8.5 Hz), 7.50 (1 H, d, J = 8.8 Hz), 7.32 (1 H, d, J
= 2.0 Hz), 6.92 (1 H, dd, J= 8.8, 985 124-125 404.21 ** 2.0 Hz), 4.12 (2H, d, J = 6.7 Hz), 4.07 (211, t, J = 6.8 Hz), 3.84 (3H, s), 1.65 (2H, hx, J = 7.3 Hz), 0.94 (3H, t, J= 7_3 Hz), 0_93-0.89 (1H, m), 0.33-0.26 (2H, m), 0.05-0.00 (2H, m).
'H NMR (300 MHz, DMSO-ds): 6 9.90 (1H, s), 7.67 (2H, d, J = 8.5 Hz), 7.53-7.49 (3H, rn), 7.32 (11-t, d, J= 2.0 Hz), 6-92 (1 H, dd, J =
986 157-158 404.21 - ** 8.8, 2.0 Hz). 4.92 (1 H, hp, J = 6.3 Hz), 4.12 (2H, d, J= 6.7 Hz), 3.84 (311, s), 1.27 (6H, d, J= 6.3 Hz), 1.00-0.90 (1 H, m), 0.33-0.26 (2H, m), 0.07-0.01 (2H, m).
'H NMR (300 MHz, DMSO-de): 6 8.59 (1 H, s), 7.56 (2H, d, J= 8.5 987 183-184 403.26 ** Hz), 7.47 (1 H, d, J = 8.8 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.29 (1H, d, J
= 2.0 Hz), 6.89 1 H, dd, J = 8.8, Compound Melting Mass Replicon Replicon Number Point ( C) Spec IC50 }iM ICSO NM 'H NMR Data [M+H] 2-day 3-day 2.0 Hz), 6.11 (1H, d, J = 7_6 Hz), 4.10 (2H, d, J = 7.0 Hz), 3.82 (3H, s), 3.75 (1 H, m, J = 7.0 Hz), 1.08 (6H, d, J= 6.5 Hz), 0.97-0.88 (1 H, m), 0.31-0.25 (2H, m), 0.04--0.02 (2H, m).
'H NMR (300 MHz, DMSO-de): S
10.22 (1 H, s), 7.63 (2H, d, J= 8.8 Hz), 7.54 (1 H, d, J= 8.5 Hz), 7.39 988 168-169 398.25 ** (2H, d, J = 8.8 Hz), 7.35 (1 H, d, J
(M-H+) = 2.0 Hz), 6.96 (1 H, dd, J= 8.8, 2.0 Hz), 5.46 (2H, s), 3.84 (3H, s), 3.22 (2H, q, J= 7.3 Hz), 3.17 (3H, s), 1.23 (3H, t, J = 7.3 Hz).
'H NMR (300 MHz, DMSO-d6): b 7.68 (2H, d, J = 8.8 Hz). 7.54 (1 H, 380.18 d, J = 8.5 Hz), 7.38 (2H, d, J= 8.8 989 195-196 (M- ** Hz), 7.36 (1 H, d, J = 2.2 Hz), 6_97 CH30 ) (1 H, dd, J= 8.5, 2.2 Hz), 5.47 (2H, s), 3.86-3.81 (2H, m), 3.84 (3H, s), 3.58 (2H, t, J = 7.3 Hz), 3.17 (3H, s), 2.47-2.41 (2H, m).
'H NMR (300 MHz, DMSO-de): b 10.22 (1H, s), 7.63 (2H, d, J= 8.8 Hz), 7.54 (1 H, d, J = 8.5 Hz), 7.38 (2H, d, J = 8.8 Hz), 7.34 (1 H, d, J
990 179-180 ~M H+~ ** 2.0 Hz), 5.46 (2H, 's), 3.84 (3H, s), 3.20 (2H, t, J= 7.6 Hz), 3.16 (3H, s), 1-72 (2H, hx, J = 7.6 Hz), 0.96 (3H, t, J = 7.5 Hz).
'H NMR (300 MHz, DMSO-ds): b 9.97(1H,s),7.67(2H,d,J=8.8 348.17 Hz), 7.58 (2H, d, J = 8.8 Hz), 7.53 991 179-180 (M- ** (1 H, d, J = 8.8 Hz), 7.33 (1 H. d, J
CH30") = 2.0 Hz), 6.96 (1 H, dd, J= 8.8, 2.0 Hz), 5.45 (2H, s), 4.15 (2H, q, J = 7.0 Hz), 3.83 (3H, s), 3.16 (3H, s), 1.26 (3H, t, J= 7.0 Hz).
'H NMR (300 MHz, DMSO-d6): 6 9.67 (1 H, s), 7.68 (2H, d, J= 8.8 Hz), 7.58 (2H, d, J= 8.8 Hz), 7.53 362.23 (1 H, d, J= 8.5 Hz), 7.34 (1 H, d, J
992 155-157 (M- ** =2.0 Hz), 6.96 (1 H, dd, J= 8.5, CH30") 2.0 Hz), 5.45 (2H, s), 4.07 (2H, t, J = 6.7 Hz), 3.84 (3H, s), 3.31 (3H, s), 1.65 (2H, hx, J = 7.0 Hz), 0.94 (3H, t, J = 7.3 Hz).

'H NMR (300 MHz, DMSO-de): 6 9.90 (1 H, s), 7.67 (2H, d, J = 8.6 146-148 ** Hz), 7.57 (2H, d, J = 8.6 Hz), 7.53 (1H,d,J=8.8Hz),7-33(1H,d,J

Mass Replicon Replicon Compound Melting , Number point C) Spec ICSO NM IC50 pM H NMR Data [M+Hj 2-day 3-day = 2_0 Hz), 6.96 (1 H. dd, J= 8.8, 2.0 Hz), 5.45 (2H, s), 4.92 (1H, 392.29 hp, J = 6.3 Hz), 3.83 (3H, s), 3.15 993 (M-H+) (3H, s), 1.26 (6H, d, J= 6.3 Hz).
'H NMR (300 MHz, DMSO-ds): b 11.32 (1 H, s), 7.83 (2H, d, J = 8.8 Hz), 7.52 (2H, d, J= 8.8 Hz), 7.52 994 266-267 375.22 (1 H, d, J= 8.5 Hz), 7.25 (1 H, d, J
= 2.0 Hz), 6.93 (1 H, dd, J = 8.5, 2.0 Hz), 4.52 (2H, s), 4.20 (2H, q, J 7.0 Hz), 3.85 (3H, s), 1.18 (3H,t,J=7.0Hz).
995 179-181 384.2 ** **
996 200-201 398.2 *** *'' 997 169-171 412.2 **
998 166-167 410.2 **
999 172-174 377.3 **
1000 156-158 391.3 **
1001 120-124 389.3 ** **
1002 166-158 422.15 **
1003 189-191 436.15 **
1004 191-193 450.15 **
1005 169-171 436.15 **
1006 187-188 450.15 *'* **
1007 179-180 464.20 ***
1008 114-115 405.3 1009 202-203 363.3 **
1010 196-197 377.3 **
1011 205-206 377.3 **
1012 165-166 391.3 **
1013 192-193 375.3 'H NMR (DMSO-ds, 300MHz), b 8.80 (s, 1 H), 7.58 (d, J=6.3Hz, 2H), 7.48-7.42 (m, 3H), 7.29 (t, J=5.1 Hz, 2H), 7.24-7.19 (m, 4H), 1014 178.1-183.5 453.1 6.89 (d, J=6.6Hz, I H), 6.22 (br, 1 H), 4.16-4.08 (m, 4H), 3.35-3.33 (m, 2H), 2.75 (t, J=5.1Hz, 2H), 1.34 (t, J=5.1 Hz, 3H), 1.16 (t, J=5.7Hz, 3H).
'H NMR (CD3CN, 300Hz), 6 8.06 1015 150.1-155.6 424.0 ** (s, 1H), 7.66 (d, J=8.7Hz, 2H), 7.55-7.50 (m, 3H), 7.04 (d, J=1.8Hz, 1 H), 6.91 (dd, J=6.6Hz Mass Replicon Replicon Compound Melting Spec 1C5o NM IC50 uM 'H NMR Data Number Point ( C) [M+H] 2-day 3-day and 2.1 Hz, 1 H), 4.73 (t, J=3.9 Hz.
1 H), 4.57 (t, J=3.9Hz, 1 H). 4.43 (t, J=3.9Hz, 1H), 4.34 (t, J=3.9Hz, IH), 4.16-4.09 (m, 4H), 1.65-1.61 (m, 2H), 1.40 (t. J=7.2Hz, 3H), 1.18-1.06 (m, 2H), 0.74 (t, J=7.2Hz, 3H).
'H NMR (DMSO-d6, 300Hz), 6 8.74 (s, 1H), 7.59 (d, J=8.4Hz, 2H), 7.49-7.42 (m, 3H), 7.20 (s, 1H), 6.90 (dd, J=8.4Hz and 2.4Hz, 1016 204.2-209.7 405.2 ** 1 H), 6.22 (t, J=5.7Hz, 1 H), 4.17-4.09 (m, 4H), 3.14-3.10 (m, 2H), 1.52-1.50 (m, 2H), 1.32 (t, J=7.2Hz, 3H), 1.13-1.03 (m, 5H), 0.68 (t, J=6.9Hz, 3H).
'H NMR (DMSO-de, 300Hz), 6 8.67 (s, I H), 7.58 (d, J=8.7Hz, 2H), 7.49-7.41 (m, 3H), 7.20 (s, 1 H), 6.92 (dd, J=8.7 Hz and 1017 181.3-187.8 419.2 .** 2.4Hz, 1 H), 6.16 (d, J=7.2, 1 H), 4.32-4.02 (m, 4H), 3.80-3.70 (m, 1 H), 1.50-1.49 (m, 2H), 1.35 (t, J=6,6Hz, 3H) 1.11-1.00 (m, 8H), 0.68 (t, J=7.2Hz, 3H).
'H NMR (DMSO-de, 300Hz), 6 8.71 (s, 1 H), 7.59 (d, J=8.1 Hz, 2H), 7.49-7.41 (m, 3H), 7.20 (s, 1 H), 6.90 (dd, J=8.7 Hz and 1018 172.7-177.6 433.2 *"* ** 2.4Hz, 1 H), 6.23 (br, 1 H), 4.17-4.09 (m, 4H), 3.10-3.09 (m, 2H) 1.50-1.30 (m, 9H), 1.05-1.03 (m, 2H), 0.88 (t, J=6.6Hz, 3H), 0.69 (t, J=7.2Hz, 3H).
'H NMR (DMSO-ds, 300Hz), 6 8.80 (s, 1 H), 7.59 (d, J=8.4Hz, 2H), 7.46-7.45 (m, 3H), 7.31-7.20 (m, 6H), 6.90 (dd, J=8.7 Hz and 1019 153.7-160 481.2 *** *** 2-4Hz; 1H), 6.25-6.24 (m, 1H), 4.17-4.09 (m, 4H), 3.37-3.31 (m, 2H), 2.78-2.71 (m. 2H), 1.53-1.51 (m, 2H), 1.35 (t, J=6.9Hz, 3H), 1.13-1.00 (m. 2H), 0.67 (t, J=7.2Hz, 3H).
'H NMR (CD3CN, 300Hz), 6 7.91 (s, 1H), 7.68 (d, J=8.7Hz, 2H), 7.55-7.49 (m, 3H), 7.36 (d, J=2.1 Hz, 1 H), 6.91 (dd, J=6.3Hz 1020 135-141.7 406.0 ** ** and 2.4Hz, 1H), 4.36-4.02 (m, 4H), 1.66-1.56 (m, 2H), 1.40 (t, J=7.2Hz, 3H), 1.31 (t, J=7.2Hz, 3H), 1.22-1.07 (m, 2H), 0.74 (t, J=7.2Hz, 3H).

Compound Melting Mass Replicon Replicon 'Number Point ( C) Spec IC50 NM IC50 NM H NMR Data [M+H] 2-day 3-day 'H NMR (CD3CN, 300Hz), 8 7.94 (s, 1 H), 7.65 (d. J=8.7Hz, 2H), 7.55-7.49 (m, 3H), 7.37 (d, J=2.1 Hz, 1 H), 6.91 (dd, J=6.6Hz 1021 112.1-119.5 420.0 and 2.1Hz, 1H), 4.16-4.07 (m, 4H), 1.72-1.56 (m, 4H), 1.40 (t, J=7.2Hz, 3H), 1.16-1.06 (m, 2H), 0.98 (t, J=7.2Hz, 3H), 0.76 (t, J=7.2Hz, 3H).
'H NMR (DMSO-de, 300Hz), 8 9.87 (s, 1 H), 7.67 (d, J=8.7Hz, 2H), 7.51-7.47 (m, 3H), 7.21 (s, I H), 6.90 (dd, J=8.7 Hz and 1022 104.3-109.7 420.0 "** * 2.4Hz, 1 H), 4.96-4.89 (m, 1 H), 4.16-4.06 (m, 4H), 1.51-1.47 (m, 2H), 1.35 (t, J=6.9Hz, 3H), 1.21-1.27 (m, 6H), 1.06-0.99 (m, 2H), 0.67 (t, J=7.2Hz, 3H).
'H NMR (DMSO-ds, 300Hz), 6 8.71 (s, I H), 7.58 (d, J=9.OHz, 1 H), 7.49-7.42 (m, 3H), 7.20 (d, J=1.8Hz, 1 H), 6.89 (dd, J=6.6 Hz 1023 152.7-161.3 433.2 and 2.1 Hz, 1 H), 6.23 (br, 1 H), 4.17-4.09 (m, 4H), 3.13-3.06 (m, 2H), 1.53-1.28 (m, 9H), 1.05-1.03 (m, 2H), 0.89 (t, J=7.2Hz, 3H), 0.68 (t, J=7.2Hz, 3H).
'H NMR (DMSO-de, 300Hz), 6 8.80 (s, 1 H), 7.59 (d, J=8.7Hz, 2H), 7.49-7.42 (m, 3H), 7.33-7.20 (m, 6H), 6.90 (dd, J=6.9 Hz and 1024 160.2-167.8 481.2 ="* ~x 2=1 Hz, 1 H), 6.23 (br, 1 H), 4.17-4.07 (m, 4H), 3.39-3.34 (m, 2H), 2.79-2.71 (m, 2H), 1.52-1.49 (m, 2H), 1.36 (t, J=6.9Hz, 3H), 1.08-1.01 (m, 2H), 0.68 (t, J=7.2Hz, 3H).
'H NMR (CDCI3, 300MHz), b 7.98 (s, 1H), 7.71 (d, J=7.8Hz, 2H), 7.61 (d, J=8.4Hz, 1 H), 7.41(d, 1025 133.3-141.8 459.2 J=7-8Hz, 2H), 6.91-6.88 (m, 2H), 4.49 (br, 2H), 4.12-4.02 (m, 6H), 3.73-3.53 (m, 4H), 3.09 (br, 2H), 1.64 (br, 1 H), 1.28-1.26 (m, 3H), 1.11 (br, 2H), 0.89-0.87 (m, 2H),.
1026 220-222 432.16 ** "~x 1027 138-140 443.31 *xx xxx 1029 188 412.8 1030 173 440.2 1031 195 426.2 Compound Melting Mass Replicon Replicon ~
Number Point ( C) Spec IC50 NM IC60 NM H NMR Data jM+H] 2-day 3-day 1032 145 424.2 1033 181 444.2 ***
1034 154-155 491.3 *' *
1035 173-175 497.3 **
1036 230-235 510.3 **
1037 155-156 430.25 **
(M-H+) 1038 236-238 410.2 **
1039 243-248 391.3 **
1040 215-217 392.2 ** " `
1041 164-166 412.2 ** **`
1042 135-138 505.4 **
1043 165-166 476.3 **
1044 167-168 511.3 ***
1045 117 460.3 1046 232-234 422.21 *** **
1047 422.24 * ***
1048 200-203 440.0 1049 247-249 481.3 1050 246-248 381.2 1051 177 423.2 1052 194 424.2 **
1053 236-238 460_2 'H NMR (CDCI3, 300MHz), b 7.91 (br, 1 H), 7.71 (d, J=8.1 Hz, 2H), 7.61 (d, J=8_7Hz, 1 H), 7.42 (d, J=8.4Hz, 2H), 6.95-6.88 (m, 2H), 1054 187.6-195.2 443.2 4.44 (br, 2H), 4.08 (q, J=6.9Hz, 2H), 3.94-3.90 (m, 2H), 3.62-3.56 (m. 2H), 3.14 (br, 1 H), 2.90 (br, 2H), 2.17-2.07 (m, 4H), 1.28 (t, J=7.2Hz, 3H), 1.15-1.11 (m, 2H), 0.87-0.73 (m, 2H).
'H NMR (DMSO-d6, 300Hz), b 9.94 (s, 1 H), 7.67 (d, J=8.7Hz, 2H), 7.51-7.47 (m, 3H), 7.23 (d, 1055 148.1-153.2 406.0 ** *** J=2=4Hz, 1H), 6.90 ( dd, J=1.8Hz and 6.6Hz, 1 H), 4.15-4.04 (m, 6H), 1.68-1.52 (m, 4H), 1.35 (t.
J=6.9Hz, 3H), 0.94 (t, J=7.2Hz, 3H), 0.63 (t, J=7.2Hz, 3H).
1056 169-173.9 406.0 *=* *** 'H NMR (DMSO-ds, 306Hz), 6 9.87 s, 1 H, 7.67 d, J=8.7Hz, Compound Melting Mass Replicon Replicon ~
Number Point ( C) Spec IC60 NM lCSO M H NMR Data [M+H] 2-day 3-day 2H), 7.51-7.47 (m, 3H), 7.23 (d, J=1.8Hz, 1 H), 6.90 (dd, J=2.1 Hz and 6.6Hz, 1 H), 4.94-4.90 (m, 1H), 4.15-4.09 (m, 4H), 1.54-1.52 (m, 2H), 1.35 (t, J=6.9Hz, 3H), 1.28-1.25 (m, 6H), 0.63 (t, J=7.2Hz, 3H).
'H NMR (DMSO-d6, 300Hz), 6 9.41 (s, 1H), 8.26 (d, J=6.9Hz, 2H), 8.01-7_94 (m, 3H), 7.70 (d, J=2.1 Hz, 1 H), 7.41 (dd, J=2.1 Hz 1057 184.5-193.9 406.0 ** and 6.6Hz, 1 H), 5.21-5.15 (m, 1 H), 4.64-4.53 (m, 4H), 2.17-2.12 (m, 21-1), 2.07 (d, J=6.9Hz, 6H), 1.86 (t, J=6.9Hz, 3H), 1.41 (t, J=7.5Hz, 3H).
'H NMR (DMSO-de, 300Hz), 6 9.87 (s, 1 H), 7.66 (d, J=8.4Hz, 2H), 7.51-7.43 (m, 3H), 7.20 (d, J=2.1 Hz, 1 H), 6.92 (dd, J=2.1 Hz 1058 160.1-166.5 406.0 *** *`* and 6.6Hz, 1 H), 4.94-4.89 (m, 1 H), 4_57-4.53 (m, 1 H), 4.10 (q, J=6.9Hz, 2H), 1.52 (d, J=6.6Hz, 6H), 1.35 (t, J=6.9Hz, 31-1), 1_25 (d, J=6.6Hz, 6H).
1H NMR (CD3CN, 300Hz), 68.07 (s, 1 H),7.65 (d, J=8.7Hz, 2H), 7.55-7.49 (m, 2H), 7.04 (d, J=1.8Hz, 1 H), 6.91 (dd, J=6.6Hz and 2.1 Hz, 1 H), 5.30 (br, 1 H), 1059 135-142.6 424_0 4.16-4.09 (m, 4H), 4.73 (t, J=4.2Hz, 1 H), 4.57 (t, J=3.9Hz, 1 H). 4.43 (t, J=4.2Hz, 1 H), 4.34 (t, J=3.9Hz, 1H), 4.15-4.01 (m, 4H), 1.40 (t, J=6.9Hz, 3H), 0.87-0.85 (m, 6H).
1H NMR (CD3CN, 300Hz), 67.65-7.51 (m, 3H), 7.45-7.42 (m, 2H), 7.36-7.31 (m, 1 H), 7.04 (d, 1060 193.2-199,2 405.1 J=2=1 Hz, 1 H), 6.94-6.89 (m, 1 H), 5.25 (br, 1H), 4.15-4.07 (m, 4H), 3.20 (br, 2H), 1.39 (t, J=6Hz, 3H), 1.10 (t, J=7.2Hz, 3H), 0.63 (d, J=6.6Hz, 6H).
'H NMR (CD3CN, 300Hz), 57.66-7_53 (m, 3H), 7.45-7.43 (m, 2H), 7.38-7.33 (m, 1 H), 7.06-7.05 (m, 1061 182.7-186.3 419.1 ** 1H), 6.94-6.91 (m, 1H), 5.34 (br, 1 H), 4.15-4.02 (m, 4H), 3.16-3_ 13 (m, 2H), 1.55-1.50 (m, 21-1), 1.50-1.39 (m, 3H), 0.98 (t, J=7.2Hz, 3H), 0.63 (d, J=6.6Hz, 6H).
1062 156.7-162.2 378.0 'H NMR (CDC13, 300MHz), 67.62 (d, J=8.7Hz, IH), 7.56 d, Mass Replicon Replicon Compound Melting Spec IC50 M IC50 NM 'H NMR Data Number Point { C) [M+H] 2-day 3-day J=8.1Hz, 2H), 7.46 (d, J=8.7Hz, 2H), 6.94 (d, J=8.4Hz, 1H), 6.85 (m, 2H), 4.11 (q, J=6.9Hz, 2H), 4.03 (t, J=7.8Hz, 2H), 3.82 (s, 3H), 1.72 (q, J=7.5Hz, 2H), 1.49 (t, J=6.9Hz, 3H), 0.78 (t, J=7.5Hz, 3H).
'H NMR (CDCI3, 300MHz), S 7.62 (d, J=8.4Hz, 1H), 7.56 (d, J=7.8Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 6.94 (d, J=8.4Hz, 1H), 6.86 1063 183.2-187.6 392.1 ** (s, 1 H), 6.81 (s, 1 H), 4.26 (q, J=6.9Hz, 2H), 4.11 (q, J=6.9Hz, 2H), 4.03 (t, J=7.8Hz, 2H), 1.72 (q, J=7.5Hz, 2H), 1.49 (t, J=6.9Hz, 3H), 1.34 (t, J=7.2Hz, 3H), 0.77 (t, J=7.5Hz, 3H).
'H NMR (CDCI3i 300MHz), 67.62 (d, J=8.7Hz, 1H), 7.57 (d, J=8.7Hz, 2H), 7.47 (d, J=8.7Hz, 2H), 6.97 (s, 1 H), 6.95 (dd, J=8.7Hz and 2.1 Hz, 1 H), 6.86 (d, 1064 103.2-107.7 410.0 .1=2-1 Hz, 1 H), 4.75 (t, J=4.2Hz, 1 H), 4.59 (t, J=4.2Hz, 1 H), 4.50 (t, J=4.5Hz, I H), 4.41 (t, J=4.2Hz, I H), 4.11 (q, J=6.9Hz, 2H), 4.03 (t, J=7.5Hz, 2H), 1.72 (q, J=7.5Hz, 2H), 1.47 (t, J=6.9Hz, 3H), 0.78 (t, J=7.2Hz, 3H).
'H NMR (CDCI3i 400MHz), 6 7.63 (d, J=8.8Hz, 1 H), 7.56 (d, J=8.4Hz, 2H), 7.42 (d, J=8.4Hz, 2H), 7.10 (s, 1H), 6.94 (d, 1065 196.3-220.2 392.0 ** *** J=8.4Hz, 1H), 6.85(s, 1H), 4.68-4.61 (m, 1 H), 4.26 (q, J=7.2Hz, 2H), 4.12 (q, J=6.8Hz, 2H), 1.58 (d, J=6.8Hz, 6H), 1.48 (t, J=7.2Hz, 3H), 1.34 (t, J=7.2Hz, 3H).
'H NMR (CD3CN, 300Hz), 8 7.61 (d, J=8.7Hz, 2H), 7.53 (d, J=8.7Hz, 1H), 7.44 (d, J=8.7Hz, 2H), 7.38 (s, 1 H) 7.03 (d, J=1.8Hz, 1 H), 6.91 (dd, J=6.6Hz 1066 198.3-205.6 419.0 ** and 2.1 Hz, 1 H), 5.30 (br, 1 H), 4.16-4.09 (rn, 4H), 3.18-3.11 (m, 2H), 1.66-1.46 (m, 4H), 1.40 (t, J=6.9Hz, 3H), 1.16-1.06 (m, 2H), 0.92 (t, J=7.5Hz, 3H), 0.76 (t, J=7.5Hz, 3H).
1067 95-100 504.4 1068 170-174 474.3 **
1069 155-156 475.3 Compound Melt'tng Mass Replicon Replicon 1 Number Point ( C) Spec ICso NM IC$o pM H NMR Data [M+H] 2-day 3-day 'H NMR (300 MHz, DMSO-de): 6 8.86 (1 H, s), 7.67 (1 H, d, J = 2.0 Hz), 7.65 (1 H, d, J = 8-5 Hz), 7.61 (2H, d, J= 8.8 Hz), 7.47 (2H, d, J
= 8.8 Hz), 7.25(1H,t, J = 74.4 Hz), 7.11 (1 H, dd, J = 8.5, 2.0 Hz), 6.40 (1 H, t, J = 5.8 Hz), 5.86 1070 208-209 437.22 ** (1 H, ddt, J = 17.1, 10.4, 5.1 Hz), 5.15 (1 H, ddt, J= 17.1, 1.8, 1.7 Hz), 5.06 (1H, ddt, J= 10.4, 1.8, 1.7 Hz), 4.12 (2H, d, J = 7.0 Hz), 3.73 (2H, narrow m), 0.93-0.84 (1H, m), 0.32~0.23 (2H, m), 0.05-0.00 (2H m). F NMR (300 MHz, DMSO-d6): 6 -82.03 (2F, d, J =
73.3 Hz).
'H NMR (300 MHz, CDCI3): b 7.69 (1H, d, J = 8.2 Hz), 7.56 (2H, d, J
'= 8.5 Hz), 7.44 (2H, d, J = 8.5 Hz), 7.24 (1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.2, 1.8 Hz), 6.80 (1 H, s), 6.52 (1 H. t, J = 74.0 Hz), 1071 125-126 {M ~~ ** * 3.98 (2H, d, J = 7.0 Hz), 3.96 (2H, d,J=7Hz),1.97(1H,rn,J=6.7 Hz), 1.03-0.94 (1H, m), 0.95 (6H, d, J = 6.7 Hz), 0.46-0.39 (2H, m), 0.05-0.00 (2H, m).19F NMR (300 MHz, CDCI3): 8-80.76 (2F, d, J
73.3 Hz).

