CA2636905A1 - 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

DEMANDE OU BREVET VOLUMINEUX

LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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VOLUME

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NOTE POUR LE TOME / VOLUME NOTE:

METHODS FOR TREATING HEPATITIS C
CROSS REFERENCE 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 wliich applications claim the benefit of U.S. Provisional Application No. 60/587,487, filed July 14, 2004, U.S. Provisional Application No. 60/634,979, 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 TIiE 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 tuzn 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 (IRES) 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 IItES-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, III, 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 IIId 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 mRNA. The translation initiation mechanism of the HCV and other viral IRES 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 functionally replaces the 5' cap structure, allowing the 40S ribosomal subunit 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, e1F3, 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 IRES-mediated initiation of translation is unclear. Recently, 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 proteins, 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 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 a more effective means of treating patients afflicted with HCV. Specifically, a need exists for novel antiviral drugs 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.

SUlVI1VIARY 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.

DETAILED DESCRIPTION OF THE INVENTION
A. Compounds of the Invention In another embodiment, the present invention includes a compound of Formula (1) R x Ri L Y
N
Ra Z

m wherein:

X is:
-hydrogen;
-a cyano group;
-a nitro group;
-a formyl group;
-a -COOH group;
-a CORx group, wherein R,, is a C1 to C6 alkyl;
HC

N
-a ____~Cq to Cg alkoxy;
HC
\` =
N
----,amino optionally substituted with one or -a more C, to C6 alkyl groups -a halo;
-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a C, to C6 alkyl optionally substituted with one or more independently selected halo or cyano groups;
-an oxime;
-SO2Rx;
-SO2NH2;
-SOZNH(Rx);
-SO2N(RX)2;
-an amino optionally substituted with one or more CI to C6 alkyl groups or C1 to C6 alkylcarbonyl groups;
-an amide group optionally substituted with one or more independently selected C, to C6 allcyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more halos;

-a C6 to C$ aryl group optionally substituted with one or more of the following:
-CI to C6 alkyl optionally substituted with one or more halos, -halo, or -cyano;
Y is:
-a hydrogen;
-a haloalkyl;
-a halo;
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to C6 alkyls;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl or an -SO2R,, group;
O

O

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

w I

- , where & is a hydrogen, a-CONHR,,, where R, is a C, to C6 alkyl, or an -SO2R, where RX is a C, to C6 alkyl; or \\~--~
N~ ~\
*~~N
- , where Rd is a C, to C6 alkyl or a C6 to C$ aryl;
-a -NHCOR,, group, where R,, is:
-a C, 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 halo;
-a -NHCOORX group, where R,, is a Cl ta C6 alkyl;
-a -NRgRh group, where R. is a C, to C6 alkyl or a hydrogen and Rh is a hydrogen, Cl to C6 alkyI, or C6 to C8 aryl, the C, to C6 alkyl or C6 to C8 aryl optionally substituted with an alkoxy;
-a Cl to C6 alkyl;
-a 5 or 6 membered heteroaryl, optionally substituted with one or more of the following:
-a Ci to C6 alkyl, optionally substituted with one or more halos or a C6 to C$
aryl, -a C6 to C$ aryl, optionally substituted with -COORx, where R,, is a C 1 to C6 alkyl, -an amino group, or -a substituent from Group A;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR,, group, where R, is as defined above, or -a -NHCOORX group, where RX 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 halos, -a 5 or 6 membered heterocycle, optionally substituted with:
-a C, to C6 alkyl, or -a hydroxy, -a C6 to C8 aryl, optionally substituted with one or more substituents independently selected from Group A, -a a 5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from Group A, -an amino optionally substituted with one or more C, to C6 alkyls, -a -NR;SOZR., group, where R,e is a C, to C6 alkyl and R; is:
-a hydrogen, -a C, to C6 alkyl, -a -COR,, group, where R,, is as defmed 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 C, to C6 alkyls, and Rj is:
-a hydrogen, -a C, to C6 alkyl, - a-CORX group, where RJe is a C, to C6 alkyl, -a haloalkyl, or -a haloalkoxy, -a -N=N =N" group, or -a -COR,, where R, is a 5 or 6 membered heterocycle optionally substituted with a hydroxy, -an amino, -a C, to C6 alkyl group, optionally substituted with:
-a -NHSO2R, group, where R,, is as defined above, or -a -NRSOZRx group, where RX is as defined above, -a haloalkoxy, -a halo, -a hydroxy, -OC(O)NHR,,, -OC(O)N(RX)2, -OC(O)NH(ORx), -OC(O)NRõ(ORx), -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -COORx group, where Rõ is a Cl to C6 alkyl, -a -COR,,, group, where R,,, is:
-an amino optionally substituted with one or more CI to C6 alkyls, where the Cl 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 alkyls, -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a Ci 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 halos, -a nitro group, or -one or more alkoxys, -a -NRoCORP group, where Rp is:
-a C, to C6 alkyl optionally substituted with:
-a halo, -an alkoxy, or -a C6 to C8 aryl, -a 5 or 6 membered heterocycle, optionally substituted with one or more Cl to C6 alkyl or C6 to C8 aryl groups, -a C6 to C$ aryl, optionally substituted with a halo, -a 5 or 6 membered heteroaryl optionally substituted with one or more Cy to C6 alkyls, -a hydrogen, O
* O or I
O
~ N

and where R. is:
-a hydrogen, -a Cl to C6 alkyl, -a -COR., group, where RX is a Ci to C6 alkyl, -a haloalkyl, or -a haloalkoxy, -a -NRqCONRqR, group, where R. is:
-a hydrogen, -a C1 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
-halo, -a C1 to C6 alkyl optionally and independently substituted with one or more C6 to C8 aryl, halo and/or Ct to C6 alkoxy groups, -a C I to C6 alkoxy, -a C1 to C6 haloalkoxy, -a -ORs group, where RS is a C6 to C8 aryl, or -a -COORx group, where Rx is as defined above, -a Ci to C6 alkyl optionally substituted with one or more of the following:
-a halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle optionally substituted with one or more halo, C, to C6 alkyl, C, to C6 haloalkyl, C, to C6 alkoxy, Ci to C6 haloalkoxy, -a 5 or 6 membered heteroaryl optionally substituted with one or more halo, Cl to C6 alkyl, C, to C6 haloalkyl, C, to C6 alkoxy, C, to C6 haloalkoxy, -a C6 to C$ aryl optionally substituted with with one or more halo, C, to C6 alkyl, Ci to C6 haloalkyl, C, to C6 alkoxy, C, to C6 haloalkoxy, or -a -COOR,, group, where Rx is as clefined above, -a C2 to C6 alkylene group, -a Ci to C6 alkoxy group, -a 5 or 6 membered heterocycle group optionally substituted with with one or more halo, C, to C6 alkyl, Cl to C6 haloalkyl, C, to C6 alkoxy, C1 to C6 haloalkoxy, -a -COORx group, where RX is as defined above, -a -NRtCOORõ group, where Rõ is:
-a C, to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C$ aryl optionally substituted with one or more halo, Cl to C6 alkyl, C1 to C6 haloalkyl, C, to C6 alkoxy, C, to C6 haloalkoxy, -an alkylene, -an alkoxy, -an alkyne, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C1 to C6 alkyl, -halo, or -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, - a C2 to C6 alkylene, -a C6 to C8 aryl, optionally substituted with:
-an alkoxy, -a halo, or -a C, to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a CI to C6 alkyl, -a -COR,, group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRõSO2R, group, where Rõ is:
-a hydrogen, -a -COR,,, where Rx is as defined above, or -a Cz to C6 alkyl, optionally substituted with:
-a halo, -a -COR,, group, where Rx is as defined above, -a -OCOR,, group, where R, is as defined above, -a hydroxyl, or -an alkoxy, and where R,N is:
-a Cl to C6 alkyl optionally substituted with:
-a halo, -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 halo, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with one or more of the following:
-halo, -a Cl to C6 alkyl, -CI to C6 haloalkyl, -Cy to C6 alkoxy, - Ct to C6 haloalkoxy, -a 5 or 6 membered heterocycle, or - ~ N/
O
``:~,,O
" N"---a , O
* N
N substituted Ry - a , where RY is a hydrogen, C1 to C6 alkyl optionally substituted with a C, to C6 alkoxy, C1 to C6 haloalkyl, C6 to C8 aryl, 5 or 6 membered heteroaryl, or 5 or 6 membered heterocycle, where the C6 to C$ aryl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocycle are each optionally and independently substituted with one or more halo, C, to C6 alkyl, Ci to C6 alkoxy, C1 to C6 haloalkyl, Cl to C6 haloalkoxy, O

N substituted with Ry -a O ,where Ry is as described above, Rz O

N Ry -a O , where RY is as described above and R. is hydrogen or a Ct to C6 alkyl optionally substituted with a C6 to C8 aryl, O

D
-a *'' N

- ~./
a -a N

Y
e O S'~ N /
-a "--- N
'~'>
where Ry is as described above, -a -SRX group, where R,, is as defined above, -a -SO2Raa group, where R,,,, is:
-a C1 to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a-COOR,t group, where Rx is as defmed above, -a 5 or 6 membered heteroaryl, -a 5 or 6 heterocycle optionally substituted with hydroxy, a Cl to C6 alkoxy, or a a C, to C6 alkyl, where the alkyl is optionally substituted with one or more hydroxy, -aC6toC$aryl,or -a -NHRbb group, where Rbb is:

N

N

-a -C(=S)NH2 group, or -a -PO(OR,,)a, where Rx is as defined above;
-a " Rcc group, where R., is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a O
O
-a O
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, -an hydroxy, -a halo, -a C, to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Ct to C6 alkyls, -a -NHPOR,eR,,, where RX is as defined above, -a -NRaCONRffRff group, where Rce is a hydrogen or a Ci to C6 alkyl, optionally substituted with a halo, and Rtr is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a CF 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 halo, or -an amino optionally substituted with one or more Ct to C6 alkyls, -an amino optionally substituted with one or more Ca to C6 alkyls, where the alkyls are optionally substituted with a halo, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, and Rgg is:
-a hydrogen, -a Cl to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR,t group, where R,, is as defmed above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more Cy to C6 alkyls, -a NR;;SOaRX group, where R,, is as defmed above, and R;; is:
-a hydrogen, -a C, to C6 alkyl, -a haloalkyl, -a haloalkoxy, -a -CORX group, where R, is as defmed above;
.Z is:
-a hydrogen;
-a C1 to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halos, - a 5 or 6 membered heterocycle, or -a C6 to C8 aryl;
-a 5 or 6 membered heterocycle;
-a C2 to C6 alkylene;
-a C6 to Cg aryl optionally substituted with an alkoxy or one or more C, to C6 alkyls;
-a -COOR, group, where Rx is as defined above; or ' / .
R is a hydrogen, a halo or an alkoxy;
R, is:
-a hydrogen;
-a hydroxy;
-a halo;
-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 halos, -a C6 to C$ aryl optionally substituted with one or more halo, Ct to C6 alkyl, CI to C6 alkoxy, Ci to C6 haloalkyl, C, to C6 haloalkoxy, C, to C6 hydroxy, and/or SO2Rx groups, -a 5 or 6 membered heterocycle optionally substituted with one or more halo, C, to C6 alkyl, CI to C6 alkoxy, CI to C6 haloalkyl, CI to C6 haloalkoxy, C1 to C6 hydroxy, and/or SOZR,, groups, -a 5 or 6 membered heteroaryl optionally substituted with one or more halo, C, to C6 alkyl, CI to C6 alkoxy, CI to C6 haloalkyl, Ci to C6 haloalkoxy, CI to C6 hydroxy, and/or SO2RX groups, -an amino optionally substituted with a heterocycle;
-a C6 to C8 aryl optionally substituted with an alkoxy;
-a -COR. group, where Rq is as defined above;
-a C1 to C6 alkyl optionally substituted with one or more dialkyl-amino, a C6 to C8 aryl, a 5 or 6 membered heteroaryl, and/or a 5 or 6 membered heterocycle, where each of the C6 to C8 aryl, 5-or 6 membered heteroaryl, and 5 or 6 membered heterocycle is optionally substituted with one or more halo, C1 to C6 alkyl, Ct to C6 alkoxy, Cl to C6 haloalkyl, Cl to C6 haloalkoxy, Cl to C6 hydroxy, and/or SO2RX groups; or Ri joins together with R2 to form:
O O
O
O ~-, ., .
R2 is:
-a nitro group;
-a hydrogen;
-a halo;
-a hydroxy group;
-a Cl to C6 alkyl group, optionally substituted with one or more of the following:
-halos, -5 or 6 membered heterocycle group, optionally substituted with one or more halo, C, to C6 alkyl, CI to C6 alkoxy, C, to C6 haloalkyl, Cl to C6 haloalkoxy, C, to C6 hydroxy, and/or SO2R, groups, -5 or 6 membered heteroaryl group, is optionally substituted with one or more halo, C, to C6 alkyl, C, to C6 alkoxy, CI to C6 haloalkyl, Cl to C6 haloalkoxy, Cl to C6 hydroxy, and/or SO2Rx groups, -C6 to C8 aryl group, is optionally substituted with one or more halo, Ci to C6 alkyl, Cl to C6 alkoxy, C, to C6 haloalkyl, C, to C6 haloalkoxy, C, to C6 hydroxy, and/or SO2RX groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group optionally substituted with one or more Cl to C6 alkyl groups;
-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-halos, -hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an -OCORX group, where RX is as defined above, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or - an amino optionally substituted with one or more alkyl groups;
-a dialkyl-amino optionally substituted with an alkoxy, -a 4 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C, to C6 alkyl group, the C t to C6 alkyl group optionally substituted with one or more independently selected C, to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more independently selected halo, C, to C6 alkyl, CI to C6 alkoxy, C, to C6 haloalkyl, Ci to C6 haloalkoxy, C, to C6 hydroxy, and/or SOZRX groups, or -a C6 to C$ aryl group optionally substituted with one or more independently selected halo, Cl to C6 allcyl, Cl to C6 alkoxy, C, to C6 haloalkyl, Cl to C6 haloalkoxy, Cl to C6 hydroxy, and/or SOZR. groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to Cg aryl groups;
- a -COOH group;
-a -COORx group, where R,, is as defined above;
-a haloalkyl;
-a -C(O)NH2 optionally substituted with one or more of the following:
-C1 to C6 alkyl groups optionally substituted with one or more independently selected halo, C, to C6 alkoxy, Cl to C6 hydroxy, a 5 or 6 membered heterocycle and/or a 5 or 6 membered heteroaryl, -hydroxy groups, or -C6 to C8 aryl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-C I to C6 alkyl, -SO2R,, -C(O)-C6 to C8 aryl, -C(O)OR,,; or -hydroxy, -a 5 or 6 membered heteroaryl optionally substituted with one or more independently selected halo, C, to C6 alkyl, C1 to C6 alkoxy, Cl to C6 haloalkyl, C, to C6 haloalkoxy, C, to C6 hydroxy, and/or SOzRx groups;
-a -OCOR,e group, where Rx. is as defined above;
-a -NHCORij group, where Rjj is:

-an alkyl, -a C6 to C8 aryl, -an alkoxy, or -an amino optionally substituted with one or more Cl to C6 alkyls;
-an -ORkk group, where Rkk is -a C6 to C$ aryl optionally substituted with one or more independently selected halo, Ct to C6alkyl, CI to C6 alkoxy, C1 to C6 haloalkyl, Ci to C6 haloalkoxy, Ct to C6 hydroxy, and/or SO2Rx groups, -a 5 to 6 membered heteroaryl, optionally substituted with a halo, C, to C6 alkyl, Ci to C6 alkoxy, C, to C6 haloalkyl, C, to C6 haloalkoxy, Ct to C6 hydroxy, and/or SO2Rx groups, -a 5 to 6 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an Si(Rx)3;
-a -NHSO2R,e group, where Rx is as defined above; or R2 joins together with Rl to form:
O O `
O
=
O
R3 is:
-a hydrogen; or -CH2OCORx, and R,, is as defined above;
Group A is -a halo, -CI to C6 alkyl, -C1 to C6 alkoxy, -Ct to C6 haloalkyl, -CI to C6 haloalkoxy, -a -NRoCORp group, where RP is:
-a CI to C6 alkyl optionally substituted with:
-a halo, -an alkoxy, or -a C6 to C$ aryl, -a 5 or 6 membered heterocycle, optionally substituted with one or more Ca to C6 alkyl or Cb to C$ aryl groups, -a C6 to C$ aryl, optionally substituted with a halo, -a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls, -a hydrogen, O
~ or !
o'z>
_ and where Ro is:
-a hydrogen, -a Cl to C6 alkyl, -a -CORX group, where RX is a C, to C6 alkyl, -a haloalkyl, or -a haloalkoxy, -a NRyCONRqRr group, where Rq is:
-a hydrogen, -a C, to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR,, group, where Rx is as defined above, and where Rr is:
-a C6 to C8 aryl optionally substituted with:
N

, -halo, -a C, to C6 alkyl optionally and independently substituted with one or more Cg to Cg aryl, halo and/or CI to C6 alkoxy groups, -a Ci to C6 alkoxy, -a Ci to C6 haloalkoxy, -a -ORs group, where Rs is a C6 to C8 aryl, or -a -COORJe group, where R,, is as defined above, -a C1 to C6 alkyl optionally substituted with one or more of the following:
-a halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle optionally substituted with one or more halo, Ci to C6 alkyl, CI to C6 haloalkyl, C1 to C6 alkoxy, C, to C6 haloalkoxy, -a 5 or 6 membered heteroaryl optionally substituted with one or more halo, C, to C6 alkyl, C, to C6 haloalkyl, C, to C6 alkoxy, Ci to C6 haloalkoxy, -a C6 to C$ aryl optionally substituted with with one or more halo, C, to C6 alkyl, C, to C6 haloalkyl, C, to C6 alkoxy, C, to C6 haloalkoxy, or -a -COOR,, group, where R,, is as defined above, -a C2 to C6 alkylene group, -a Ci to C6 alkoxy group, -a 5 or 6 membered heterocycle group optionally substituted with with one or more halo, Ci to C6 alkyl, Ci to C6 haloalkyl, C, to C6 alkoxy, C1 to C6 haloalkoxy, -a -COOR,. group, where RX is as defmed above, -a -NRtCOORõ group, where Rõ is:
-a Ci to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C$ aryl optionally substituted with one or more halo, Ct to C6 alkyl, C, to C6 haloalkyl, C, to C6 alkoxy, C, to C6 haloalkoxy, -an alkylene, -an alkoxy, -an alkyne, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C, to C6 alkyl, -halo, or -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, - a C2 to C6 alkylene, -a C6 to C8 aryl, optionally substituted with:
-an alkoxy, -a halo, or -a C] to C6 alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a C, to C6 alkyl, -a -CORR group, where Rx is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRSOaRu, group, where R, is:
-a hydrogen, -a -CORX, where R,, is as defmed above, or -a C i to C6 alkyl, optionally substituted with:
-a halo, -a -CORX group, where R,, is as defmed above, -a -OCORX group, where R, is as defined above, -a hydroxyl, or -an alkoxy, and where RW is:
-a CI to C6 alkyl optionally substituted with:
-a halo, -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 halo, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl optionally substituted with one or more of the following:
-halo, -a Ci to C6 alkyl, -CI to C6 haloalkyl, -Ci to C6 alkoxy, - Cl to C6 haloalkoxy, -a 5 or 6 membered heterocycle, or - N
-a -SOZRaa group, where R,,,, is:
-a Ct to C6 alkyl, -an amino group, -an alkyl- or dialkyl-amino group optionally substituted with a hydroxy, a 5 or 6 membered heterocycle, a 5 or 6 membered heteroaryl, or a-COORx group, where RX is as defined above, -a 5 or 6 membered heteroaryl, -a 5 or 6 heterocycle optionally substituted with hydroxy, a C, to C6 alkoxy, or a a CI to C6 alkyl, where the alkyl is optionally substituted with one or more hydroxy, -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or -a -PO(ORx)2, where RX is as defined above;
-a -CORm group, where Rm is:
-an amino optionally substituted with one or more Cl to C6 alkyls, where the C, 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 alkyls, -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 -CH2CONT-12, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halos, -a nitro group, or -one or more alkoxys;
and L is a direct bond, C, to C12 alkylene, C2 to C12 alkenylene or C2 to C12 alkynylene, wherein one or more -CH2- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -0-, -S-, -SO2- and/or NRmm , and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s), halos, and/or hydroxy(s), where Rmm is hydrogen or C, to C6 allcyl;
or a pharmaceutical salt thereof.

In a further embodiment, the present invention includes compounds of Formula T, with the proviso that at least one of Y, Z, Rl and R2 is selected from the following:
y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Cl to C6 alkyls;
-an indole substituted on the nitrogen with an -SOZRX group;
-a C6 to C$ aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following:
-SO2R,, or -Ci to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRx, -OC(O)N(R,)2i -OC(O)NH(ORX), -OC(O)NRx(ORx), -OC(O)N(ORx)2, -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRoCORp group, where Rp is:
-an amino group optionally substituted with one or more Cl to C6 alkyl groups where the C, to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more CI to C6 alkyl or C6 to C8 aryl groups, -a -NRqCONRQRr group, where R, is:
-a C, to C6 alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl substituted with a halo, -a C2 to C6 alkylene group, -a Ci to C6 alkoxy group, or -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Rõ is:
-a C1 to C12 alkyl, substituted with one or more of the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C, to C6 alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, or ~
N/ \o V
-a , Z is:
-a Cl to C6 alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; or R, is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle;
R2 is:
-a Ci to C6 alkyl group, substituted with one or more of the following:
-5 or 6 membered heterocycle groups, or -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:

-a hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a 7 membered heterocycle group;
-a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Cl to C6 alkyl groups substituted with CI to C6 alkoxy, or -a 5 or 6 membered heteroaryl group substituted with one or more C, to C6 alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -COOH group;
-an amide group substituted with one or more C, to C6 alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-CI to C6 alkyl, -SOaRX, -C(O)-C6 to C8 aryl, or -C(O)OR. groups;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a Cy ta C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an -Si(Rx)3i or a pharmaceutically acceptable salt thereof.