1072 197-198 430.30 *** ***
(M-H+) 9 073 191-192 390.25 1074 140-141 404.27 **
1075 140-141 418.27 ** **
1076 175-176 404.27 *** ***
1077 187-188 418.27 *** ***
1078 188-189 430.30 ' *** **
(M-H+) 1079 178-179 452.25 *** ***
'H NMR (300 MHz, CDCI3): 7.61 (1H,d,J=8.5Hz),7.58(2H,d,J
= 8.3 Hz), 7.37 (2H, d, J = 8.3 Hz), 7.23 (1 H, d, J = 1.0 Hz), 6.96 1080 221-223 417.28 *** *** (1H, dd, J = 8.8, J= 1.7 Hz), 4.90 (1H, s), 4.15 (2H, q, J = 6.9), 4.01 (1 H, m), 2.82 (2H, m), 2.33 (2H, m), 1.81 (2H, m), 1.48 (3H, t, J
6.9 Hz)), 1.21 (6H, d, J = 6.6 Hz).
'~081 179-180 1 452.23 Mass Replicon Replicon Compound Melting Spec IC50 pM IC50 NM 'H NMR Data Number Point ( C) [M+H] 2-day 3-day (M-H+) 1083 156 495.3 ***
1084 167 457.2 1085 162 458.4 ***
1086 170 378.2 ***
1087 205 405.2 **
1088 215 403.2 **
1089 195 389.2 **
'H NMR (CD3OD, 300MHz), b 7.80 (d, J=8.7Hz, 2H), 7.58-7.49 (m, 3H), 7.22 (d, J=2.1Hz, 1H), 7.04 (d, J=2.1 Hz and 8.7Hz, 1 H), 1090 145.6-149.7 475.2 ** 4.48 (t, J=4.8Hz, 2H), 4.23 (q, J=6.9Hz, 2H), 4.01-3.73 (m, 6H), 3.02(br, 4H), 1.86-1.77 (m, 1 H), 1.28 (t, J=7.2Hz, 3H), 1.00-0.87 (m, 4H).
'H NMR (CD3OD, 300MHz), b 7.78 (d, J=8.4Hz, 2H), 7.55-7.47 (m, 3H), 7.20 (d, J=1.8Hz, 1 H), 7.02 (dd, J=1.8Hz and 8.4Hz, 1 H), 1091 81.4-86.2 461.2 ** 4.46 (t, J=4.8Hz, 2H), 4.21 (q, J=6.6Hz, 2H), 3.81-3.64 (m, 6H), 3.55 (s, 3H), 3.03 (s, 3H), 1.84-1.78 (m, 1 H), 1.26 (t, J=7.2Hz, 3H), 0.99-0.86 (m, 4H).
'H NMR (CD3OD, 300MHz), 6 9.03 (s, 2H), 7.79 (d, J=8.7Hz, 2H), 7.56-7.49 (m, 3H), 7.14 (d, J=1.8Hz, 1 H), 6.99 (dd, J=2.1 Hz 1092 193.8-197.4 441.2 and 8.4Hz, 1 H), 4.68 (t, J=4.8Hz, 2H), 4.44 (t, J=5.1 Hz, 2H), 4.21 (q. J=6.9Hz, 2H), 1.85-1.77 (m, 1 H), 1.27 (t, J=6.9Hz, 3H), 1.01-0.93 (m, 2H), 0.91-0.87 (m, 2H).
1093 130.7-134.3 441.2 **
'H NMR (DMSO-ds, 300Hz), b 8.74 (s, 1 H), 7.59 (d, J=8.4Hz, 2H), 7.49-7.41 (m, 3H), 7.22 (s, I H), 6.89 (dd, J=9.8Hz and 6.9Hz, 1094 205.3-208 391.0 ** 1 H), 6.22 (t, J=5.4Hz, 1 H), 4.15-4.06 (m, 4H), 3.14-3.10 (m, 2H), 1.58-1.51 (m, 2H), 1.35 (t, J=6.9Hz, 3H), 1.05 (t, J=7.2Hz, 3H), 0.63 (t, J=7.5Hz, 3H).
'H NMR (DMSO-ds, 300Hz), b 1095 195.3-200.1 405.1 *** *** 8.72 (s, 1 H), 7.59 (d, J=8.7Hz, 2H), 7.49-7.41 (m, 311), 7.22 (s, Compound Melting Mass Replicon Replicon Number Point ( C) Spec ICso NM ICSo NM
iH NMR Data [M+H] 2-day 3-day 1H), 6.89 (dd, J=1.8Hz and 6.9Hz, 1 H), 6.26 (t, J=5.4Hz, 1 H), 4.20-4.07 (m, 4H), 3.09-3.03 (m, 2H), 1.58-1.41 (m, 4H), 1.35 (t, J=6.9Hz, 3H), 0.87 (t, J=6.9Hz, 3H), 0.64 (t, J=7.2Hz, 3H).
'H NMR (DMSO-d6, 300Hz), 6 8.60 (s, 1 H), 7.58 (d, J=8.4Hz, 2H), 7.49-7.41 (m, 3H), 7.22 (s, 1H), 6.89 (dd, J=2.1Hz and 6.6Hz, 1096 192.1-196.2 405.1 *** *"* 1 H), 6.12 (d, J=7.5Hz, 1 H), 4.15-4.06 (m, 4H), 3.80-3.73 (m, 1 H), 1.58-1.50 (m, 2H), 1.35 (t, J=6.9Hz, 3H), 1.10 (d, J=6.6Hz, 6H), 0.64 (t, J=7.2Hz, 3H).
'H NMR (DMSO-ds, 300Hz), 6 8.72 (s, I H), 7.59 (d, J=8.4Hz, 2H), 7.49-7.41 (m, 3H), 7.22 (s, 1 H), 6.89 (dd, J=1.8Hz and 6.9Hz, 1097 196.4-202.3 419.1 "" *** 1 H), 6.24 (t, J=5.4Hz, 1 H), 4.15-4.06 (m, 4H), 3.12-3.06 (m, 2H), 1.58-1.51 (m, 2H), 1.44-1.21 (m, 7H), 0_89 (t, J=7.2Hz, 3H), 0.83 (t, J=7.2Hz, 3H).
'H NMR (DMSO-ds, 300Hz), 6 8.74 (s, I H), 7.59 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, 1 H), 7.38 (d, J=8.4Hz, 2H), 7.20 (d, J=2.1 Hz, 1 H), 6.92 (dd, J=2.1 Hz 1098 217.8-221.4 391.0 ** and 6.6Hz, 1 H), 6.22 (t, J=5.4Hz, 1 H), 4.62-4.53 (m, 1 H), 4.11 (q, J=6.9Hz, 2H), 3.16-3.07 (m, 2H), 1.52 (d, J=6.6Hz, 6H), 1.35 (t, J=6.9Hz, 3H), 1.05 (t, J=7.2Hz, 3H).
'H NMR (DMSO-ds, 300Hz), 6 8.73 (s, 1 H), 7.59 (d, J=8.4Hz, 2H), 7.49 (d, J=8.1 Hz, 1 H), 7.38 (d, J=8.7Hz, 2H), 7.20 (d, J=2.1 Hz, 1 H), 6.92 (dd, J=2.1 Hz 1099 162.1-165.1 405.1 ** and 6.6Hz, 1 H), 6.26 (t, J=5.7Hz, 1H), 4.62-4.53 (m, 1H), 4.11 (q, J=6.9Hz, 2H), 3.09-3.02 (m, 2H), 1.52 (d, J=6.6Hz, 6H), 1.48-1.41 (m, 2H), 1.35 (t, J=6.9Hz, 3H), 0.87 (t, J=7.2Hz, 3H).
1H NMR (DMSO-d6, 300Hz), 6 8.60 (s, 1 H), 7.57 (d, J=8.1 Hz, 2H), 7.49 (d, J=8.7Hz, 1 H), 7.38 1100 228.6-231.4 405.1 (d, J=8.7Hz, 2H), 7.20 (d, J=2,1Hz, 1H), 6.92 (dd, J=2.1Hz and 6.6Hz, 1 H), 6.11 (d, J=7.8Hz, 1 H), 4.62-4.52 (m, 1 H), 4.11 (q, J=6_9Hz, 2H , 3_79-3_72 m, 1H , Mass Replicon Replicon Compound Melting Spec IC50 NM iCso NM 'H NMR Data Number Point ( C) [M+H] 2-day 3-day 1.53-1.51 (m, 6H), 1.35 (t, 'J=6.9Hz, 3H), 1.11-1.09 (m, 6H).
(DMSO, 300Hz), b 8.72 (s, 1 H), 7.58 (d, J=8.7Hz, 2H), 7.49 (d, J=8.7Hz, IH), 7.37 (d, J=8.4Hz, 2H), 7.20 (d, J=2.1Hz, 1H), 6.92 1101 157.2 160.5 419.1 *=* (dd, J=2.1 Hz and 6.6Hz, 1 H), 6.23 (t, J=5.7Hz, 1H), 4.62-4.55 (m, 1H), 4.11 (q, J=6.9Hz, 2H), 3.12-3.06 (m, 2H), 1.52 (d, J=6.6Hz, 6H), 1.47-1.21 (m, 7H), 0.86 (t, J=6.9Hz, 3H).
'H NMR (CD3CN, 300Hz), 57.58-7.46 (m, 4H), 7.38 (d, J=8.7Hz, 2H), 7.30-7.15 (m, 5H). 7.15 (s, 1 H), 6.89 (dd, J=2.1 Hz and 6_6Hz, 1102 197.3-201.6 467.0 ** ` *** 1 H), 5.31 (br, 1 H), 4.64-4.59 (m, 1 H), 4.09 (q, J=6.9Hz, 2H), 3.44-3.42 (m, 2H), 2.80 (t, J=6.6Hz, 2H), 1.54 (d, J=6.6Hz, 6H), 1.38 (t. J=6.9Hz, 3H).
1103 162-163 424.27 **
1104 245-248 422.29 1105 175-176 422.27 **
1106 217-219 429.32 *** ***
1107 157-158 428.25 ** ***
(M-H+) 1108 213-215 435.28 *** ***
1109 155-156 444.31 1110 191-195 425.2 **
111=1 180-183 406.2 **
1112 173-175 463.2 1113 151.155 495.4 **
1114 171-176 511.2 ***
1115 155-156 497.2 1116 218-220 511.2 **
1117 106-109 509.2 **
1118 126-130 462.2 **
1119 184-186 405.31 **
'H NMR (300 MHz, CDCI3): 7.61 (1 H, d, J = 9.2 Hz), 7.51 (2H, d, J
1120 223-225 417.37 *** *** = 8.5 Hz), 7.43 (2H, d, J = 8.5 Hz), 7.10 (2H, m). 4.90 (2H, m), 4.13 (2H, q, J= 6.9 Hz), 3.97 (2H, d,J=6.6Hz, 1.47 3H,t,J=7.0 Compound Melting Mass Replicon Replicon Number Point ( C) Spec ICeo uM IC50 uM
iH NMR Data [M+H] 2-day 3-day Hz), 1.20 (6H, d, J 8.6 Hz), 1.05 (1H, m), 0.43 (2H, m), 0.06 (2H, m) 1121 162-164 501.17 ***
1122 170-173 491.4 ***
1123 75-80 525.4 ***
**" ~
1124 100-104 474.5 [M-H]-1125 188-190 488.4 *** ***
1126 130-134 510.3 **
1127 112-115 418.3 *** ***
1128 203-204 432.3 *** ***
1129 115-116 432.3 *** **"
'H NMR (300 MHz, DMSO-d6): b 10.02 (1 H, s), 7.69 (2H, d, J= 8.8 Hz), 7.67 (1 H, d, J = 8.5 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.55 (2H, d, J
1130 177-178 386.26 ** = 8.8 Hz), 7.28 (1 H, t, J= 74.4 Hz), 7_13 (1H, dd, J = 8.5, 2.0 Hz), 4.20 (2H, q, J = T.3 Hz), 3.70 ~3H, s), 1.18 (3H, t, J = 7.3 Hz).
' F NMR (300 MHz, DMSO-d6): 8 -81.95 (2F, d, J = 73.3 Hz).
~H NMR (300 MHz, D MSO-d6): 6 9.98 (1 H, s), 7.69 (2H, d, J = 8.8 Hz), 7.67 (1 H, d, J = 8.8 Hz), 7.61 (1 H, d, J = 2.0 Hz), 7.54 (2H, d, J
= 8.8 Hz), 7.28 (1 H, t, J = 74.4 1131 174-175 400.26 ** Hz), 7.13 (1 H, dd, J = 8.8, 2.0 Hz), 4.20 (2H, q, J = 7.0 Hz), 4.15 (2H, q, J= 7.3 Hz), 1.26 (3H, t, J
= 7.0 Hz), 1.18 (3H, t, J = 7.3 Hz).
'9F NMR (300 MHz, DMSO-d6): 6 -81.95 (2F, d, J = 75.3 Hz).
'H NMR (300 MHz, DMSO-ds): 5 9.99 (1 H, s), 7.70 (2H, d, J= 8.8 Hz), 7.67 (1 H, d, J = 8.5 Hz), 7.61 (1 H, d, J = 2.0 Hz), 7_54 (2H, d, J
= 8.8 Hz), 7.28 (1 H, t, J = 74.4 1132 148-149 414.25 ** Hz), 7.13 (1 H, dd, J = 8.5, 2.0 Hz), 4.20 (2H, q, J = 7.0 Hz), 4.07 (2H, t, J= 6.7 Hz), 1.65 (2H, hx, J
= 7.6 Hz), 1.18 (3H, t, J~~7.2 Hz), 0.94 (3H, t, J = 7.5 Hz). F NMR
(300 MHz, DMSO-ds): 8 -81.96 (2F, d, J = 73.3 Hz).
1H NMR (300 MHz, DMSO-d6): ii 1133 139-140 428.25 ** 9.98 (1H, s), 7.72-7.66 (3H, m), 7.61 (1 H, d, J= 2.0 Hz), 7.54 (2H, d, J=8.8 Hz), 7.28 (1 H, tJ

Mass Replicon Replicon Compound Melting 1 Number Point ( C) Spec IC50 NM ICso NM H NMR= Data [M+H} 2-day 3-day 74.4 Hz), 7.13 (1 H, dd, J = 8.8, 2.0 Hz), 4.20 (2H, q, J = 7.3 Hz), 4.11 (2H, t, J = 6.9 hz), 1.66-1.56 (2H, m), 1.45-1.35 (2H, m), 1.18 (3H, t, J = 7.3 Hz), 0.91 (3H, t, J=
7.3 Hz).19F NMR (300 MHz, DMSO-d6): b -81.92 (2F, d, J =
73.3 Hz).
'H NMR (300 MHz, DMSO-d6): 5 9.99 (1H, s), 7.70 (2H, d, J= 8.8 Hz), 7.67 (1 H, d, J = 8.8 Hz), 7.61 (1 H, d, J = 2.0 Hz), 7.54 (2H, d, J
= 8.8 Hz), 7.28 (1 H, t, J = 74.4 1134 142-143 426.30 Hz), 7.13 (1 H, dd, J = 8.8, 2.0 (M-H+) Hz), 4.20 (2H, q, J = 7.0 Hz), 3.90 (2H,d,J=6.7Hz),1.93(1H,m,J
= 6.7 Hz), 1.18 (3H, t, J = 7.0 Hz), 0.93 (6H, d, J = 6.7 Hz).'gF NMR
(300 MHz, DMSO-ds): 6 -81.92 (2F, d, J = 73.3 Hz).
'H NMR (300 MHz, DMSO-ds): b 10.10 (1 H, s), 7.72-7.66 (3H, m), 7.62 (1 H. d, J= 2.0 Hz), 7.55 (2H, d,J=8.8Hz),7.28(1H,t,J=
74.4 Hz), 7.13 (1 H, dd, J = 8.5, 1135 144-145 412.24 *** 2.0 Hz), 6.06-5.93 (1H, m), 5.41-5.22 (2H, m), 4.64 (2H, dt, J = 5.5, 1.3 Hz), 4.20 (2H, q, J= 7.3 Hz), 1.18 (3H, t, J= 7.3 Hz).79F NMR
(300 MHz, DMSO-dg): 6 -81.92 (2F, d, J = 73.3 Hz).
'H NMR (300 MHz, DMSO-de): b 8.77 (1H, s), 7.66 (1H, d, J = 8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.46 (1 H, d, J
=2.0Hz),7.27(1H,t,J=74.4 Hz),7.13(1H,dd,J=8.8,2.0 1136 172-174 413.25 ** Hz), 6.28 (1 H, t, J= 5.7 Hz), 4.20 (2H, q, J = 7.3 Hz), 3.05 (2H, q, J
= 6,2 Hz), 1.44 (2H, hx, J = 6_7 Hz), 1.19 (3H, t, J = 7.2 Hz), 0.87 (3H, t, J = 7.5 Hz). 19F NMR (300 MHz, DMSO-d6): b -81.92 (2F, d, J = 73.3 Hz).
'H NMR (300 MHz, DMSO-ds): 6 8.65 (1 H, s), 7.66 (1 H, d, J = 8.8 Hz), 7.61 (1H, d, J= 2.0 Hz), 7.60 (2H, d, J = 8.8 Hz), 7.47 (2H, d, J
= 8.8 Hz), 7.27 (1 H, t, J = 74.4 1137 180-182 413.26 ** Hz), 7.13 (11-1, dd, J = 8.8, 2.0 Hz), 6.14 (1 H, d, J = 7.6 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.77 (1 H, m, J
= 7.3 Hz), 1.18 (3H, t, J = 7.3 Hz), 1.10 (6H, d, J = 6.5 Hz).'gF NMR
(300 MHz, DMSO-dfi : 6 -81.92 Mass Replicon Replicon Compound Melting Spec ICSO NM iCso NM 'H NMR Data Number Point ( C} [M+H] 2-day 3-day (2F, d, J = 73.3 Hz).
'H NMR (300 MHz, DMSO-d6): b 8.760 H,s),7.66(1H,d,J=8.8 Hz), 7.62 (2H, d, J = 8.8 Hz), 7.61 (1 H, d, J = 2.0 Hz), 7.47 (2H, d, J
= 8.8 Hz), 7.27 (1 H, t, J= 74.4 Hz), 7.13 (1 H, dd, J = 8.8, 2.0 1138 146-149 427.27 ** Hz), 6.25 (1 H, t, J = 5.7 Hz), 4.21 (2H, q, J= 7.3 Hz), 3.09 (2H, q, J
= 5.8 Hz), 1.47-1.25 (4H, m), 1.18 (3H, t, J = 7.0 Hz), 0.89 (3H, t, J
7.0 Hz).'aF NMR (300 MHz, DMSO-de): b -81.92 (2F, d, J =
73.3 Hz).
'H NMR (300 MHz, DMSO-de): 6 8.92(1H,s),7.66(1H,d,J=8.8 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.61 (1 H, d, J = 2.0 Hz), 7.48 (2H, d, J
= 8.8 Hz), 7.28 (1 H, t, J = 74.4 1139 179-180 411.27 ** Hz), 7.13 (1 H, dd, J = 8.8, 2.0 Hz), 6.43 (1 H, t, J= 5.8 Hz), 5.95-5.80 (1 H, m), 5.22-5.07 (2H, m), 4.21 (2H, q, J = 7.3 Hz), 3.75 (2H, t, J=6Hz), 1.19 (3H, t, J=7_3 Hz).19F NMR (300 MHz, DMSO-de): 8-81.92 (2F, d, J = 73.3 Hz).
1140 198-202 450.2 **
[M-H].
1141 156-160 448'2 **
[M-H]' 1142 110-111 487.41 **" **a 1143 215-218 417.5 1144 207-210 429.5 *** ** `
1145 205-208 445.2 1146 187-191 430.32 'H NMR (300 MHz, d6-acetone): S
8.92 (s, 1H), 7.82 (d, 2H, J = 8.7 Hz), 7.62-7.49 (m, 3H), 7.30 (d, 1 H, J= 2.1 Hz), 6.98 (dd, 1 H, J=
8.7, 2.1 Hz), 5.095 (pentet, 1 H, J
1147 154-158 444.25 *** *" = 9.0 Hz), 4.32 (m, 1 H), 4.17 (q, 2H, J = 6.9 Hz), 2.7-2.8 (m, 2H), 2.35-2.5 (m, 2H), 1.8-2.0 (m, 2H), 1.42 (t, 3H, J= 6.9 Hz), 1.34 (d, 3H, J = 6.3 Hz), 1.0-1.1 (m. 1H).
0.6-0.8 (m, 3H), 0.5-0.59 (m, 1 H) 402.24 1148 193-195 **" **
(M-H+) 1149 158-159 416.37 **" ***

Mass Replicon Replicon Compound Me{ting Spec IC50 NM IC30 pM 'H NMR Data Number Point ( C) [M+H] 2-day 3-day (M-H+) 'H NMR (300 MHz, CDCI3): 5 7.62 (1 H, d, J = 9.3 Hz), 7.58 (2H, d, J
-8.8 Hz), 7.46 (2H, d, J = 8.8 416.32 Hz), 7.10 (2H, m), 6.77 (1 H, s), 1150 173-175 *** *"* 5.05 (1 H, m), 4.13 (2H, q, J= 7.2 (M-H+) Hz), 3.97 (2H, d, J= 6.6 Hz), 1.47 (3H, t, J = 6.9 Hz), 1.32 (6H, d, J
= 6.0 Hz), 1_05 (1 H, m), 0.43 (2H, m), 0.05 (2H, m) 1151 171-172 432.30 "** ***
1152 . 198-199 444.31 *** ***
(M-H+) 1153 154-155 466.28 *** ***
1154 207-208 444.31 *** ***
(M-H+) 1155 200-202 466.28 1156 226-228 444.31 *** ***
(M-H+) 1157 199-201 466.28 *** ***
1158 173-179 442'27 **` ***
(ES-) (Weak 1159 206-208 ionizati *** ***
on) 1160 193-194 422.3 *** "*
1161 183-185 410.2 *** **
1162 192-193 403.3 1163 188-189 403.2 **
1164 188-190- 417.2 *** *
1165 190-192 429.3 ** **
1166 260-266 4445.25 **
1167 208-212 430.25 *** ***
'H NMR (300 MHz, da-acetone): S
8.08 (s. 1 H), 7.69 (d, 2H, J = 8.7 Hz), 7.54 (d, 1 H. J= 8.7 Hz), 7.43 (d, 2H, J= 8.7 Hz), 7.30 (d, 1 H, J
(Weak = 2.1 Hz), 6.97 (dd, 1 H, J = 8.7, 1168 218-221 ionizati *** *** 2.1 Hz), 6.10 (d, 1 H, J = 8.1 Hz), on) 5.08 (pentet, 1 H, J = 9.3 Hz), 4.32 (sextet, 1 H, J = 8.1 Hz), 4.16 (q, 2H, J = 6.9 Hz), 2.7-2.85 (m, 2H), 2.35 2.5 (m, 2H), 2.15-2.35 (m, 2H , 1.8 2.0 m, 4H , 1.6-1.7 m Compound Melting Mass Replicon Replicon ~
Number Point ( C) Spec ICso {~M ICso NM H NMR Data [M+H] 2-day 3-day 2H), 1.42(t,3H,J=6.9Hz) 1169 224-226 432.3 "** ***
1170 180-181 469.3 **
1171 219-220 431.2 *** "**
1172 198-199 431.33 1173 203-205 443.31 *** "**
1174 180-181 436.28 `** ***
1175 202-203 456.27 *** ***
1176 170-172 390.2 1177 145-147 404.2 *** *"
1178 182-183 418.3 *** ***
1179 173-174 430.2 **
1180 179-180 402.2 1181 179-180 424.2 **
1182 162-163 422.2 *** *
'H NMR (CD3CN, 300MHz), 5 8.86 (s, 1 H), 8.66 (s, 1 H), 7.80 (d, J=8.7Hz, 2H), 7.58-7.49 (m, 4H), 7.42 (s, 1H), 7.09 (d, J=2.1Hz, 1183 202.3-205.9 440.3 **" 1 H), 6.95 (dd, J=2.1 Hz and 8.7 Hz, 1 H), 4.58 (t, J=4.8Hz, 2H), 4.42 (t, J=4.8Hz, 2H), 4.16 (q, J=6.9Hz, 2H), 1.76-1 _67 (m, 1 H), 1.25 (t, J=7.2Hz, 3H), 0.95-0.89 (m, 4H).
'H NMR (CD3CN, 300MHz), S
8.81 (s, 1 H), 7.79 (d, J=8.7Hz, 2H), 7.70 (d, J=2.1 Hz, 1 H), 7.54-7.49 (m, 4H), 7.02 (d, J=2.1 Hz, ** 1 H), 6.88 (dd, J=2.1 Hz and 8.7 1184 165.4-170.1 440.3 Hz, 1 H), 6.30 (t, J=1.8Hz, 1 H), 4.57 (t, J=4.8Hz, 2H), 4.44 (t, J=5.1 Hz, 2H), 4.13 (q, J=7.2Hz, 2H), 1.73-1.68 (m, 1 H), 1.24 (t, J=7.2Hz, 3H), 0.95-0.82 (m, 4H).
IH NMR (300 MHz, DMSO-ds): 6 8.76-8.70 (2H, m), 8.53 (1 H, d, J
= 4.7 Hz), 7.91 (1H, d, J=7.9 Hz), 7.60 (2H, d, J = 8.5 Hz), 7.51 (1H, d, J = 8.5 Hz), 7.46-7.38 (8H, 1185 211-213 454.30 *** m), 7.00 (1 H. dd, J = 8.5, 1.2 Hz), 6.27 (1 H. t, J = 5.5 Hz), 5.25 (211, s), 4.18 (2H, q, J = 7.0 Hz), 3.05 (2H, q, J = 6.4 Hz), 1.44 (2H, hx, J
= 7.3 Hz), 1.17 (3H, t, J = 7.0 Hz), 0.87 (3H, t, J = 7.4 Hz).
1186 150. 464.34 ** 'H NMR (300 MHz, DMSO-d6): 6 Compound Melting Mass Replicon Replicon ~
Number Point ( C) Spec IC6o NM IC50 NM H NMR Data [M+H] 2-day 3-day (M-H+) 9.90 (1H, s), 7.67 (1H, d, J = 8.8 Hz), 7.66 (2H, d, J= 8.8 Hz), 7.58 (1 H, d, J = 2.0 Hz), 7.48 (2H, d, J
= 8.8 Hz), 7.29 (1 H, t, J = 74.4 Hz), 7_ 15 (1 H, dd, J = 8.8, 2.0 Hz), 5.13-5.08 (1 H, m), 4.99 (1 H, p, J = 8.5 Hz), 2.55-2.40 (2H, m), 2.37-2.24 ~21-1, m), 1.92-1.57 (10H, m). ' F NMR (300 MHz, DMSO-d6): 6 -82.08 (2F, d, J =
73.3 Hz).
'H NMR (300 MHz, DMSO-d6): b 8.76(1H,s),7.67(1H,d,J=8.5 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.58 (1H,d,J=2.0Hz),7.42(2H,d,J
= 8.8 Hz), 7.29 (1 H, t, J = 74.4 Hz), 7.14 (1 H, dd, J = 8.5, 2.0 1187 198-199 439.29 *= Hz), 6.28 (1 H, t, J = 5.7 Hz), 5.00 (1 H, P, J = 8.6 Hz), 3.05 (2H, q, J
= 6.1 Hz), 2.59-2.42 (2H, m), 2.39-2.24 (2H, m), 1.84-1.66 (2H, m), 1.44 (2H, hx, J= 7.0 Hz), 0.87 (3H, t, J = 7.4 Hz).'9F NMR (300 MHz, DMSO-ds): 6 -82.05 (2F, d, J = 73.3 Hz).
'H NMR (300 MHz, DMSO-d6): 6 10.26 (1 H, s), 7.70 (1 H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.40 (1H,d,J=2.0Hz),7.39(2H,d,J
= 8.8 Hz), 7.29 (1 H, t, J = 74.4 1188 222-223 474.25 ** Hz), 7.16 (1 H, dd, J= 8.8, 2.0 Hz), 4.71 (1 H, p, J= 9.1 Hz), 3.24-3.19 (2H, m), 2.22-1.60 10H, m), 0.97 (3H, t, J = 7.4 Hz).
9F NMR (300 MHz, DMSO-de): b -82.05 (2F, d, J = 73.3 Hz).
'H NMR (300 MHz, DMSO-ds): 6 10.24 (1 H, s), 7.70 (1 H, d, J = 8.8 Hz), 7.55 (2H, d, J= 8.8 Hz), 7.44 (2H,d,J=8.8Hz),7.40(1H,d,J
= 2.0 Hz), 7.30 (1 H, t, J = 74.4 Hz), 7.16 (1 H, dd, J = 8_8, 2.0 1189 183-158 472.24 Hz), 4.71 (1 H, p, J = 9.1 Hz), 2.84-2.75 (1 H, m), 2.20-1.84 (61-1, m), 1.65-1.60 (2H, m), 1.05-0.95 (2H, m), 0.60-0.49 (2H, m). 19F
NMR (300 MHz, DMSO-d6): b -82.05 (2F, d, J = 75.3 Hz).
~H NMR (300 MHz, DMSO-de): 6 8.60 (1 H, s), 7.67 (1 H, d, J = 8.8 Hz), 7.58 (1 H, d, J = 1.9 Hz), 7.57 1190 185 186 465.27 ** (2H, d, J = 8.8 Hz), 7.42 (2H, d, J
=8.8Hz),7.29(1H,t,J=74.4 Hz), 7.14 (1 H, dd, J = 8.8, 1.9 Hz,6.30 1H,d,J=7.3Hz,5.00 Compound Melting Mass Replicon Replicon 1 Number Point ( C) Spec ICso NM ICso pM H NMR Data [M+H] 2-day 3-day (1H,p,J=8.6Hz),3.94(1H,hx,J
= 6.7 Hz), 2.60-2.40 (2H, m), 2.38-2.23 ~2H, m), 1.90-1.34 (10H, m)_ i F NMR (300 MHz, DMSO-ds): 6 -82.05 (2F, d, J =
75.3 Hz).
1191 216-219 415.31 **
1192 159-162 489_37 **
1193 213-214 404.3 **"
1194 196-197 418.3 *** ***
1195 114-115 418.3 1196 124-125 416.3 **" ***
1197 118-119 432.3 ** **
1198 181-182 432.3 *** ***
1199 187-188 444.3 **" '**
1200 188-189 446.3 *** ***
1201 182-183 466.3 *** **`
1202 195-197 406.3 **" ***
1203 184-187 420.3 **" ***
1204 188-169 420.3 1205 155-157 445.3 *** ***
1206 178-180 434.3 **t ***
1207 204-205 448.3 1208 186-190 444.30 1209 189-192 456.30 *** ,**
(ES-) 1210 148-152 503.36 1211 203-205 458.3 *** ***
1212 192-193 480.34 *** ***
1213 192-193 480.33 *** **"
1214 170-173 457.3 **" '**
1215 200-204 446.26 *** 1216 205-209 460.31 1217 135-141 388.34 **

Mass Replicon Replicon Compound Melting Spec iCso NM IC50 NM 'H NMR Data Number Point ( C} [M+H] 2-day 3-day 1218 192-193 481.31 *** ***
1219 192-193 507.35 "` ***
1220 192-193 481.28 *** ***
1221 222-225 431.3 *** ***
1222 191-192 446-35 1223 206-208 417.3 *** ***

1224 191-192 417.3 **
1225 183-184 431.3 ** ***
1226 189-190 443.3 *** ***
1227 168-169 479.3 *** ***
1228 174-175 423.5 **
1229 163-164 438.3 **
1230 179-180 436.3 1231 189-191 424.2 1232 184-185 404.2 *** **
1233 192-193 430.4 *** ***
1234 204-205 390.1 1235 209-211 410.1 **
1236 196-197 404.14 *** ***
1237 150-151 432_1 1238 176-177 458.4 **
1239 187-193 360.35 *** ***
1240 168-170 460.38 *** ***
1241 151-168 432.3 *** ***
1242 134-136 446.3 *** ***
1243 161-163 446.3 1244 145-147 446.3 *** **`
1245 245-246 318.3 1246 157-163 434.4 *** *`*
1247 188-190 432_4 *** ***
1248 207-210 462.4 *** ***