In another embodiment, a compound of Formula I is included, with the proviso that at least one of X, Y, Z, Rl, and R2 is selected from the following:

X is:
-a -COOH group;

CH
I( N
-a C. to C6 alkoxy;
CH
!I
N
~'amino optionally substituted with one or more C1 to C6 alkyl -a groups -a halo;
-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a C1 to C6 alkyl optionally substituted with one or more halo or cyano groups;
-an oxime;
-SO2RX;
-S O2NH2;
-SO2NH(R,,);
-SOzN(Rx)2;
-an amino optionally substituted with one or more C, to C6 alkyl groups or C(O)- Ci to C6 alkyl groups;
-an amide group optionally substituted with one or more independently selected C, to C6 alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl substituted with one or more Cl to C6 alkyl groups substituted with one or more halos; or -a C6 to C8 aryl group substituted with one or more of the following:
-Cl to C6 alkyl optionally substituted with one or more halos, -halo, or -cyano;
I'' is:
-a benzothiazole substituted with an amino group optionally substituted with one or more CI to C6 alkyls;
-an indole substituted on the nitrogen with an SO2Rx group;
-a C6 to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following:
-SOzR7e, or -Cy to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRX, -OC(O)N(Rx)a, -OC(O)NH(ORX), -OC(O)NRX(ORx), -OC(O)N(ORx)2, -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a NRoCORp group, where Rp is:
-an amino group optionally substituted with one or more C, to C6 alkyl groups where the C, to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more C, to C6 alkyl or C6 to C$ aryl groups, -a -NRyCONRyRr group, where Rr is:
-a C, to C6 alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl substituted with a halo, -a C2 to C6 alkylene group, -a Cl to C6 alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Rõ is:
-a C, to C12 alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Cl to C6 alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, or N Q

-a ;

Z is:
-a Cl to C6 alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
Rl is:
-a Cl to C6 alkyl substituted with:
-an amide optionally substituted with a Ct to C6 alkyl, or -a 5 or 6 membered heteroaryl;
-a Cl to C6 alkoxy substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Ci to C6 alkyl, -a 5 or 6 membered heterocycle substituted with a Cl to C6 alkyl, or -a 5 or 6 membered heteroaryl;
-an (O)-5 or 6 membered heterocycle;
-an (O)-5 or 6 membered heteroaryl;
-an -SOZR,, group optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 t0 C8 aryl, -a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 to C8 aryl, -a 5 or 6 membered heteroaryl; or R2 is:
--a C, to C6 alkyl group, substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -5 or 6 membered heteroaryl groups, -C6 to C8 aryl groups, -an amide optionally substituted with a C, to C6 alkyl, or -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
-an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
-an alkylthio group optionally substituted with a C6 to C$ aryl group;

-an alkylthio group optionally substituted with a C, to C6 alkyl group;
-an SOzRX group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyl groups;
-an SO2R,. group optionally substituted witli a 5 or 6 membered heterocycle group;
-an SO2Rx group optionally substituted with a C6 to Cg aryl group;
-an SOzRx group optionally substituted with a Ct to C6 alkyl group;
-an S(O)R,e group optionally substituted with a 5 or 6 membered heteroaryl group;
-an S(O)R, group optionally substituted with a 5 or 6 membered heterocycle group;
-an S(O)R,, group optionally substituted with a C6 to Cs aryl group;
-an S(O)RX group optionally substituted witli a C, to C6 alkyl group;
-an alkoxy group substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-an amide optionally substituted with a C, to C6 alkyl, -S-5 or 6 membered heterocycle, -S-5 or 6 membered heteroaryl optionally substituted with a C, to C6 alkyl, -S-Ci to C6 alkyl, -S-C6 to C8 aryl, -sulfinyl-5 or 6 membered heterocycle, -sulfinyl-5 or 6 membered heteroaryl, -sulfinyl-C, to C6 alkyl, -sulfinyl-C6 to Cg aryl, -sulfonyl-5 or 6 membered heterocycle, -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a C, to C6 alkyl, -sulfonyl- C i to C6 alkyl, -sulfonyl- C6 to C8 aryl, -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Cl to C6 alkyl groups substituted with Ct to C6 alkoxy, or ' -a 5 or 6 membered heteroaryl group substituted with one or more Cl to C6 alkyl groups -a C6 to C8 aryl group;

-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -C(O)- C6 to C8 aryl;
-a -COOH group;
-an amide group substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more C i to C6 alkoxy;
-a 5 or 6 membered heterocycle, substituted with one or more of the following:
-hydroxy, -C, to C6 alkyl, . groups, -SO2R, -C(O)-C6 to C8 aryl, or -C(O)ORx groups;
-an -ORkk group, where Rkk is:
-a C6 to C8 aryl, -a 5 to 6 membered heterocycle, optionally substituted with a Ct to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an -5'i(RX)3;
-an (0)-5 or 6 membered heterocycle; or -an (0)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C, to C6 alkyl groups;

or a pharmaceutically acceptable salt thereof.
In another embodiment the present invention includes compounds of Formula I, with the proviso that with the proviso that at least one of Y, Z, and R2 is selected from the following:
Y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Ct to C6 alkyls;
-an indole substituted on the nitrogen with an -S zR,, group;
-a C6 to C$ aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following:
-S02R, or -C I to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR,,, -OC(O)N(RX)2, -OC(O)NH(ORX), -OC(O)NRx(ORx), -OC(O)N(ORx)z, -OC(O)R;,b, wherein RIIb is a 5 or 6 membered heterocycle group, -a -NRCORp group, where Rp is:
-an amino group optionally substituted with one or more Cr to C6 alkyl groups where the CI to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, substituted with one or more C1 to C6 alkyl or C6 to Cs aryl groups, -a -NRqCONRqRr group, where Rr is:
-a Ci to C6 alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl substituted with a halo, -a C2 to C6 alkylene group, -a C1 to C6 alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Ru is:
-a CI to C12 alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C, to C6 alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, N)t'.~' O
-a Z is:
-a C, to C6 alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
R2 is:

-a Ct to C6 'alkyl group, substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:
-hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a 7 membered heterocycle group;
-a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Cl to C6 alkyl groups substituted with C, to C6 alkoxy, or -a 5 or 6 membered heteroaryl group substituted with one or more C, to C6 alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to Cg aryl groups;
-a -COOH group;
-an amide group substituted with one or more C, to C6 alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-CI to C6 alkyl, -SO2RX group, -C(O)-C6 to C8 aryl, or -C(O)OR. groups;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a CI to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an -Si(Rx)3;
or a pharmaceutically acceptable salt thereof.

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 Ci to C12, or C1 to C8 or Cl to C6 alkyl groups.
As used herein, "alkylene" generally refers to straight, 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, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene, fiuran, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole, oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine, pyrrole, quinoline, 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 defined 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 funetionalities encompassing X, Y, Z, R, Ri, R2, and R3, are incorporated into a compound of the present invention, 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 another embodiment, the present invention includes compounds of Formula (I-X) R X

y N

Z

(I-X) wherein:

X is:
-a cyano group;

Y is:
-a hydrogen;
-a haloalkyl;
-a halo;
-an amino optionally substituted with one or more C1 to C6 alkyls;
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more C, to C6 alkyls;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a Ci to C6 alkyl or an -SO2RX group;
O

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

- , where & is a hydrogen, a-CONHR,,, where R,. is a C, to Cg alkyl, or an -SO2RX, where R., is a C, to C6 alkyl; or ~\ ~

N-' \\

- , where Rd is a C, to C6 alkyl or a C6 to C8 aryl;
-a -NHCO& group, where Re is:
-a C1 to C6 alkyl;
-a C6 to C8 aryl optionally substituted with:
-a C, to C6 alkyl, -an alkoxy, -a cyano group, -a nitro group, or -a halo;
-a -NHCOOR,, group, where R,. is a CI to C6 alkyl;
-a -CH2O-Rfgroup, where Rf is a C6 to C8 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 C8 aryl, -a C6 to C8 aryl, optionally substituted with -COOR,t, where Rx is a Ci to C6 alkyl, 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 C$ aryl, optionally substituted with one or more of the following:
-an alkoxy, optionally substituted with:
-an alkoxy, -a hydroxy, -one or more halos, -a 5 or 6 membered heterocycle, optionally substituted with:
-a C, to C6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more C, to C6 alkyls, -a -NR;SO2Rx group, where R,, is a C, to C6 alkyl 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 -NR;CORk group, where Rk is:
-a C, to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more C, to C6 alkyls, and Rj is:
-a hydrogen, -a Cl to C6 alkyl, -a -COR, group, where RX is a C, to C6 alkyl, -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, -aan amino optionally substituted with one or more of the following:
-SO2(RX), or -C1 to C6 alkyl, the C, to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -a nitro group, -a C, to C6 alkyl group, optionally substituted with:
-a -NHSOaRx group, where R,, is as defined above, or -a -NR,,SO2RR group, where RX is as defined above, -a haloalkoxy, -a halo, -a hydroxy, -OC(O)NHRx, -OC(O)N(RX)2, -OC(O)NH(OR,t), -OC(O)NRx(ORx), -OC(O)N(ORx)Z, -OC(O)Rxb, wherein Rab is a 5 or 6 membered heterocycle group, -a -COOR,, group, where RX is a C, to C6 alkyl, -a -CORm group, where R,,, is:
-an amino optionally substituted with one or more Ci to C6 alkyls, where the Cl to C6 alkyls are optionally substituted with:
-a hydroxy, -a 5 or 6 mernbered heterocycle, -an amino optionally substituted with one or more C, to C6 alkyls, or -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a Ct to C6 alkyl, optionally substituted with a dialkyl-amino, or -a -NHRõ group, where Rõ is:
-a -CH2CONH2, or -a C6 to C8 aryl optionally substituted with:
-an alkyl, -one or more halos, -a nitro group, or -one or more alkoxys, -a -NRCORp group, where Rp is:
-a Ci to C6 alkyl optionally substituted with:
-a halo, -an alkoxy, or -a C6 to C8 aryl, -an amino group optionally substituted with one or more C1 to C6 alkyl groups where the C1 to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more C, to C6 alkyl or C6 to C8 aryl groups, -a C6 to Cs aryl, optionally substituted with a halo, -a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls, -a hydrogen, cx> O
* or and where Ro is:

-a hydrogen, -a C1 to C6 alkyl, -a -CORX group, where RX is a Cl to C6 alkyl, -a haloalkyl, or -a haloalkoxy, -a -1VRyCONRqRr group, where Rq is:
-a hydrogen, -a CI to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR, group, where RX is as defined above, and where Rr is:
-a C6 to C8 aryl optionally substituted with:
N
O
-N
-a C1 t0 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 halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, -a C6 to CS aryl optionally substituted with a halo, or -a -COORx group, where R,, is as defined above, -a C2 to C6 alkylene group, -a Ci to C6 alkoxy group, -a 5 or 6 membered heterocycle group, or -a -COOR,, group, where R7e is as defined above, -a NR,COORõ group, where Rõ is:
-a CI to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo, C, to C6 alkyl, or alkoxy, -an alkylene, -an alkoxy, -an alkyne, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C, to C6 alkyl, -halo, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to Cs aryl, optionally substituted with:
-an alkoxy, -a halo, or -a CI to Cb alkyl, or -a 5 or 6 membered heterocycle, and Rt is:
-a hydrogen, -a C, to C6 alkyl, -a -CORx group, where R, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NRõSO2R, group, where Rõ is:
-a hydrogen, -a -CORx, where Rx is as defined above, or -a Ci to C6 alkyl, optionally substituted with:
-a halo, -a -CORx group, where R,; is as defined above, -a -OCORX group, where R,, is as defined above, -a hydroxyl, or -an alkoxy, and where RW is:
-a C, to C6 alkyl optionally substituted with:
-a halo, -a halo alkyl, -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 halo, -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 , O
``%
N~

-a , O
" N
NH
-a , O

NH
*~-N

-a O , Ry N Ry -a O , optionally substituted with a C1 to C6 alkyl, where Ry is a C, to C6 alkyl or hydrogen, O

n ''~N
*~

~
N O
-a O O
-a *_'-N
i), O Rz II j O S

-a N 1--> , where R. is hydrogen or a CI to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SRx group, where RX is as defined above, -a -SO2Raa 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-COOR,, group, where RX is as defined above, or -a 5 or 6 membered heteroaryl, -a C6 to C$ aryl, or -a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or -a -PO(ORX)2, where Rx is as defined above; or -a Roe group, where &c is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a -a C6 to CS aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halo, -a C, to C6 alkyl, optionally substituted with a cyano group, -an amino optionally substituted with one or more Cl to C6 alkyls, -a -NHPORRX, where R,e is as defined above, -a -NR,,.CONRffRff group, where Rce is a hydrogen or a C1 to C6 alkyl, optionally substituted with a halo, and Rtr is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a Ci to C6 alkyl, or -a -CORX, 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 halo, or -an amino optionally substituted with one or more Cl to C6 alkyls, -an amino optionally substituted with one or more C, to C6 alkyls, where the alkyls are optionally substituted with a halo, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl, and Rgs is:
-a hydrogen, -a. CI to C 6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR,t group, where RX is as defined above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more C, to C6 alkyls, or -a -NR;iSOzR,, group, where RX is as defined above, and R;; is:
-a hydrogen, -a C, to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORX group, where RR is as defined above;
Z is:
-a hydrogen;
-a Cl to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halos, -a 5 or 6 membered heterocycle, or -a C6 to Cg aryl;
-a 5 or 6 membered heterocycle;
-a C2 to C6 alkylene;
-a C6 to Cg aryl optionally substituted with an alkoxy or otie or more C, to C6 alkyls;
-a -COORõ group, where Rx is as defined above; or O

O--J
R is a hydrogen, a halo or an alkoxy;
R, is:
-a hydrogen;
-a hydroxy;
-a halo;
-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 halos, -a C6 to C8 aryl, -a 5 or 6 membered heterocycle, or -an amino optionally substituted with a heterocycle;
-a C6 to C$ aryl optionally substituted with an alkoxy;
-a -COR,, group, where R., is as defined above; or -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 ~
or O
. 0 R2 is:
-a nitro group;
-a hydrogen;
-a halo;
-a hydroxy group;

-a C1 to C6 alkyl group, optionally substituted with one or more of the following:
-halos, -5 or 6 membered heterocycle groups, or -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group;
-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-halos, -a hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an -OCORX group, where R. is as defined above, or -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C, to C6 alkyl group, the C, to C6 alkyl group optionally substituted with one or more independently selected CI to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more C, to C6 alkyl groups, or -a C6 to C8 aryl group;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -COOH group;
-a -COORX group, where R, is as defined above;
-a haloalkyl;
-an amide group optionally substituted with one or more of the following:
-Ci to C6 alkyl groups, -hydroxy groups, or -C6 to C8 aryl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:

-C I to C6 alkyl, -SO2R,ef -C(O)-C6 to C8 aryl, or -C(O)ORx groups;
-a 5 or 6 membered heteroaryl;
-a -OCORx group, where R,, is as defined above;
-a -NHCORjj group, where Rjj is:
-an alkoxy, or -an amino optionally substituted with one or more Ci to C6 alkyls;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heteroaryl, -a 5 to 6 membered heterocycle, optionally substituted with a Cy to C6 alkyl, optionally substituted with a C6 to Cs aryl group, or -an Si(Rx)3; or -a NHSO2Rx group, where R,e is as defined above; or R2 joins together with R, to form:
O O
or O
`. '~.
% 0 ; and R3 is:
-a hydrogen; or -CHzOCOR., and Rx is as defined above;

or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention includes compounds of Formula (I-Xa) R x R, \ ` .
y N

z (I-Xa) wherein X is:
-a cyano group;
Y is:
-a hydrogen;
-a haloalkyl;
-a halo;
-an amino optionally substituted with one or more Ct to C6 alkyls;
-a benzofuran;
-a benzothiophene;
-a dibenzofuran;
-a dibenzothiophene;
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more CI to C6 alkyls;
-a naphthalene;
-an indole, optionally substituted on the nitrogen with a C, to C6 alkyl or an -SO2RX;
X O

p w O
(CHA
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-CONHR,t, where R,, is a C, to C6 alkyl, or an -SO2R, where R,, is a C, to C6 alkyl; or O
\ /-.Rd N \\ r - , where Rd is a CI to C6 alkyl or a C6 to C$ aryl;
-a -NHCORC group, where Re is:
-a C, 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 halo;
-a -NHCOORx group, where RX is a C, to C6 alkyl;
-a -CH2O-Rfgroup, where Rf is a C6 to CS aryl;
-a -NRFRh group, where Rg is a Ci 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 CI to C6 alkyl, optionally substituted with a C6 to C$ aryl, -a C6 to C8 aryl, optionally substituted with -COOR, where R,, is a Ci to C6 alkyl, or -an amino group;
-a 5 or 6 membered heterocycle optionally substituted with:
-a -COOR,, group, where RR is as defmed above, or -a -NHCOOR,, 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 halos, -a 5 or 6 membered heterocycle, optionally substituted with:
-a C, to C6 alkyl, or -a hydroxy, -an amino optionally substituted with one or more Cl to C6 alkyls, -a -NR;SO2R,e group, where RX is a C, to C6 alkyl and R; is:
-a hydrogen, -a Cl to C6 alkyl, -a -COR,, group, where R,, is as defined above, -a haloalkyl, or -a haloalkoxy, -a -NR;CORk group, where Rk is:
-a C, to C6 alkyl, -a hydrogen, or -an amino optionally substituted with one or more C, to C6 alkyls, and Rj is:
-a hydrogen, -a C I to C6 alkyl, -a -CORX group, where R. is a C, to C6 alkyl, -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 of the following:
-SO2(Rx), or -Cl to C6 alkyl, the C, to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -a nitro group, -a C, to C6 alkyl group, optionally substituted with:
-a -NHSO2RX group, where Rx is as defined above, or -a -NR,tSO2Rx group, where R7z is as defined above, -a haloalkoxy, -a halo, -a hydroxy, -OC(O)NHR,c, -OC(O)N(RX)2a -OC(O)NH(OR,,), -OC(O)NRX(ORX), -OC(O)N(ORX)2a -OC(O)Rab, wherein Rgb is a 5 or 6 membered heterocycle group, -a -COORX group, where Rx is a C i to C6 alkyl, -a -COR,,, group, where R,,, is:
-an amino optionally substituted with one or more C, to C6 alkyls, where the C, 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 alkyls, or -an alkoxy, -a 3 to 7 membered heterocycle, optionally substituted with a Ct 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 halos, -a nitro group, or -one or more alkoxys, -a -NRoCORQ group, where Rp is:
-a Cl to C6 alkyl optionally substituted with:
-a halo, -an alkoxy, or -a C6 to C8 aryl, -an amino group optionally substituted with one or more C1 to C6 alkyl groups where the Ci to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more C, to C6 alkyl or C6 to C8 aryl groups, -a C6 to C8 aryl, optionally substituted with a halo, -a 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls, -a hydrogen, O
~.~N`
* Q or o N

and where Ra is:
-a hydrogen, -a Cl to C6 alkyl, -a -COR,e group, where RX is a C, to C6 alkyl, -a haloalkyl, or -a haloalkoxy, -a -NRyCONRqRr group, where Rq is:
-a hydrogen, -a C1 to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR, group, where RX is as defined above, and where Rr is:
-a C6 to C8 aryl optionally substituted with:
N

-N
-a C I to C6 alkyl, -a haloalkyl, -a -OR, group, where RS is a C6 to C8 aryl, or -a -COORx group, where RR is as defined above, -a C, to C6 alkyl optionally substituted with one or more of the following:
-a halo, -a hydroxyl, -an alkoxy, -an alkylene, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl optionally substituted with a halo, or -a -COORX group, where Rx is as defined above, -a Cz to C6 alkylene group, -a C, to C6 alkoxy group, -a 5 or 6 membered heterocycle group, or -a -COORR group, where RX is as defined above, -a NR,COORõ group, where Ru is:
-a C, to C12 alkyl, optionally substituted with one or more of the following:
-a C6 to C8 aryl optionally substituted with halo, Ci to C6 alkyl, or alkoxy, -an alkylene, -an alkoxy, -an alkyne, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C1 to C6 alkyl, -halo, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to C8 aryl, optionally substituted with:
-an alkoxy, -a halo, or -a C1 to C6 alkyl, or -a 5 or 6 membered heterocycle, and R, is:
-a hydrogen, -a CI to C6 alkyl, -a -COR, group, where RX 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 C 1 to C6 alkyl, optionally substituted with:
-a halo, -a -CORX group, where R, is as defined above, -a -OCOR,. group, where RX is as defined above, -a hydroxyl, or -an alkoxy, and where RN, is:
-a CI to C6 alkyl optionally substituted with:
-a halo, -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 halo, -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 . * ~

- \ N/
O

%
D
-a , O
* N
NH
-a , O

NH
,.,_N

-a O , Ry O

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

,N
-a rv o -a O

-a N
O Rz 11 , ~
N
O S
I
-a *'~N , where RL is hydrogen or a Ci to C6 alkyl, optionally substituted with a C6 to C8 aryl, -a -SR,e group, where R,t is as defined above, -an -SOZRaa grOUp, where Raa 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, or -a 5 or 6 membered heteroaryl, -a C6 to C8 aryl, or -a -NHRbb group, where Rbb is:
.
N

*+ ~ N
-a -C(=S)NH2 group, or -a -PO(ORx)Z, where Rx is as defined above; or -a " Rcc group, where &, is:
-a naphthalene, -a 5 or 6 membered heteroaryl, O
-a O , or -a C6 to C8 aryl, optionally substituted with one or more of the following:
-an alkoxy, -a hydroxy, -a halo, -a Ct to C6 alkyl, optionally substituted with a cyan.o group, -an amino optionally substituted with one or more C, to C6 alkyls, -a NHPOR,,RX, where RX is as defmed above, -a -NRceCONRffRff group, where R,,, is a hydrogen or a Cl to C6 alkyl, optionally substituted with a halo, and Rff is:
-a hydrogen, -a haloalkyl, -a haloalkoxy, -a Cl to C6 alkyl, or -a -COR,,, where R,; is as defined above, -a -NR$gCORhh group, where Rhh is:
-a hydrogen, -a Ci to C6 alkyl optionally substituted with:
-an alkoxy, -a halo, or -an amino optionally substituted with one or more C, to C6 alkyls, -an amino optionally substituted with one or more C, to C6 alkyls, where the alkyls are optionally substituted with a halo, -a 5 or 6 membered heterocycle, or -a 5 or 6 membered heteroaryl, and Rgg is:
-a hydrogen, -a C t to C g alkyl, -a haloalkyl, -a haloalkoxy, or -a -COR,, group, where R,, is as defmed above, -a haloalkyl, -5 or 6 membered heterocycle groups, -an amino optionally substituted with one or more C, to C6 alkyls, or -a -NRiiSO2RX group, where R,, is as defined above, and R;i is:
-a hydrogen, -a C I to C6 alkyl, -a haloalkyl, -a haloalkoxy, or -a -CORX group, where RX is as defmed above;
Z is:
-a hydrogen;
-a C, to C6 alkyl optionally substituted with:
-an alkoxy, -one or more halos, -a 5 or 6 membered heterocycle, or -a C6 to C$ aryl;
-a 5 or 6 membered heterocycle;

-a C2 to C6 alkylene;
-a C6 to C8 aryl optionally substituted with an alkoxy or one or more C, to C6 alkyls;
-a -COOR, group, where R, is as defined above; or I /
O
_ Q'/

R is a hydrogen, a halo or an alkoxy;
R, is:
-a hydrogen;
-a hydroxy;
-a halo;
-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 halos, -a C6 to C8 aryl, -a 5 or 6 membered heterocycle, or -an amino optionally substituted with 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; or -a C, to C6 alkyl optionally substituted with a dialkyl-amino or a 5 or 6 membered heterocycle;
or R.1 joins together with R2 to form:
O
O

or O
)%""
O

Ra is:
-a nitro group;

-a hydrogen;
-a halo;
-a hydroxy group;
-a C1 to C6 alkyl group, optionally substituted with one or more of the following:
-halos, -5 or 6 membered heterocycle groups, or -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an amino group;
-an alkoxy group optionally substituted with one or more of the following:
-halos, -a hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an -OCORx group, where Rx is as defined above, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a dialkyl-amino optionally substituted with an alkoxy, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C, to C6 alkyl group, the C, to C6 alkyl group optionally substituted with one or more independently selected C, to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Cl to C6 alkyl groups, or -a C6 to C8 aryl group;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C$ aryl groups;
-a -COOH group;
-a -COORx group, where Rx is as defined above;
-a haloalkyl;
-an amide group optionally substituted with one or more of the following:
-CI to C6 alkyl groups, --hydroxy groups, or -C6 to Cg aryl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-C I to C6 alkyl, -SOZRx groups, -C(O)-C6 to Cs aryl, or -C(O)OR,, groups;
-a 5 or 6 membered heteroaryl;
-a -OCORx group, where R, is as defined above;
-a -NHCOR;; group, where R;; is:
-an alkoxy, or -an amino optionally substituted with one or more C1 to C6 allcyls;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heteroaryl, -a 5 to 6 membered heterocycle, optionally substituted with a C1 to C6 alkyl, optionally substituted with a C6 to Cg aryl group, or -an -Si(RX)3;
-a -NHSOzR, , group, where RX is as defined above; or R2 joins together with R, to form:

or O
~ ~.
O
and R3 is:
-a hydrogen; or -CH2OCOR,,, and RX is as defined above;

with the proviso that at least one of Y, Z, R, and R2 is selected from the following:
Y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Cl to Cg alkyls;
-an indole substituted on the nitrogen with an -SO2R,, group;
-a C6 to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following:
-SO2RX, or -CI to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR,, -OC(O)N(Rx)2>
-OC(O)NH(OR,j, -OC(O)NRx(ORX), -OC(O)N(ORX)2, -OC(O)Ra6, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRoCORP group, where Rp is:
-an amino group optionally substituted with one or more C, to C6 alkyl groups where the Cl to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups andlor alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more Cl to C6 alkyl or C6 to C& aryl groups, -a -NRqCONRQRr group, where Rr is:
-a C, to C6 alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C$ aryl substituted with a halo, -a C2 to C6 alkylene group, -a Ct to C6 alkoxy group, or -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where R. is:
-a Cl to C12 alkyl, substituted with one or more of the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C3 to C6 alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, or . Jj ~./
-a - 63 -Z is:
-a C, to C6 alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle; or R, is an alkoxy substituted with an amino, where the amino is optionally substituted with a heterocycle;

R2 is:
-a Ct to C6 alkyl group, substituted with one or more of the following:
-5 or 6 membered heterocycle groups, or -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:
-a hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a 7 membered heterocycle group;
-a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Cl to C6 alkyl groups substituted with Ct to C6 alkoxy, or -a 5 or 6 membered heteroaryl group substituted with one or more C1 to C6 alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to Cg aryl groups;
-a -COOH group;
-an amide group substituted with one or more C1 to C6 alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-CI to C6 alkyl, -SO2Rx, -C(O)-C6 to C8 aryl, or -C(O)ORX groups;

-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an -S1(RX)3i or a pharmaceutically acceptable salt thereof.