*** ***
1250 144-148 448.38 *** ***
(Weak 1251 137-142 ionizati *` **
on) 1252 131-134 446.37 **

Compound Melting Mass Replicon Replicon Number Point ( C) Spec IC50 NM ICso NM
'H NMR Data [M+H] 2-day 3-day 1253 224 517.3 **
'H NMR (300 MHz, DMSO-ds): 8 9.89 (1 H), 7.64 (3H), 7.46 (3H), 1254 189 498.6 *** *** 7.19 (2H), 6.94 (111), 6.87 (1H), 4.91 (2H), 4.19 (2H), 4.01 (2H), 2.48 (2H), 2.21 (2H), 2.17 (2H), 1.71 (2H), 1.27 (61-1) 'H NMR (300 MHz, DMSO-de): S
9.91 (1 H), 8.53 (1 H), 7.97 (1 H), 1255 208 499.4 *** *** 7.65 (2H), 7.46 (3H), 7.19 (1H), 6.92 (1 H), 4.95 (2H), 4.39 (2H), 4.06 (2H), 2.48 (2H), 2.67 (41i), 1.72 (2H), 1.24 (6H).
'H NMR ((CD3CN, 300Hz), 6 7.60 (d, 1=9.0Hz, 2H), 7.53 (d, J=8.7Hz, 1H), 7.47-7.23 (m, 7H), 7.04 (s, 1H), 6.91 (dd, 1256 188.4-191.3 467.1 1=2.1Hz and 6.6Hz, 1H), 5.31-5.27 (m, 1H), 4.16-4.07 (m, 4H), 4.45 (q, J=6.6Hz, 2H), 2.83 (t, J=6.6Hz, 2H), 1.69-1.61 (m, 2H), 1.41 (t, J=6.9Hz, 3H), 0.71 (t, J=7.5Hz, 3H).
1257 541.55 **"
1258 527.55 ***
1259 526.57 ***
1260 208 503.5 ***
1261 156 530.5 ***
1262 167 533.5 **
1263 155-157 458.4 *, *
(ES-) 1264 177-180 467.40 ***
1265 164-167 432.37 **"
'H NMR (300 MHz, CDCI3): 6 7.70 (1 I-!, d, J = 8.8 Hz), 7.55 (211, d, J
= 8.8 Hz), 7.42 (21-1, d, J = 8.8 Hz), 7.29 (1 H, d, J = 1.8 Hz), 7.22 (1 H, br s), 7.13 (1 H, dd, J = 8.8, 1.8 Hz),~6.81 (1 H, t, J= 74.4 Hz), 1266 175-176 453.34 ** 4.02 (2H, d, J = 6.7 Hz), 3.82 (1 H, hx, J = 6.4 Hz), 1.51 (2H, p, J =
7.1 Hz), 1.17 (3H, d, J= 6.7 Hz), 1.07-0.99 (1 H. m), 0.94 (3H, t, J=
7.4 Hz), 0.48 0.41 (21-1, m), 0.09-0.04 (2H, rn). F NMR (300 MHz, CDCI3): 6 -80.81 (2F, d, J = 73.3 Hz).

Mass Repticon Replicon Compound Melting Number Point( C) Spec ICSo M IC50 NM 'H NMR Data [M+H] 2-day 3-day 'H NMR (300 MHz, CDCI3): 6 7.72 (1 H. d, J = 8.8 Hz), 7.59 (2H, d, J
=8.8Hz),7.47(2H,d,J=8.8 Hz), 7.28 (1 H, d, J = 1.8 Hz), 7.12 (1 H, dd, J = 8.8, 1.8 Hz), 6.79 (1 H, br s), 6.56 (1 H, t, J = 74.4 1267 139-140 466.06 Hz), 4.35 (1 H, dq, J = 8.6, 6.7 Hz), 4_02 (2H, d, J = 6.7 Hz), 1.39 (3H, d, J = 6.7 Hz), 1.11-0.99 (2H, m), 0.64-0.43 (5H, m), 0.34-0.28 (1H, m), 0.09-0.04 (2H, m). F
NMR (300 MHz, CDC13): b -80.75 (2F, d, J = 75.3 Hz).
'H NMR (300 MHz, CDC13): S 7.73 (1 H, d, J = 8.5 Hz), 7.60 (2H, d, J
= 8.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.28 (1H, d, J = 1.8 Hz), 7.12 (1 H, t, J= 8.5, 1.8 Hz), 6.76 (1 H, br s), 6.56 (1 H, t, J = 74.4 Hz), 1268 145-146 454.30 ** 4.89 (1 H, hx, J = 6.4 Hz), 4.02 (2H, d, J = 6.7 Hz), 1.74-1.59 (2H, m), 1.30 (3H, d, J= 6.1 Hz), 1.11-1.00 (1 H, m), 0.97 (3H, t. J = 7.4 Hz), 0.49-0.43 (2H, m), 0.09-0.04 (2H, m).t9F NMR (300 MHz, CDCI3): 6 -80.75 (2F, d, J 73.3 Hz).
1269 112 461.4 ***
1270 158 475.5 ***
1271 192 503.5 ***
1272 199 515.6 *"*
1273 212 519.5 **
1274 139 505.5 ***
1275 115 484.5 *" *
1276 214 485.4 ***
1277 208 473.5 "**
1278 181 489.5 ***
1279 205-207 473_43 ***
1280 175-176 490.35 ***
(M-H+) 1281 168-169 500.47 ***
1282 196-197 486.43 '**
1283 169-170 486.42 ** `
(M-H+) 1284 154-155 498.31 **~

Compound Melting Mass Replicon Replicon Number Point ( C) Spec ICSo pM IC50 NM H NMR Data [M+H] 2-day 3-day (M-H+) 1285 168-170 472.39 (M-H+) 1286 161-163 486.43 ***

1287 141-143 498.27 ***
(M-H+) 1288 211-213 485.42 **' 1289 178-185 478.32 (ES-) 1290 172-174 444.39 (ES-) 1291 177-178 430.4 ***
1292 202-203 430.4 "**
1293 193-194 430.4 *'*
1294 155-157 444.4 ***
1295 174-175 444.4 ***
1296 170-171 444.4 **
1297 163-165 446.4 1298 178-180 446.4 1299 150-152 448.4 **
1300 201-203 432.31 ***
1301 216-218 431.37 ***
1302 226-227 417.4 **
1303 215-216 417.3 **
1304 209-211 415.3 1305 443.4 ***
1306 155-160 516.5 **
1307 115-119 529.5 1308 109-110 497.7 ***
1309 210-212 500.6 ***
1310 129-131 374.4 1311 205-207 346.4 ***
1312 180-185 458.43 *õ*
(ES-) 1313 155-160 448.07 "**
1314 88-90 498.5 ***
1315 125-130 502.5 Compound Melting Mass Replicon Replicon Spec ICSo }~M IC50 NM 'H NMR Data Number Point ( C) [M+H] 2-day 3-day 1316 110-112 472.5 1317 122-125 472.5 1318 130-134 484.5 1319 108-113 460.5 *"*
1320 98-101 474.5 ***
1321 83-87 504.6 1322 112-115 483.5 1323 148-150 432.4 1324 227-229 433.4 1325 195-198 417.4 ***
1326 246-248 431.4 1327 93 487.5 1328 162 510.5 1329 98 511.4 Compound Melting Mass Spec Replicon IC50 iH NMR Data Number Point ( C) [M+H] pM 3-day 2129 175-180 472.4 (M-1) 2130 180-182 450.2 2131 521.1 *
2132 541.2 "
2133 221-227 445.4 2134 185-190 446.4 2135 180-185 444.3 (M-1) 2136 'H NMR (CDCI3, 300MHz), 67.57 (d, J=8.7Hz, 2H), 7.47 (d, J=9.OHz, 2H), 7.37 (d, J=6.6Hz, 1 H), 7.18 (d, J=1.5Hz, 1 H), 6.97 (dd, J=6.6Hz and 1.5Hz, 1H), 6.73 (s, 1 H), 5.09-5.03 (m, 1 H), 4.01 (d, J=4.8Hz, 2H), 3.90 (s, 404.2 3H), 1.33 (d, J=4.8Hz, 6H), 1.07-1.04 (m. I H), 0.43 (q, J=6.9Hz, 135-137 2H), 0.07 (q, J=3.6Hz, 2H).

Compound Melting Mass Spec Replicon ICSO 'H NMR Data Number Point ( C) [M+H] uM 3-day 2137 'H NMR (CDCI3, 300MHz), 67.54 (d, J=8.7Hz, 2H), 7.46 (d, J=8.7Hz, 2H), 7.36 (d. J=9.DHz, 1H), 7.18(d, J=2.4Hz, 1H), 6.97 (dd, J=6.6Hz and 1.5Hz, 14-t), 6.73 (s, 1 H), 4.01 (d, J=6.6Hz, 2H), 3.89 (s, 3H), 1.55 (s, 9H), 440.1 (M+Na) 1.07-1.02 (m, 1H), 0.43 (q, J=6.9Hz, 2H), 0.05 (q, J=3.6Hz, 176-177 ** 2H)_ 2138 'H NMR (CDCI3, 300MHz), 67.66.
(d, J=8.7Hz, 2H), 7.46 (d, J=8.7Hz, 2H), 7.36 (d, J=9.OHz, 1 H), 7.17 (d, J=2.4Hz, 1 H), 6.97 (dd, J=9.OHz and 2.1 Hz, 1 H), 6.72 (s, 1 H), 5.07-5.03 (m, 1 H), 4.11 (q, J=6.9Hz, 2H), 4.00 (d, J=6.6Hz, 2H), 1.46 (t, J=7.2Hz, 418.1 3H), 1.32 (d, J=6.3Hz, 6H), 1.09-1.01 (m, 1 H), 0.48-0.40 (m, 2H), 181-182 0.08-0.01 (m, 2H).
2139 'H NMR (DMSO, 400MHz), 68.77 (s, 1 H), 7.65 (d, J=8.8Hz, 1 H), 7.59 (d, J=8.4Hz, 2H), 7.45 (d, J=8.4Hz, 2H), 7.04 (d, J=2.OHz, 1 H), 6.94 (dd, J=9.2Hz and 2.4Hz, 1 H), 6.30 (t, J=8.8Hz, 1 H), 4.10-4.07 (m, 4H), 3.05 (q, J=6.8Hz, 2H), 1.47-1.43 (m, 2H), 417.1 1.37 (t, J=6.8Hz, 3H), 0.89-0.85 (m, 4H), 0.31-0.27 (m, 2H), 0.04-185-186. 0.00 (m, 2H).
2140 'H NMR (CDCl3, 400MHz), 67.58-7.51 (m, 3H), 7.43 (d, J=8.4Hz, 2H), 7.18 (d, J=2.4Hz, 1 H), 6.93 (dd, J=9.2Hz and 2.4Hz, 1 H), 6.72 (s, 1 H), 5.09-392.3 5.03 (m. I H), 4.69-4.62 (m. 1 H), 3.89 (s, 3H), 1.59 (d, J=7.2Hz.
169-170 x 6H), 1.33 (d, J=6.OHz, 6H).
2141 'H NMR (CDCI3i 300MHz), 67.52 (dd, J=8.7Hz and 2.1 Hz, 2H), 7.37 (dd, J=7.2Hz and 1.8Hz, 2H), 7.32 (d, J=9.OHz, 1 H), 7.17 (d, J=2.1Hz, 1H). 6.99 (dd, J=9.OHz and J=2.4Hz, 1 H), 6.81 398.2 (s, 1 H), 4.18-4.08 (m, 4H), 3.25 (q, J=7.5Hz, 2H), 1.49-1.42 (m, 201-202 ** 6H), 1.36 (t, J=7.2Hz, 3H).

Compound Melting Mass Spec Replicon IC50 i Number Point ( C) [M+H] NM 3-day H NMR Data 2142 'H NMR (CDC13, 300MHz), 67.52 (d, J=8.1 Hz, 2H), 7.47-7.38 (rn, 3H), 7.18 (s, 1 H), 6.98 (d, J=9.OHz, 1 H), 6.90 (s, 1 H), 4.19-4.04 (m, 4H), 3.23 (t, J=7.2Hz, 412.2 2H), 1.99-1.83 (m, 2H), 1.46 (t, J=6.6Hz, 3H), 1.36 (t, J=7.2Hz, 164-165 ** 3H), 1.06 (t, J=7.2Hz, 3H).
2143 'H NMR (CDC13, 400MHz), 67.52 (d, J=8.7Hz, 2H), 7.42 (d, J=8.7Hz, 2H), 7.33 (d, J=9.OHz, 1 H), 7.17 (d, J=2.1 Hz, 1 H), 7.03 (s, I H), 6.99 (dd, J=9.0Hz and 2.4Hz, 1 H), 4.19-4.08 (m, 4H), 2.66-2.27 (m, I H), 1.46 (t, 410.0 J=6.9Hz, 3H), 1.36 (t, J=7.2Hz, 3H), 1.27-1.23 (m, 2H), 1.08-1.03 204-205 ** (m, 2H).
2144 'H NMR (CDC13, 400MHz), 57.70 (br, 1 H), 7.52 (d, J=8.OHz, 2H), 7.45 (d, J=B.OHz, 2H), 7.38 (d, J=8.8Hz, 1 H), 7.17 (d, J=2.OHz, 1 H), 6.99 (dd, J=9.2Hz and 2.4Hz, 1H), 4.12 (q, J=7.2Hz, 2H), 4.01 (d, J=6.4Hz, 2H), 3.37 (q, J=6.8Hz, 2H), 1.47 (t.
403.3 J=6.8Hz, 3H), 1.24 (t, J=7.2Hz, 3H), 1.10-1.04 (m, 1 H), 0.45 (q, 167-169 * J=4.2Hz, 2H), 0.09-0.03 (m, 2H).
2145 'H NMR (CDCi3, 400MHz), 67.50-7.43 (m, 4H), 7.38 (d, J=9.2Hz, 1H), 7.22 (s, 1H), 7.17 (d, J=2.4Hz, 1 H), 6.99 (dd, J=9.2Hz and 2.4Hz, IH), 4.12 (q, J=6.8Hz, 2H), 4.04-3.97 (m, 3H), 1.47 (t, J=7.2Hz, 31-1), 1.21 (d, 417.3 J=6.4Hz, 6H), 1.06-1.04 (m, 1H), 0.42 (q, J=6.4Hz, 2H), 0.06 189-192 (q, J=4.8Hz, 2H).
2146 ~H NMR (CDC13, 400MHz), 57.57-7.44 (m, 4H), 7.18-7.17 (m, 2H), 6.94 (dd, J=9.2Hz and 2.4Hz, 1 H), 6.70 (s, 1 H), 5.06-5.00 (m, 1 H), 4.73-4.66 (m, I H), 406.3 4.11 (q, J=6.8Hz, 2H), 1.61 (d, J=6.8Hz, 6H), 1.46 (t, J=7.2Hz, 162-163 * 3H), 1.31 (d, J=6.4Hz, 6H).
2147 182-184 360.2 ***
2148 142-146 416.4 ***
2149 134-136 346.4 ***

Compound Melting Mass Spec Replicon IC50 1 Number Point ( C) [M+H] NM 3-day H NMR Data 2151 'H NMR (CDC13r 400MHz), 61.33 (d, 6H), 1.73-1.95 (m, 2H), 2.26-2.38 (m, 2H), 2.71-2.85 (m, 2H), 4.90-5.10 (m, 2H), 6.72 (s, br, 1 H), 7.08(t, 1 H), 7.14-7.18 (dd, 1 H), 7.43 (d, 2H), 7.56 (s, 1 H), 7.59 (t, 2H), 7.79 (d, 1 H), 8.60 (d, 202-204 468.1 2H) 2152 164-168 ' 393.3 **`
2153 207-211 392.3 ***
2154 185-195 470.3 (M-1) 2155 'H NMR (CDCI3, 300MHz), 67.57 (d, J=8.4Hz, 2H), 7.48 (d, J=8.7Hz, 2H), 7.31 (d, J=9.OHz, 1H), 7.17 (d, J=1.8Hz, 1H), 6.99 (dd, J=9.0Hz and 1.8Hz, 1 H), 378 2 6.76 (s, IH), 4.26 6 q, J=6.9Hz, 2H b, 4.19-4.07 (m, 4H), 1.46 (t, 194-195 J=6.9Hz, 3H), 1.37-1.32 (m, 6H).
2156 'H NMR (CDCI3, 300MHz), 57.57 (d, J-8.7Hz, 2H), 7.48 (d, J=8.7Hz, 2H), 7.31 (d, J=9.OHz, 1 H), 7.17 (d, J=2.1 Hz, 1 H), 6.97 (dd, J=8.7Hz and 2.4Hz, 1 H), 392.1 6.71 (s, 1 H), 5.07-5.03 b m, I H b,.
4.19-4.07 (m, 4H), 1.46 (t, 179-180 J=6.9Hz, 3H), 1.37-1.32 (m, 9H).
2157 'H NMR (CDCI3, 400MHz), 67.52 (d, J=8.4Hz, 2H), 7.44 (d, J=8.4Hz, 2H), 7.32 (d, J=9.2Hz, 1 H), 7.17-7.13 (m, 2H), 6.98 (dd, J=8.8Hz and 2.4Hz, 1 I-t), 5.10 (br, 1 H), 4.17-4.10 (rn 4H), 3_32 6 q, 377.2 J=7.2Hz, 2H b, 1.47 (t, J=7.2Hz, 3H), 1.34 (t, J=7.2Hz, 3H) 1.20 (t, 223-224 * J=7.2Hz, 3H).
2158 'H NMR (CDCl3, 300MHz), 57.72 (br, I H), 7_52-7.42 (m, 4H), 7.33 (d, J=9.OHz, 1 H), 7.17 (d, J=2.4Hz, 1 H), 6.99 (dd, J=8.7Hz and 2.1 Hz, 1 H), 4.18-4.08 (m, 391.2 4H), 4.06-3.97 b m, 1 H 8, 1.47 (t, J=6.9Hz, 3H), 1.35 (t, J=7.2Hz, 193-194 3H), 1.23 (d, J=6.6Hz, 6H).

Compound Melting Mass Spec Replicon ICSa 'H NMR Data Number Point ( C) [M+H] pM 3-day 2159 'H NMR (CDCI3, 400MHz), 67.54-7.52 (m, 3H), 7.37 (d, J=8.4Hz, 2H), 7.30 (s, 1 H), 7.15 (d, J=2.4Hz, 1 H), 6.94 (dd, J=8.8Hz and 2.4Hz, 1 H), 5.25 (br, 1 H), 4.72-4.65 (m, 1 H), 4.11 b q, J=6.8Hz, 2H 8, 3.24 (t, J=7.2Hz, 405.3 2H), 1.62-1.52 (m, 8H), 1.47 (t, J=7.2Hz, 3H), 0.95 (t, J=7.6Hz, 199-200 * 3H).
2160 'H NMR (CDCI3i 300MHz), 67.57 (d, J=8.4Hz, 2H), 7.47 (d, J=8.7Hz, 2H), 7.37 (d, J=9.OHz, 1 H), 7.17 (d, J=2.4Hz, 1 H), 6.97 (dd, J=9.0Hz and 2.4Hz, 1H), 6.75 (s, 1 H), 4.26 (q, J=7.2Hz, 2H), 4.11 (q, J=7.2Hz, 2H), 4.00 (d, J=6.6Hz, 2H), 1.46 (t, 404.3 J=7.2Hz, 3H), 1.34 (t, J=6.9Hz, 3H), 1.09-1.01 (m, 1 H), 0.47-226-227 0.40 (m, 2H), 0.08-0.01 (m, 2H).
2161 177-183 456.3 (M-1) ***
2162 210-212 504.3 ***
2163 136-138 505_3 ***
2164 160-164 442.3 (M-1) ***
2165 'H NMR (DMSO, 400MHz), 69.69 (s, 1H), 7.67 (d, J=8.4Hz, 2H), 7.60 (d, J=8.8Hz, 1H), 7.49 (d, J=8.8Hz, 2H), 7.05 (d, J=2.OHz, 1 H), 6.94 (dd, J=8.8Hz and 2.4Hz, 1 H), 4.16 (q, J=6.4Hz, 406.2 2H), 4.07 b q, J=6.8Hz, 2H 5, 1.49 (s> 9H), 1.34 (t, J=6.8Hz, 179-180 3H), 1.18 (t, J=6.8Hz, 3H).
2166 'H NMR (CDCI3, 300MH7-), 67.54 (d, J=8.4Hz, 2H), 7.46 (d, J=8.4Hz, 2H), 7.36 (d, J=9.OHz, 1 H), 7.17 (d, J=2.7Hz, 1 H), 6.97 (dd, J=8.7Hz and 2.1 Hz, 1 H), 6.65 (s, 1 H), 4.11 (q, J=6.9Hz, 2H), 3_99 (d, J=6.6Hz, 2H), 1_55 430_1 (s, 9H), 1.46 (t, J=6.9Hz, 3H), 1.08-1.01 (m, 1 H), 0.47-0.40 (m, 181-182 ** 2H), 0.09-0.02 (m, 2H).
2167 185-187 538.3 ***
2168 148-149 539.4 ***
2169 197-198 555.4 ***
2170 141-143 513.4 ***
2171 202-204 429_3 ***
2172 179-183 421.3 **

Compound Melting Mass Spec Replicon IC60 INumber Point ( C) [M+H] pM 3-day H
NMR Data 2173 190-194 420.3 2174 161-166 442.3 (M-1) ***
2175 193-195 502.3 ***
2176 187-189 502.3 2177 167-196 476.3 2178 235-237 530.3 ***
2179 195-197 504.4 ***
2180 203-205 488.3 ***
2181 530.4 207-209 (M-1) **"
2182 202-204 494.3 ***
2183 225-227 474.9 ***
2184 220-222 503.4 **"
2185 212-215 487.4 ***
2187 = 'H NMR (CDCI3, 400MHz), 58.08 (d, J=7.6Hz, 2H), 7.67-7.65 (m, 3H), 7.19 (s, 1H), 6.99 (d, J=8.8Hz, 1 H), 4.94-4.88 (m, 3H), ?250. 4.14 (q, J=6.8Hz, 2H), 2.80-2.72 395.8 (m, 2H), 2.40-2.35 (m, 2H), 2.01-(decompos 1.83 (m, 2H), 1.50 (t, J=6.8Hz, ed) ** 3H).
2188 'H NMR (CDCI3, 400MHz), b 8.03 (d, J=8.4Hz, 2H), 7.67-7.63 (m, 3H), 7.18 (d, J=1.6Hz, 1 H), 6.99 (dd, J=8.8Hz and 2.0Hz, 1 H), 4.91-4.87 (m, I H), 4.35 (d, J=7.6Hz, 1 H), 4.14 (q, J=6.8Hz, 2H), 3.61-3.56 (m, 1H), 2.77-2.72 (m, 2H), 2.38-2.32 (m, 2H), 437.9 1.96-1.82 (m, 2H), 1.49 (t, J=7.2Hz, 3H), 1.16 (d, J=6.8Hz, 210-212 ** 6H).
2189 'H NMR (CDCI3, 400MHz), 6 8.01 (d, J=8.OHz, 2H), 7.67-7.63 (m, 3H), 7.18 (s, 1 H), 6.99 (d, J=8.8Hz, 1 H), 4.94-4.85 (m, 1 H), 4.45 (t, J=6.4Hz, 1 H), 4.14 (q, J=7.2Hz, 2H), 3.03 (q, J=6.4Hz, 2H), 2.81-2.70 (m, 2H), 2.39-2.32 (rn, 2H), 1.99-1.80 (m, 2H), 1.62-1 _54 (m, 2H), 1 _49 (t, J=7.2Hz, 438.0 3H), 0.95 (t, J=7.2Hz, 3H).
170-171 **

Compound Melting Mass Spec Replicon IC50 'H NMR Data Number Point ( C) [M+H] pM 3-day 2190 'H NMR (CDCI3, 400MHz), 6 8.03 (d, J=8.4Hz, 2H), 7.67-7.63 (m, 3H), 7.17 (d, J=1.6Hz, 1 H), 6.98 (dd, J=8.8Hz and 2.0Hz, 1H), 4.93-4.85 (m, 1 H), 4.31 (d, J=8.4Hz, 1 H), 4.13 (q, J=7.2Hz, 2H), 3.40-3.33 (m, 1 H), 2.78-2.68 (m, 2H), 2.38-2.32 (m, 2H), 2.01-451.9 1.81 (m, 2H), 1.57-1.42 (m, 5H), 1.12 (d, J=7.2Hz, 3H), 0.82 (t, 191-193 * J=7.2Hz, 3H).
2191 'H NMR (CDCI3, 400MHz), 6 8.00 (d, J=8.0Hz, 2H), 7.67-7.62 (m, 3H), 7.17 (d, J=1.6Hz, 1 H), 6.99 (dd, J=8.8Hz and 2.0Hz, 1 H), 4.91-4.84 (m, 1H), 4.69 (d, J=8.8Hz, 1 H), 4.12 (q, J=6.8Hz, 2H), 3.92-3.86 (m, 1 H), 2.79-2.69 (m, 2H), 2.38-2.32 (m, 2H), 2.26-2.18 (m, 2H), 1.98-1.82 (m, 4H), 1.80-1.61 (m, 4H), 1.50 (t, 185-187 450.0 J=7.2Hz, 3H).
2192 'H NMR (CDCI3, 400MHz), 6 8.00 (d, J=B.OHz, 2H), 7.67-7.63 (m, 3H), 7.18 (s, 1 H), 6.99 (d, J=8.8Hz, 1 H), 4.94-4.85 (m, 1 H), 4.45 (d, J=6.8Hz, 1 H), 4.14 (q, J=7.2Hz, 2H), 3.72-3.67 (m, 1 H), 463.9 2.80-2.70 (m, 2H), 2.38-2.32 (m, 2H), 1.98-1.80 (m, 4H), 1.65-* 1.43 (m, 9H).
2193 1H NMR (CDCI3, 400MHz), 6 8.02.
(d, J=8.4Hz, 2H), 7.67-7.59 (m, 3H), 7.19 (d, J=2.0Hz, 1H), 7.00 (dd, J=8.8Hz and 2.0Hz, 1 H), 4.94-4.85 (m,1 H), 4.40-4.37 (q, =
J=5.2Hz, 1 H), 4.14 (q, J=6.8Hz, 410.2 2H), 2.82-2.73 (m, 5H), 2.36 (q, J=8.4, 2H), 2.01-1.83 (m, 2H), 218-221 * 1.57 (t, J=7.2Hz, 3H).
2195 203-210 431.3 ***
2196 203-210 431.3 ***
2197 180-182 525.46 ***
2198 197-200 524.37 ***
2199 160-163 511.44 ***
2200 196-198 510.43 ***
2201 146-147 486.4 ***
2202 152-153 474.4 ***
2203 215-216 485.4 ***
2204 164-165 500.4 ***

Compound Melting Mass Spec Replicon IC50 'H NMR Data Number Point ( C) [M+H] NM 3-day 2205 'H NMR (300 MHz, CDCI3): ^
7.62 (1 H, d, J = 8.8 Hz), 7.58 (2H, d, J = 8.5 Hz). 7.43 (2H, d, J
=8.5Hz),7_20(1H,d,J=2.0 Hz), 6.95 (1 H, dd, J = 8.8, 2.0 Hz), 6.81 (1 H, br s), 4.94 (1 H, p, J = 8. 7 Hz), 4.40 (1 H, q, J = 0.7 Hz), 4.13 (2H, q, J = 7.0 Hz), 2.89-2.76 (2H, m), 2.39-2.28 (2H, m), 2.00-1.50 (7H, m), 1.25-1.12 (2H, m), 1.17 (3H, s), 1.12 (3H, 179-181 510.4 (M-1) "** s), 0.88 (3H, s).
2206 'H NMR (300 MHz, CDCI3): ^
7.63 (1 H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.43 (2H, d, J
= 8.5 Hz), 7.20 (1 H, d, J = 2.0 Hz),6.95(1H,dd,J=8.8,2.0 Hz), 6.76 (1 H, br s), 5.11 (1 H, p, J=5.1 Hz),4.94(1H, p, J =8.5 Hz), 4.13 (2H, q, J = 7.0 Hz), 2.90-1.65 (7H, m), 1.48 (3H, t, J
7.0 Hz), 1.25 (3H, s), 1.17 (3H, d, 138-139 529 J = 7.6 Hz), 1.00 (3H, s).
- 2207 'H NMR (300 MHz, CDC13): ^
7.62 (1 H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.5 Hz), 7.50 (2H, d, J
= 8.5 Hz), 7.20 (1 H, d, J = 2.0 H z), 6.95 (1 H, dd, J = 8.8, 2.0 Hz), 6_83 (1H, br s), 4_96 (1H, narrow m), 4.13 (2H, q, J = 7.0 Hz), 2.88-2.77 (2H, m), 2.40-2.29 166-168 510.4 ** (2H, m), 2.17-1.50 (19H, m).
2208 foam 482.1 2209 foam 482.1 '**
2210 'H NMR (300 MHz, CDCI3):
^0.27-0.37(m, 1 H), 0,44-0.65(m, 3H), 0.98-1.11 (m, 1 H), 1.40 (d, 3H), 1.69-1.97 (m. 2H), 2.25-2.38 (m, 2H), 2.69-2.87 (m, 2H), 4.29-4.41 (m, 1H), 4.88-5.04 (m, 1H), =
6.76 (s, br, 1 H), 7.07 (t, 1 H), 7.14-7.19 (dd, 1 H), 7.40-7.46 (m, 2H), 7.53-7.62 (m, 3H), 7.79 (d, 194-196 494.4 *** 1 H), 8.59 (d, 2H) 2211 119-120 510.4 ***
2212 151-153 448.4 "**
2213 202-204 472.4 2214 213-215 472.4 "**
2215 80-82 486.4 *"*
2216 498.4 Compound Melting Mass Spec Replicon IC50 'H NMR Data Number Point ( C) (MtH) pM 3-day 2217 'H NMR (300 MHz, CDCI3):
^ 0.26-0.35(m, 1 H ), 0.44-0.73(m, 5H), 0.96-1.10 (m, 3H), 1.40 (d, 3H), 3.36-3.45 (m, 1 H), 4.30-4.41 (m, 1 H), 6.77 (s, br, 1 H), 7.06 (t, 1 H), 7.13-7.17 (dd, 1 H), 7.51 (d, 1 H), 7.56-7.64 (q, 4H), 7.76 (d, 154-156 480.1 *** 1 H), 8.59 (d, 21-1) 2218 233-235 446.1 **
2219 241-244 460.2 ***
2220 189-192 474.2 ***
2221 218-220 474.2 ***

(decomp.) 472.2 2223 1H NMR (CDCI3, 300MHz), b 8.06 (d, J=8.4Hz, 2H), 7.68-7.65 (m, 3H), 7.18 (d, J=2.1 Hz, 1 H), 6.99 (dd, J=8.4Hz and 1.8Hz, 1 H), 4.93-4.87 (m, 2H), 4.18-4.11 (m, 2H), 2.79-2.71 (m, 2H), 2.41-2.35 434.2 (M-1) (m, 3H), 1_97-1.82 (m, 2H), 1.49 (t, J=6.9Hz, 3H), 0.71-0.68 (m, 195-197 **" 4H).
2224 161-163 480.2 ***
2225 174-175 494.2 **`
2226 163-164 494.2 ***
2227 174-176 492.2 ***
2228 208-210 492.2 **
2229 192-195 460.2 ***
2230 220-222 474.2 ***
2231 259-261 488.2 2232 178-180 488.2 ***
2233 239-240 486.2 ***
2234 120-123 488.3 ***
2235 140-147 423.2 (M-1). **
2236 glass 516.5 (M-1) ***
2237 178 - 179 504.2 ***
2238 glass 536.4 (M-1) ***
2239 209-211 454.5 ***
2240 91-93 482.5 ***' 2241 122-124 470.4 2242 186-188 466.4 ***

Compound Melting Mass Spec Replicon IC50 'H NMR Data Number Point ( C) [M+Hj pM 3-day 2243 480.4 2244 'H NMR (CDCI3, 400MHz), 57.65 (d, J=8.4Hz, 1 H), 7.55-7.52 (m, 4H), 7.24 (d, J=1.6Hz, 1H), 6.98 (dd, J=8.8Hz and 2.0Hz, 1 H), 4.94-4.89 (m, 1 H), 4.14 (q, J=6.8Hz, 2H), 3.59 (b, 2H), 3.34 (b, 2H), 2.88-2.83 (m, 2H), 2.36-2.29 (m, 2H), 1.97-1.80 (m, 2H), 1.49 (t, J=6.8Hz, 3H), 1.43-1.18 178-180 416.2 (m, 6H).
2245 'H NMR (CDCI3, 400MHz), 67-90 (d, J=8.4Hz, 2H), 7.64 (d, J=8.8Hz, 1H), 7.56 (d, J=8.OHz, 2H), 7.19 (s, 1 H), 6.97 (dd, J=8.8Hz and 2.0Hz, 1 H), 5.97 (d, J=7.6Hz. 1H), 4.94-4.90 (m, 1H), 4.35-4.30 (m, 1 H), 4.13 (q, J=6.8Hz, 2H), 2.80-2.74 (m, 2H), 402.1 2.37-2.33 (m, 2H), 1.95-1.79 (m, 2H), 1.49 (t, J=6.8Hz, 3H), 1.30 235-236 ** (d, J=6.8Hz, 6H).
2246 'H NMR (CDCI3, 300MHz), 67.65 (d, J=8-7Hz, I H), 7.59-7.52 (m, 4H), 7.23 (d, J=2.1 Hz, 1 H), 6.98 (dd, J=8.7Hz and 2.1 Hz, 1 H), 4.94-4.88 (m, 1 H), 4.14 (q, J=6.9Hz, 2H), 3.79-3.54 (m, 8H), 2.88-2.80 (m, 2H), 2.37-2.29 (m, 2H), 1.98-1.80 (m, 2H), 1.49 (t, 201-202 ** J=6.9Hz, 3H).
2247 'H NMR (CDCI3, 400MHz), 67.77 (d, J=8.OHz, 2H), 7.65 (d, J=8.8Hz, 1 H), 7.53 (d, J=8.0Hz, 2H), 7.19 (d, J=1.6Hz, 1H), 6.98 (dd, J=8.8Hz and 2.0Hz, 1H), 4.93-4.88 (m, 1 H), 4.33 (t, J=6.8Hz, 4H), 4.14 (q, J=6.8Hz, 400.2 2H), 2.82-2.76 (m, 2H), 2.44-2.30 (m, 4H), 1.95-1.80 (m, 2H), 1.49 154-156 ** (t, J=6.8Hz, 3H).
2248 'H NMR (CDCI3, 400MHz), 87_89 (d, J=8.OHz, 2H), 7.64 (d, J=8.8Hz, 1 H), 7.56 (d, J=8.OHz, 2H), 7.19 (d, J=1.6Hz, 1 H), 6.97 (dd, J=8.4Hz and 2.0Hz, 1H), 6.29 (d, J=7.6Hz, 1 H), 4.94-4.89 (m, 1H), 4.64-4.62 (m, 1H), 4.13 (q, J=6.8Hz, 2H), 2.80-2.74 (m, =
414.2 2H), 2.48-2.47 (m, 2H), 2.38-2.31 (m, 2H), 2.02-1.78 (m, 6H) 1.49 217-218 ** (t, J=6.8Hz, 3H).
2252 105-109 419.9 ***

Compound Melting Mass Spec Replicon ICSa 'H NMR Data Number Point ( C) [M+H] pM 3-day 2253 261-265 304.6 **

(decomp.) 515.3 ***
2255 228-231 426.2 ***
2256 194-196.5 440.3 2257 208-210.5 438.3 ***
2258 182-187.5 440.3 **
2259 62-65 456.3 ***
2260 155-157 486.3 ***
2261 glass 494.4 **
2262 glass 496.4 ***
2263 'H NMR (300 MHz, CDCI3):
^1.15 (d, 6H), 1.70-1.92 (m, 2H), 2.31-2.45 (m, 2H), 2.64-2.81 (m, 2H), 3.52-3.63 (m, 1 H), 5.05-5.16 (m, 1H), 6.62 (d, 1H), 7.15-7.25 (m, 2H), 7.47-7.52 (m, 2H), 7.56-7.61 (m, 2H), 7.70-7.75 (m, 2H), 223-224 503.4 *** 8.562 (d, 2H), 9.03 (s, br, 1 H) 2264 196-201 373.0 *
2265 168-173 443.5 *
2266 298-223 473_5 2267 206-211 465.5 2268 172-178 485 **`
2269 442.3 2270 228-233 484.2 ***
2278 glass 496.1 '**
2279 200-205 494.1 2280 155-160 458,5 2281 180-185 456.5 *
2282 181-185 470.5 ***
2283 198-203 459.5 ***
2284 glass 514.2 (M-1) ***
2285 glass 518.2 ***
2286 191-193 389.0 Compound Melting Mass Spec Replicon ICso ~
Number Point ( C) [M+H] pM 3-day H NMR Data glass 488.3 ***
2288 216-217 475.4 ***
2289 145-150 490.5 *
2290 195-200 490.5 *
2291 240-245 470.5 2292 195-196 475.1 **
2298 172-177 496.5 2299 146-148 539.4 ***
2300 186-189 484.6 **
2301 241-243 481.5 **' 2302 197-202 467.4 2303 'H NMR (CDCI3, 300MHz), 67.69-7.64 (m, 3H), 7.52 (d, J=8.1 Hz, 2H), 7.22 (d, J=2.1 Hz, 1 H), 6.97 (dd, J=8.7Hz and 2.1 Hz, 1 H), 4.94-4.88 (m, 1 H), 4.14 (q, J=6.9Hz, 2H), 2.73-3.50 414.3 (m, 4H), 2.87-2.79 (m, 2H), 2.35-2.32 (m, 2H), 1.97-1.83 (m, 6H), * 1.49 (t, J=6.9Hz, 3H).
2304 'H NMR (CDCI3, 300MHz), 67_65 (d, J=8.7Hz, 1 H), 7.57-7.50 (m, 4H), 7.23 (d, J=2.1 Hz, 1H), 6.98 (dd, J=8.7Hz and 2.1 Hz, 1 H), 4.91-4.88 (m, 1 H), 4.14 (q, J=7.2Hz, 2H), 3.75 (b, 2H), 3.43 428.2 (b. 21-1), 2.88-2.81 (m, 2H), 2.34-2.30 (m, 2H), 1.97-1.58 (m, BH), 1.49 (t, J=6.9Hz, 3H).
2305 glass 516.4 (M-1) 2306 glass 536.4 (M-1) **~
2307 509.3 444.4 78-80 (M-1) 2309 217-222 470.5 2310 178-183 496.5 ***
2311 172-175 468.2 *