In some embodiments, R is selected from the R substituents of compounds 1330-and 2600-3348.
In some embodiments of the invention, compounds are provided wherein R is selected from the following non-limiting substituents:

CI *
H
In other embodiments of the invention, R is hydrogen.
In some embodiments of the invention, Rt is selected from the following non-limiting substituents:

0~*
O ~Ol ~* N
-O' connects Rl and R2 F F O\*
(0~Br~,* CI"*
0-1*
connects R1 and R2 F~=
* F

"1O
F,* / I H.O'*
N~*
~ *

0 CO) N *
H

In some embodiments of the invention, R2 is selected from the following non-limiting substituents:

4 :
* ~O~* H\011 N+
O O~

H O
CN~ N O~N~
N O O H F O

O~* (0"1*
O O
O -r connects Rl and R2 connects R1 and R2 H N ~* N N~ HO- N~*

F~ *
F~ ~ CI~* F~\
F
O
N'- N"---\O~* O") N

CI S \ N~ \O~
N0 N~/=~O~* N~~0 i N, ~O
N -_~\\N
N F
N H
~ N 0 F ~O
O-*

O O OO.-<J N ~N

O *
O p 0 N
N
CN ~ N
N~N p~/' 0 S,p N~
H N
H N ~p~~' 0 ~SO
, O O N
H
F

S * ~,O
-o F .N OS`N `ON
F H H H
O

N~N~ * H * Br H H

* H, ~
Br~ p~ N Q
H
p N / J p * * * ~
O N~ L J ~'N J
v 0 .11* ~ O p O pi ~
H O-*
O
p~* \~N0 p--N_,_, 'ONO~= N

N ov CN O~

In some embodiments, R3 is selected from the R3 substituents of compounds 1330-2128, and 2600-3348.

In some embodiments of the invention, compounds are provided wherein R3 is selected from the following non-limiting subsituents:

*
0 *
~ H
O

In other embodiments of the invention, compounds are provided wherein R3 is hydrogen.
In another embodiment, the present invention includes a compound of Formula (I-XI) R x R, ~. \
Y
N

z (I-XI) wherein:
X is:
-hydrogen;
-a cyano group;
-a nitro group;
-a formyl group;
-a -COOH group;
-a CORx group, wherein Rx is a C1 to C6 alkyl;
CH
I I

-a C, to C6 alkoxy;
CH
I!
N
"~amino optionally substituted with one or rnore C, to C6 alkyl -a groups -a halo;

-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a Ci to C6 alkyl optionally substituted with one or more independently selected halo or cyano groups;
-an oxime;
-SO2RX;
-SO2NH2;
-SO2NH(R,);
-SO2N(Rx)2;
-an amino optionally substituted with one or more Cl to C6 alkyl groups or C(O)- Ct to C6 alkyl groups;
-an amide group optionally substituted with one or more independently selected Cl to C6 alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl optionally substituted with one or more Ci to C6 alkyl groups optionally substituted with one or more halos; or -a C6 to C$ aryl group optionally substituted with one or more of the following:
-C1 to C6 alkyl optionally substituted with one or more halos, -halo, or -cyano;
Y is:
-a benzothiazoie optionally substituted with an amino group optionally substituted with one or more C1 to C6 alkyls;
-an indole, optionally substituted on the nitrogen with an -SO2RX group; or -a C6 to C8 aryl, optionally substituted with one or more of the following:
-halo;
-a C, to C6 alkyl;
-an alkoxy, -an amino optionally substituted with one or more of the following:
-SO2RX, -Ci to C6 alkyl, the C, to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or -PO2RX, -OC(O)NHRX, -OC(O)N(Rx)2, -OC(O)NH(ORX), -OC(O)NR,e(ORX), -OC(O)N(ORX)2, -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRoCORp group, where RP is:
-a C i to C6 alkyl, -an amino group optionally substituted with one or more C, to C6 alkyl groups where the C, to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, optionally substituted with one or more CI to C6 alkyl or C6 to C8 aryl groups, and where Ro is:
-a hydrogen, or -a C, to C6 alkyl, -a -NRqCONRyRr group, where Ry is a hydrogen, and where Rr is:
-a Ci to C6 alkyl optionally substituted with one or more of the following:
-halo, -hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl optionally substituted with a halo, -a C2 to C6 alkylene group optionally substituted with one or more halo, -a CI to C6 alkoxy group, or -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where R,, is:
-a CI to Ci2 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Cl to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C2 ta C6 alkylene, or -a C6 to C8 aryl, optionally substituted with halo, and Ri is:
-a hydrogen;
-a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or -a -PO(ORX)2, where R. is as defined above;
-a -NRõSOaRw group, where R,, is a hydrogen, and where R,,, is a Cl to C6 alkyl, O
`` ~O

* N~-a , or 4~ yJ
N/^\O
-a Z is:
-a Cl to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;

R is a hydrogen;
Rl is:
-a hydrogen;
-a C1 to C6 alkyl optionally substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Cl to C6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Ct to C6 alkyl, -a 5 or 6 membered heteroaryl, or -a C6 to CS aryl;
-a Cl to C6 alkoxy optionally substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Cl to C6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a Cl to C6 alkyl, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl;
-an (O)-5 or 6 membered heterocycle;
-an (0)-5 or 6 membered heteroaryl;
-an -S02R,e group optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 to C8 aryl, -a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 to C8 aryl, -a 5 or 6 membered heteroaryl;
R2 is:
-a Ci to C6 alkyl group, optionally substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -5 or 6 membered heteroaryl groups, -C6 to C8 aryl groups, -an amide optionally substituted with a C1 to C6 alkyl, or -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
-an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
-an alkylthio group optionally substituted with a C6 to C8 aryl group;
-an alkylthio group optionally substituted with a CI to C6 alkyl group;
-an SOZRX group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted witli one or more Ct to C6 alkyl groups;
-an SO2RX group optionally substituted with a 5 or 6 membered heterocycle group;
-an SO2Rx group optionally substituted with a C6 to C8 aryl group;
-an S02RX group optionally substituted with a C, to C6 alkyl group;
-an S(O)R,, group optionally substituted with a 5 or 6 membered heteroaryl group;
-an S(O)R,, group optionally substituted with a 5 or 6 membered heterocycle group;
-an S(O)RX group optionally substituted with a C6 to C8 aryl group;
-an S(O)Rx group optionally substituted with a C, to C6 alkyl group;

-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-halo, -hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an amino group optionally substituted with one or more 5 or 6 membered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-5 or 6 membered heterocycle, or -amino optionally substituted with one or more alkyl groups, -an amide optionally substituted with a C1 to C6 alkyl, -S-5 or 6 membered heterocycle, -S-5 or 6 membered heteroaryl optionally substituted with a C, to C6 alkyl, -S-Cl to C6 alkyl, -S-C6 to Cg aryl, -sulfinyl-5 or 6 membered heterocycle, -sulfinyl-5 or 6 membered heteroaryl, -sulfinyl-Cl to C6 alkyl, -sulfinyl-C6 to Cs aryl, -sulfonyl-5 or 6 membered heterocycle, -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ct to C6 alkyl, -sulfonyl- C, to C6 alkyl, -sulfonyl- C6 to Cg aryl, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the Ci to C6 alkyl group optionally substituted with one or more independently selected CI to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more Cl to C6 alkyl groups, -a C6 to C8 aryl group;
-a C6 to Cg aryl group;
-an (O)-5 or 6 membered heterocycle;
-an (0)-5 or 6 membered heteroaryl optionally substituted viwith one or more independently selected C1 to C6 alkyl groups;

-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -C(O)-5 or 6 membered heteroaryl;
-a -C(O)- C6 to C$ aryl;
-a -COOH group;
-an amide group optionally substituted with one or more C, to C6 alkyl groups optionally substituted with one or more Cl to C6 alkoxy;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-hydroxy, -C a to C6 alkyl, -SO2Rx, -C(O)-C6 to C8 aryl, or -C(O)ORX groups;
-an -ORkk group, where Rkk is:
-a C6 to Cg ary1, -a 5 to 6 membered heteroaryl, -a 5 to 6 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an -Si(Rx)3i and R3 is a hydrogen;

or a pharmaceutically acceptable salt thereof.

In a further embodiment of the present invention, compounds of the present invention include compounds of Formula (I-XIa) R x R, y N

Z

(I-XIa) wherein:
X is:

-hydrogen;
-a cyano group;
-a nitro group;
-a formyl group;
-a -COOH group;
-a COR,, group, wherein R,, is a C, to C6 alkyl;
CH
II
N
-a Cl to C6 alkoxy;
CH
ll N
~ amino optionally substituted with one or more C, to Cs alkyl -a groups -a halo;
-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a C, to C6 alkyl optionally substituted with one or more halo or cyano groups;
-an oxime;
-SO2Rx;
-SO2NH2;
-SO2NH(Rx);
-SO2N(Rx)2i -an amino optionally substituted with one or more C, to C6 alkyl groups or C(O)- C, to C6 alkyl groups;
-an amide group optionally substituted with one or more independently selected Cl to C6 alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl optionally substituted with one or more CI to C6 alkyl groups optionally substituted with one or more halos; or -a C6 to C8 aryl group optionally substituted with one or more of the following:
-Cl to C6 alkyl optionally substituted with one or more halos, -halo, or -cyano;
Y is:

-a benzothiazole optionally substituted with an amino group optionally substituted with one or more C, to C6 alkyls; I
-an indole, optionally substituted on the nitrogen with a-SO2R,, group;
-a C6 to C8 aryl, optionally substituted with one or more of the following:
-halo;
-a Ci to C6 alkyl;
-an allcoxy, -an amino optionally substituted with one or more -SO2RX groups, -CI to C6 alkyl, the C, to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, or -PO2R,, groups, -OC(O)NHRx, -OC(O)N(RX)2, -OC(O)NH(ORx), -OC(O)NRX(ORx), -OC(O)N(ORX)2, -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRoCORp group, where Rp is:
-a C 1 to C6 alkyl, -an amino group optionally substituted with one or more C, to C6 alkyl groups where the Cl to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more C, to C6 alkyl or C6 to C$ aryl groups, and where Ro is:
-a hydrogen, -a Ci to C6 alkyl, -a -NRgCONR9R,. group, where Rq is a hydrogen, and where Rr is:
-a Cl to C6 alkyl optionally substituted with one or more of the following:
-halo, -hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl optionally substituted with a halo, -a C2 to C6 alkylene group optionally substituted with one or more halo, -a C I to C6 alkoxy group, or -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Ru is:
-a C, to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to CS aryl optionally substituted with halo, -an allcoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C, to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to C8 aryl, optionally substituted with halo, and RI is a hydrogen;
-a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or -a -PO(OR7e)2a where Rx is as defined above;
-a -NRSO2R,y group, where Rv is a hydrogen, and where Rw is a C, to C6 alkyl, O

~ ``~O
-a N , or (i ~ N~1" p -a Z is:
-a Cl to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;

R is a hydrogen;

R, is:
-a hydrogen;
-a Cl to C6 alkyl optionally substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl;
-a C, to C6 alkoxy optionally substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a C1 to C6 alkyl, -a 5 or 6 membered heterocycle optionally substituted with a C, to C6 alkyl, -a 5 or 6 membered heteroaryl, or -a C6 to C$ aryl;
-an (0)-5 or 6 membered heterocycle;
-an (0)-5 or 6 membered heteroaryl;
-an -S 2RX group optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 to C8 aryl, -a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 to C8 aryl, -a 5 or 6 membered heteroaryl;
R2 is:
-a Cl to C6 alkyl group, optionally substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -5 or 6 membered heteroaryl groups, -C6 to Cg aryl groups, -an amide optionally substituted with a C1 to C6 alkyl, or -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;

-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
-an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
-an alkylthio group optionally substituted with a C6 to C8 aryl group;
-an alkylthio group optionally substituted with a C1 to C6 alkyl group;
-an SO2R,; group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more Cl to C6 alkyl groups;
-an SO2RX group optionally substituted with a 5 or 6 membered heterocycle group;
-an SO2RX group optionally substituted with a C6 to Cg aryl group;
-an SO2RX group optionally substituted with a C1 to C6 alkyl group;
-an S(O)RX group optionally substituted with a 5 or 6 membered heteroaryl group;
-an S(O)RX group optionally substituted with a 5 or 6 membered heterocycle group;
-an S(O)R,, group optionally substituted with a C6 to Cs aryl group;
-an S(O)R,, group optionally substituted with a Cl to C6 alkyl group;
-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-halo, -hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an amino group optionally substituted with one or more 5 or 6 membered heteroaryl groups, 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups, -an amide optionally substituted with a Cl to C6 alkyl, -S-5 or 6 membered heterocycle, -S-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl, -S-C1 to C6 alkyl, -S-C6 to Cg aryl, -sulfinyl-5 or 6 membered heterocycle, -sulfinyl-5 or 6 membered heteroaryl, -sulfinyl-Ct to C6 alkyl, -sulfinyl-C6 to C8 aryl, -sulfonyl-5 or 6 mernbered heterocycle, -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a Ct to C6 alkyl, -sulfonyl- C1 to C6 alkyl, -sulfonyl- C6 to C8 aryl, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C, to C6 alkyl group, the Ci to C6 alkyl group optionally substituted with one or more independently selected Ci to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more CI
to C6 alkyl groups, -a C6 to C8 aryl group;
-a C6 to C$ aryl group;
-an (0)-5 or 6 membered heterocycle;
-an (0)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C3 to C6 alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -C(O)-5 or 6 membered heteroaryl;
-a -C(O)-C6 to C8 aryl;
-a -COOH group;
-an amide group optionally substituted with one or more of the following:
-C1 to C6 alkyl groups optionally substituted with one or more C1 to C6 alkoxy, -a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-hydroxy, -C i to C6 alkyl, -S02RX, -C(O)-C6 to C8 aryl, or -C(O)OR,r groups;
-an -ORkk group, where Rkk is:
-a C6 to C8 aryl, -a 5 to 6 membered heteroaryl, -a 5 to 6 membered heterocycle, optionally substituted with a Cl to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an -Si(Rx)3; and R3 is a hydrogen;

with the proviso that at least one of X, Y, Z, RI, and R2 is selected from the following:

X is:
-a -COOH group;
CH
II
N
-a Cl to C6 alkoxy;
CH
Il N
'~_'amirso optionally substituted with one or more C1 to C6 alkyl -a groups -a halo;
-an alkyl optionally substituted with one or more halo;
-an alkyne optionally substituted with a CI to C6 alkyl optionally substituted with one or more halo or cyano groups;
-an oxime;
-SO2Rx;
-SO2NH2;
-SO2NFi(RX);
-SO2N(Rx)2;
-an amino optionally substituted with one or more C, to C6 alkyl groups or C(O)- Cl to C6 alkyl groups;
-an amide group optionally substituted with one or more independently selected Cl to C6 alkyl group;
-a 5 or 6 membered heterocycle;
-a 5 or 6 membered heteroaryl substituted with one or more CI to C6 alkyl groups substituted with one or more halos; or -a C6 to C$ aryl group substituted with one or more of the following:
-CI to C6 alkyl optionally substituted with one or more halos, -halo, or -cyano;
Y is:
-a benzothiazole substituted with an amino group optionally substituted witli one or more C, to C6 alkyls;
-an indole substituted on the nitrogen with an SOaRX group;
-a C6 to Cg aryl substituted with one or more of the following:

-an amino optionally substituted with one or more of the following:
-SO2RX, or -CI to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR,,, -OC(O)N(Rx)2, -OC(O)NH(ORX), -OC(O)NRX(OR,,), -OC(O)N(ORx)2, -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRaCORP group, where Rp is:
-an amino group optionally substituted with one or more Ct to C6 alkyl groups where the C, to C6 alkyl groups are optionally and independently substituted with one or more C6 to C$ aryl groups and/or alkoxy groups, or -a 5 or 6 membered heterocycle, substituted with one or more C, to C6 alkyl or C6 to Cg aryl groups, -a -NR.gCONRqRr group, where Rr is:
-a C, to C6 alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a Cr6 to C8 aryl substituted with a halo, -a C2 to C6 alkylene group, -a C1 to C6 alkoxy group, 25, -a 5 or 6 membered heterocycle group;
-a NRtCOORõ group, where Rõ is:
-a C, to C12 alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more CI to C6 alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, or ~N~~///~~\0 -a Z is:
-a C, to C6 alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 mernbered heterocycle;
R, is:
-a C, to C6 alkyl substituted with:
-an amide optionally substituted with a C, ta C6 alkyl, or -a 5 or 6 membered heteroaryl;
-a C1 to C6 alkoxy substituted with:
-an amino optionally substituted with a heterocycle, -an amide optionally substituted with a Ci to C6 alkyl, -a 5 or 6 membered heterocycle substituted with a C1 to C6 alkyl, or -a 5 or 6 membered heteroaryl;
-an (O)-5 or 6 membered heterocycle;
-an (O)-5 or 6 membered heteroaryl;
-an -SO2Rx group optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 t0 Cg aryl, -a 5 or 6 membered heteroaryl; or -alkylthio optionally substituted with the following:
-a 5 or 6 membered heterocycle, -a C6 to C8 aryl, -a 5 or 6 membered heteroaryl; or R2 is:
--a C, to C6 alkyl group, substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -5 or 6 membered heteroaryl groups, -C6 to Cs aryl groups, -an amide optionally substituted with a Ci to C6 alkyl, or -amino groups optionally substituted with one or more heteocycle, alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups;
-an alkylthio group optionally substituted with a 5 or 6 membered heteroaryl group optionally substituted with an alkyl group;
-an alkylthio group optionally substituted with a 5 or 6 membered heterocycle group;
-an alkylthio group optionally substituted with a C6 to C8 aryl group;
-an alkylthio group optionally substituted with a Ci to C6 alkyl group;
-an SO2R,, group optionally substituted with a 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyl groups;
-an SO2R,t group optionally substituted with a 5 or 6 membered heterocycle group;
-an SO2RX group optionally substituted with a C6 to C8 aryl group;
-an SOzRX group optionally substituted with a C1 to C6 alkyl group;
-an S(O)R,, group optionally substituted with a 5 or 6 membered heteroaryl group;
-an S(O)Rx group optionally substituted with a 5 or 6 membered heterocycle group;
-an S(O)RX group optionally substituted with a C6 to C$ aryl group;
-an S(O)Rx group optionally substituted with a Ct to C6 alkyl group;
-an alkoxy group substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heteroaryl, 5 or membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-an amide optionally substituted with a Ct to C6 alkyl, -S-5 or 6 membered heterocycle, -S-5 or 6 membered heteroaryl optionally substituted with a Ci to C6 alkyl, -S-CI to C6 alkyl, -S-C6 t0 C8 aryl, -sulfinyl-5 or 6 membered heterocycle, -sulfinyl-5 or 6 membered heteroaryl, -sulfinyl-C1 to C6 alkyl;
-sulfinyl-C6 to C8 aryl, -sulfonyl-5 or 6 membered heterocycle, -sulfonyl-5 or 6 membered heteroaryl optionally substituted with a C1 to C6 alkyl, -sulfonyl- C, to C6 alkyl, -sulfonyl- C6 to C8 aryl, -a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Cl to C6 alkyl groups substituted with C1 to C6 alkoxy, or -a 5 or 6 membered heteroaryl group substituted with one or more Cl to C6 alkyl groups -a C6 to C8 aryl group;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -C(O)- C6 to C8 aryl;
-a -COOH group;
-an amide group substituted with one or more C1 to C6 alkyl groups optionally substituted with one or more CI to C6 alkoxy;
-a 5 or 6 membered heterocycle, substituted with one or more of the following:
-hydroxy, -C1 to C6 alkyl, -SOzRX groups, -C(O)-C6 to C8 aryl, or -C(O)OR,, groups;
-an -ORkk group, where Rkk is:
-a C6 to C8 aryl, -a 5 to 6 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a C6 to C8 aryl group, or -an -Si(Rx)3;
-an (O)-5 or 6 membered heterocycle; or -an (O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C, to C6 alkyl groups;
or a pharmaceutically acceptable salt thereof.

In another embodiment, Formula I-Xlb, a compound is provided wherein all substituents except X are as stated for Formula I-XI, and X is an electron withdrawing group.
In a further embodiment, Formula I-Xlc, a compound is provided wherein all substituents except X are as stated for Formula I-XIa, and X is an electron withdrawing group. As an example, an electron withdrawing group includes any electronegative element, which may be attached to or adjacent to an aromatic ring. By way of non-Iimiting example, an electron withdrawing group can include a cya.no group, an alkynyl group, a nitro group, an oxime, a halo, a halosubstituted alkyl, a carbonyl group, a sulfonyl group, and a heterocycle. In an embodiment of the present invention, X is a cyano group. In another embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or Ile, X is a halo. In an embodiment of Formulas I, I-XI, I-XIa, I-Xlb, I-XIc, IIa, IIb, IIc, IId, or IIe, X is a fluorine, chlorine, bromine or iodine.
In an embodiment of 1, I-XI, I-XIa, I-.XIb, I-XIc, IIa, IIb, IIc, IId, or Ile, X is a fluorine, bromine or iodine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or Ile, X is a fluorine or chlorine. In an embodiment of Formulas 1, I-XI, I-XIa, I-Xtb, I-Xic, IIa, Ilb, Ile, IId, or Ile, X is a fluorine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, Ile, IId, or Ile, X is a chlorine. In an embodiment of Formulas I, I-XI, I-Xta, I-XIb, I-Xlc, IIa, IIb, Ile, IId, or Ile, X is bromine. In an embodiment of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb,1Ic, IId, or Ile, X is iodine. In a further embodiment of Formulas I, I-XI, I-Xla, I-Xlb, I-XIc, IIa, IIb, IIc, IId, or Ile, X is an alkyl substituted with one or more halos. In another embodiment, X is a trifluoromethyl group.
In some embodiments, X is selected from the X substituents of compounds 1330-2128, and 2600-3348.
In an embodiment of Formulas 1, I-XI, I-XIa, I-Xlb, I-XIc, IIa, IIb, IIc, IId, or Ile, X is selected from the group consisting of:

H-* F-* Br~*
F

F

F F
N= F-~-* ~-- *
F F

HO
O >* H /!
O "`

/>
/O
s - ~ 0 OS_ O *

>---N~O

~
+
\-O -N *-N,O
N_ * .N_ * 0_ ~ "-NH N N,-T,-"' *_N /'-Q ~.-O
~ 0 .
,o;~
~jN N 'N NO 1 Yp N
* * *

O
N N ~
NO N ~',0 .