Compound Melting Mass Spec Replicon IC50 'H NMR Data Number Point ( C) [M+H] pM 3-day 2313 glass 502.3 (M-1) ***
2314 glass 488.4 ***
2315 glass 488.5 ***
2316 glass 502.4 ***
2317 glass 474.8 ***
2318 199-201 500.1 (M-1) ***

(decomp.) 503.2 ***

(deomp.) 503.2 ***
2321 234-235 489.2 ***
2322 187-189 480.3 ***
2323 247-250 470.3 ***
2324 224-226 497.4 ***
2325 203-207 510 `**

142-144 462.4 ***
2327 496.4 (M-1) 153-155 ***

74-80 466.1 ***
2329 500.0 (M-1) 78-84 `

160-163 480.2 ***
2331 188-192 472.1 ***
2332 180-184 486.2 2333 198-202 460.2 **
2334 199-203 474.1 ***
2335 208-212 472.1 ***
2336 486.5 179-180 ***
2337 225-226 458.3 ***
2338 262-263 444.2 2339 165-165.5 502.0 ***
2340 186-187 506.5 ***
2341 93-95 469.4 ***
2342 163-165 498.6 ***

Compound Melting Mass Spec Replicon IC50 1 Number Point ( C) [M+H] NM 3-day H NMR Data 2343 174-175 490.5 2344 98-99 482.6 2345 498.5 166-167 (M-1) **
2346 177-178 476.6 ***
2347 glass 476.6 2348 glass 440.5 **
2349 183-184 476.3 "
2350 223-224 504.3 **
2351 500.3 180-181 (M-1) ***
2352 520.0 255-256 *
2353 148-149 498.6 ***
2354 217-219 483.7 2355 205-207 490-5 **
2356 200-201 472.4 (M-1) *
2357 181-182 456.4 (M-1) *
2358 194-196 458.3 (M-1) *
2359 234-236 486.5 **
2360 177-179 488.5 ***
2361 243-245 454.7 **`
2362.
260-262 448.5 *

225-227 462.7 250-251 476.6 *'*

202-204 474.6 241-243 490.6 ***

214-216 476.5 2368 178-182 460.6 2369 189-191 474.6 2370 177-179 502.6 Compound Melting Mass Spec Replicon ICso i Number Point ( C) [M+H] pM 3-day H NMR Data 2371 213-215 492.5 *"*
2372 225-227 518.6 2373 179-180 472.5 ***
2374 113-115 446.5 ***
2375 'H NMR (300 MHz, CDCI3):
^8.58 (d, 2H, J= 4.5 Hz), 7.79 (d, 1 H, J = 8.7 Hz), 7.51 (d, 1 H, J
= 8.7 Hz), 7.05-7.36 (m, 6H), 6.58 (s, 1H), 3.99 (d, 2H, J= 6.6 Hz), 3.20 (t, 2H, J = 7.8 Hz), 1.96 (m, 2H), 1.09 (t, 3H, J = 7.5 Hz), 1.04 (m, 1 H), 0.56 (m, 2H), 0.04 (m, 227-229 488.8 *"* 2H).
2376 181-183 494.6 ***
2377 166-168 488.6 ***
2378 179-180 499.8 2379 'H NMR (300 MHz, CDCI3): 0 8.58 (d, 2H, J = 4.5 Hz), 7.79 (d, I H, J = 8.4 Hz), 7.60 (d, 1 H, J =
1.5 Hz), 7.06-7.46 (m, 6H), 6.42 (s, 1 H), 4.85 (m, 1 H), 4.02 (t, 1 H, J = 8.1 Hz), 2.57-2.79 (m, 4t-i), 2.30-2.37 (m, 4H), 1.78-2.07 (m, 211-213 498.9 (M-1) 4H).
2380 221-223 502.9 218-221 488.0 ***

113-118 488.6 114-122 503.3 ***
2384 183-185 472.6 2385 211-213 470.4 2386 194-196 472.7 *
2387 222-224 484.4 2388 215-216 470.7 **"
2389 201-202 472.7 "
2390 234-238 487.0 ***
2391 222-224 488.9 ***

106-109 456.4 ***
2393 512.8 143-144 *'"*

Compound Melting Mass Spec Replicon IC50 1H NMR Data Number Point ( C) [M+H] NM 3-day 2394 203-204 488.2 **
2395 221-222 494.0 **"
2396 179-180 468.8 **' 2397 143-145 452.7 *
2398 glass 466.7 **

94-104 468.7 ***

193-196 442.7 **' 107-110 477.7 ***
2402 193-195 400.6 **
2403 189-191 414.6 *
2404 168-170 450.9 **
2405 173-175 456.9 2406 176-178 474.6 2407 210-212 436.9 2408 230-236 466.8 *
2409 168-174 438.7 **
2410 143-144 462.7 **
2411 91-92 492.7 **
2412 144-145 472.7 `**
2413 92-93 497.9 ***
2414 91-93 485.9 ***
2415 88-90 513.0 ***

215-219 477.7 118-120 477.8 ***

235-237 478.8 **

212-214 478.6 ***
2420 237-241 436.7 **
2421 211-215 450.8 **
2422 157-165 452.8 ***
2423 218-220 488.7 **

Compound Melting Mass Spec Replicon IC50 i Number Point ( C) [M+H] NM 3-day H NMR Data 2424 220-222 501.0 ***
2425 233-236 448.6 **
2426 243-246 478.9 **
2427 150-154 451.0 **
2428 216-222 477.1 **
2429 189-192 472.7 ***
2430 198-201 471.6 ***
2431 234-237 472.7 2432 478.9 *
2433 glass 478.7 ***
2434 'H NMR (300 MHz, CDCI3):
^0.67-0.76 (m, 2H), 0.96-1.05 (m, 2H), 1.27 (d; 6H), 3.33-3.42 (m, 1 H), 3.64-3.79 (m, 1 H), 3.82 (d, br, I H), 6.68 (d, 2H), 7.05 (t, 1H), 7.10-7.13 (dd, 1H), 7.45-7.53 (m, 3H), 7.72 (d, 1 H), 8.458 215-217 410.1 '** (d, 2H) 108-113 467.0 *
2436 'H NMR (300 MHz, CDCI3):
^7.78-7.74 (2H, m), 7.56 (2H, d, J=6.9 Hz), 7.44 (2H, d, J=6.9 Hz), 7.33-7.29 (2H, m), 6.77 (1H, br s), 4.99 (1H, 5, J=9.3 Hz), 4.37-4.33 (1H, m), 2.89-2.82 (2H, m), 2.39-2.33 (2H, m), 2.02-1.76 (2H, m), 1.39 (3H, d, J=6.6 Hz), 1.12-0.98 (1 H, m), 0.62-0.44 (3H, m), 0.36-0.27 (1H, m) 186-190 451.3 ***

234-237 485.3 209-211 501.3 ***

152-154 450.1 '**

434.8 ***

228-230 448.9 *"*

Compound Melting Mass Spec Replicon IC50 'H NMR Data Number Point ( C) [M+H] uM 3-day 208-210 471.3 ***

105-110 477.3 2445 94-95 487.9 ***
2446 82-83 501.8 ***
2447 89-90 481.8 2448 192-195 487.9 2449 209-210 467.0 2460 211-213 490.8 (M-1) **
2451 194-196 424.6 (M-1) 2452 267-269 459.7 2453 165-169 486.6 2454 182-185 501.8 72-84 511.0 *' *

176-178 485.0 '**

152-155 504.7 ***
2458 209-211 446.0 *`*
2459 205-207 458.9 ***
2460 200-202 469.9 ***
2461 230-232 472.1 2462 218-219 471.4 2463 228-230 483.6 2464 222-223 497.6 **"
2465 227-229 485.6 2466 144-145 499.9 *`*
2467 89-90 442.8 ***
2468 153-154 441.6 2469 210-212 423.5 *"*
2470 187-189 423.5 '**
2471 171-176 436.5 ***
2472 191-194 436.4 ***
2473 87-88 469.4 2474 91-92 443.4 *"*

Compound Melting Mass Spec Replicon IC50 ~H NMR Data Number Point ( C) [M+H] pM 3-day 2475 90-91 463.3 **
2476 228-229 450.6 ***
2477 178-179 477.8 ***
2478 157-159 451.8 ***
2479 102-103 527.8 ***
2480 221-222 474.1 ***
2481 193-194 440.0 ***
2482 212-214 442.4 ***

92-98 485.0 ***
2484 207-208 502.0 ***
2485 222-224 383.1 ***
2486 239-241 469.0 ***
2487 199-201 528.9 ***
2488 226-228 528.8 ***
2489 166-169 527.7 ***
2490 114-115 508.0 ***
2491 177-178 516.0 ***
2492 215-216 502.0 *
2493 170-171 507.9 ***
2494 466.0 ***
2495 159-160 477.6 (M-1) *"*
2496 195-196 465.8 ***
2497 195-196 453.9 ***
2498 452.8 ***
2499 475.4 226-228 (M-1) **
2500 524.4 ***
2501 516.0 *
2502 529.9 **
2503 497.9 2504 82-88 460.9 ***
2505 203-204 410.1 ***
2506 214-215 487.6 ***
2507 222-223 501.9 ***
2508 203-205 488.1 ***
2509 126-130 522.0 *"*

Compound Melting Mass Spec Replicon IC.50 1H NMR Data Number Point ( C) [M+H] pM 3-day 2510 165-169 477.7 (M-1) 2511 452.9 ***

2512 453.9 *'*

2513 206-208 425.7 **
2514 150-152 416.1 **
2515 410.1 **"`

2516 201-203 436.0 **"
2517 469.9 190-191 [M-1] ***
2518 486.0 140-142 (M-1) ***
2519 472.0 204-207 (M-1) ***
2520 469_9 170-171 (M-1) ***
2521 485.9 198-200 (M-1) ***
2522 248-258 440.0 ' **
2523 521.9 ***
2524 236-245 438.9 `**
2525 169-195 466.0 ***
2526 196-197 467.9 *'*
2527 151-152 471.8 "**
2528 168-169 485.6 (M-1) ***
2529 174-175 493.9 "**
2530 165-166 497.8 ***
2531 173-174 511.8 (M-1) 2532 67-68 442_1 "**
2533 94-95 468.8 2534 108-115 505.8 ***
2535 192-194 516.0 2536 231-238 502.1 *"*
2537 190-201 486.1 2538 229-237 499.9 ***
2539 216-218 517.9 2540 149-152 505.9 ***
2541 96-108 528.2 *"*

Compound Melting Mass Spec Replicon IC50 ~
Number Point ('C) [M+H] pM 3-day H NMR Data 2542 115-122 549.7 2543 115-124 550.6 *'*
2544 483.5 148-150 (M-1) *"*
2545 485.5 87-89 (M-1) *==

Example 7: Evaluation of the activity of compounds usinix an HCV-poliovirus chimera In an HCV-poliovirus (HCV-PV) chimera, the PV 5' UTR is replaced by the HCV 5' UTR and partial (the first 123 amino acids) core coding sequences (nucleotides 18 to 710 of HCV lb) as shown in Fig. 1 (139, 140). As a consequence, the expression of poliovirus proteins is under regulation of the HCV IRES. Poliovirus is a picomavirus in which protein translation initiation is mediated by an IRES element located in the 5' UTR.
At the 5' end of the HCV-PV chimeric genome, there is the cloverleaf-like RNA structure of PV, an essential cis-acting replication signal ending with the genome-linked protein VPg.
Replication kinetics of the HCV-PV chimera matches that of the parental poliovirus (Mahoney) and can result in cytopathic effects (CPE) in cell culture. Heptazyme (29), a ribozyme that targets the HCV
IRES, was shown to be active against the chimeric virus in cell culture (76, 77).
To evaluate compounds for activity against the chimeric virus, HeLa cells are seeded and incubated at 37 C under 5% CO2 for 24 hours. The cells are then infected with HCV-PV
at a multiplicity of infection (MOI) at 0.1 for 30 min and then treated with compound for 1 day (treatment time will be optirnized). The activity of compounds is determined by a change in cytopathic effect, plaque assay, and/or viral RNA production (see e.g., Table 1).

Example 8: Evaluation of the activity of compounds against a wild-type poliovirus (WT-PV) and the poliovirus IRES translation assay (WT-PV mono luc) A DNA construct is prepared, termed pPVIRESmono, in which PV IRES sequences are inserted (nucleotide number 1-742) between a promoter and the firefly ]uciferase (Fluc) reporter gene. A stably transfected 293 T cell line, is established by transfection with the pPVIRESmono DNA by selecting for resistance to hygromycin. As previously described, cells are treated with compounds for 20 hours, and activity is determined by quantifying the Fluc signal. Additionally, to evaluate compounds activity against wild-type poliovirus, Helacells are seeded and incubated at 37 C under 5% CO2 for 24 hours. Cells are then infected with wild-type poliovirus at a MOI at 0.1 for 30 minutes, and then treated with compound for one day.
The activity of compounds is determined by changes in cytopathic effect, plaque assay, and RT-PCR using poliovirus IRES primers and probes (see e.g., Table 2).
Furthennore, if compounds are active against the poliovirus and other virus IRES, then the compounds are useful for treating viral infection by any virus containing an IRES.

Compound No. WT-PV CPE WT-PV CPE WT-PV CPE WTPV mono luc (100 EcM} (10 M} 0 N.M) IC50 (l~) 4 3 2 1 0.8 9 3 2 2 >100 3 2 2 >100 24 3 2 2 1.5 Example 9: In vitro translation assay In vitro translation assays can be used to distinguish between the compounds that act on HCV IRES RNA or cellular translation factors. In exemplary assays, the mRNA
that will direct translation is a transcribed runoff product from the T7 RNA polymerase promoter of the pHCVIRESmono plasmid DNA generated with Ambion RNA MegaTranscript kit (Ambion, Inc., Austin, TX). In vitro translation is performed using HeLa cell lysates using methods known to one of skill in the art. Preliminary results indicate that one or more of the compounds of the present invention has significantly higher activity against HCV IRES
regulated translation after preincubating the compound with the HCV IItES RNA
transcripts than after preincubating with HeLa cell lysate for 30 min at 37 C or without preincubation (data not shown). This suggests that this compound may interact with the HCV IRES RNA in the in vitro translation assay. To demonstrate whether the compounds selectively act on the HCV
IRES, pLuc is used together with cellular IRES mRNA transcripts as controls for fn vitro translation.

All publications and patent applications cited herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims of the invention.

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All documents referred to herein are incorporated by reference into the present application as though fully set forth herein.

Claims (75)

1. A compound of formula I

wherein:
X is:
-a nitro group;
-a cyano group;
-a -COR a group, where R a is:
-a C1 to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or a halogen, or -a dialkyl-amino;
-a -COOR, group, where R x is a C1 to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl, -a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s), or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;
-a halogen;
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;

-an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;

where R b is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;

where R c is a hydrogen, a-CONHR x, where R x is as defined above, or an -SO2R x, where R x is as defined above; or where R d is a C1 to C6 alkyl or a C6 to C8 aryl;
-a -NHCOR e group, where R e is:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with:
-a C1 to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halogen;
-a -NHCOOR x group, where R x is as defined above;
-a -CH2O-R f group, where R f is a C6 to C8 aryl;

-a -NR g R h group, where R g is hydrogen or a C1 to C6 alkyl and R h is hydrogen or a C6 to C8 aryl optionally substituted with an alkoxy;
-a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a C6 to C8 aryl, optionally substituted with -COOR x, where R x is as defined above, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR x group, where R x is as defined above, or -a -NHCOOR x group, where R x is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halogen(s), -a 5 or 6 membered heterocycle, optionally substituted with:
-a C1 to C6 alkyl, or -a hydroxy, -an amino group optionally substituted with one or more C1 to C6 alkyl(s), -a -NR i SO2R x group, where R x is as defined above and R i is:
-a hydrogen, -a C1 to C6 alkyl, -a -COR x group, where R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR j COR k group, where R k is:
-a C1 to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more C1 to C6 alkyl(s), and R j is:
-a hydrogen, -a C1 to C6 alkyl, - a-COR x group, where R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -N=N+=N- group, or -a -COR1, where R1 is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino optionally substituted with one or more C1 to C6 alkyl(s), -a C1 to C6 alkyl group, optionally substituted with:
-a -NHSO2R x group, where R x is as defined above, or -a -NR x SO2R x group, where R x is as defined above, -a haloalkoxy, -a halogen, -a hydroxy, -a -COOR x group, where R x is as defined above, -a -COR m group, where R m is:
-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the one or more C1 to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy -a 5 or 6 membered heterocycle, -an amino optionally substituted with one or more C1 to C6 alkyl(s), -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino, -a -NHR n group, where R n is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halogen(s), -a nitro group, or -one or more alkoxy(s), -a -NR o COR p group, where R p is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen, -an alkoxy, or -a C6 to C8 aryl, -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with a halogen, -a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl(s), -a hydrogen, and where R o is:
-a hydrogen, -a C1 to C6 alkyl, -a -COR x group, where R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR q CONR q R r group, where R q is:
-a hydrogen, -a C1 to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR x group, where R x is as defined above, and where R r is:
-a C6 to C8 aryl optionally substituted with:

-a C1 to C6 alkyl, -a haloalkyl, -a -OR s group, where R s is a C6 to C8 aryl, or -a -COOR x group, where R x is as defined above, -a C1 to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, -a C6 to C8 aryl, and/or -a -COOR x group, where R x is as defined above, -a -COOR x group, where R x is as defined above, -a -NR t COOR u group, where R u is:
-a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with:
-an alkoxy, -a halogen, or -a C1 to C6 alkyl, or -a 5 or 6 membered heterocycle, and R t is:
-a hydrogen, -a C1 to C6 alkyl, -a -COR x group, where R x is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR v SO2R w group, where R v is:
-a hydrogen, -a -COR x, where R x is as defined above, or -a C1 to C6 alkyl, optionally substituted with:
-a halogen, -a -COR x group, where R x is as defined above, -a -OCOR x group, where R x is as defined above, -a hydroxy, or -an alkoxy, and where R w is:
-a C1 to C6 alkyl optionally substituted with:

-a halogen, -a haloalkyl, -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, -a C2 to C6 alkylene, -an alkyl- or dialkyl-amino optionally substituted with a halogen, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl, -a 5 or 6 membered heterocycle, or optionally substituted with a C1 to C6 alkyl, where R y is a C1 to C6 alkyl or hydrogen, where R z is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SR x group, where R x is as defined above, -a -SO2R aa group, where R aa is:
-a C1 to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COOR x group, where R x is as defined above, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, and/or -a -NHR bb group, where R bb is:

-a -C(=S)NH2 group, or -a -PO(OR x)2 group, where R x is as defined above;
group, where R cc is:
-a naphthalene, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halogen, -a C1 to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more C1 to C6 alkyl(s), -a -NHPOR x R x, where R x is as defined above, -a NR ee CONR ff R ff group, where R cc is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and R ff is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a C1 to C6 alkyl, or -a -COR x where R x is as defined above, -a -NR gg COR hh, group, where R hh is:
-a hydrogen, -a C1 to C6 alkyl optionally substituted with:
-an alkoxy, -a halogen, or -an amino optionally substituted with one or more C1 to C6 alkyl(s), -an amino optionally substituted with one or more C1 to C6 alkyl(s), where the one or more C1 to C6 alkyl(s) is/are optionally substituted with a halogen, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and R gg is:
-a hydrogen, -a C1 to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR x group, where R x is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more C1 to C6 alkyl(s), and/or -a -NR jj SO2R x group, where R x is as defined above, and R ii is:
-a hydrogen, -a C1 to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -COR x group, where R x is as defined above;
Z is:
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);
-a -COOR x group, where R x is as defined above; or R is a hydrogen, a halogen or an alkoxy;

R1 is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR x group, where R x is as defined above;
-a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R1 joins together with R2 to form:

R2 is:

-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR x group, where R x is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group;
-a -COOR x group, where R x is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group, or -a C6 to C8 aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR x group, where R x is as defined above;
-a -NHCOR jj group, where R jj is:
-an alkoxy, or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -OR kk group, where R kk is a 5 to 6 membered heteroaryl;
-a -NHSO2R x group, where R x is as defined above; or R2 joins together with R1 to form:

R3 is:

-a hydrogen; or -CH2OCOR x, and R x is as defined above;
provided that when X is phenyl substituted with alkoxy, Y is phenyl, R is hydrogen, R1 is a halogen, R2 is hydrogen, and R3 is hydrogen, and provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, R1 is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:
-a C1 to C6 alkyl substituted with:
-an alkoxy, -one or more halogen(s), or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);

-a -COOR x group, where R x is as defined above; or or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein X is a nitro group or a cyano group.

3. The compound of claim 1, wherein X is a cyano group.

4. The compound of claim 1, wherein:
Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more C1 to C6 alkyl(s), -a C1 to C6 alkyl group, optionally substituted with a-NHSO2R x group, -a -NR o COR p group, where R p is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen, or -a C6 to C8 aryl, or -a 5 or 6 membered heterocycle, and where R o is a hydrogen, -a -NR q CONR q R r group, where R q is:
-a hydrogen, or -a C1 to C6 alkyl, and where R r is a C1 to C6 alkyl optionally substituted with one or more of the following:
-a halogen, -an alkylene, or -a C6 to C8 aryl, -a -NRCOOR u group, where R u is:
-a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy, -an alkylene, -an alkoxy, -an alkyne, -a halogen, or -a 5 or 6 membered heterocycle, -a C6 to C8 aryl, optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle, and where R t is:
-a hydrogen, or -a C1 to C6 alkyl, -a NR v SO2R w group, where R v is a hydrogen, and where R w is a C1 to C6 alkyl optionally substituted with a halogen;

where R2 is a C1 to C6 alkyl, and/or -a -NHR bb group, where R bb is a-PO(OR x)2 group.

5. The compound of claim 4, wherein Y is a C6 to C8 aryl substituted with:
-a -NR q CONR q R r group, -a NR t COOR u group, -a -NR v SO2R w group, or -a -NHR bb group, where R bb is -a -PO(OR x)2 group.

6. The compound of claim 5, wherein the C6 to C8 aryl is phenyl.

7. The compound of claim 6, wherein the phenyl is substituted at the para position.

8. The compound of claim 7, wherein Y is phenyl substituted with a -NR q CONR q R r group at the para position.

9. The compound of claim 7, wherein Y is phenyl substituted with a-NR t COOR u group at the para position.

10. The compound of claim 7, wherein Y is phenyl substituted with a-NR v SO2R
w group at the para position.

11. The compound of claim 7, wherein Y is phenyl substituted with a NHPO(OR x)2 group at the para position.

12. The compound of claim 1, wherein Z is:
-a C1 to C6 alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or -a C2 to C6 alkylene.

13. The compound of claim 1, wherein Z is a C1 to C6 alkyl.

14. The compound of claim 13, wherein Z is a -a C2 to C5 alkyl.

15. The compound of claim 14, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.

16. The compound of claim 1, wherein R is hydrogen.

17. The compound of claim 1, wherein R1 is:
-a hydrogen;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl group, or -a 5 or 6 membered heterocycle; or R1 joins together with R2 to form:

18. The compound of claim 1, wherein R2 is:
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR x group, where R x is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group;
-a -COOR x group; or R2 joins together with R1 to form:

19. The compound of claim 1, wherein:

at least one of R1 and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl group, or -a 5 or 6 membered heterocycle group; or R2 is a -OCOR x group, a -OR kk group, or an alkoxy group substituted- with:
-an -OCOR x group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

20. The compound of claim 19, wherein R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

21. The compound of claim 20, wherein R2 is a C1 to C6 alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

22. The compound of claim 1, wherein R3 is a hydrogen.

23. The compound of claim 1, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with:
-a -NR q CONR q R r group, -a -NR t COOR u group, -a NR v SO2R w group, or -a -NHPO(OR x)2 group;
Z is:
-a C1 to C6 alkyl optionally substituted with -an alkoxy, or -one or more halogen(s), or -a C2 to C6 alkylene;

R is hydrogen;
at least one of R1 and R2 is a hydroxy group or an alkoxy group optionally substituted with:
-one or more halogen(s), -a C6 to C8 aryl group, or -a 5 or 6 membered heterocycle group; or R2 is a -OCOR x group, a -OR kk group, or an alkoxy group substituted with:
-an -OCOR x group, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group; and R3 is hydrogen.

24. The compound of claim 23, wherein Y is a phenyl substituted with a -NR y CONR q R r group.

25. The compound of claim 24, wherein:
Z is a C1 to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

26. The compound of claim 23, wherein Y is a phenyl substituted with a -NR t COOR u group.

27. The compound of claim 26, wherein:
Z is a C1 to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 - to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

28. The compound of claim 23, wherein Y is a phenyl substituted with a -NR v SO2R w group.

29. The compound of claim 28, wherein:
Z is a C1 to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

30. The compound of claim 23, wherein Y is -a -NHPO(OR x)2 group.

31. The compound of claim 30, wherein:
Z is a C1 to C6 alkyl; and R2 is an alkoxy group optionally substituted with:
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group.

32. The compound of claim 1, wherein:
X is:
-a cyano group; or -a formyl group;
Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a C6 to C8 aryl, optionally substituted with -COOR x, where R x is as defined above; or -a C6 to C8 aryl, optionally substituted with one or more of the following:
-a C1 to C6 alkyl group;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a halogen;
-a hydroxy;
-a -COR m group, where R m is an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -NR o COR p group, where R p is a C1 to C6 alkyl optionally substituted with an alkoxy, and where R o is a hydrogen;
-a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl;
-a halogen; or -a 5 or 6 membered heterocycle;
-a -NRSO2R w group, where R v is hydrogen and where R w is -a C1 to C6 alkyl; or -an alkyl- or dialkyl-amino;

where R z is hydrogen or a C1 to C6 alkyl;
-a -SO2R aa group, where R aa is:
-an amino group; or -an alkyl or dialkyl amino group; or -a -NHR bb group, where R bb is a-PO(OR x)z group, where R x is as defined above;
Z is:
-a C1 to C6 alky; or -a -COOR x group, where R x is as defined above;
R is a hydrogen, R1 is:
-a hydrogen;
-a 5 or 6 membered heterocycle; or -an alkoxy optionally substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle;
R2 is:
-a hydrogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an alkoxy group optionally substituted with:
-one or more halogen(s);

-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group;
-a -COOR x group, where R x is as defined above;
-an amide group;
-a 5 or 6 membered heteroaryl; or -a -OR kk group, where R kk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.

33. The compound of claim 32, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl, optionally substituted with a C6 to C8 aryl; or -a -NR v SO2R w group, where R v is hydrogen and where R w is a C1 to C6 alkyl;
Z is a C1 to C6 alky;
R is a hydrogen, R1 is a hydrogen;
R2 is an alkoxy group optionally substituted with:
-one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group; or R3 is a hydrogen.

34. The compound of claim 32, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with one or more of the following:
-a C1 to C6 alkyl group;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a halogen;
-a -NR t COOR u group, where R t is hydrogen, and where R u is:
-a C1 to C 12 alkyl;
-a -NR v SO2R w group, where R v is hydrogen and where R w is:

-a C1 to C6 alkyl; or -an alkyl- or dialkyl-amino;
Z is a C1 to C6 alky;
R is a hydrogen;
R1 is a hydrogen;
R2 is a-OR kk group, where R kk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.

35. The compound of claim 32, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with one or more of the following:
-a C1 to C6 alkyl;
-a halogen;
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl;
-a -NR v SO2R w group, where R v is hydrogen and where R w is:
-a C1 to C6 alkyl; or -an alkyl- or dialkyl-amino; or -a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen, R1 is a hydrogen;
R2 is:
-an alkoxy group optionally substituted with one or more halogen(s);
-an amide;
-a -OR kk group, where R kk is a 5 to 6 membered heteroaryl; or -a 5 or 6 membered heteroaryl; and R3 is a hydrogen.

36. The compound of claim 35, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with one or more of the following:
-a halogen;
-a -NR t COOR u group, where R1 is hydrogen, and where R u is a C1 to C12 alkyl; or -a -NR v SO2R w group, where R v is hydrogen and where R w is a C1 to C6 alkyl;
Z is a C1 to C6 alkyl;

R is a hydrogen;
R1 is a hydrogen;
R2 is a -OR kk group, where R kk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.

37. The compound of claim 36, wherein the C6 to C8 aryl is phenyl.

38. The compound of claim 37, wherein the phenyl is substituted at the para position.

39. The compound of claim 38, wherein Y is a phenyl substituted with a -NR t COOR u group, where R t is hydrogen, and where R u is:a C1 to C12 alkyl.

40. The compound of claim 38, wherein Y is a phenyl substituted with a halogen and a -NR t COOR u group, where R t is hydrogen, and where R u is C1 to C12 alkyl.

41. The compound of claim 38, wherein Y is a phenyl substituted with a-NR v SO2R w group, where R v is hydrogen and where R w is C1 to C6 alkyl.

42. The compound of claim 38, wherein Y is a phenyl substituted with a C1 to alkyl and a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl.

43. The compound of claim 35, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen;
R1 is a hydrogen;
R2 is an alkoxy group optionally substituted with one or more halogen(s); and R3 is a hydrogen.

44. The compound of claim 35, wherein R2 is an alkoxy group substituted with one or more halogens.

45. The compound of claim 43, wherein the C6 to C8 aryl is phenyl.

46. The compound of claim 45, wherein the phenyl is substituted at the para position.

47. The compound of claim 35, wherein:

X is a cyano group;
Y is a C6 to C8 aryl substituted with one or more of the following:
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl; or -a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen, R1 is a hydrogen;
R2 is a 5 or 6 membered heteroaryl; and R3 is a hydrogen.

48. The compound of claim 47, wherein the C6 to C8 aryl is phenyl.

49. The compound of claim 48, wherein the phenyl is substituted at the para position.

50. The compound of claim 49, wherein Y is a phenyl substituted with a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl.

51. The compound of claim 49, wherein Y is a C6 to C8 aryl substituted with a NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl.

52. The compound of claim 35, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen;
R1 is a hydrogen;
R2 is an amide; and R3 is a hydrogen.

53. The compound of claim 52, wherein the C6 to C8 aryl is phenyl.

54. The compound of claim 53, wherein the phenyl is substituted at the para position.

55. The compound of claim 35, wherein R2 is an alkoxy group substituted with one or more halogen(s).

56. The compound of claim 35, wherein R2 is a -OR kk group, where R kk is a 5 to 6 membered heteroaryl.

57. The compound of claim 32, wherein:
X is a formyl group;
Y is a C6 to C8 aryl substituted with one or more of the following:
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl; or -a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen;
R1 is a hydrogen;
R2 is an alkoxy group; and R3 is a hydrogen.

58. The compound of claim 32, wherein:
X is a cyano group;
Y is a C6 to C8 aryl substituted with one or more of the following:
-a C1 to C6 alkyl group;
-a halogen;
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl, optionally substituted with a C6 to C8 aryl;
-a -NR v SO2R w group, where R v is hydrogen and where R w is:
-a C1 to C6 alkyl; or -an alkyl- or dialkyl-amino; or Z is a C1 to C6 alkyl;
R is a hydrogen;
R1 is a hydrogen;
R2 is an alkoxy group substituted with one or more halogen(s); and R3 is a hydrogen.

59. The compound of claim 32, wherein:

X is a cyano group;
Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-a -NR o COR p group, where R p is a C1 to C6 alkyl optionally substituted with an alkoxy, and where R o is a hydrogen;
Z is a C1 to C6 alkyl;
R is a hydrogen;
R1 is a hydrogen;
R2 is an alkoxy group substituted with a 5 or 6 membered heteroaryl group; and R3 is a hydrogen.

60. The compound of claim 32, wherein:
X is a cyano group;
Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-a C1 to C6 alkyl group;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a halogen;
-a -NR o COR p group, where R p is a C1 to C6 alkyl, and where R o is a hydrogen;
-a -NR q CONR q R r group, where R q is hydrogen, and where R r is a C1 to C6 alkyl;
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl;
-a -NR v SO2R w group, where R v is hydrogen, and where R w is a C1 to C6 alkyl; or -a -NHR bb group, where R bb is a -PO(OR x)2 group, and where R x is as defined above;
Z is a C1 to C6 alkyl;
R is a hydrogen, R1 is a hydrogen;
R2 is a 5 or 6 membered heteroaryl; and R3 is a hydrogen.

61. The compound of claim 32, wherein:
X is a cyano group;
Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle;
-a -NR v SO2R w group, where R v is hydrogen and where R w is a C1 to C6 alkyl;
; or where R z is hydrogen or a C1 to C6 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen, R1 is:
-a 5 or 6 membered heterocycle; or -an alkoxy substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle;
R2 is a hydrogen; and R3 is a hydrogen.

62. The compound of claim 61, wherein R1 is a 5 or 6 membered heterocycle.

63. The compound of claim 61, wherein R1 is an alkoxy substitued with one or more halogen.

64. The compound of claim 61, wherein:

Y is a C6 to C8 aryl substituted with a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle; and R1 is an alkoxy substitued with one or more halogen.

65. A compound of formula IIIa wherein:
X is hydrogen;
Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
-a -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl; or -a NR v SO2R w group, where R v is hydrogen and where R w is a C1 to C6 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen, R1 is a hydrogen;
R2 is:
-an alkoxy group optionally substituted with one or more halogen(s); or -a -OR kk group, where R kk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.

66. The compound of claim 65, wherein:
X is hydrogen;
Y is a C6 to C8 aryl substituted with a NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl;
Z is a C1 to C6 alkyl;
R is a hydrogen;
R1 is a hydrogen;
R2 is a -OR kk group, where R kk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.

67. The compound of claim 65, wherein the C6 to C8 aryl is phenyl.

68. The compound of claim 65, wherein the phenyl is substituted at the para position.

69. A pharmaceutical composition comprising:

(i) a compound of formula I

wherein:
X is:
-a nitro group;
-a cyano group;
-a -COR a group, where R a is:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with an alkoxy or a halogen; or -a dialkyl-amino;
-a -COOR x group, where R x is a C1 to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s); or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;

, where R b is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
, where R c is a hydrogen, a -CONHR x, where R x is as defined above, or an -SO2R x where R x is as defined above;

, where R d is a C1 to C6 alkyl or a C6 to C8 aryl;
-a -NHCOR e group, where R e is:
-a C1 to C6 alkyl; or -a C6 to C8 aryl optionally substituted with:
-a C1 to C6 alkyl;
-an alkoxy;
-a cyano group;
-a nitro group; or -a halogen;
-a -NHCOOR x group, where R x is as defined above;
-a -CH2O-R f group, where R f is a C6 to C8 aryl;

-a -NR g R h group, where R g is a C1 to C6 alkyl or a hydrogen and R h is a C6 to C8 aryl optionally substituted with an alkoxy;
-a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl;
-a C6 to C8 aryl, optionally substituted with -COOR x where R x is as defined above; or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR x group, where R x is as defined above; or -a -NHCOOR x group, where R x is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy;
-a hydroxy;
-one or more halogen(s);
-a 5 or 6 membered heterocycle, optionally substituted with:
-a C1 to C6 alkyl; or -a hydroxy;
-an amino group optionally substituted with one or more C1 to C6 alkyl(s);
-a -NR i SO2R x group, where R x is as defined above, and where R i is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR j COR k group, where R k is:
-a C1 to C6 alkyl;
-a hydrogen; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
and where R j is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -N=N+=N- group; or -a -COR l, where R l is a 5 or 6 membered heterocycle optionally substituted with a hydroxy;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a nitro group;
-a C1 to C6 alkyl group, optionally substituted with:
-a -NHSO2R x group, where R x is as defined above; or -a -NR x SO2R x group, where R x is as defined above;
-a haloalkoxy;
-a halogen;
-a hydroxy;
-a -COOR x group, where R x is as defined above;
-a -COR m group, where R m is:
-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the C1 to C6 alkyls are optionally substituted with:
-a hydroxy;
-a 5 or 6 membered heterocycle;
-an amino optionally substituted with one or more C1 to C6 alkyl(s); or -an alkoxy;
-a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino;
-a -NHR n group, where R n is:
-a -CH2CONH2; or -a C6 to C8 aryl optionally substituted with:
-an alkyl;
-one or more halogen(s);
-a nitro group; or -one or more alkoxy(s);
-a -NR o COR p group, where R p is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen;
-an alkoxy; or -a C6 to C8 aryl;

-a 5 or 6 membered heterocycle;
-a C6 to C8 aryl, optionally substituted with a halogen;
-a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl(s);
-a hydrogen;

and where R o is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR q CONR q R r group, where R q is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above, and where R r is:
-a C6 to C8 aryl optionally substituted with:

-a C1 to C6 alkyl;
-a haloalkyl;
-a -OR s group, where R s is a C6 to C8 aryl; or -a -COOR x group, where R x is as defined above;
-a C1 to C6 alkyl optionally substituted with one or more of the following:

-a halogen;
-an alkylene;
-a C6 to C8 aryl; and/or -a -COOR x group, where R x is as defined above; or -a -COOR x group, where R x is as defined above;
-a -NR t COOR u group, where R u is:
-a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy;
-an alkylene;
-an alkoxy;
-an alkyne;
-a halogen; or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl, optionally substituted with:
-an alkoxy;
-a halogen; or -a C1 to C6 alkyl; or -a 5 or 6 membered heterocycle;
and R t is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR v SO2R w group, where R v is:
-a hydrogen;
-a -COR x, where R x is as defined above; or -a C1 to C6 alkyl, optionally substituted with:
-a halogen;
-a -COR x group, where R x is as defined above;
-a -OCOR x group, where R x is as defined above;
-a hydroxy; or -an alkoxy;
and where R w is:

-a C1 to C6 alkyl optionally substituted with:
-a halogen;
-a haloalkyl;
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle;
-a C2 to C6 alkylene;
-an alkyl- or dialkyl-amino optionally substituted with a halogen;
-a 5 or 6 membered heterocycle; or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl;
-a 5 or 6 membered heterocycle; or optionally substituted with a C1 to C6 alkyl, where R y is a C1 to C6 alkyl or hydrogen;

where R z is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl;
-a -SR x group, where R x is as defined above;
-a -SO2R aa group, where R aa is:
-a C1 to C6 alkyl;
-an amino group;
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COOR x group, where R x is as defined above, or -a 5 or 6 membered heteroaryl;
-a C6 to C8 aryl; and/or -a -NHR bb group, where R bb is:

-a -C(=S)NH2 group; or -a -PO(OR x)2 group, where R x is as defined above; or group, where R cc is:
-a naphthalene;
-a 5 or 6 membered heteroaryl;
-a -a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy;
-a hydroxy;
-a halogen;
-a C1 to C6 alkyl, optionally substituted with a cyano group;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -NHPOR x R x, where R x is as defined above;
-a -NR ee CONR ff R ff group, where R ee is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and R ff is:
-a hydrogen;
-a haloalkyl;
-a haloalkoxy;
-a C1 to C6 alkyl; or -a -COR x, where R x is as defined above;
-a -NR gg COR hh group, where R hh is:
-a hydrogen;
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy;
-a halogen; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);

-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the alkyls are optionally substituted with a halogen;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl;
and R gg is:
-a hydrogen;
-a C1 to C 6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
-a haloalkyl;
-5 or 6 membered heterocycle groups;
-an amino optionally substituted with one or more C1 to C6 alkyl(s); and/or -a -NR ii SO2R x group, where R x is as defined above, and R ii is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
Z is:
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy;
-one or more halogen(s); or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);
-a -COOR x group, where R x is as defined above; or R is a hydrogen, a halogen or an alkoxy;
R1 is:

-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s);
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR x group, where R x is as defined above;
-a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R1 joins together with R2 to form:

R2 is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s), -an -OCOR x group, where R x is as defined above, -a dialkyl-amino optionally substituted with an alkoxy, -a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl, -a 5 or 6 membered heteroaryl group, or -a C6 to C8 aryl group, -a -COOR x group, where R x is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
-a hydroxy group; or -a C6 to C8 aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR x group, where R x is as defined above;
-a NHCOR jj group, where R jj is:
-an alkoxy; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -OR kk group, where R kk is a 5 to 6 membered heteroaryl;
-a -NHSO2R x group, where R x is as defined above; or R2 joins together with R1 to form:

R3 is:
-a hydrogen; or -CH2OCOR x, and R x is as defined above;

provided that when X is phenyl, hydroxyphenyl or pyridyl, Y is alkyl, R is hydrogen, R1 is hydrogen or hydroxy, R2 is hydrogen or hydroxy, and R3 is hydrogen, then Z is:
-a C1 to C6 alkyl substituted with:
-an alkoxy;
-one or more halogen(s); or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);
-a -COOR x group, where R x is as defined above; or or one or more pharmaceutically acceptable salt(s) thereof; and (ii) one or more pharmaceutically acceptable excipient(s).