H
N N
N
*

H
NN NN ~ NN I
~
* * *
~F
O~N O_ I
F
N
N
*

p" I S~N S~
YN Y N
F F
~p S~F N N
YN
*
F
F F
N

N
~
*
*

F N
N= N
NNH
/ * .
*

Cl CI
and In other non-limiting examples of Formulas I, I-XI, I-XIa, I-XIb, I-XIc, IIa, IIb, IIc, or IIe, X is selected from the group consisting of o~ o`\ 1 o o/
Y'\
* ?~ \`C__o O O ~ O O
O-O' P
N NN N IN
O-O N
N N~ j O~-N~-O
/ * *
O 0~=`~N
N N
Y ~ r * * *
*

N
S, i` S~'N * N S` N
* *

Ci Ci p --N
.
N N~ I
*

N
*

In some embodiments, Ri is selected from the Ri substituents of compounds 1330-2128, and 2600-3348.
In an embodiment of Formulas I, I-XI, I-Xla, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, R, is selected from the group consisting of O-* N

O
hit * ~ *
>-NH O N N
NII~N \

~N~Oi Oi and In another embodiment, the present invention includes compounds of Formula (I-XII) R x RI

y N

z (I-XII) wherein:
X is:
-a cyano group;

Y is:
-a benzothiazole optionally substituted with an amino group optionally substituted with one or more C, to C6 alkyls;
-an indole, optionally substituted on the nitrogen with an SO2Rx group;
-a C6 to C$ aryl, optionally substituted with one or more of the following:
-an alkoxy, -an amino optionally substituted with one or more of the following:
-SO2Rx group, or -CI to C6 alkyl, the Ci to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRXa -OC(O)N(Rx)a, -OC(O)NH(ORX), -OC(O)NRX(OR.), -OC(O)N(ORX)2, -OC(O)RBb, wherein R,,b is a 5 or 6 membered heterocycle group, -a NRoCORp group, where Rp is:
-a C, to C6 alkyl, -an amino group optionally substituted with one or more Cl to C6 alkyl groups where the Cl to C6 alkyl groups are optionally and independently substituted with one or more C6 to C$ aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more C, to C6 alkyl or C6 to C8 aryl groups, and where R. is:
-a hydrogen, -a C, to C6 alkyl, -a -NRyCONRqRr group, where Rq is a hydrogen, and where Rr is:
-a C, to C6 alkyl optionally substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C$ aryl optionally substituted with a halo, -a C2 to C6 alkylene group, -a CI to C6 alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Rõ is:
-a C, to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C) to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to C8 aryl, optionally substituted with halo, and Rt is:
-a hydrogen;
-a -NHRbb group, whexe Rbb is:
-a -C(=S)NH2 group, or -a -PO(ORX)Z, where R, is as defined above;
-a -NRSO2R,,, group, where R, is a hydrogen, and where R, is a C, to C6 alkyl, O
p " N

-a R\~
N O
-a Z is:
-a CI to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
R is a hydrogen;
R1 is a hydrogen;

iZ.2 is:
-a C, to C6 alkyl group, optionally substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an allcoxy group optionally substituted with one or more groups independently selected from the following:
-halo, -hydroxy group, -an alkoxy group optionally substituted with an allcoxy group, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C, to C6 alkyl group, the C, to C6 alkyl group optionally substituted with one or more independently selected Cl to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more C, to C6 alkyl groups, -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -COOH group;
-an amide group optionally substituted with one or more -C I to C6 alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-C1 to C6 alkyl, -SO2RX, -C(O)-C6 to Cs aryl, or -C(O)ORx groups;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a C6 to C$ aryl group, or -an -Si(Rx)3;

R3 is a hydrogen;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention includes compound of Formula (I-XIIa) R X

Ri y N

Z

(I-XIIa) wherein:
X is:
-a cyano group;
Y is:

-a benzothiazole optionally substituted with an amino group optionally substituted with one or more Ci to C6 alkyls;

-an indole, optionally substituted on the nitrogen with an SO2Rx group;
-a C6 to C$ aryl, optionally substituted with one or more of the following:
-an alkoxy, -an amino optionally substituted with one or more of the following:
-SO2R, or .-CI to C6 alkyl, the Ct to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR,, -OC(O)N(RX)2, -OC(O)NH(ORX), -OC(O)NR,(ORX), -OC(O)N(ORx)2, -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRoCORp group, where R. is:
-a C 1 to C6 alkyl, -an amino group optionally substituted with one or more C, to C6 alkyl groups where the C i to C6 alkyl groups are optionally and independently substituted with one or more C6 to C$ aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more C, to C6 alkyl or C6 to C8 aryl groups, and where Ro is:
-a hydrogen, -a C, to C6 alkyl, -a -NRyCONRqR, group, where Rq is a hydrogen, and where Rr is:
-a Ct to C6 alkyl optionally substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl optionally substituted with a halo, -a C2 to C6 alkylene group, -a C1 to C6 alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Rõ is:
-a Cl to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more CI to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to C$ aryl, optionally substituted with halo, and Rt is:
-a hydrogen;
-a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or -a -PO(OR,,)2, where R,, is as defined above;

-a -NRSO2R, group, where R, is a hydrogen, and where RW is a Ct to C6 alkyl, O
O
" N

-a Jj N / \=O
-a Z is:
-a Cl to C6 alkyl optionally substituted with: a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
R is a hydrogen;
Rt is a hydrogen;
R2 is:
-a C, to C6 alkyl group, optionally substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group optionally substituted with one or more groups independently selected from the following:
-halo, -hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an amino group optionally substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C1 to C6 alkyl group, the Cl to C6 alkyl group optionally substituted with one or more independently selected C, to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more C, to C6 alkyl groups, -a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -COOH group;
-an amide group optionally substituted with one or more Cl to C6 alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-Ci to C6 alkyl, -SOZRX, -C(O)-C6 to C8 aryl, or -C(O)ORX groups;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a C, to C6 alkyl, optionally substituted with a C6 to Cg aryl group, or -an, -Si(Rx)3;
R3 is a hydrogen;
with the proviso that at least one of Y, Z, and R2 is selected from the following:
Y is:
-a benzothiazole substituted with an amino group optionally substituted with one or more Ct to C6 alkyls;
-an indole substituted on the nitrogen with an -SO2Rx group;
-a C6 to C8 aryl substituted with one or more of the following:
-an amino optionally substituted with one or more of the following:
-SOaR7ea or -CI to C6 alkyl substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHR,,, -OC(O)N(RX)2, -OC(O)NH(ORX), -OC(O)NR,.(ORx), -OC(O)N(ORX)2a -OC(O)Rab, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRoCORp group, where RP is:

-an amino group optionally substituted with one or more C, to C6 alkyl groups where the CI to C6 alkyl groups are optionally and independently substituted with one or more C6 to C8 aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, substituted with one or more C, to C6 alkyl or C6 to C8 aryl groups, -a -NRnCONRqRr group, where Rr is:
-a C, to C6 alkyl substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl substituted with a halo, -a C2 to C6 alkylene group, -a CI to C6 alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Rõ is:
-a C, to C12 alkyl, substituted with one or more groups independently selected from the following:
-an alkoxy group substituted with one or more alkoxy groups, -an amino optionally substituted with one or more C, to C6 alkyl, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, NJ" O
-a Z is:
-a CI to C6 alkyl substituted with a 5 or 6 membered heterocycle, or -a 5 or 6 membered heterocycle;
R2 is:
-a C I to C6 alkyl group, substituted with one or more of the following:
-5 or 6 membered heterocycle groups, -amino groups optionally substituted with one or more alkoxy groups or alkyl groups optionally substituted with one or more alkoxy groups, -an alkoxy group substituted with one or more groups independently selected from the following:
-hydroxy group, -an alkoxy group optionally substituted with an alkoxy group, -an amino group substituted with one or more 5 or 6 membered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more of the following:
-a 5 or 6 membered heterocycle, or -an amino optionally substituted with one or more alkyl groups;
-a 7 membered heterocycle group;
-a 5 to 7 membered heterocycle group substituted with one or more independently selected hydroxy groups or substituted with one or more independently selected Ci to C6alkyl groups substituted with Cl to C6 alkoxy, or -a 5 or 6 membered heteroaryl group substituted with one or more C, to C6 alkyl groups;
-a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups;
-a -COOII group;
-an amide group substituted with one or more Ci to C6 alkyl groups;
-a 5 or 6 membered heterocycle, optionally substituted with one or more of the following:
-C1 to C6 alkyl, -SO2R. group, -C(O)-C6 ta C8 aryl, or -C(O)OR,. groups;
-an -ORkk group, where Rkk is:
-a 5 to 6 membered heterocycle, optionally substituted with a Ci to C6 alkyl, optionally substituted with a C6 to Cs aryl group, or -an -Sl(Rx)3;
or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Y is a C6 to C8 aryl, optionally substituted with one or more of the following:
-a NRyCONRyRr group, where Rq is a hydrogen, and where Rr is:

-a C, to C6 alkyl optionally substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C8 aryl optionally substituted with a halo, -a C2 to C6 alkylene group, -a C, to C6 alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where R,, is:
-a CI to C1a alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo, -an alkoxy group optionally substituted with one or more alkoxy groups, --an amino optionally substituted with one or more Ct to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to Cg aryl, optionally substituted with halo, and Rt is:
-a hydrogen;
-a -NHRbb group, where Rbb is:
-a -C(=S)NH2 group, or -a -PO(ORX)2, where R, is as defmed above;
or -a -NR,,SOzRW group, where R,, is a hydrogen, and where R , is a Ci to C6 alkyl.
In another embodiment, the present invention includes compounds wherein Y is a C6 to Cs aryl, optionally substituted with:
-a NRqCONRqRr group, where Rq is a hydrogen, and where Rr is:
-a Ci to C6 alkyl optionally substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to Cg aryl optionally substituted with a halo, -a C2 to C6 alkylene group, -a Cl to C6 alkoxy group, or -a 5 or 6 membered heterocycle group.
In a further embodiment, the present invention includes compounds wherein Y is a-NRtCOORu group, where Rõ is:
-a Ct to C12 alkyl, optionally substituted with one or more groups independently selected from the following:
-a C6 to C8 aryl optionally substituted with halo, -an alkoxy group optionally substituted with one or more alkoxy groups, -an amino optionally substituted with one or more Cl to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to C$ aryl, optionally substituted with halo, and Rt is:
-a hydrogen.

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

R3 (IIa) or a pharmaceutically acceptable salt thereof, wherein:
X is:
-cyano;
-nitro;
-formyl;
-COOH;

-CORx, wherein R,t is C, to C6 alkyl;
-CH=N-(CI to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C, to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C, to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SOzRx;
-SOZNH2;
-SO2NH(RX);
-SO2N(Rx)2;
-amino optionally substituted with one or more C, to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected C, to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C$ aryl optionally substituted with one or more substituents independently selected from:
-Ci to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;
Y is:
-benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more C, to C6 alkyls;
-indolyl optionally substituted on the nitrogen with -SO2R,s;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-halos;
-C i to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-one or more halos; and -5 or 6 membered heterocyclo;
-hydroxy;
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx;
-C3 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls; and -PO2Rx;
-OC(O)NHRX;
-OC(O)N(Rx)2;
-OC(O)NH(OR,);
-OC(O)NRx(ORx)a -OC(O)N(ORx)a, -OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo;
-NRoCORp, wherein Rp is:
-CI to C6 alkyl;
-amino optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally and independently substituted with one or more Cb to Cg aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C$ aryls;
and wherein Ro is:
-hydrogen; or -CI to C6 alkyl;
-NRgCONRRr, wherein Rq is hydrogen;
and wherein Rr is:
-C3 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl optionally substituted with one or more halos;

-C2 to C6 alkenyl optionally substituted with one or more halos;
-Ci to C6 alkoxy; or -5 or 6 membered heterocyclo;
-SO2R., wherein Raa is:
-5 or 6 heterocyclo optionally substituted with hydroxy;
-Q to C6 alkoxy; or -CI to Q alkyl;
-CORm, wherein R,,, is:
-amino optionally substituted with one or more C, to C6 alkyls, wherein the C, to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with C, to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
-NR,COOR,,, wherein Rt is hydrogen, and wherein R. is:
-CI to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-halo;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;
-C2 to C6 alkenyl; or -C6 to Cg aryl optionally substituted with halo;
-NHRbb, wherein Rbb is:
-C(=S)NH2; or -PO(ORX)2;
-NRõSO2RN,, wherein R,, is hydrogen, and wherein R,, is:
-C, to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo;

O
~~
U
; or N/k O

a Z is:
-C1 to C6 alkyl optionally substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
R is hydrogen;
R, is:
-hydrogen;
-5 or 6 membered heterocyclo;
-Ct to C6 alkyl optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C 1 to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with C, to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to Cg aryl;
-C1 to C6 alkoxy optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with Cl to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with C, to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-(0)-5 or 6 membered heterocyclo;
.25 -(0)-5 or 6 membered heteroaryl;
-SO2R,, optionally substituted with one or more substituents independently selected from:

-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C$ aryl; and -5 or 6 membered heteroaryl;
R2 is:
-Cl to C6 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 t0 C8 aryl;
-amido optionally substituted with Ct to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo;
-alkylthio optionally substituted with C6 to Cs aryl;
-alkylthio optionally substituted with Ci to C6 alkyl;
-SO2RX optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more CI to C6 alkyls;
-S02Rx optionally substituted with 5 or 6 membered heterocyclo;
-S aR,, optionally substituted with C6 to C8 aryl;
-SOaRX optionally substituted with C, to C6 alkyl;
-S(O)RX optionally substituted with 5 or 6 membered heteroaryl;
-S(O)R,, optionally substituted with 5 or 6 membered heterocyclo;
-S(O)RX optionally substituted with C6 to C8 aryl;
-S(O)Rx optionally substituted with C1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:

-halo;
-hydroxy;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -arnino optionally substituted with one or more alkyls;
-amido optionally substituted with CI to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Cy to C6 alkyl;
-S-CI to C6 alkyl;
-S-C6 to Cs aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfmyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl;
-sulfmyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C3 to C6 alkyl;
-sulfonyl-C, to C6 alkyl;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C, to C6 alkyl, which alkyl is optionally substituted with one or more C i to C6 alkoxys;
-5 or 6 membered heteroaryl optionally substituted with one or more CI to C6 alkyls; and -C6 to C8 aryl;
-C6 to C8 aryl;
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected CI to C6 alkyls;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
-C(O)-C6 to Cg aryl;

-COOH;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more C, to C6 alkoxys;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C I to C6 alkyl; and -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-CI to C6 alkyl;
-SO2R,,;
-C(O)-C6 to C8 aryl; and -C(O)ORx; or -ORkk, wherein Rkk is:
-C6 to C8 aryl;
-5 or 6 membered heterocyclo optionally substituted with Cl to C6 alkyl, which alkyl is optionally substituted with C6 to C$ aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, Cl to C6 alkoxy, and C, to C6 haloalkyl;
-SO2RX; or -Si(Rx)3; and R3 is hydrogen;

with the proviso that at least one of X, Y, Z, Ri, and R2 is selected from the following:
X is:
-COOH;
-CH N-(Ct to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C, to C6 alkyls);
-halo;

-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C, to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2R,,;
-SOaNH2i -SO2NH(Rx);
-SO2N(R.)2;
-amino optionally substituted with one or more Ci to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected Ci to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C, to C6 alkyls, which alkyls are substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-Cj to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;
Y is:

-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ct to C6 alkyls;
-indolyl substituted on the nitrogen with S02RX; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from:
-SO2Rx, and -CI to C6 alkyl substituted with one or more 5 or 6 membered heteroaryls;
-OC(O)NHR,e;
-OC(O)N(RX)a;
-OC(O)NH(ORX);
-OC(O)NRx(OR,,);
-OC(O)N(ORX)2;
-OC(O)R$b, wherein Rab is 5 or 6 membered heterocyclo;

-NRoCORp, wherein Rp is:
-amino optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys, or -5 or 6 membered heterocyclo substituted with one or more C, to C6 alkyls and/or C6 to Cg aryls, -NRqCONRyRr, wherein R, is:
-Cy to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with one or more halos;
-C2 to C6 alkenyl;
-Cl to C6 alkoxy; or -5 or 6 membered heterocyclo;
-NRtCOOR,,, wherein Rõ is:
-C1 to Cl 2 alkyl substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C, to C6 alkyls;
and -5 or 6 membered heteroaryl; or -C2 to C6 alkenyl; and j N/ \O

- V .
~
Z is:
-CI to C6 alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
Ri is:
-CI to C6 alkyl substituted with:

-amido optionally substituted with C, to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-C1 to C6 alkoxy substituted with:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C, to C6 alkyl;
-5 or 6 membered heterocyclo substituted with CI to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-(0)-5 or 6 membered heterocyclo;
-(0)-5 or 6 membered heteroaryl;
-SOZR,, optionally substituted with:
-5 or 6 membered heterocyclo;
-C6 to C$ aryl; and/or -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and/or -5 or 6 membered heteroaryl;
R2 is:
-CI to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to Cs aryl;
-amido optionally substituted with C, to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo;
-alkylthio optionally substituted with C6 to C8 aryl;
-alkylthio optionally substituted with CI to C6 alkyl;
-S02RX optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C1 to C6 alkyls;
-S02RX optionally substituted with 5 or 6 membered heterocyclo;

-SO2R, optionally substituted with C6 to C8 aryl;
-SO2Rx optionally substituted with C, to C6 alkyl;
-S(O)Rx optionally substituted with 5 or 6 membered heteroaryl;
-S(O)Rx optionally substituted with 5 or 6 membered heterocyclo;
-S(O)R,, optionally substituted with C6 to Cg aryl;
-S(O)Rx optionally substituted with Cl to C6 alkyl;
-alkoxy substituted with:
-alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclos; and -amino optionally substituted with one or more alkyls;
-amido optionally substituted with C, to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C, to C6 alkyl;
-S-Ci to C6 alkyl;
-S-C6 to Cg aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl;
-sulfmyl-C6 to C$ aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with CI to C6 alkyl;
-sulfonyl-C1 to C6 alkyl;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is substituted with one or more Ci to C6 alkoxys;
-5 or 6 membered heteroaryl substituted with one or more Cl to C6 alkyls; or -C6 to C8 aryl;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C$
aryls;

-C(O)-C6 to C8 aryl;
-COOH;
-amido substituted with one or more CI to C6 alkyls optionally substituted with one or more C i to C6 alkoxys;
-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-C t to C6 alkyl;
-SOZRX;
-C(O)-C6 to Cg aryl; and -C(O)ORx;
-ORkk, wherein Rkk is:
-C6 t0 Cg aryl;
-5 or 6 membered heterocyclo optionally substituted with Cl to C6 alkyl and/or C6 to C8 aryl; or -S i(Rx)3;
-(0)-5 or 6 membered heterocyclo optionally substituted with one or more independently selected C, to C6 alkyls; or -(0)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C, to C6 alkyls.

2. The compound of embodiment 1, wherein:
X is:
-COOH;
-CH=N-(C I to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C, to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C, to C6 alleyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SOaRX;
-SO2NH2;
-SOzNH(RX);
-SO2N(RX)2i -amino optionally substituted with one or more Ct to C6 alkyls and/or -C(O)-CI
to C6 alkyls;
-amido optionally substituted with one or more independently selected Cl to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C, to C6 alkyls, which alkyls are substituted with one or more halos; or -C6 to C$ aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano.

3. The compound of embodiment 2, wherein X is cyano, halo, or alkyl substituted with one or more halos.

4. The compound of embodiment 3, wherein X is cyano.

5. The compound of embodiment 3, wherein X is fluoro, bromo, chloro, or iodo.
6. The compound of embodiment 3, wherein X is trifluoromethyl.

7. The compound of embodiment 1, wherein:
Y is C6 to C8 aryl substituted with one or more of the following:
-amino optionally substituted with one or more substituents independently selected from:
-SO2R,,; and -Cl to C6 alkyl substituted with one or more 5 or 6 membered heteroaryls;
-OC(O)NHRx;
-OC(O)N(RX)2;
-OC(O)NH(OR,.);
-OC(O)NRX(ORX);
-OC(O)N(ORx)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo;
-NRoCORp, wherein Rp is:
-amino optionally substituted with one or more CI to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;

-NR9CONRqRr, wherein Rr is:
-CI to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl;
-C t to C6 alkoxy; or -5 or 6 membered heterocyclo;
-NRtCOOR,,, wherein Ru is:
-C1 to C12 alkyl substituted with one or more substituents independently selected from the following:
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C, to C6 alkyls; and -5 or 6 membered heteroaryl;
-C2 to C6 alkenyl, or N/\O
- ~ .
S. The compound of embodiment 7, wherein C6 to Cs aryl is phenyl.

9. The compound of embodiment 8, wherein phenyl has at least one substituent at the para position.

10. The compound of embodiment 1, wherein Z is:
-C] to C6 alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo.

11. The compound of embodiment 1, wherein Z is C1 to C6 alkyl.

12. The compound of embodiment 11, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.

13. The compound of embodiment 1, wherein:

R, is:
-C] to C6 alkyl substituted with:
-amido optionally substituted with C, to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-Ci to C6 alkoxy substituted with:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C, to C6 alkyl;
-5 or 6 membered heterocyclo substituted with Cl to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl;
-SO2R,. optionally substituted with:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and/or -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and/or -5 or 6 membered heteroaryl.

14. The compound of embodiment 1, wherein:
R2 is:
-CI to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C$ aryl;
-amido optionally substituted with C, to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo;
-alkylthio optionally substituted with C6 to C8 aryl;
-alkylthio optionally substituted with CI to C6 allcyl;

-SO2Rx optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C, to C6 alkyls;
-SO2RX optionally substituted with 5 or 6 membered heterocyclo;
-SOzRx optionally substituted with C6 to C8 aryl;
-SOaR,. optionally substituted with C, to C6 alkyl;
-S(O)R. optionally substituted with 5 or 6 membered heteroaryl;
-S(O)R,e optionally substituted with 5 or 6 membered heterocyclo;
-S(O)RX optionally substituted with C6 to C8 aryl;
-S(O)RX optionally substituted with Cl to C6 alkyl;
-alkoxy substituted with:
-alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more. substituents independently selected from:
-5 or 6 membered heterocyclos; and -amino optionally substituted with one or more alkyls;
-amido optionally substituted with Ci to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C, to C6 alkyl;
-S-C1 to C6 alkyl;
-S-C6 t0 CS aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-CI to C6 alkyl;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C, to C6 alkyl;
-sulfonyl-C, to C6 alkyl;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C, to C6 alkyl, which alkyl is substituted with Ci to C6 alkoxy;
-5 or 6 membered heteroaryl substituted with one or more C, to C6 alkyls; or -C6 to Cg aryl;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
-C(O)-C6 to C8 aryl;
-COOH;
-amido substituted with one or more C, to C6 alkyls optionally substituted with one or more C, to C6 alkoxys;
-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-Ct to C6 allcyl;
-SOZRX;
-C(O)-C6 to C$ aryl; and ' -C(O)OR,;
-ORkk, wherein Rkk is:
-C6 to Cs aryl;
-5 or 6 membered heterocyclo optionally substituted with C, to C6 alkyl and/or C6 to C8 aryl; or -Si(Rx)3;
-(O)-5 or 6 membered heterocyclo; or -(0)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C 1 to C6 alkyls.

15. The compound of embodiment 1, wherein:
X is:
-cyano;
-halo; or -alkynyl optionally substituted with Cl to C6 alkyl;
Y is:
-C6 to C8 aryl substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-alkoxy optionally substituted with:
-one or more halos; or -5 or 6 membered heterocyclo;

-C) to C6 alkyl;
-amino optionally substituted with one or more substituents independently selected from:
-SOzRx; and -CI to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls;
-OC(O)NHRxa -NR,,CORp, wherein Rp is:
-CI to C6 alkyl; or -amino optionally substituted with one or more C, to C6 alkyls;
and wherein Ra is hydrogen;
-NRqCONRyRr, wherein Rq is hydrogen, and wherein Rr is:
-Ci to C6 alkyl optionally substituted with one or more halos; or -C6 to Cg aryl optionally substituted with halo;
-SO2R., wherein R. is:
-5 or 6 heterocyclo optionally substituted with hydroxy;
-Cl to C6 alkoxy; or -C i to C6 alkyl;
-CORnõ wherein R. is:
-amino optionally substituted with one or more C1 to C6 alkyls, wherein the Cl to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with C I to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
-NRCOOR,,, wherein R, is hydrogen, and wherein Ru is:
-Ca to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-halo; and -5 or 6 membered heteroaryl;
-C6 to C8 aryl optionally substituted with halo; or -5 or 6 membered heterocyclo;
-NHRbb, wherein Rbb is:

-C(=S)NH2; or -PO(ORx)2i -NR.VSO2R,,,, wherein Rõ is hydrogen, and wherein RN, is:
-CI to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; or O
\\//O
* N'~

Z is:
-Cl to C6 alkyl; or -5 or 6 membered heterocyclo;
R is hydrogen;
Ri is:
-hydrogen;
-CI to C6 alkoxy substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl;
-(0)-5 or 6 membered heterocyclo;
-(0)-5 or 6 membered heteroaryl; or -5 or 6 membered heterocyclo;
Rz is:
-alkoxy substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-alkdxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amido optionally substituted with C, to C6 alkyl;
-S-5 or 6 membered heteroaryl optionally substituted with Ct to Q alkyl;

-S-Ct to C6 alkyl;
-sulfinyl-Ci to C6 alkyl;
-sulfonyl-C i to C6 alkyl;
-5 to 7 membered heterocyclo optionally.substituted with one or more substituents independently selected from hydroxy and C, to C6 alkyl, which alkyl is optionally substituted with one or more independently selected C, to C6 alkoxys; and -5 or 6 membered heteroaryl optionally substituted with one or more Cl to C6 alkyls;
-SO2R,, optionally substituted with CI to C6 alkyl;
-S(O)RX optionally substituted with C, to C6 alkyl;
-(0)-5 or 6 membered heteroaryl optionally substituted with one or more independently.
selected C1 to C6 alkyls;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C$
aryls;
-C(O)-C6 t0 C8 aryl;
-COOHa -C(O)NH2 optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Cti to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and=
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-one or more halos;
-C1 to C6 alkyl; and -SOaRX;
-amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C, to C6 alkoxys; or -ORkk, wherein Rkk is:

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, Cl to C6 alkoxy, and C, to C6 haloalkyl; or -5 or 6 membered heterocyclo optionally substituted with Cl to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; and R3 is hydrogen.

16. The compound of embodiment 15, wherein:
X is:
-cyano; or -halo;
Y is:
-phenyl substituted with one or more substituents independently selected from:
-halo; and -NRtCOORti,, wherein Rt is hydrogen, and wherein Rõ is:
-CI to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C$ aryl optionally substituted with one or more halos;
-halo; and -5 or 6 membered heteroaryl;
-C6 to C8 aryl optionally substituted with halo; or -5 or 6 membered heterocyclo;
Z is Cl to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is:
-alkoxy substituted with one or more substituents independently selected from:
-halo; and -alkoxy optionally substituted with alkoxy;
-(O)-5 or 6 membered heterocyclo;
-amido optionally substituted with one or more Ct to C6 alkyls, which alkyls are optionally substituted with one or more Ct to C6 alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-one or more halos;

-Ci to C6 alkyl; and -SOzRX; and R3 is hydrogen.

17. The compound of embodiment 15, wherein:
X ls cyano;
Y is C6 to C$ aryl substituted with one or more substituents independently selected from NRtCOOR,,, wherein is hydrogen, and wherein Ru is C, to C12 alkyl optionally substituted with one or more C6 to Cs aryls;
Z is 5 or 6 membered heterocyclo;
R is hydrogen;
Ri is hydrogen;
R2 is alkoxy; and R3 is hydrogen.

18. The compound of embodiment 15, wherein:
X is cyano;
Y is C6 to C$ aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with C, to C6 alkyl;
-NRyCONRyRr, wherein Rq is hydrogen, and wherein Rr is CI to C6 alkyl;
-CORn,, wherein Rm is:
-amino optionally substituted with one or more C, to C6 alkyls, wherein the Cl to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo; and -NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is:
-CI to C 12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more haloalkyls; and -halo; or -5 or 6 membered heterocyclo;
Z is C, to Cg alkyl;
R is hydrogen;
R, is hydrogen;
R2 is alkoxy substituted with alkoxy; and R3 is hydrogen.

19. The compound of embodiment 15, wherein:
X is cyano;
Y is C6 to C$ aryl substituted with one or more substituents independently selected from:
-NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl optionally substituted with one or more halos; and -NRõSO2R,,,, wherein Rõ is hydrogen, and wherein Rw is Cl to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R, is hydrogen;
R2 is amido optionally substituted with one or more C, to C6 alkyls, which alkyls are substituted with one or more C1 to C6 alkoxys; and R3 is hydrogen.

20. The compound of embodiment 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more C, to C6 alkyls;
-NRtCOORu, wherein Rt is hydrogen, and wherein Rõ is Ct to C12 alkyl optionally substituted with one or more halos;
-NRSO2RW, wherein R,, is hydrogen, and wherein RW is Cl to C6 alkyl; and O
*

N
Z is C 1 to C6 alkyl;
R is hydrogen;
Rt is hydrogen;
R2 is alkoxy substituted with sulfonyl-Cl to C6 alkyl; and R3 is hydrogen.

21. The compound of embodiment 15, wherein Y is C6 to C8 aryl substituted with one or more substituents independently selected from NRtCOOR,,, wherein Rt is hydrogen, and wherein Ru is C, to Cr2 alkyl optionally substituted with one or more halos.

22. The compound of embodiment 15, wherein:
X is cyano;
Y is C6 to C$ aryl substituted with one or more substituents independently selected from:
-C, to C6 alkyl;
-amino optionally substituted with one or more CI to C6 alkyls;
-NRqCONRqRr, wherein R9 is hydrogen, and wherein Rr is C, to C6 alkyl;
-NRACOOR,,, wherein Rt is hydrogen, and wherein Rõ is CI to C12 alkyl;
-NR,SO2RW, wherein RV is hydrogen and wherein R,,, is:
-C I to C6 alkyl; or -alkyl- or dialkyl-amino;
Z is CI to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C, to C6 alkyl, Cl to C6 alkoxy, and C, to C6 haloalkyl; and R3 is hydrogen.

23. The compound of embodiment 22, wherein:
X is cyano;
T' is C6 to C$ aryl substituted with one or more substituents independently selected from:
-NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl; and -NRõSOaR,,,, wherein Rõ is hydrogen, and wherein RW is:
-C I to C6 alkyl; or -alkyl- or dialkyl-amino;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Cl to C6 alkyl, C, to C6 alkoxy, and C, to C6 haloalkyl; and R3 is hydrogen.

24. The compound of embodiment 22, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more C1 to C6 haloalkyls.

25. The compound of embodiment 22, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with one or more C, to C6 alkyls:

26. The compound of embodiment 1, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR,COOR,,, wherein R, is hydrogen, and wherein Rõ is C, to C12 alkyl; and -NR.,SO2R,, wherein Rõ is hydrogen, and wherein RW is Cl to C6 alkyl;
Z is Ci to C6 alkyl;
R is hydrogen;
R, is hydrogen;
R2 is C(O)-5 or 6 membered heterocyclo; and R3 is hydrogen.

27. The compound of embodiment 1, wherein:
X is halo;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino;
-NRqCONRgR,, wherein Rq is hydrogen, and wherein Rr is Cl to C6 alkyl; and -NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is Cl to C12 alkyl;
Z is Cl to C6 alkyl;
R is hydrogen;
R, is hydrogen;
R2 is alkoxy; and R3 is hydrogen.

28 The compound of embodiment 15 wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-halo;
-NRqCONRyR,, wherein R. is hydrogen, and wherein Rr is Ci to C6 alkyl;
-NRtCOORu, wherein Rt is hydrogen, and wherein Rõ is Cl to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos; and -halo;
-NRVS02R,,,, wherein Rõ is hydrogen, and wherein R, is:

-CI to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; and O
~,O
TO, Z 1S C1 t0 C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is 5 or 6 membered heterocyclo; and R3 is hydrogen.

29. The compound of embodiment 28, wherein Y is C6 to C$ aryl substituted with NRSO2Rw, wherein R, is hydrogen, and wherein RW is Ci to C6 alkyl.

30. The compound of embodiment 28 wherein Y is C6 to Cg aryl substituted with O

N
31. The compound of embodiment 15, wherein:
X is cyano;
Y is C6 to C$ aryl substituted with one or more substituents independently selected from:
-halo;
-amino optionally substituted with one or more Ct to C6 alkyls;
-OC(O)NHR,,;
NRqCONRqRr, wherein Rq is hydrogen, and wherein R, is C, to C6 alkyl;
-NRtCOORu, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls; and -halo;
-NHRbb, wherein RUb is -C(=S)NH2;
-NR,SO2Rw, wherein Rõ is hydrogen, and wherein RW is:

-C 1 to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; and O
* \\~o N

Z is Cl to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is (0)-5 or 6 membered heterocyclo; and R3 is hydrogen.

32. The compound of embodiment 31, wherein Y is C6 to Cg aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl optionally substituted with one or more substituents independently selected from C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls.

33. The compound of embodiment 15, wherein:
X is cyano;
Y is C6 to C$ aryl substituted with one or more substituents independently selected from NR,COOR,,, wherein Rt is hydrogen, and wherein Rõ is Ct to C12 alkyl substituted with one or more halos;
Z is Ct to C6 alkyl;
R is hydrogen;
Rl is -hydrogen;
-(0)-5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
R2 is:
-alkoxy substituted with one or more substituents independently selected from:
-halo;
-alkoxy;
-sulfonyl-C, to C6 alkyl;
-5 to 7 membered heterocyclo;
-5 or 6 membered heteroaryl;

-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl;
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo; or -ORkk, wherein Rkk is 5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkoxys; and R3 is hydrogen.

34. The compound of embodiment 33, wherein Rl is hydrogen, and R2 is alkoxy substituted with one or more halos.

35. The compound of embodiment33, wherein Rl is hydrogen; and R2 is alkoxy stibstituted with one or more alkoxys.

36. The compound of embodiment 15, wherein:
X is cyano;
Y is C6 to CS aryl substituted with one or more substituents independently selected from:
-NR9CONRqRr, wherein Rq is hydrogen; and wherein Rr is C6 to C8 aryl substituted with halo; and -NRtCOOR,,, wherein Rt is hydrogen, and wherein R. is Cl to C12 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more halos and/or haloalkyls;
Z is CI to C6 alkyl;
R is hydrogen;
Rl is hydrogen;
R2 is:
-alkoxy substituted with one or more substituents independently selected from:
-alkoxy; and -5 or 6 membered heteroaryl;
-(0)-5 or 6 membered heterocyclo; or -(0)-5 or 6 membered heteroaryl; and R3 is hydrogen.

37. The compound of embodiment 36, wherein Y is C6 to Cg aryl substituted with NRqCONRqRr, wherein R9 is hydrogen, and wherein R, is C6 to Cg aryl substituted with halo.
38. The compound of embodiment 36, wherein Y is C6 to C8 aryl substituted with one or more substituents independently selected from NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is Cl to C12 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more halos and/or haloalkyls.

39. A compound of formula llb R X
R, Y
N

Z
R3 (jlb) or a pharmaceutically acceptable salt thereof, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-C, to C6 alkyl;
-amino substituted with C, to C6 alkyl -NRtCOOR,,, wherein Ri is hydrogen, and wherein Rõ is Cl to Q2 alkyl optionally substituted with one or more halos;
-NRvSO2RW, wherein R,, is hydrogen, and wherein R , is C, to C6 alkyl;
Z is Ct to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is:
-alkoxy substituted with one or more halos;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C i to C6 alkyl; and NOZ;
-C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and -ORkk, wherein Rkk is:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, and C, to C6 alkyl; or -5 or 6 membered heterocyclo optionally substituted with one or more =0; and R3 is hydrogen.

40. The compound of embodiment 39, wherein:
X is a cyano group;
Y is C6 to C$ aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl substituted with one or more halos;
Z is C1 to C6 alkyl;
R is a hydrogen, R, is a hydrogen;
R2 is alkoxy substituted with one or more halos; and R3 is a hydrogen.

41. The oompound of embodiment 40, wherein the C6 to C8 aryl is phenyl.

42. The compound of embodiment 41, wherein the phenyl is substituted at the para position.

43. The compound of embodiment 41, wherein Rõ is C, to C12 alkyl substituted with fluoro.
44. The compound of embodiment 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-CI to C6 alkyl;
-amino substituted with C, to C6 alkyl; and -NR,SOZRW, wherein Rõ is hydrogen, and wherein RW is C, to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
Rl is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with cyano;
and R3 is hydrogen.

45. The compound of embodiment 44, wherein Y is C6 to C8 aryl para substituted with NRõSO2R,,, wherein R, is hydrogen, and wherein R,,, is C, to C6 alkyl.

46. The compound of embodiment 44, wherein Y is C6 to C$ aryl para substituted with Cl to C6 alkyl and NRSOaRW, wherein Rõ is hydrogen, and wherein Rw is C, to C6 alkyl.

47. The compound of embodiment 44, wherein Y is C6 to C8 aryl para substituted with amino substituted with C, to C6 alkyl.

48. The compound of embodiment 44, wherein R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with cyano at the ortho position.

49. The compound of embodiment 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C1 to C12 alkyl; and -NRSO2R,,, wherein RV is hydrogen, and wherein R,N is C, to C6 alkyl;
Z is Cl to C6 alkyl;
R is hydrogen;
R, is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl substituted with CI to C6 alkyl; and R3 is hydrogen.

50. The compound of embodiment 49, wherein the C6 to Cg aryl is phenyl.
51. The compound of embodiment 50, wherein Y is phenyl substituted at the para position with NRSO2R,,,, wherein Rõ is hydrogen, and wherein Rw is Cl to C6 alkyl.

52. The compound of embodiment 50, wherein Y is phenyl substituted at the para position with NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl.

53. The compound of embodiment 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is Cl to C12 alkyl substituted with one or more halos;
Z is Cl to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl; and R3 is hydrogen.

54. The compound of embodiment 53, wherein the C6 to Cg aryl is phenyl.

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

56. The compound of embodiment 55, wherein Rõ is C, to Q2 alkyl substituted with fluoro.
57. The compound of embodiment 39, wherein:
X is cyano;
Y is C6 to C$ aryl substituted with NRcCOORu, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl optionally substituted with one or more halos;

Z is CI to C6 alkyl;
R is hydrogen;
Rl is hydrogen;
R2 is 5 or 6 membered heteroaryl optionally substituted with C, to C6 alkyl;
and R3 is hydrogen.

58. The compound of embodiment 57, wherein the C6 to C$ aryl is phenyl.

59. The compound of embodiment 58, wherein Y is phenyl substituted at the para position with NR,COOR,,, wherein Ri is hydrogen, and wherein Rõ is C, to C12 alkyl.

60. The compound of embodiment 58, wherein Y is phenyl substituted at the para position with NR,COOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl substituted with one or more halos.

61. The cotnpound of embodiment 60, wherein Rõ is C1 to C12 alkyl substituted with fluoro.
62. The compound of embodiment 39, wherein:
X is cyano; .
Y is C6 to C$ aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein R. is Cl to C12 alkyl;
Z is C, to C6 alkyl;
R is hydrogen;
Rl is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heterocyclo; and R3 is hydrogen.

63. The compound of embodiment 62, wherein the C6 to C$ aryl is phenyl.

64. The compound of embodiment 63, wherein the phenyl is -substituted at the para position.

65. The compound of embodiment 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NRCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl;
Z is Cl to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is 5 or 6 membered heterocyclo; and R3 is hydrogen.

66. The compound of embodiment 65, wherein the C6 to C$ aryl is phenyl.

67. The compound of embodiment 66, wherein the phenyl is substituted at the para position.

68. The compound of embodiment 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with N&COOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl;
Z is Cl to C6 alkyl;
R is hydrogen;
RI is hydrogen;
R2 is 5 or 6 membered heteroaryl substituted with NO2a and R3 is hydrogen.

69. The compound of embodiment 68, wherein the C6 to C8 aryl is phenyl.

70. The compound of embodiment 69, wherein the phenyl is substituted at the para position.

71. The compound of embodiment 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein Ru is C1 to C12 alkyl;
Z 1S CI t0 C6 alkyl;
R is hydrogen;
Rl is hydrogen;
R2 is -C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and R3 is hydrogen.

72. The compound of embodiment 71, wherein the C6 to C$ aryl is phenyl.

73. The compound of embodiment 72, wherein the phenyl is substitLited at the para position.

74. The compound of embodiment 39, wherein:
X is cyano;

Y is C6 to C$ aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl;
Z is CI to C6 alkyl;
R is hydrogen;
Ri is hydrogen;
R2 is ORkk, wherein Rkk is -5 or 6 membered heterocycle substituted with one or more =O; and R3 is hydrogen.

75. The compound of embodiment 74, wherein the C6 to Cg aryl is phenyl.

76. The compound of embodiment 75, wherein the phenyl is substituted at the para position.

77. A compound of formula IIc R X
R, Y
N

Z
R3 (IIc}
or a pharmaceutically acceptable salt thereof, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
NRqCONRqRr, wherein Rq is hydrogen, and wherein Rr is C, to C6 alkyl;
-NR,COOR,,, wherein R= is hydrogen, and wherein Rõ is C, to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos;
-halo; and -5 or 6 membered heteroaryl; and -NR,,SO2RW, wherein Rõ is hydrogen, and wherein R, is Cl to C6 alkyl;
Z is:
-C1 to C6 alkyl; or -5 or 6 membered heterocyclo;
R is hydrogen;
R, is:

-Ci to C6 alkoxy substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl;
-(0)-5 or 6 membered heterocyclo;
-(0)-5 or 6 membered heteroaryl; or -5 or 6 membered heterocyclo;
R2 is hydrogen; and R3 is hydrogen;

with the proviso that when R, is CI to C6 alkoxy substituted with a 5 or 6 membered heterocyclo or when R, is a 5 or 6 membered heterocyclo, Y is a C6 to C$ aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is:

Cl to C12 alkyl substituted with one or more halos; or aryl substituted with one or more halos.

78. The compound of embodiment 77, wherein:
Y is C6 to C8 aryl substituted with NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C1 to C12 aikyl;
Z is Cl to C6 alkyl; and Ri is Cl to C6 alkoxy substituted with 5 or 6 membered heteroaryl.

79. The compound of embodiment 77, wherein Rl is C1 to C6 alkoxy substituted with 5 or 6 membered heteroaryl.

80. The compound of embodiment 77, wherein Ri is (0)-5 or 6 membered heterocyclo.

81. The compound of embodiment 77, wherein R, is (0)-5 or 6 membered heteroaryl.

82. The compound of embodiment 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl.

83. A compound of formula IId R x R, y N

Z
R3 (IId) or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-N.RyCONRqR,, wherein R. is hydrogen, and wherein Rr is C, to C6 alkyl; and -NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is C, to C12 alkyl optionally substituted with one or more halos;
Z is Cl to C6 alkyl;
R is hydrogen;
R, is hydrogen;
R2 is ORkk, wherein Rkk is:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo; or -5 or 6 membered heteroaryl optionally substituted with one or more independently selected halos; and R3 is hydrogen.

84. The compound of embodiment 83, wherein:
X is hydrogen;
Y is C6 to Cg aryl substituted with NRCOOR,õ wherein R, is hydrogen, and wherein Rõ is Ct to C12 alkyl substituted with one or more halos;
Z 1S Cl t0 C6 alkyl;
R is hydrogen;
RI is hydrogen;
R2 is ORkk, wherein Rkk is 5 or 6 membered heteroaryl; and R3 is hydrogen.

85. The compound of embodiment 84, wherein the C6 to Cg aryl is phenyl.

86. The compound of embodiment 84, wherein Y is phenyl substituted at the para position with NRtCOOR,,, wherein R, is hydrogen, and wherein Rõ is CS to C12 alkyl substituted with fluoro.

87. The compound of embodiment 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.

88. The compound of embodiment 83, wherein R2 is (0)-5 or 6 membered heterocyclo.

89. A compound of formula IIe R X
Rl y .~~ N

z R3 (IIe) or a pharmaceutically acceptable salt thereof, wherein:

X is:
-hydrogen;
s -cyano;
-nitro;
-formyl;
-COOH;
-COR, wherein R,, is C, to C6 alkyl;
-CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C, to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with Cl to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SOzRX, -SO2NH2;
-SO2NH(R,,);
-SO2N(R, )2;
-amino optionally substituted with one or more independently selected C, to C6 alkyls and/or -C(O)-Cl to C6 alkyls;
-amido optionally substituted with one or more independently selected C, to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl optionally substituted with one or more substituents independently selected from:

-C i to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;
Y is:
-benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more Ct to C6 alkyls;
-indolyl optionally substituted on the nitrogen with -SO2RX;
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from:
-halo;
-C I to C6 alkyl;
-alkoxy, optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo;
-C(O)NH2 optionally substituted with C6 to C8 allcyl;
-C(O)NH-(C1 to C6)-alkyl;
-hydroxy;
-haloalkyl;
-cyano;
-nitro;
-COOH;
-N=CHN(RX)2;
-amino optionally substituted with one or more substituents independently selected from:

-S02Rxa -6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR, and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C$ aryl optionally substituted with halo;

-5 or 6 rnembered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, -0, alkyl and haloalkyl;
-Cl to C-7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
-alkoxy; and -halo; and -POaR,;
-OC(O)NHRX wherein R,, is optionally substituted with vinyl;
-OC(O)N(Rõ)Z, wherein Rõ is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino;
-OC(O)NH(OR,,,), wherein R,,,, is -C6 to Cg aryl optionally substituted with dialkylamino;
-OC(O)NRx(ORX);
-OC(O)N(ORx)2;
-OC(O)R.ab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
-NRQC(O)Rp, wherein Rp is:
-CI to C6 alkyl;
-amino optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C$ aryl and alkoxy; or -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from C, to C6 alkyl and C6 to Cs aryl;
and wherein Ro is:
-hydrogen; or -C 1 to C6 alkyl;
-NRyCONRqR,, wherein R9 is hydrogen, and wherein R, is:
-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
- halo;
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl optionally substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-Cl to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-SO2Ra,,, wherein Raa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-Ci to C6 alkoxy; and -CI to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy;
-hydroxy;
-halo;
-COR, wherein R,,, is:
-amino optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with 5 or 6 membered heterocyclo or C6 to C$ aryl, which heterocyclo or aryl is optionally substituted one or more substituents independently sel'ected from halo and alkoxy;
-heterocyclo optionally substituted with hydroxy;

-3 to 7 membered heterocyclo optionally substituted with C, to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
-NRtCOORu, wherein Rt is hydrogen, and wherein Rõ is:
-CI to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-halo;
-SO2Rwa -SOZRX;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;
-C2 to C6 alkenyl;
-C6 to C$ aryl optionally substituted with halo;
-4 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=0;
-SO2R,,,;
-CORp; and -(CO)O-(Ci to C4 alkyl)-O-(C1 to C4 alkyl);
-NHRbb, wherein Rbb is:
-C(=S)NH2;
-C(=S)NHRX, -C(=S)NRXRx;
-C(=N-CN)NHR,; or -PO(ORX)2;
-N(CONHRW)2;
-NH(SOR,N);
-N(SO2R,N)2;
NRVSO2R,,,, wherein R,, is hydrogen or alkyl optionally substituted with 4 to membered heterocyclo;
and wherein RW is:

-C t to C6 alkyl optionally substituted with C6 to C8 aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to Cs aryl;
-C6 to Cg heteroaryl; or -amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 allcoxy, alkoxycarbonyl, (CO)O-(C1 to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

N

O
N

N

- a O

N/ O
. - ~. /

*-N
- O~S0 * \ ~ NH
O
; or H
N O

-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-halo;
-Ci t0 C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to C8 alkyl;
-hydroxy;
-haloalkyl;
-cyano;
-nitro;
-COOH;
-amino optionally substituted with one or more substituents independently selected from:
-SO2RX;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR7e and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
- C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and -Cl to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted With one or more alkyls, halos, and/or haloalkyls;
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-NRoCORp, wherein RP is:
-C f to C6 alkyl;
-amino optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more Cl to C6 alkyls and/or C6 to C8 aryls;
and wherein Ro is:
-hydrogen; or -C1 to C6 alkyl;
-NRyCONRqR,., wherein Rq is hydrogen, and wherein Rr is:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
- halo;
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to Cg aryl optionally substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-CI to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-NRtCOOR,,, wherein Rt is hydrogen, and wherein R,, is:

-Cl to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more Cl to C6 alkyls;
-halo;
-SOzRw,;
-SO2R,,;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; and -NR,SO2RW, wherein R,, is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo;
and wherein RW is:
-CI to C6 alkyl optionally substituted with C6 to C8 aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 t0 C8 aryl;
-C6 to C$ heteroaryl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
O
* \\ ~o N

- ;

- ;

N

; or N )~ O
_ ~./ .
Z is:
-C1 to C6 alkyl optionally substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;

R is hydrogen;
R, is:
-hydrogen;
-a 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-CI to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-CORp; and -C(O)ORx; or -5 or 6 membered heteroaryl optionally substituted with one or more independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;

-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;

-CO2 Rxa _CORx;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Cl to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ci to C6 alkyl, which alkyl is optionally substituted with one or more Cl to C6 alkoxys;
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-amido optionally substituted with Cl to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with C, to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-SO2 Rx;
-C2 to C6 alkenyl optionally substituted with -SO2 RX;
-Cl to C6 alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-cyano;

-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one oi more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C1 to C6 alkyl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkoxy; and -C6 to C$ alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and -4 to 7 membered heterocyclo;
-alkoxy; and -C6 to C8 aryl;
-(0)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-Ct to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C$ aryl;
- -CORp; and -C(O)OR,,; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, CI to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
_COR,,;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Cl to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Ct to C6 alkyl, which alkyl is optionally substituted with one or more CI to C6 alkoxys;
-C(O)NH2 optionally substituted with one or more CI to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C$ aryl;
-5 or 6 membered heteroaryl; and -Ct to C6 alky further optionally substituted with one or more substituted with hydroxys;
-SOZRx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C$ aryl; and -5 or 6 membered heteroaryl;
-C6 t0 Cs aryl;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C$ aryl;
-COOH; or -ORkk, wherein Rkk is:
-C6 to Cg aryl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkyl, C, to C6 alkoxy, and C, to C6 haloalkyl;
R2 is:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to Cg aryl;
-amido optionally substituted with Cl to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and -SO2 R,;
-C2 to C6 alkenyl optionally substituted with SO2R,,;
-alkylthio optionally substituted with one or more substituents independently selected from:

-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C I to C6 alkyl;
-SO2Rx optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more Ct to C6 alkyls;
-5 or 6 membered heterocyclo;
-C6 to C$ aryl; and -C I to C6 alkyl;
-S(O)R,, optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to C$ aryl; and -C 1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with oiie or more substituents independently selected from -SOa-CI to C4 alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido optionally substituted with Cl to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-S-CI to C6 alkyl optionally substituted with one or more substituents independently selected from:

-C6 to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -CS to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-S-C6 to C$ aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-Cl to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -CS to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfinyl-C6 to C$ aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C, to C6 allcyl;
-sulfonyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, heterocyclo, and Cl to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ct to C6 alkoxy; and -C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-CI to Cg alkyl optionally substituted with one or more alkoxys;
-4 to 7 membered heterocyclo; and -alkoxy; and -C6 to C$ aryl;
-C6 to C$ aryl;
-(0)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=0;
-C i to C6 alkyl;
-SO2RX;
-C(O)-C6 to C8 aryl;
-CORp; and -C(O)OR.; or -(0)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Cl to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-C 2Rx;
-CO%;
-C(O)NHa optionally substituted with one or more C, to Cs alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and CI to C6 alkyl, which alkyl is optionally substituted with one or more CI to C6 alkoxys;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl;
-5 or 6 membered heteroaryl; and -C, to C6 alkyl optionally substituted with one or more hydroxys;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C8 aryl;
-COOH;
-C(O)NH2 optionally substituted with one or more C s to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C, to C6 alkoxys;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R,.;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORX
and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
-C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;
-Cy to.C7 alkyl optionally substituted with one or more substituents independently selected from:

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-C6 to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Cl to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which.alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-COzRx;
_CORx;
-C(O)NH2 optionally substituted with one or more Cz to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C, to C6 alkyl, which alkyl is optionally substituted with one or more C, to C6 alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=0;
-C i to C6 alkyl;
-SO2R,ea -C(O)-C6 to Cg aryl;
-CORp; and -C(O)ORX;
-ORkk, wherein Rkk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkyl, C1 to C6 alkoxy, and C2 to C6 haloalkyl;
-5 to 6 membered heterocyclo optionally substituted with C} to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, CI to C6 alkyl, C, to C6 alkoxy, and C, to C6 haloalkyl;
-SO2RX; or -Si(Rx)3;
-OC(O)NHR,e wherein R,, is optionally substituted with -C6 to C$ aryl;
-OC(O)N(Rx)2i or N

- ; and R3 is hydrogen; or nitro;

with the proviso that at least one of X, Y, Z, RI, R2 and R3 is selected from the following:
X is:
-CH=N-(Cl to C6 alkoxy);
-CH N-(amino optionally substituted with one or more C, to C6 alkyls);

-halo;
-alkyl optionally substituted with one, or more halos;
-alkynyl optionally substituted with C, to C6 allcyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2R,,;
-SO2NH2;
-SOZNH(Rx);
-SO2N(Rx)2;
-amino optionally substituted with one or more independently selected C, to C6 alkyls and/or -C(O)-Cl to C6 alkyls;
-amido optionally substituted with one or more independently selected Cl to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;
Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ct to C6 alkyls;
-indolyl substituted on the nitrogen with -SOzRX;
-C6 to C$ aryl substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more substituents independently selected from:
-C(O)NHa optionally substituted with C6 to C$ alkyl; and -C(O)NH-(Ci t0 C6)-alkyl;
-haloalkyl;
-cyano;
-COOH;
-N=CHN(RX)2;
-amino substituted with one or more substituents independently selected from:
-SOaR,,;

-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORx and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to Cg aryl optionally substituted with halo;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, alkyl and haloalkyl;
-Ct to C7 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
-alkoxy; and -halo; and -PO2Rx;
-OC(O)NHRX wherein Rx is optionally substituted with vinyl;
-OC(O)N(Rõ)z, wherein R,, is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with diallcylamino;
-OC(O)NH(OR,,,,), wherein R,,,, is -C6 to C8 aryl optionally substituted with dialkylamino;
-OC(O)NRx(ORx);
-OC(O)N(ORx)2;
-OC(O)Rab, wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloallcyl;
-NRaC(O)RP, wherein Rp is:

-amino optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C$ aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from C 1 to C6 alkyl and C6 to C8 aryl;
-NRyCONRqRr, wherein Rr is:
-CI to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-CI to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-S02R,,,, wherein Ra2, is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-CI to C6 alkoxy; and -CI to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy;
-hydroxy;
-halo;
-CORm, wherein R. is:
-amino substituted with one or more C, to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys;
-heterocyclo substituted with hydroxy;
-NRtCOOR,,, wherein Rõ is:
-Cl to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C$ aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more Ci to C6 alkyls;
-SO2R;
-SO2RX; and -5 or 6 membered heteroaryl;
-C2 to C6 alkenyl;
-4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
=0;
-SO2Ru;
-CORp; and -(CO)O-(Cl to C4 alkyl)-O-(C1 to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=0;
-SO2Rw,;
-CORp; and -(CO)O-(Cl to C4 alkyl)-O-(Cl to C4 alkyl);
-NHRbb, wherein Rbb is:
-C(=S)NHRx;
-C(=S)NRXRX; or -C(=N-CN)NHRX;
-N(CONHRw)2;
NH(SORw);
-N(S02RH,)2;
-NRõSO2R,,,, wherein R,, is alkyl substituted with 4 or 7 membered heterocyclo;

or wherein R, is:
-CI to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, alkoxycarbonyl, (CO)O-(Cl to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
O
N

-a Nõ/// \\\O
*-N
\
S
~

* CtN H
~==O

; or H
* ~ / N O

-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-halo;
-C 1 to C6 alkyl;

-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to Cs alkyl;
-hydroxy;
-haloalkyl;
-cyano;
-nitro;
-COOH;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R,.;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR,, and haloalkoxy; .
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
- C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl ' and haloalkyl; and -CI to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-NRaCOR.p, wherein Rp is:

-amino optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C, to C6 alkyls and/or C6 to C8 aryls;
-NRqCONRRqRT, wherein Rr is:
-CI to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-CI to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-NRICOORu, wherein Rõ is:
-CI to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more Cl to C6 alkyls;
-SOzR,,,;
-SO?R,; and -5 or 6 membered heteroaryl;
-NRõSOaR,,, wherein Rõ is alkyl substituted with 4 to 7 membered heterocyclo;
or wherein R,y is:
-CI to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected,from haloalkyl, halo, alkoxy, and alkyl;
-C6 to C8 aryl;

-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, Cl to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
O

S
O
N

;
O
N

- ; or ~

_ ~./.
Z is:
-CI to C6 alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;

RI is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;

-Ct to C6 alkyl;

-S02Rxa -C(O)-C6 t0 C8 aryl;
-CORp; and -C(O)ORX; or -5 or 6 membered heteroaryl substituted with one or more independently selected from:
-Ct to C6 alkyl optionally substituted with one or more substituents independently selected from halo, CI to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2 Rx;
_CORx;
-C(O)NH2 optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C, to C6 alkyl, which alkyl is optionally substituted with one or more C, to C6 alkoxys;
-Ci to C6 alkyl substituted with one or more substituents independently selected from: -165--amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo substituted with C, to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to Cs a.ryl;
-SO2 RX;
-C2 to C6 alkenyl optionally substituted with -SO2RX;
-Cl to C6 alkoxy substituted with one or more substituents independently selected from:
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amino optionally substituted with heterocyclo;
-amido optionally substituted with Cl to C6 alkyl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and Cl to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C I to C6 alkoxy; and -C6 to C8 alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and -4 to 7 membered heterocyclo; and -alkoxy;
-(0)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:

-hydroxy;
-Ct to C6 alkyl;
-SO2Rx;
-C(O)-C6 to C8 aryl;
-CORp; and -C(O)ORx; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Ct to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, CI to C6 alkoxy, hydrbxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R.;
_CORX;
-C(O)NHz optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, Cl to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and Cl'io C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C(O)NH2 optionally substituted with one or more Ct to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to Cg aryl;
-5 or 6 membered heteroaryl; and -CI to C6 alky further optionally substituted with one or more substituted with hydroxys;
-SO2RX optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to Cx aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to Cg aryl;
-COOH;
-ORkk, wherein Rkk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkyl, C, to C6 alkoxy, and Cl to C6 haloalkyl;

R2 is:
-Cl to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;

-amido optionally substituted with C, to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and -S02 RX;
-C2 to C6 alkenyl optionally substituted with SO2Rx;
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C I to C6 alkyl;
-SO2RX optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more C, to C6 alkyls;
-5 or 6 membered heterocyclo;
-C6 to C$ aryl; and -C, to C6 alkyl;
-S(O)RX optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -Ci to C6 alkyl;
-alkoxy substituted with one or inore substituents independently selected from:
-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino substituted with one or more substituents independently selected from -S02-C, to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido substituted with Ci to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C, to C6 alkyl;
-S-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-S-C6 to Cs aryl;
-sulfmyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-Ci to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to Cs aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfinyl-C6 to C8 ary1;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C, to C6 alkyl;
-sulfonyl-C, to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to CS aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, heterocyclo, and Cl to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Ct to C6 alkoxy; and -C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-Cl to C6 alkyl optionally substituted with one or more alkoxys;
-4 to 7 membered heterocyclo; and -alkoxy; and -C6 to C8 aryl;
-C6 to C8 aryl;
-(0)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
=0;
-Cl to C6 alkyl;
-SOZRX;
-C(O)-C6 t0 C8 aryl;
-CORp; and -C(O)ORX; or -(0)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, CI to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;

-COOH;
-COzRX;
-CORX;
-C(O)NHa optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and CI to C6 alkyl, which alkyl is optionally substituted with one or more Cl to C6 alkoxys;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C$ aryl;
-5 or 6 membered heteroaryl; and -Ct to C6 alkyl optionally substituted with one or more hydroxys;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C8 aryl;
-COOH;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido substituted with one or more CI to C6 alkyls, which alkyls are optionally substituted with one or more Cl to C6 alkoxys;
-amino substituted with one or more substituents independently selected from:
-SO2RX;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORX
and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;

-CS to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;
-CI to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2Rx;
_CORX;
-C(O)NH2 optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C, to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=0;
-C7 to C6 alkyl;
-SO2Rx;
-C(O)-C6 to Ca aryl;
-CORP; and -C(O)ORx;
-ORkk, wherein Rkk is:
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkyl, C1 to C6 alkoxy, and Cl to C6 haloalkyl;.
-5 to 6 membered heterocyclo optionally substituted with CI to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C, to C6 alkoxy, and Ci to C6 haloalkyl;
-SOzRX; or -Si(Rx)3;
-OC(O)NHR,, wherein R, is optionally substituted with -C6 to C8 aryl;
-OC(O)N(R,)z; or N

- ; an.d R3 is nitro.

90. The compound of embodiment 89, wherein:

X is:
-CH=N-(Cl to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more Cl to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2RX;
-SO2NH2;
-SOaNH(Rx);
-SO2N(Rx)2;
-amino optionally substituted with one or more independently selected Cl to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected Cl to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C$ aryl substituted with one or more substituents independently selected from:
-Cl to C6 allcyl optionally substituted with one or more halos;
-halo; and -cyano.

91. The compound of embodiment 89, wherein:
Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more Ct to C6 alkyls;
-indolyl substituted on the nitrogen with -SO2Rx; or -C6 to C$ aryl substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more substituents independently selected from:
-C(O)NH2 optionally substituted with C6 to C8 alkyl; and -C(O)NH-(Cl to C6)-alkyl;
-haloalkyl;

-cyano;
-COOH;
-N=CHN(RX)z;
-amino substituted with one or more substituents independently selected from:
-SOaR,,;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloallcyl, cyano, alkoxy, COR,, and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-C1 to C7 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl; ' -C6 to C$ aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
-alkoxy; and -halo; and -P02R., -OC(O)NHRx wherein Rx is optionally substituted with vinyl;
-OC(O)N(Ru)2, wherein Ru is allcyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with diallcylarnino;
-OC(O)NH(ORõu), wherein R,,,, is -C6 to Cg aryl optionally substituted with dialkylamino;
-OC(O)NRx(ORX);
-OC(O)N(ORx)2;

-OC(O)Raba wherein Rab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
-NRoC(O)Rp, wherein Rp is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from Cr #o C6 alkyl and C6 to C8 aryl;
-NRyCONRqRr, wherein R, is:
-C, to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-CI to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-SO2R., wherein Raa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-C, to C6 alkoxy; and -Ct to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy;
-hydroxy;
-halo;
-COR,,,, wherein R,,, is:

-amino substituted with one or more C1 to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C6 to Cs aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys;
-heterocyclo substituted with hydroxy;
-NRtCOOR,,, wherein Rõ is:
-Cl to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C$ aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more CI to C6 alkyls;
-S02RW;
-SOaRX; and -5 or 6 membered heteroaryl;
-C2 to C6 alkenyl;
-4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
=0;
-SO2Rw, -CORp; and -(CO)O-(Cl to C4 alkyl)-O-(CI to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=0;
-SO2R,,;
-CORp; and -(CO)O-(Cl to C4 alkyl)-O-(CI to C4 alkyl);
-NHRbb, wherein Rbb is:
-C(=S)NHRXa -C(=S)NRXR,,; or -C(=N-CN)N.HR.;
N(CONHRw)2;

-NH(SOR,,,);
-N(SO2RW)2;
-NR,,SOZR,,,, wherein R, is alkyl substituted with 4 or 7 membered heterocyclo;
or wherein RW is:
-C, to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C i to C6 alkoxy, alkoxycarbonyl, (CO)O-(Cl to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

N

O
j \=N/ \=O

_ ~.
*-N
\
l,S
* Q NH

; or H
N O

-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-halo;
-CI to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to C8 alkyl;
-hydroxy;
-haloalkyl;
-cyano;
-nitro;
-COOH;
-amino optionally substituted with one or more substituents independently selected from:
-SO2RX;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORX and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to Cg aryl optionally substituted with halo;
- C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and -CI to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
-C6 to C8 aryl optionally substituted with one or more substituents independently'selected from alkyl, halo and haloalkyl;

-alkoxy; and -halo;
-NRoCORp, wherein RP is:
-amino optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C, to C6 alkyls and/or C6 to C$ aryls;
-NRqCONRqR,, wherein Rr is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to Cs aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-CI to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-NRtCOOR,,, wherein Ru is:
-CI to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-SO2R,N;
-SOzRX; and -5 or 6 membered heteroaryl; and -NRvSO2Rv,,, wherein Rõ is alkyl substituted with 4 to 7 membered heterocyclo;
or wherein RW is:

::~

-CI to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to Cg aryl;
-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, CI to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
O
\\i ., N/ .
O

N

O
N
- ; or N )~' O

92. The compound of embodiment 89, wherein:
Z is:
-C, to C6 alkyl substituted with 5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo.

93. The compound of embodiment 89, wherein:
Ri is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-C I to C6 alkyl;
-SOzR.;
-C(O)-C6 to C$ aryl;
-CORP; and -C(O)ORx; or -5 or 6 membered heteroaryl substituted with one or more independently selected from:
-C 1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Cj to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2 RX;
_COR,,;
-C(O)NH2 optionally substituted with one or more CI to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Cl to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

-amido optionally substituted with one or more or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C, to C6 alkyl, which alkyl is optionally substituted with one or more C, to C6 alkoxys;
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with C, to C6 alkyl;
-5 or 6 membered heterocyclo substituted with C, to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 tO C8 aryl;

-SO2 Rx;
-C2 to C6 alkenyl optionally substituted with -SO2R7zi -Cl to C6 alkoxy substituted with one or more substituents independently selected from:
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C, to C6 alkyl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C, to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-Cl to C6 alkoxy; and -C6 to C8 alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:

-CI to C6 alkyl; and -4 to 7 membered heterocyclo; and -alkoxy;
-(0)-5 o`r 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-CI to C6 alkyl;
-S02R,;
-C(O)-C6 to C8 aryl;
-CORp; and -C(O)ORX; or -(0)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Ct to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Cl to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-30 -C02RX;
_CORx;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:

-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6'mernbered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more subst7ituents =
independently selected from halo, Ci to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and CI to.
C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C(O)NH2 optionally substituted with one or more Ci to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected froni halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl;
-5 or 6 membered heteroaryl; and -C1 to C6 alky further optionally substituted with one or more substituted with hydroxys;
-SO2R,; optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 tO C8 aryl;
-COOH; or -ORkk, wherein Rkk is:

-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkyl, Cl to C6 alkoxy, and C, to C6 haloalkyl.

94. The compound of embodiment 89, wherein:
R2 is:
-CI to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with Cl to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and -SO2 Rx;
-C2 to C6 alkenyl optionally substituted with SQaR.,;
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-S02R,, optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more Ct to C6 alkyls;
-5 or 6'membered heterocyclo;
-C6 to C$ aryl; and -C, to C6 alkyl;
-S(O)R, optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;

-alkoxy substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino substituted with one or more substituents independently selected from -S02-C1 to C4 aileyl and alkyl, which alkyl is substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido substituted wnth Cl to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with Ct to C6 alkyl;
-S-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-S-C6 to C8 aryl;
-sulfmyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C, to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to Cg aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfin.yi-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with Cl to C6 alkyl;
-sulfonyl-Cl to C6 alkyl optionally substituted with one or more substituents independently selected from:

-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =0, heterocyclo, and CI to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-CI to C6 alkoxy; and -C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more alkoxys;
-4 to 7 membered heterocyclo; and -alkoxy; and -C6 to C8 aryl;
-C6 to C8 aryl;
-(0)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
=0;
-C 1 to C6 alkyl;
-S02R_,;
-C(O)-C6 to C$ aryl;
-CORp; and -C(O)OR,,; or -(0)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-CI to C6 alkyl optionally substituted with one or more substituents independently selected from halo, Cl to Cb alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;

-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, Ci to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-COZRX;
-COR,,;
-C(O)NH2 optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C, to C6 alkyl, which alkyl is optionally substituted with one or more C, to C6 alkoxys;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl;
-5 or 6 membered heteroaryl; and -C1 to C6 alkyl optionally substituted with one or more hydroxys;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to Cs aryl;
-COOH;
-C(O)NH2 optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

-amido substituted with one or more Cl to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys;
-amino substituted with one or more substituents independently selected from:
-S02Rx;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, CORX
and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C$ aryl optionally substituted with halo;
-CS to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;
-Ci to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-C6 to CS aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-Cl to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alleyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C, to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and or 6 membered heteroaryl;
-heterocyclo;
-nitro;
5 -hydroxy;
-COOH;
-C02RX;
_CORX;
-C(O)NH2 optionally substituted with one or more C, to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, Ct to C6 allcoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C, to,C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C, to C6 alkyl, which alkyl is optionally substituted with one or more C, to C6 alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=0; .
-CI to C6 alkyl;
-SOaRX;
-C(O)-C6 to Cg aryl;
-CORP; and -C(O)OR,t;
-ORkk, wherein Rkk is:
-C6 to C8 aryl optionally substituted with one or more substituents i.ndependently selected from halo, CI to C6 alkyl, C, to C6 alkoxy, and CI t0 C6 haloalkyl;
-5 to 6 membered heterocyclo optionally substituted with Ct to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, Cl to C6 alkyl, C, to C6 alkoxy, and CI
to C6 haloalkyl;

-SO2R,,; or -Si(R.)3;
-OC(O)NHRX wherein Rx is optionally substituted with -C6 to Cg aryl;
-OC(O)N(Rx)2a or N

95. The compound of embodiment 89, wherein R3 is nitro.

96. The compound of embodiment 89, wherein:
X is cyano or hydrogen;
Y is:
-C6 to Cg aryl optionally substituted with one or more substituents independently selected from:
-halo;
-Ct to C6 alkyl;
-amino optionally substituted with one or more substituents independently selected from:
-SO2RX;
-5 or 6 membered heteroaryl optionally substituted with one or more alkyl;
-C1 to C7 alkyl;
-NRtCOOR,,, wherein R.t is hydrogen, and wherein Rõ is Cl to C12 alkyl;
-NRõSO2RW, wherein Rõ is hydrogen, and wherein RW is Ci to C6 alkyl or amino optionally substituted withalkyl;
O
`//O
N

U
;or N

a Z is C 1 to C6 alkyl;
R is hydrogen;
R, is hydrogen;
R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano; and R3 is hydrogen.

97. The compound of embodiment 96, wherein the C6 to C8 aryl is phenyl.

98. The compound of embodiment 97,wherein:

X is cyano;
Y is phenyl para substituted with NR.S02RW, wherein R, is hydrogen, and wherein RW is C, to C6 alkyl; and R2 is -(0)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.

99. The compound of embodiment 97, wherein:
X is cyano;
Y is phenyl substituted with C, to C6 alkyl and NRS02R,, wherein Rõ is hydrogen, and wherein RH, is Cl to C6 alkyl; and R2 is -(0)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.

100. The compound of embodiment 97, wherein:
X is cyano;
Y is phenyl substituted with halo and NRSOaR,,,, wherein R, is hydrogen, and wherein Ru, is Cl to C6 alkyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.

101. The compound of embodiment 97, wherein:
X is hydrogen;
Y is phenyl is para substituted with -NRtCOOR,,, wherein Rt is hydrogen, and wherein Rõ is Ct to C12 alkyl;
Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl; and R2 is -(0)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.~

102. The compound of embodiment 89, wherein:
X is cyano;
Y is:
-C6 to C$ aryl optionally substituted with one or more substituents independently selected from:
-NRtCOOR,,, wherein. Rt is hydrogen, and wherein Rõ is C1 to C12 alkyl optionally substituted with one or more halo; or -NRõS02RW, wherein RV is hydrogen, and wherein RW is Cl to C6 alkyl;
Z is CI to C6 alkyl;
R is hydrogen;
R, is hydrogen;
R2 is -(O)-5 or 6 membered heterocyclo substituted with one or more =0; and R3 is hydrogen.

103. A compound which is selected from the compound range: 1330-2128 and 2600-3348.

104. The compound of embodiment 103 selected from:

/I N~
o T--o 0 \ N NH CN~O NH

/ ~ b 2722 2701 N N' N /-C>-+ F N N F N
N H i\N ~ i N 'H
0 6 ~ (--' b F F, F N
II o F F II o ~-o F~~, N NH 0 0 ~o I/ \ /
N N
O 'H
N' N ~

N
/f O\\
N \ p p~-~] Ta f _ p\\
T-' CN~o I/ N N~ NH N~o NH p F

b 2895 2922 N o rN /N F F
F.
- ~ 6 O` O
N S-o O
N 'H NH N~p N / NH
N

N N
II p\\ %-Q N ~ O
\ - T
0 C0/J N jN - Oi N \ 0 N H N p N . H C N N H
,N b b N N N
N i o,Q o 0 ll O\\
~ - N 'N= o I O
C~ NH p1 ~
~N 0 N o =H N NH
b N b % /N
N O, .p i N p` N
NH ~ ( ~ s ( \ / NIi~\ N
N
N 0 N \ l ~N 0 N N O N H

N
O
NH
O

105. A composition comprising the compound of embodiment 1 and one or more pharmaceutically acceptable excipient(s).

106. A composition comprising the compound of embodiment 39 and one or more pharmaceutically acceptable excipient(s).

107. A composition comprising the compound of embodiment 77 and one or more pharmaceutically acceptable excipient(s).

108. A composition comprising the compound of embodiment 83 and one or more pharmaceutically acceptable excipient(s).

109. A composition comprising the compound of embodiment 89 and one or more pharmaceutically acceptable excipient(s).

110. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical compbsition comprising an effective amount of one of more compound(s) according to embodiment 1.

111. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 39.

112. A inethod for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77.

113. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 83.

114. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.

115. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 1.

116. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 39.

117. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 77.

118. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodim.ent 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 83.

119. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to embodiment 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to embodiment 89.

In yet another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-Xlb, I-XIc, IIa, IIb, IIc, IId, or Ile, wherein Y is a-NRtCOORõ group and Rõ is a Ct to C6 alkyl. In an embodirnent, compounds are provided wherein Y is a-NRtCOORõ group and Rõ is a CI to C6 alkyl in the para position.
In another embodiment, the present invention includes compounds of-Formulas I, I-X, I-XI, I-XH, I-Xa, I-XIa; I-XIIa, I-XIb, I-XIc, IIa, Ilb, Ile, IId, or Ile, wherein Y is a-NRtCOORõ
group and R. is a branched C1 to C6 alkyl. In an embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, Y is a-NRtCOORõ group and Rõ is a branched Cl to C6 alkyl in the para position. In another embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-X1Ta, I-Xlb, I-XIc, IIa, Ilb, IIc, IId, or Ile, wherein Y is a-NR.,COORõ group and R. is an isopropyl. In another embodiment, the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, Ilb, Ile, IId, or Ile, wherein Y is a-NRtCOOR, group and Rõ is a methyl cyclopropyl. In another embodiment, the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa,.
I-XIb, I-XIc, IIa, Ilb, IIc, IId, or Ile, wherein Y is a-NRtCOORõ group and Rõ
is an ethyl cyclopropyl.
In another embodiment, the present invention includes compounds of I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, Ilb, He, IId, or He, wherein Y is a-NR
SOzRW group, Rõ is a hydrogen, and where Rw is a Cl to C6 alkyl. In a further embodiment, the present invention includes compounds wherein Y is a-NRSO2R,,, group and R.,, is a propyl group.
. In an embodiment of the present invention, compounds are provided wherein Y
is a C6 to C8 aryl that is substituted. In an embodiment of the present invention, compounds are provided wherein Y is a phenyl that is substituted. In anembodiment of the present invention, compounds are provided wherein Y is a C6 to C$ aryl that has one, two, three, or four substituents. In another embodiment of the compounds of the present invention, Y is a C6 to C8 aryl that has one, two, or three substituents. In another embodiment, Y is a C6 to C8 aryl that has one or two substituents. In a further embodiment, Y is a C6 to C8 aryl that has three substituents. In a further embodiment, Y is a C6 to C$ aryl that has two substituents. In a fiu ther embodiment, Y is a C6 to Cg aryl that has one substituent.

In another embodiment of the present invention, compounds are provided wherein Y is a C6 to Cs aryl with at least one substituent in the ortho, meta, or para position. In a further embodiment, Y is a C6 to C8 aryl with at least one substituent in the meta or para position. In yet another embodiment, Y is a C6 to Cg aryl with a substituent in the para position.
In an embodiment of the present invention, compounds are provided wherein Y is a C6 to C$ aryl, optionally substituted with one of the following in the para position:
-an alkoxy, -an amino optionally substituted with one or more of the following:
-SO2RX groups, or -C1 to C6 alkyl, the Cti to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryl group, -OC(O)NHRX, -OC(O)N(RX)2, -OC(O)NH(OR.), -OC(O)NRX(ORX), -OC(O)N(ORx)a, -OC(O)R,lb, wherein Rab is a 5 or 6 membered heterocycle group, -a -NRoCORp group, where Rp is:
-a C 1 to C6 alkyl, -an amino group optionally substituted with one or more Cl to C6 alkyl groups where the CI to C6 alkyl groups are optionally and independently substituted with one or more C6 to C$ aryl groups and/or alkoxy groups, -a 5 or 6 membered heterocycle, optionally substituted with one or more C, to C6 alkyl or C6 to Cg aryl groups, and where Ro is:
-a hydrogen, -a C, to C6 alkyl, -a -NRqCON.RqR, group, where Rq is a hydrogen, and where Rt is:
-a CI to C6 alkyl optionally substituted with one or more of the following:
-a hydroxyl, -an alkoxy, -a 5 or 6 membered heterocycle, -a 5 or 6 membered heteroaryl, or -a C6 to C$ aryl optionally substituted with a halo, -a C2 to C6 alkylene group, -a C 1 to C6 alkoxy group, -a 5 or 6 membered heterocycle group, -a -NRtCOORõ group, where Rõ is:
-a Ci to C12 alkyl, optionally substituted with one or more groups independently selected from*the following:
-a C6 to C8 aryl optionally substituted with halo, -an alkoxy group optionally substituted with one or more alkoxy groups,' -an amino optionally substituted with one or more Ct to C6 alkyl, -halo, or -a 5 or 6 membered heteroaryl, -a C2 to C6 alkylene, -a C6 to C$ aryl, optionally substituted with halo, and Ri is:
-a hydrogen;
-a -NHRbb groUp, where Rbb is:
-a -C(=S)NH2 group, or -a -PO(OR,,)2, where R, is as defined above;
-a -NRSOZRw group, where Rõ is a hydrogen, and where R, is a C, to C6 alkyl, O

N O
-a j ~Nii// \\O
-a In some embodiments, Y is selected from the Y substituents of compounds 1330-2128, and 2600-3348.
In other embodiments of the present invention, compounds are provided wherein Y is selected from the group consisting of the following substituents:

O
<S
N
f O N
. ,o O
O
.
O N
. \ ~
O NH O

NH NH
~ ~ .
H
N O

O
H O rN
aN

= N O p N

N

\
, N
N~ N H
~
H
w \ O

OH
/ N~N~/N V N N
H H H H
N ~N
H
N p/~\

II ~
0 N ~ ll~ N p ~~ .
O

o N H
/~ ~ci ~ O" ~
H
= = O\
O aN)~ O
HN

I I /
)t" O
H~ N H H

laN O N O
H H

H~ H H H

O O
I ~ I
N`
N O
H ~ H

O
N H

0 I { =
"k, H a I ~`N H o ~
N`
.~
+ \ O

= \ / I

H p \
= +

~ \ p { \ o H p \ H ~ ( ~
~ / F

1 ~ O p O

~ { O
H H N N ~
H H
aN
H H J", O
1 \ 0 NN
H H H~

F

O
O
{ ~ ~ F
N p =
H p H
F

. *
O O

H~ p H )~, O y o d ,,~ 0 N p o H

i In other non-limiting embodiments of the present invention, compounds are provided wherein Y is selected from the group consisting of ' 3:~
*-N H

''-N

0 *-~ O
O
/

O

*-N
O H

*_N '-N
H

~ / Br -NH +-O
I H -N

F~ H O\\ O
p F x ~ I NH *-NJ-1-f = * \ f * \ f * \ /
O-*

'H * / \ O
* N
H O
j-F O
O * \ f 0 O~-a O~ H
/O

NH NH O~~
O - H H
O ;S/ " \ f N ~O * \ / NS ~O
O~\ O
O *
~

. ~ f O * \ f N . \ f N
~) O O OT`-~O \/-O
* \ / I H * \ f N H * \ / NH

F F
Ct F

O
* ! \ f * \ / ~ * = N
Br H
O ,O- - - -.
* ` \ f N~
H

N
CI

* - \ f Cl * - ~ f O * - \ f F
O
* \ / N

F H H % 0.\, 0-H

N NN Cl -* - * O
-' \ f N - \ f ` * ` \ f H

O N~ O., ~N-H
N, _ ~--' NH - \ / NH H NH
O Br _ H O _ O " S~
N NH O
H

! \ f _ S
H-N
H

O ~ / -H N-H N
H

O~\
OIS
Oi * \ / N O * \ / NH
- O~ \O HN 0 +-_ _ - -NH

~N ~ N-S-_ O
H O
N-S-/ HN-SK HN O
O O

'N 'N \ / \
N
%
H ~~\\F

N O O
~_N - *_N

'H H "-NH

-,\
O H N

H HN~CI H
O O
.N / O~~
-\O N
N N
O

C

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

CI
Br O.~S .
O N-H
H H
CD N
N- ~~0 ,-~ j--~ N
* \ / O
o O
HO

6 * N
~ / o * - N
N S ,N+
O
\ 'O
H
HN-H O%,N-H N-O
p ~

p H H
p N S \~O H , .
o p ~-C{

N O O
~-N * \ / O N~O
* \ /

H - p H N4 N * \ / S-N - ~/ N
O O `H O H
H *
~ O

S O
\ / -' O
I * - ~
\ / O N H
~01 H O H
%N-S-1 O
O

O
H C{ 0 H
~
O
N N
N-S O !-/ I
H
* \ / 0 NH * \ /
= * \ /

O l-- 0 0 H
* \ / * \ l * \ /

HN \ ~ O
"~-, HN HN--~
_ O p~
"` ~ ~ * \ 0 ~ * \ l ~ o I =

p 0 0 * \ / O-\_O
"

HN4 HN HN--~
O-\ _ O~! - O~
`-\ * \ / F * \ /
CI
0 p O
HN4 HN- ~ f HN4 -* p \ / p * - O \ / C1 O/ \ \ /
* \ /

HN~ HN4 - HN4 O \ / F O Br \e \v \/

o o O
~O - ~-O ~-O
* \ / NH * \ / NH * \ j NH

p // p Cl r-O - T -O OJill * \ / NH * \ / NFi *\ j - NH

CI F
F

/-j v\ v\

* \ / NH O ~--p - ~-O -* \ / NH \ / NH
Br H
- ~ O
_ -H
O N
*\ / NH *\ / NH H

H O.
O H H 0 % N
N N~
C~ . *
* ~ ~ f N O
O"."O

N N
-N
._,b O
H p H 0 H

N N O`N
N d~o N
,O * .H

O Op O
N~O FjN H-~
H ~ H O
CI
*
S~

,- _ O
Nj O'1-1-O

H H
*-N * _ H
N ~O
- p ~ p~~ \
O-HN'N * - O

~
HN--t HN-~~ HN--~
* \ / * \ I / * \ / ~~
~

0- O-\ 0 C+ * \ /

NH
* \ / NH \ / N~.O \ /
O O O/-` O O
N~O * \/ NH ~ N~o O , HN

o N"

O-H
O. /
o o ~
S-N * \ / N `
O H O H

H
os e ~
O
* \ / \ * \ f N .O o 0 H
H

S-N * \ / S-N` 0-1 1 H % p H

O / \ r~,j *
\ / N-H N~
N~ ~
N
N,y ~ H-N ~- /
H N

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

CI \ ~ O
CI CI
H O * ~ \ O * / \ O
N

O O . / \ O
N-H
N-H N

_H-Os - N-H
N H --\

O
~ \ HN--/_CI HN~-~ N-H HN- ~ HN-~\
O
. \ f = -O

HN ~ HN~
HN ~ HN HN~
~O HN-~ 0 '\ / = * O * \ /

CI
HN~ HN-1 H1N \ /
HN--~ HN \~ HN-\\
O O O=

HN HN ~ e HN HN ~~ HN
HN-~
O O O
HN
- o HN 0 HN~ \/ p 0 H
HN ~ 0 O NH
O
\ / , \ e - O O\\ C{ - 0 * \eNH * - ~ / NH~ \ e NH--/

O O O
NH NH `-. NH
\ / \ /

N w / \ O
* / * \ / NH * \ e NH
HN \ I ~-NH ~-NH
O \--\ 0 CI CE
/ NH ~j}--NH H H
0~NH N N

p-/ / o HN--~ H N N
H r I
* 0 N N
OK S
O O~ ~

H
\\
* NI~ ~ NS S \ * \ / NS
o I H O' `O O N

H

~--0 ~ \ I N ~--0 * \ / H \N HH
H
W-N N H N
\ /
N
S /
N H
N
O HN O-<D O.
HN-~ O N
O N H
OO
* _ I \ ~ HN-.~( ~~~---~~---///
H \\p N OO

/O O õ
HN-\\ O HN-~ O
O Q N ~
H ~O

/ F F
*~ -HN~-1 / HN ~"
F -N
H
N-~ O N-~
Fi O H O

H o H H o H H 0 H
'N-S-N N-S-N 'N-S- ~
O \ O ~" O

O~-Cl O~-O
_ HN-~ HN-~
\ , NH * \ / O * \ / O

_ H O
O - HN~ \ l O\ ~N
HN-~\ \\O
O
* \ /

O O
HN O HN-S HN-S
o O-* N H * / \ N% * / \ NH ~N H jH
\

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

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

H O H
N-S-N~ N
O

0--~
O-/ HN-~\
HN-\~ HN--<\ p * \ f O * \ f p * \ /
F

N-(/ F
O. p"
F -.O
NH
/ \ / \ f H H
H
* \ / NS~ * \ / NS\ / * \ f N ~`""
O~ ~O O' O ~ I O~NH

O
~
--NS\O OThH

,H
N~ * \ / O * \ / N

* \ / N ~--p *\ / . N~-O
O--O * \ ~ NH

* \ / 'O * / \ ~ \ O * / \ \ ~
01A NJ~
H ~ H
H
'N-S O -. * \ / \ / O~

* \ / O ~ -5- 4O
O

= * - H . * 0 ~
N = ~~ =
H
~ ~S
O
* \ / ~,N O. T-1 N O--/ H
H - ~S'z~O ,S=O
NSO OS

O H
H H ~N` _ ,N-S-N N-S=O \ / ~DNH
O ~ - O

C~ * \ / H

0 H _~CI o ~N-S- O. N O.,~/ _ H
O _ S
O * \ / N~
* \ / * \ / NH

O
O / - O\SO 0 N
~
O

I__ O O ~
H %
.
N "
H i-i ~ ~-N 0 ~
O
-N
~-N _N ~H *\ / _._ N H
* \ / N H 'H H
'H

O\\ - O\\ O_S:O
* \ / NIH- `H * \ / NIH- H _ N
* \ /

O O,N O N O N
N ~ I * N S-N * / \ N
H H H
O O O~~
QjK H H N 'O 'H

H O ~NH
H 'N-H Qo N~ ~ * \ / O~ * \ /

* ~ N NH ~P~'O
O O ~--N O-\
O J -\ (7 Fi H
- H CI O * ~~ IV H
NN ~-- O
OH ~' H O

* - -N,H * N ,H
NN
O ~N p1/

0 = 0 S^

~ * N p/ NJ ~( p~
IV ~ \~ *-N N
O O
_/ H

*-N NH * N 0 p p ' u O~
Ipl . ~ ~ N
, H
--JO~ O- ~O
O N~
N ~~O O
F
O~~

~O
N ~ % -H
O /- F
*
S%O * ~ ~ O
F
ON~~
F
~--~ o_~-- ~--~ o 0 *- N JN-S *- N-S--a O O
O
' ' I - c *-N N-S >.=
O O' / O

0____/
HN-1 / \ HN~
= NH2 . ~ \ o N

s/ = / \ NS ~ o\ ~/
Ns H

HN HN

~ \ o O
F
~ p=-' ` e~\
\ N
N
. / \ g a O II
O'I \ / \ NH \ / F = \ ~ HI \p~ '~' ~
. / \

O
_ \ / \ NC~
S--* \ I N - N' \ ~ H

HN-H O O' * \ / \ ~ H * \ / N O
F
F H
CI O
~-O
O. S \ = Q
\O * \ / N O NH
H H
F F F
O~0 QT0 O O' * H F F F

F H
O /-/ F
O
- ~.O - NS, * \ ` N H * \ / NH2 ~~.
F

H H H
* \ / N5~0 / NS~O * \ / ~O
O )--- O ~ 0 O \ / O / \ * -N \ / NH 'H
* / \ NH 'H F

O O '- - H
- ~~=-N - ,U-N * \ / N
* \ / N H * \ / N H
H 'H 0 F F

N-S-G * - NH
* \ / H H O

' O

H

r''p ~N~' p~ ~! õ \ / N 'H \ / H
H

`S. O"S~ O.
~O - .~
NH \ NH O NH ~p Oi \O
= / \ p~-O
- O p \\-O * \ / N
~--0 H
N * \/ N
H
H

/~
* \ / N 'H A:::~N o H o.S~O
~. ^v _ 0 N" H * N \
O i i H H

O~ / O. ~ O,~
SO ~ 'S`O
\ / N

~//

~
NN- 0 o~
i ~-N * / \
H H * O N
H H

H ~NH N~
* ~ N uO ~ I / ~
~ If I * \ /
`~~/ O ~i ` p~
O O^~

F

~-O * \/ N p - p ~
* \ / NH t * \ / NH

O

ND N H H
~N N
~
O H O

,~--O ~-O

NH NH N
H
\\ \\
O O
O
T-N - r--No ~--* / NH ~ / NH * / ~ M 'NH
H
O, )aN ,OH
O\\
- T-O N J O~O
'H

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

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

O N~
() ! ~
\\p ~
- I~N. ~%\N~O~ 0 * ~ / N H H - ~--0 H * ~ / NH

p O

~-O O p 0 _-0 / NH N~-O \ / N-0 \ / H H
% 0 O~--O * \ / N) * \ / N
* \ / N
H
0 0 0 - O O O~ ~
~
\ / NH * \ ~ NH * \ N% O
H

O ~ 0 O
y- \f l ~-O
- - ~O - N
N 0 * \ / N * \
'H H

O\\ 0 O
* I- - ~-O
N N ~- o \ / * \ / N N
% H
) H

H ~
\ /N \ / ~J - O~-O
O~O * \ / N H N
H
H

O
07- 0 * \ / NW O W * \ / N - O-, O

NH
O~\-O~ O~\ N~ . 0 I \\^O
* \ / NH * \ / NH W * \ NI
H

_ 0 0 \\-NH N~o . I' \ / NH and In an embodiment, the present invention includes compounds of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Z is a 5 or 6 membered heterocycle. In another embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, Ilb, IIc, IId, or IIe, Z is a 5 membered heterocycle. In a further embodiment of Formulas I, I-X, I-XI, I-XII, I-Xa, I-Xla, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, Z is a 6 membered heterocycle. In another embodiment, the present invention includes compounds of FormuIas I, I-X, I-XI, I-XII, I-Xa, I-XIa, I-XIIa, I-XIb, I-XIc, IIa, IIb, IIc, IId, or IIe, wherein Z
is a C, to C6 alkyl optionally substituted with a 5 or 6 membered heterocycle.
In another embodiment, the present invention includes compounds wherein Z is a C1 to C6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C, alkyl. In another embodiment, the present invention includes compounds wherein Z is a C2 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C3 alkyl. In another embodiment, the present invention includes compounds wherein Z is a C4 alkyl. In another embodiment, the present invention includes compounds wherein Z is a Cs alkyl. In another embodiment, the present invention includes compounds wherein Z is a C6 alkyl.
In another embodiment, the present invention includes compounds wherein Z is a straight chain Cl to C6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a cyclic CI to C6 alkyl. In another embodiment, the present invention includes compounds wherein Z is a Cl to C6 alkyl that is a combination of straight and cyclic.
In yet another embodiment, the present invention includes compounds wherein Z
is selected from the group consisting of cyclobutyl, cyclopropyl, cyclopropyl methyl, ethyl, cyclopentyl, and isopropyl. In a further embodiment, the present invention includes compounds wherein Z
is cyclobutyl, cyclopropyl or ethyl. In a further embodiment, the present invention includes compounds wherein Z is cyclobutyl, cyclopropyl, or cylcopropyl methyl. In an embodiment, the present invention includes compounds wherein Z is cyclobutyl or cyclopropyl. In an embodiment of the present invention, a compound is provided wherein Z is cyclobutyl.
In some embodiments, Z is selected from the Z substituents of compounds 1330-2128, and 2600-3348.
In a non-limiting embodiment of the compounds of the present invention, Z is selected from the group consisting of O
O

w~ \
and In another non-Iimiting embodiment of the present invention, compounds are provided wherein Z is selected from the following:

w n ~ \ w w *

H F
O,VO
w w w w * w w *

\/J\ ZO
w w w w A, and In some embodiments, the Z substituent is a hydrogen. In other embodiments, Z
is a C, to C6 alkyl optionally substituted with a five membered heterocycle. In other embodiments, Z
is a C1 to C6 alkyl optionally substituted with a six membered heterocycle. In an embodiment of the present invention, compounds are provided wherein R2 is an alkoxy group. Tn an embodiment, the present invention provides compounds wherein R2 is a methoxy or an ethoxy group. In an embodiment of the compounds of the present invention, R2 is a methoxy group.
In an embodiment of the compounds of the present invention, R2 is an ethoxy group. In an embodiment, the present invention provides compounds wherein R2 is an alkoxy group optionally substituted with one or more groups independently selected from the following:
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected Ct to C6 alkyl, alkoxy, or hydroxy groups, or -a 5 or 6 membered heteroaryl group optionally substituted with one or more Ci to C6 alkyl groups.
In an embodiment, the present invention provides compounds wherein R2 is an alkoxy group substituted with an imidazole, a triazole, a thiazole. In another embodiment, R2 is an alkoxy group substituted with a hydroxy group and an imidazole, a triazole, or a thiazole.
In an embodiment, the present invention provides compounds wherein R2 is an -ORkk group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a CI to C6 alkyl, optionally substituted with a C6 to C8 aryl group.
In an embodiment of the present invention, compounds are provided wherein R2 is a Cl to C6 alkyl group, optionally substituted with one or more 5 or 6 membered heterocycle groups:
In a further embodiment of the present invention, compounds are provided wherein R2 is a -C(O)-5 or 6 membered heterocycle optionally substituted with one or more C6 to C8 aryl groups.
In some embodiments, R2 is selected from the R2 substituents of compounds 1330-2128, and 2600-3348.

In an embodiment of the present invention, compounds are provided wherein R2 is selected from the group consisting of the following substituents:

O!-I

O

N * I
(N) -N-O O N O-- I-O
*
\ N '~/ O
N ~ N
~
N
O

O
~N N
0 \__ ~ OO

N N

~ ~ NH
(0) N
NH
/
O
( ~ pf ~O
N
\ o ' ---- OH
N N--/ p N
v S

OH F-'% OH N~""~

N ~~*~O Nf N ~
*~O NH
OH

o = OH
/O N OH
OH
NH

O

t~o oH
y O "

=/~O oH */O 01`~, õ/O\~~
F
H ~O CI
and .

In another embodiment, compounds of the present invention are provided wherein R2 is selected from the group consisting of the following substituents:

N
^* O N~.~O~

O

ON,~Np i /., Si S 5 N`:rN 0 ~ S ~~. S

N~ NN NN
N
%) I j 0 '"~/~'`
g N O N O

N `/ ,., Ni N p l ~~
N ~f Si N ~' \/`~=
N
S O O
\N ^~N ~N `~~ \N `
~S ~ O O

NH2 O~- * ~ i~`~N /*
O rl O >-NH

~ 0 p~

N N~`~ NH2 O ~10 0 d ~ ~Lc;_________ H

N` O N~N1 ~N
N - ~ ~/ ~
-N H p O
~
H

Or -N N-N O S O

*
f ~r \ * N-N

OlN NOi~0 \0 *
\p 1 ~1 N- ~ N- N N-~ N-''~~

O N N'- N
~~ 0= `~N~O=,.
S

CN o~* N O' NO-*

N`NN
H
H
N/N\ r NNN

N

N N `O NN O O
`O~/ 0 N O1* . N
N 0.*
~~ cJ_ro*
N N
H
H H
/
N
N.N O~ N, O
~ ~N O
N p ~
H

N N_N
~ao O ~N
% ~O -< , *

/~ * N~' N I \ r ~~ i O O' N oi N O

^ O~
a ~/ w ~o." O s~~~0\* S O.
O
r". N CN2 O~\~~\/p=*

N N-N N
'N~ OsO`w 0.,.,k /~p~*
s o s N~~ ~~ ' N^N
N --* N~ ---N

N^N N'~N * ~N \\
L-N LN~ o~N
~.* ~--/ ,/ .
.y N`
O

In an embodiment of the present invention, Z is a CI to C6 allcyl group, Y is a-NRtCOOR,, group, where Rõ is-a C, to C12 alkyl and.Rt is -a hydrogen, and Rz is:
-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-an amino group optionally substituted with one or more 5 or 6 rnembered heterocycle groups or alkyl groups, the alkyl groups optionally and independently substituted with one or more 5 or 6 membered heterocycle, -a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C, to C6 alkyl group, the C, to C6 alkyl group optionally substituted with one or more independently selected Cl to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more C, to C6 alkyl groups, -an -ORkk group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a Ct to C6 alkyl, optionally substituted with a C6 to C8 aryl group.

In another embodiment of the present invention, Z is a Cl to C6 alkyl group, Y
is a-NRtCOORu group, where R,, is-a C1 to C12 alkyl and Rt is -a hydrogen, and R2 is:
-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ci to C6 alkyl group, the C, to C6 alkyl group optionally substituted with one or more independently selected C1 to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more C, to C6 alkyl groups, -an -ORkk group, where Rkk is a 5 to 6 membered heterocycle, optionally substituted with a Cl to C6 alkyl, optionally substituted with a C6 to C8 aryl group.
In another embodiment of the present invention, Z is a C, to C6 alkyl group, Y
is a-NRtCOORõ group, where R. is-a Ci to C12 alkyl and Rt is -a hydrogen, and R2 is:
-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or Ct to C6 alkyl group, the Ct to C6 alkyl group optionally substituted with one or more independently selected Cl to C6 alkoxy group, -a 5 or 6 membered heteroaryl group optionally substituted with one or more C1 to C6 alkyl groups.
In another embodiment of the present invention, Z is a C1 to C6 alkyl group, Y
is a-NRtCOORõ group, where Ru is-a C, to C12 alkyl and Rt is -a hydrogen, and R2 is:
-an alkoxy group optionally substituted with one or more groups independently selected from the following:
-a 5 to 7 membered heterocycle group optionally substituted with one or more independently selected hydroxy group or C- to C6 atkyl group, the Ci to C6 alkyl group optionally substituted with one or more independently selected Cl to C6 alkoxy group.
In another embodiment of the present invention, Z is a Cl to C6 alkyl group, Y
is a-NRLCOORu group, where Rt, is-a C, to C12 alkyl and Rt is -a hydrogen, and R2 is:
-an alkoxy group optionally substituted with one or more groups independently selected from the following:

Exemplary compounds include the following:

N N
~ - 0 N \/ N O
C ~CC ONO 0 N
~N O / N
Cw e0 \ ~ o~
'O ~y ~, `y \ I N J `=0~..~0'./ b (~ N \/ ~J 11`/ F ~/ \ I NH ~
~ F p N O~'S\

N N N
F ~. H H p H ~/ O ~ / N \. t ~NS.~ yO N o JS koyN,,J
F
& d ~--= e .

N N O O
~-o a N O NH N N! \ / NH
~NJ `- ~-~J

N N N
!( p S `/ N YN/

H F I N p )~~N ~
~, N F ~ o~ 0 J

/N N O
~ - p~;S 1 ~
y,O N NH ~O I ~ N NH
p 6 N N ~
N
H p~N p N
~N N N ,o \ ~ / \ p p~-~ 0 \- O N p ~ N

O O /N
N OOOO I Sy1 \ / NH
> > /

a~ // N O~
o ~o~~N - > \ f NH N-H
N

N ~ /N %~
5` p~o ~ S' ~ - 0 /
~N / N N \ / N /
~0 Q N~ dpl \ I

N N N
// O So \ \ // - OO^ // - O~/-I\ V NJ 1 ~ O 1 O
N \ ~ ~N s N NN I ~ \ / 'H

N N
rol 0 ~ rr o / -r rr ^ tJ
luN I s N \ / ~1 ` rj -d ~N ~ i \ ~
N N ~ 'N N H

N N N
rr o I/ ri p ~-C ~p ~ ' NH O ~ N NHZ p ~ NH oJ `-- J

N r~ N
\~, p o d p - Tp C r-'d p N NH d y/ N \/ NH p N NH

oJ OJ 1368 1369 1370 N
O~- rN p rN p\\
- ~d T-o d / NH N \ / NH d / N NH
oJ N F OJ ~, oJ C

N 0- N H p N
o~ r-J l 'N.~/ Q
_ ~
C I/ l_ NH ~, ~d i N ~/ ~~ 0 _ / NH ~

N
p\\`N~ N
- p ~--N rN - \\ O
~ N T N N~
NH NH o N N~
pi/
- ~J ~ aJ `

N N N O-0 p O
=~ ~-- TN
NH NH N NH
oJ, 0 _ !N O f N -NH ~ / N \ I NH
./ ~J ~ ) /% (" /N 0 k N NH N O~} NN O 4 / N I

N N
JJ p\\ $ p\\li N
O Fi H
NT N ~--N \O
N ~ ,- N
f b ~\/ ~

N
O\\_ N O\\ JN
I N

^O i / N \ / NH Ns \ ~O f N \ / ~ N~ \ ~ ~M~o ` ~ ~
b b N N N
O`\ r N l \ / N H p~O

O b 'H 1395 1396 1397 N , N N ^
~. !~ - p?~-O \ l! ~-'p ~~--0\l"1 N 'H ~~/~p ` / N \ / NH

N
p-NH
N N N NH

N
0 N 0 !/ N
p~
'_ y-NH 1 - I-NH - O
~ e N NH I/ ~~ NH O N NH
p ol~NbJ

N N
p N p 0 O T'NH -H
N~ N \ f k /-p / N \ / k a 0 N
J

p % ~ (N \ ~ N
~'_'o . - ~ ~-~ ^N ~ ~ ~ \ f NH ~N N ~ ~ ~ / ~ p ~p~~O ~ N ~ f NH 1 I
I /

rr" N N
/ ~
\ J ~.,1 N - "-t N
~ > N o ~ u-' ~er õ~

)~ " -~ I , p ~~
~-o N ^ = N I i ~/ NH
\ ~3 N
N
^O(~ `-/ N )A bJ " b b b N N N
`o~ ` o ~J N" N
N {~
/~ N N

141.91 T" 1421 N O ~ N N
N

`
O
1422 1423 ~
N
N 'H
O b N N
O O
o NJ
\
/\ ~ I NH
N N" N \ r ~ N O I~ N

i N N
0~~ ,~,--~j (O~ 1 ~ NH
~` t~""~' N b N p\\ ,~, N
0\\ ,, - N
N
~O~~Q I i ~ ~ ~ NH /\0 I / ~ / \ -N ~

N N
O / O

/ `~tJ~ j r r N ~ ~ N/ x / N \ ~ ~O~ ~= ~ ~ ~ / NH
l H H -/ `~N,1 14\3/4 1435 1436 o~o \ ,o - ~-o ` =, ~\ \ J ~O /= o~ \/ N}~ ~ ./~o ~ H \ e NH
b H b b O O

~\ rr - ~-NH ~ NH N~ ,~ N \ l NH
N ~ / 'H

/N "
~~ O~
~ N
Oa~ j~H
O ~ N / H b _0 M
/ Q~~ ~N \ O F
H
~ !>

N
o 0 r ;,p aaQ N NH NH 0, H' N ~/ N
'H

N /N N
o\\
O
\ - TO - NT" }-~ \ ~p Oap ~ / N \ / ~ O~p N ~ pap ~ / N \ / pNN
b b b N
O dQ /N O // N O FF
Oap ~ \ / N NH O ~ da N Ni N F

% N N O
O O ~ - ~--0 a p \ / NH p ~ N \ e NH
b b b .

N N
p p O
\ - ~-O \ - N p NH p\~ I N NH H NH
b b b N
N N
O p ~ ~r c0 \ T-O \-o NH N.O ( / N NH N NJH
O
O

N `~ N 1I o II _ a\J\'-o ~1 0 N1 ~. - ~-o Oa, ~ NH OS / ~ `%N /~S I / N \ / NN >
~

1467 d ~ \ 1469 - O
HN--/<

N N ~N N NH C N N NN a \ N~\s os tIIN I ,~N,/~S e N \/ r O
VVV

/ ~
~ 0 HN-~
o N o N, N U N a N +~ - NH O N~\Ss NN
N ~\ - N~O
~Nti~~S / N \ / ,' Os / ~ LN~~S i N \ / ~--o N

LJ --" O
HN--~
O

/% \\ N~N N p\\
N J'O ~/\ O N~ !~
LN!~,.~5 ~ / N \ / NH N ~S S NH

HN-~

lN ~N/ N

~~~ ~~ \! N~ N~SO C`%L
S O~ / N S
N

1479 ~N 1481 HN--~

/! IN` O
^ ~-NH N `
(/N~/~S N
N

HN-~

/N ~ N
0\\ N p !~fl O NH
, N NH N p ~ O / N \ ~
~NH

N ~ o N lN O
~'`~ O NH O
NH HZN N \ / NH ~ N N~
~\ p ~ N N
p N /I

O 0~O X-c/)-N'-\ /N O O N

\\
N 1 / \ f N~~ `~ l / NH O
`p N p N N O N

N o >-- ~~ N

~
N \/ NH NH p oJ N NH.
N

~/

N ~ 01/ N \ / "H ~ f N \ / NH r <N~-' N o ~

N
O\\~~ N
O,\
1~
NH NH
p N
/ N N
N'C
N

N N N

0 0 0\\~ /-o/ c-o-3- "N o~,o "J~.o 1 N "H
b ' b b N ~ N
N ~ '0 CJ` ~ ~ ~ \ / "HOr ~ N = o N
o a "~o ~ri o I XN "~p N
N ~- ~~ s o `NNa " NH a p-~ ~Q I e N \ / "H pS1 0 `a OS~o i N i N

- ar~
N
-Ir 0 `~ X N NH
N dN o N,~ b i N

HN--/HN -~

/y O N S~~p p ! i N \ / "~ N}-O \~ ~ I _'-N 0 N NH

N,~ d "
N - `\ p HN -~
1536 ~

N O /N O N
O
OO ~/ N NH N NO NH ~ `<J. NH

1539 1w 1544 p N p O
j--~~O NH NH O NH O
N
"J b N N ~ /~
O O
O
N.N N\ "" O N~,N "H
N J O \ / NH r N
N'N
N-J' // O~ /N O4~- O
~ ~--0 ~-o ~-O
N N I/ N NH N I i N "H N' N NH
b N --j b `"-' b S =
N O / O
-/=N \\
~ TO NH O
NyN I/ N NH N

N~
"` o N

H p F p F 0 I / N NH / O I ~ N F/ N" ~ O I / N NH
~ O \
~ b J b b O

CI O C1 p CI O
o,/ / NH O I N NH ~ o I i N ~ j NH ~---b c~ 6 J ~7 CI O Br Br p _ ~\~ ~
1~
0 -~
O`/ N NH O N \/ NH N \ j NH

O O
, ~ N~--O ~ - ~ O Q N
- I O j\
p / N O N NH
~ -N O
N'k O

N N
p,\ ~
cc I~0 ~ N Iv ~ - ~'Q
~ / N NH OS NH ~--V \ ` N
tNl:_~N 1571 HN--~

N o / N
/-N ~'-O N~N ,0 NyN~^S ~ i N \/ NH OS
n o ~ ~ -- N

HN---</
r O O
O ~ i N NH N NH O NH r ~ N

V NH v N N 1~!
o \ o o ~ 0 O
N f ~ N NH "ZN~O I ~ N N~
O 0 Iz? O

1578 1579 d NH

~N N O /N O
O~N ~ ~o ~ ~
o I ~ N NH o I/ N \/ NH /
N~
ON

N
N
N~ 1/ O %~ O J! o _ _ O ~N O
Y-O (/ N \/ N~ N ~,~0 ~ i N NH N NH
CN~
~~~((( N
O ~-- N O
O
p~o N N" N N~O N \ j NH

~

N^N \ ~N _ ~~o O N~

`NO 1/ N \ j N" o N

= ~ `N .
N

-" O
HN-{
NH

N N
o o N~, .~ _ ~--NH N TNH
N N" } <N NH $ /

;~N

b s b /
~N

/ \
- O

NH

N N
f~ o // o N N
O
l"'NH NH
NVN~~S I s N \/ NH N~N /~S I~ N NH
o b / b ~ N
N
1602 = 1603 _ O
HN--~
NH

/N O (N ~y N
~ NH NH
NI~~N~ ~. - l~NH fN Q
N NH S O/`i HN--~
NH

N N'N
<-N I NH NH ~NSO
~~s N

N

-" O
HN-~H

N N N
O\\
fl _ ~
/ O
NH ~NH ! N
NH
O N NH NH
N o ~ N

~NH 6 N
v N
N
o\\-~- V j' p NH TNH O NH ~ NH
~ NH H2N~Q NH ~ , N NH O

~-- N N
p ~ N /7 O
N}H-- ~--NH
` I N / N NH
, }--}.~ O

_O
lJ
N
1624 N`

N \\ ~N N
p\\ JN
/ p Y~ N S ~ N NH /` Nt~ \~, NH
`~ ~ N NH ~/ N ~/ NH r \N~ I N \ NTH_ N N N NH ~ JNH ~ ~S
G-.p N NH NH OJ ~ NH
N N~ ~/ N b L~

N p 1N O

N p J/ N "H " N p NH "
`"~ ~~

N N

D - ~-NH ~--NH
^p ~ N ~ / "H r N~~ " ~ / NH r NJf~N b b .
~-O

N N N
1/ ~--~ N.' NNH! cro0 N

CI O Ci O F F

O I Z N NH O F
~--o J b /
6 b - - ~

F F F F F F
F F F
`l o o ~l o \\I- ~- o r XCS-cJNH N r c-(JNH r CQNH
o o N o O o N
o Q (/ o ~ ~Q ~ `~--o I }~--a ~
J N \/ NH O~ N NH Q N NH
b 6 b J b /N F F F F
F 0 F ~
O \ O\-O O N NH O I/ N \/ NH
o-~ N NH r~ b b 6 b 1663 F

\ T O ` ~O}--O ~ N NH O I i N NH
b b p O o z N p N

~ ~ - " N - T-NH ~ 1`- JH
N NH \ / NH }-- ~ . ~ ~. NH
O O O N N O ~
O 1669. 1670 O\\
N O O #N

\ NH ~8`~ I~ - 7-NH
NH NH N- N NH
NJ~.Q N N \/ NH O
b b zN p O N` O
N~N}H p-~ O ~! ~N ' N ~~ N
N
d a~ d /\

1674 HN--~ HN-/<
NH NH

~ \\ N
~. - l-'NH o O N NH O ~/ N NHN NX 0 N
~ ~
N~ N
iN ~ iN V O

1679 ~

//
N )%~ 0 0 O =

N TN L %
N ~ NH Q
N O
N NH
N~N o 1681 H

N p N~ !!~ o p \ - ~"NH 0 /-N \ ` ~N
N NH S NH
, N

I;vl N
__/N

-' O
HN--~
NH

/N O N N
O
~-NH 0 iN -=NH
O NH ~O
,7_NH

N
I/ N~ O\\ O
I~ - NH NH 6i N l-NH /N,N`O \ -NH
0 N ~ p NH ~~ ~ / N NH
~ ~
,N
N
r OH Q OH Q
~ ~-r O N NH o N NH
1696 a H
N~> -,,-N O -N O ~ O

p! N \~ NH }-- 0 N NH O ~t o'! , N\ NH
~--~

J O
~ -N Q
\>- o N NH
NH O N
/-- O
D

`s'lo o p-" O 0 - O O\\
~ \ - T O}-- ,S N
J N Ny ~ O y / N NH I"-O
O N NH }--C~

O

O c~ O 0 O f~ N \/ NH
~-o\_._ .~ ~ N NH

p 1709 o') d f \
s`O O S~p 0 O` S NH
\ p N~-N NH O N\ NH O
N "
~ Z?

O
~--0 Nhl S "0 o O~ N N
N~" ~ b b C1) 1 N-O N-O ` -N\

) ~ - T o ~`- ~ -- NH O} \ N~
p N ~/ NH r O I/ N I l Q N
~, . b J b / O.
N-~ N0 O
y"O N\ ~ f NN
NH O
1 = 6 O
O

\ N- N-'" O
_ ~o ~o O ) N ~ / N" N" 0 ~-O
N
b-f~
N
N~ ,N `:~"
O~ 0 N~p 0~0 O~/ N\ N NH
o Q
N NH

0 o ,O ~ N
N N p~p NoN p N~~O 0 ~. *\
p .~ N NH N~ p}-- NI}i-p N p N
o 6 6 co 0 O

N O N ~ , p ~ p~-O O N NH
O / N NH

p 1739 N
O ~ N
_ 0 \~-NH
~ ~"p~ N \ / NlH

p l/ N NH

p 1742 ~

N N~
// ~ ~ o O \ `- O~-O NS 'i NH
O ( ~ N NH \ ` ~
._-- N

1743 d f \
_ 0 O

~

% ~N /
N N H-o NUN~~S0 OH 0~--0 ~` -N N
~~S / N \ / ~ 0~ ~ I T-O NH
a N
N

- O
HN--1<O

N N

O N \\ I1 ~
~ ~. T-O _ O
NH NH ~
N
1' NO
1753 N'~

N
O\\ ~ N 1 N
O ~ N \ - T O ~ -- _ O~--O
t~ \
N ` / NH C ~.0 ~ ~- N NH O 'N~`p ( ~ N NH

N N

tlo'C NH N NH oN!^N N NH N N.J.,/ p , b b N N
O O~ N NH O /~'`N'' \ - NH O
NH N~ f /!-N \p~ ~
O ` ~ N
b b b O
/N ~ /N O

N O I / N NH OJS ` NH
O
~

OS~iO ~N 0 NL

O ~
LJ N N N
.O
O O
HN-~ HN-~

i i o- 3:><
`. - o ~ N~o s Y'O
HN

O N
O N _ O~- p t7 i N ~ ~ p / ' p ~--~~ N \ ~ NH p I ~ N 10 H
~N N
~ a p Cl p ~~ N ~/ NH I~ H O
_ 0 XN~
o, r p H
N N
N~ N~ N~
O O p N\ NH N\ N N\ N ~
O p O
b b b O o O

p N O ( O N O
~p ~--0 p N NH 0 N NH
b b b = ~
O p F F F ~
O~ F F
N O -N rN
O
O ~ \ NH O N N~o p N NH p ~ N
o//
b o F
C. ~ O O N S 1 F
N
NH ~
N i/ N NH O!~ N \ NH
b b ~ b ~-r O 6-F F N//--O
S f F .0 N ~-o \ O N\ \ j NH
I / N NH ~
r ~ b N !N - a _ h1 ( OQ O
' ~\ o ~N~S ! s N \/ N \ s' F
~ - I-N l~ Q N ~/ NH N~o O o~ i 1814 H ~

!i N/e~S
N ~ N0 ~~S ~ / N \ / \ / F .r-8 ~ NH

~ ` N\ j I / \ / !
1815 0 NH Ol/
O
O

F F F F
S F F
0 f \
O --O NH NH O I\. \ - NH
O
~
~ O N O / N ~ /
O

F F CI
NH O I\ NH O}-- NH O
J N O / N O N

Cl I/ N N

O \ \ ._ O Q O
N N 1-t ~-o ~. _ y-o O O ~ N NH O f/ N \ J NH
O

N~ N
N\ NN O
\ - O
~ / \ , NH
O N

H p F O F 0 o~ i~-N NH o~ O I/`N \ l NH o N~
O O

1833 ' 1835 C- O\,~ ~ c{ 0 Ct O\\
T~O ~. _ '--0 - 7~0 N \ /
~y NH N NH ~ NH
J b b o1836 1838 ci O Br O\\~~ Br O
~ -- r-O ~ J~O \ -- ~ -O
NH ~ O ` / N \ ! NH ~ o I i N NH ~
O

0 o cl O
r - ~-O _ ~}-o ~ - y--O
O ~ / N \ / NH O \ ! NH I/ N \ ! NH
b O

ct 0 F F
F F
O N \ ! NH !` F F

NH NH ~--Q
O 0 N O~ O O C N -O
1845 b IN
/
O O O
~"O \ c ~--p O N NH ~ Q ~/ N NH O N NH
~

/N F F F F
F p F O
~.-I~ O~-p O N NH p N NH
N ~N / NH

b 1852 p F F
F F O
J 1 i N NH ~ p I/ N NH
~ ~ \ ~p b ~ b pH OH O
`~ ~ -- T O}--~ C _ ~--0 > pp N NH p N NH N NH
b b J ~ b ~
O ,858 p H
O N~ ~N O
\ \ \
XL1IIONH N - ~ \ O~
b V
p F
O N
o N
= ~~ O
OPy 00 /1_ / N NHTp N- N I\ - NH
b b ~N N
O

F N o /-~ %~ _ o HN `N ~-p cO -OF N NH E
~- p N
~ L"
N NH HN'V 1868 N p F F
HN N
\/ NH o \ i F N N
O O
J~ I / NH CLOI~ NH

O
o J
O-'S` o I / \ \ f NH ~-O
N NH
b J b O

O'~ p O~ o 'NH ~NH
~ \ - ! S1 O S~p 0 I / N NH ~ /

a b b 0 ~-O a O N NH N NH ~ ~=-O
J 6 6 O 6 O ( N NH

O

/
N_p N-p N-N
J N N~0 O N NH p O' N NHo O// 0 Ij J b O

/ O.
N-N\ N+ O O
~ ~ ?--a NH Q N NH
O
b O

N_ O \N- =~
7 \ ~
O c N NH }- ` / N NH NH

J ~ ~ O~ i N ~ f NH
b 01 1887 O J b O/j"

NN
N
0 O N~ O
NH ~ \ _ =
\
\
` N NH O N
O I/ N N~o O O~ O I/ N ~O
b // ~ b //
0 b O

N0 IN ON\ N

Q I/ N N}H~ p `~ NH ~--Q ~\ \ N1-~1 0 ~ O/~ p / N h--o o / ~\
~ 6 o o p o o ON
f N; 1 N T }--~
\ O O
0 O I~ \ \ N~ -O~ NH
\ \ _ ~"'p p ~ Q N
O `/ N \ J NH Q
b ~

N H H
Cy' ~ N N
p N~ f N
\ ~ _ ~=
d I/ N NH O NH I/ \ \/ NH p b 6 b 6 a ~ 6-{
NV IMN f O
NH NH
O

b b ~ 1N _ ~
N fl.
o~\
\ -O
f\ N~
( NH S ~ ~ /
/
o 0 %N' !1 N ~N 7 N
O. NIN S 0 N~N~^ NN p O NH O~`ScU
o N \ I +N ""(O N ~~ NH
N
d ~\ b HN-S--q p N F F
\ p~p N p N F
C'N 0 NH
p I N / N~p ~\ NH
h-=O
6 6 ~ p~/ 0 / N ~
O p a N S I
N -N
0 ~" ~ O O \
I/ N\ NH p O N N~ I/ N\ NH p Q
~ ~ d 6 0 O

F F F N p S/ F F r S N F p\>-O
' \ \ - ~ \ \ + \ /y p ~ / N NH O N Q~pJ Q N O~Qr`"~I ~
// ~ b a o 1937 p l-N'S
~ p p N~ S
~-o "H p N
p/ NH "}i p b b b p b p p F F F F F
F F
/ \ / \ -\ - NH NH N NH p/
J N \/ ~p p N -p p~
~ b 1947 p 1949 F CI CI

p N\ "~j -~ 0 N \ / "~p p N \ / "~"--o b p ~ p b O
p ~~
../! 1951 p /% /N

\ \ I \ J N O~o p N \ / ~~p /f ~ b 1953 p N, N H

N NH O ~\_o J/ N NH NH
N1H~
b b F F CI
\ O-N ~ / NH ~ Q N NH NH NH C/~--NH ~ ` NH
Vh CI CI GI

N~
QN NH N`H O' i N NH p N NH
0~ b ~--NH
0 b C

Br Br - `~ N !%! ~
\
O N _ ~/NH NH
~ N O`S~
~NF 1 p N ~ NH N ~/ NH
b b b N N N
C
~ _ O ~N c . - o I/ N nj~0 ~O N ~/ NH ~ N ~ 1 NH N O }~

~O `J 1~-6 N=( 1972 N N O~ ^~O
!, O.!D / o_J' S~ -_ ~O -NrrN O O \ ~ N
~ NH`o NH\
OO N N~O N

1974 1975 HN--S-G~
O

OP N N
O` / /N O~, /
O 5"O S.
O N 0 N N" o0 N NHO
NrSO
H

_ ccDNH \
O N \/ NH P O N ~--NH O I ~ N NH
C
NH
~
O
J ~ J ~ ~
~ o 0 Cf F F F F
O NH F F
N N //~ P

I ~ fl \ ~
O O N NH NH O N N),_-NH
!J"` . Ou 1983 ~ 6 