70. A method for treating an infection by a virus in a subject in need thereof, wherein the virus contains an internal ribosome entry site (IRES), comprising administering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more compound(s) of formula I

wherein:
X is:
-a nitro group;
-a cyano group;
-a -COR a group, where R a is:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with an alkoxy or a halogen; or -a dialkyl-amino;
-a -COOR x group, where R x is a C1 to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s); or -a 5 to 6 membered heteroaryl;

Y is:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;

where R b is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;
where R c is a hydrogen, a -CONHR x, where R c is as defined above, or an -SO2R x, where R x is as defined above; or where R d is a C1 to C6 alkyl or a C6 to C8 aryl;

-a -NHCOR c group, where R c is:
-a C1 to C6 alkyl; or -a C6 to C8 aryl optionally substituted with:
-a C1 to C6 alkyl;
-an alkoxy;
-a cyano group;
-a nitro group; or -a halogen;
-a NHCOOR x group, where R x is as defined above;
-a -CH2O-R f group, where R f is a C6 to C8 aryl;
-a NR g R h group, where R g is a C1 to C6 alkyl or a hydrogen and R h is a C6 to C8 aryl optionally substituted with an alkoxy;
-a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl;
-a C6 to C8 aryl, optionally substituted with -COOR x, where R x is as defined above; or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR x group, where R x is as defined above; or -a -NHCOOR x group, where R x is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy;
-a hydroxy;
-one or more halogen(s);
-a 5 or 6 membered heterocycle, optionally substituted with:
-a C1 to C6 alkyl; or -a hydroxy;
-an amino group optionally substituted with one or more C1 to C6 alkyl(s);
-a -NR i SO2R x group, where R x is as defined above and R i is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR j COR k group, where R k is:
-a C1 to C6 alkyl;
-a hydrogen; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
and where R j is:
-a hydrogen;
-a C1 to C6 alkyl;
- a-COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -N=N+=N- group; or -a -COR1, where R1 is a 5 or 6 membered heterocycle optionally substituted with a hydroxy;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a nitro group;
-a C1 to C6 alkyl group, optionally substituted with:
-a -NHSO2R x group, where R x is as defined above; or -a -NR x SO2R x group, where R x is as defined above;
-a haloalkoxy;
-a halogen;
-a hydroxy;
-a -COOR x group, where R x is as defined above;
-a -COR m group, where R m is:
-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the one or more C1 to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy;

-a 5 or 6 membered heterocycle;
-an amino optionally substituted with one or more C1 to C6 alkyls;

and/or -an alkoxy;
-a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino;
-a -NHR n group, where R n is:

-a -CH2CONH2; or -a C6 to C8 aryl optionally substituted with:
-an alkyl;
-one or more halogen(s);
-a nitro group; or -one or more alkoxy(s);
-a -NR o COR p group, where R p is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen;
-an alkoxy; or -a C6 to C8 aryl;
-a 5 or 6 membered heterocycle;
-a C6 to C8 aryl, optionally substituted with a halogen;
-a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl(s);
-a hydrogen;

and where R o is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR q CONR q R r group, where R q is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
and where R r is:
-a C6 to C8 aryl optionally substituted with:

-a C1 to C6 alkyl;
-a haloalkyl;
-a -OR s group, where R s is a C6 to C8 aryl; or -a -COOR x group, where R x is as defined above;
-a C1 to C6 alkyl optionally substituted with one or more of the following:
-a halogen;
-an alkylene;
-a C6 to C8 aryl; and/or -a -COOR x group, where R x is as defined above;
-a -COOR x group, where R x is as defined above;
-a -NR t COOR u group, where R u is:
-a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy;
-an alkylene;
-an alkoxy;
-an alkyne;
-a halogen; or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl, optionally substituted with:
-an alkoxy;
-a halogen; or -a C1 to C6 alkyl; or -a 5 or 6 membered heterocycle;
and where R t is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR v SO2R w group, where R v is:
-a hydrogen;
-a -COR x where R x is as defined above; or -a C1 to C6 alkyl, optionally substituted with:
-a halogen;
-a -COR x group, where R x is as defined above;
-a -OCOR x group, where R x is as defined above;
-a hydroxy; or -an alkoxy;
and where R w is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen;
-a haloalkyl;
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle;
-a C2 to C6 alkylene;
-an alkyl- or dialkyl-amino optionally substituted with a halogen;
-a 5 or 6 membered heterocycle; or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl;
-a 5 or 6 membered heterocycle; or -a , optionally substituted with a C1 to C6 alkyl, where R y is a C1 to C6 alkyl or hydrogen;

-a , where R z is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl;
-a -SR x group, where R x is as defined above;
-a -SO2R aa group, where R aa is:

-a C1 to C6 alkyl;
-an amino group;

-an alkyl- or dialkyl-amino group optionally,substituted with a hydroxy or a -COOR x group, where R x is as defined above; or -a 5 or 6 membered heteroaryl;
-a C6 to C8 aryl; and/or -a -NHR bb group, where R bb is:

-a -C(=S)NH2 group; or -a -PO(OR x)2 group, where R x is as defined above; or -a group, where R cc is:
-a naphthalene;
-a 5 or 6 membered heteroaryl;
-a -a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy;
-a hydroxy;
-a halogen;
-a C1 to C6 alkyl, optionally substituted with a cyano group;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -NHPOR x R x, where R x is as defined above;
-a -NR ee CONR ff R ff group, where R ee is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and R ff is:
-a hydrogen;
-a haloalkyl;

-a halo alkoxy;
-a C1 to C6 alkyl; or -a -COR x where R x is as defined above;
-a -NR gg COR hh group, where R hh is:
-a hydrogen;
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy;
-a halogen; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the alkyls are optionally substituted with a halogen;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl;
and R gg is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
-a haloalkyl;
-5 or 6 membered heterocycle groups;
-an amino optionally substituted with one or more C1 to C6 alkyl(s); and/or -a -NR ii SO2R x group, where R x is as defined above, and R ii is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
Z is:
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy;
-one or more halogen(s); or -a C6 to C8 aryl;

-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);
-a -COOR x group, where R x is as defined above; or R is a hydrogen, a halogen or an alkoxy;
R1 is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s);
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR x group, where R x is as defined above;
-a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R1 joins together with R2 to form:
R2 is:
-a nitro group;
-a hydrogen;

-a halogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s);
-an -OCOR x group, where R x is as defined above;
-a dialkyl-amino optionally substituted with an alkoxy;
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl group; or -a C6 to C8 aryl group;
-a -COOR x group, where R x is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
- a hydroxy group; or -a C6 to C8 aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR x group, where R x is as defined above;
-a -NHCOR jj group, where R jj is:
-an alkoxy; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -OR kk group, where R kk is a 5 to 6 membered heteroaryl;
-a -NHSO2R x group, where R x is as defined above; or R2 joins together with R1 to form:

R3 is:
-a hydrogen; or -CH2OCOR x, where R x is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.

71. A method for treating a Hepatitis C viral (HCV) infection in a subject in need thereof, comprising administering to the subject one or more compound(s) of formula I or a pharmaceutical composition comprising one or more compound(s) of formula I

wherein:
X is:
-a nitro group;
-a cyano group;
-a -COR a group, where R a is:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with an alkoxy or a halogen; or -a dialkyl-amino;
-a -COOR x group, where R x is a C1 to C6 alkyl;
-a formyl group;
-a C6 to C8 aryl optionally substituted with an alkoxy; or -a 5 or 6-membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more halogen(s); or -a 5 to 6 membered heteroaryl;
Y is:
-a haloalkyl;
-a halogen;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole;

-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C1 to C6 alkyl;

where R b is a hydrogen or a C1 to C6 alkyl, and n is 0 or 1;

where R c is a hydrogen, a -CONHR x where R x is as defined above, or an -SO2R x, where R x is as defined above;

, where R d is a C1 to C6 alkyl or a C6 to C8 aryl;
-a -NHCOR e group, where R e is:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with:
-a C1 to C6 alkyl;
-an alkoxy;
-a cyano group;
-a nitro group; or -a halogen;
-a -NHCOOR x group, where R x is as defined above;

-a -CH2O-R f group, where R f is a C6 to C8 aryl;
-a -NR g R h group, where R g is a C1 to C6 alkyl or a hydrogen and R h is a C6 to C8 aryl optionally substituted with an alkoxy;
-a C1 to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with:
-a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl;
-a C6 to C8 aryl, optionally substituted with -COOR x where R x is as defined above; or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR x group, where R x is as defined above; or -a -NHCOOR x group, where R x is as defined above;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy;
-a hydroxy;
-one or more halogen(s);
-a 5 or 6 membered heterocycle, optionally substituted with:
-a C1 to C6 alkyl; or -a hydroxy;
-an amino group optionally substituted with one or more C1 to C6 alkyl(s);
-a -NR i SO2R x group, where R x is as defined above and R i is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR j COR k group, where R k is:
-a C1 to C6 alkyl;
-a hydrogen; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
and R j is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;

-a haloalkyl; or -a haloalkoxy;
-a -N=N+=N- group; or -a -COR l, where R l is a 5 or 6 membered heterocycle optionally substituted with a hydroxy;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a nitro group;
-a C1 to C6 alkyl group, optionally substituted with:
-a -NHSO2R x group, where R x is as defined above; or -a -NR x SO2R x group, where R x is as defined above;
-a haloalkoxy;
-a halogen;
-a hydroxy;
-a -COOR x group, where R x is as defined above;
-a -COR m group, where R m is:
-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the one or more C1 to C6 alkyl(s) is/are optionally substituted with:
-a hydroxy;
-a 5 or 6 membered heterocycle;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-an alkoxy;
-a 3 to 7 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a dialkyl-amino; or -a NHR n group, where R n is:
-a -CH2CONH2; or -a C6 to C8 aryl optionally substituted with:
-an alkyl;
-one or more halogen(s);
-a nitro group; or -one or more alkoxy(s);
-a -NR o COR p group, where R p is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen;
-an alkoxy; or -a C6 to C8 aryl;
-a 5 or 6 membered heterocycle;
-a C6 to C8 aryl, optionally substituted with a halogen;
-a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl(s);
-a hydrogen;

and where R o is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR q CONR q R r group, where R q is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
and where R r is:
-a C6 to C8 aryl optionally substituted with:

-a C1 to C6 alkyl;
-a haloalkyl;
-a -OR s group, where R s is a C6 to C8 aryl; or -a -COOR x group, where R x is as defined above;

-a C1 to C6 alkyl optionally substituted with one or more of the following:
-a halogen;
-an alkylene;
-a C6 to C8 aryl; and/or -a -COOR x group, where R x is as defined above;
-a -COOR x group, where R x is as defined above;
-a -NR t COOR u group, where R u is:
-a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl optionally substituted with a C1 to C6 alkyl or an alkoxy;
-an alkylene;
-an alkoxy;
-an alkyne;
-a halogen; or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl, optionally substituted with:
-an alkoxy;
-a halogen; or -a C1 to C6 alkyl; or -a 5 or 6 membered heterocycle;
and R t is:
-a hydrogen;
-a C1 to C6 alkyl;
-a -COR x group, where R x is as defined above;
-a haloalkyl; or -a haloalkoxy;
-a -NR v SO2R w group, where R v is:
-a hydrogen;
-a -COR x where R x is as defined above; or -a C1 to C6 alkyl, optionally substituted with:
-a halogen;
-a -COR x group, where R x is as defined above;
-a -OCOR x group, where R x is as defined above;
-a hydroxy; or -an alkoxy;

and where R w is:
-a C1 to C6 alkyl optionally substituted with:
-a halogen;
-a haloalkyl;
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle;
-a C2 to C6 alkylene;
-an alkyl- or dialkyl-amino optionally substituted with a halogen;
-a 5 or 6 membered heterocycle; or -a 5 or 6 membered heteroaryl optionally substituted with:
-a C1 to C6 alkyl;
-a 5 or 6 membered heterocycle; or -a , optionally substituted with a C1 to C6 alkyl, where R y is a C1 to C6 alkyl or hydrogen;

-a ;
-a ;
-a , where R z is hydrogen or a C1 to C6 alkyl, optionally substituted with a C6 to C8 aryl;
-a -SR x group, where R x is as defined above;
-a -SO2R aa group, where R aa is:
-a C1 to C6 alkyl;
-an amino group;
-an alkyl- or dialkyl-amino group optionally substituted with a hydroxy or a-COOR x group, where R x is as defined above; or -a 5 or 6 membered heteroaryl;
-a C6 to C8 aryl; and/or -a -NHR bb group, where R bb is:

-a -C(=S)NH2 group; or -a -PO(OR x)2 group, where R x is as defined above;
-a group, where R cc is:
-a naphthalene;
-a 5 or 6 membered heteroaryl;

-a ;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy;
-a hydroxy;
-a halogen;
-a C1 to C6 alkyl, optionally substituted with a cyano group;
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -NHPOR x R x, where R x is as defined above;
-a -NR ee CONR ff R ff group, where R ee is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halogen, and R ff is:
-a hydrogen;
-a haloalkyl;
-a haloalkoxy;
-a C1 to C6 alkyl; or -a -COR x, where R x is as defined above;
-a -NR gg COR hh group, where R hh is:
-a hydrogen;
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy;
-a halogen; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);

-an amino optionally substituted with one or more C1 to C6 alkyl(s), where the one or more C1 to C6 alkyl(s) is/are optionally substituted with a halogen;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl;
and R gg is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
-a haloalkyl;
-5 or 6 membered heterocycle groups;
-an amino optionally substituted with one or more C1 to C6 alkyl(s); and/or -a -NR ii SO2R x group, where R x is as defined above, and R ii is:
-a hydrogen;
-a C1 to C6 alkyl;
-a haloalkyl;
-a haloalkoxy; or -a -COR x group, where R x is as defined above;
Z is:
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy;
-one or more halogen(s); or -a C6 to C8 aryl;
-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C1 to C6 alkyl(s);
-a -COOR x group, wherein R x is as defined above; or R is a hydrogen, a halogen or an alkoxy;

R1 is:
-a hydrogen;
-a hydroxy;
-a halogen;
-a haloalkyl;
-a nitro group;
-a 5 or 6 membered heteroaryl;
-a 5 or 6 membered heterocycle;
-an alkoxy optionally substituted with:
-one or more halogen(s);
-a C6 to C8 aryl; or -a 5 or 6 membered heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR x group, where R x is as defined above;
-a C1 to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R1 joins together with R2 to form:

R2 is:
-a nitro group;
-a hydrogen;
-a halogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an amino group;
-an alkoxy group optionally substituted with:
-one or more halogen(s);
-an -OCOR x group, where R x is as defined above;
-a dialkyl-amino optionally substituted with an alkoxy;
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl;

-a 5 or 6 membered heteroaryl group; or -a C6 to C8 aryl group;
-a -COOR x group, where R x is as defined above;
-a haloalkyl;
-an amide group optionally substituted with:
-a hydroxy group; or -a C6 to C8 aryl;
-a 5 or 6 membered heteroaryl;
-a -OCOR x group, where R x is as defined above;
-a -NHCOR jj group, where R jj is:
-an alkoxy; or -an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -OR kk group, where R kk is a 5 to 6 membered heteroaryl;
-a -NHSO2R x group, where R x is as defined above; or R2 joins together with R t to form:

R3 is:

-a hydrogen; or -CH2OCOR x, where R x is as defined above; or one or more pharmaceutically acceptable salt(s) thereof.

72. A compound of formula IIIb wherein:
X is hydrogen;

Y is:
-a 5 or 6 membered heteroaryl, optionally substituted with a C6 to C8 aryl, optionally substituted with -COOR x where R x is as defined above; or -a C6 to C8 aryl, optionally substituted with one or more of the following:
-an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a halogen;
-a hydroxy;
-a -COR m group, where R m is an amino optionally substituted with one or more C1 to C6 alkyl(s);
-a -NR o COR p group, where R p is a C1 to C6 alkyl optionally substituted with an alkoxy, and where R o is a hydrogen;
-a -NR q CONR q R r group, where R q is hydrogen and where R r is a C1 to C6 alkyl;
-a NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl, optionally substituted with:
-a C6 to C8 aryl;
-a halogen; or -a 5 or 6 membered heterocycle;
-a -NR v SO2R w group, where R v is hydrogen and where R w is:
-a C1 to C6 alkyl; or -an alkyl- or dialkyl-amino;

; where R z is hydrogen or a C1 to C6 alkyl;
-a -SO2R aa group, where R aa is:

-an amino group; or -an alkyl- or dialkyl-amino group; or -a -NHR bb group, where R bb is a -PO(OR x)2 group, where R x is as defined above;
Z is:
-a C1 to C6 alkyl; or -a -COOR x group, where R x is as defined above;
R is a hydrogen, R t is:
-a hydrogen;
-a 5 or 6 membered heterocycle; or -an alkoxy optionally substituted with:
-one or more halogen(s); or -a 5 or 6 membered heterocycle;
R2 is:
-a hydrogen;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more halogen(s);
-an alkoxy group optionally substituted with:
-one or more halogen(s);
-a 5 or 6 membered heterocycle group optionally substituted with a C1 to C6 alkyl; or -a 5 or 6 membered heteroaryl group;
-a -COOR x group, where R x is as defined above;
-an amide group;
-a 5 or 6 membered heteroaryl; or -a -OR kk group, where R kk is a 5 to 6 membered heteroaryl; and R3 is a hydrogen.

73. The compound of claim 72, wherein:
X is:
-hydrogen;
Y is:
-a C6 to C8 aryl, substituted with -NR t COOR u group, where R t is hydrogen, and where R u is a C1 to C12 alkyl;
Z is:
-a C1 to C6 alky;
R is:
-a hydrogen;
R1 is:
-a hydrogen;
R2 is:
-a -OR kk group, where R kk is a 5 to 6 membered heteroaryl;
R3 is:
-a hydrogen.

74. A compound which is selected from the compound range: 866-1329, 1484-2127, 2129-2545.

75. The compound of claim 74 selected from: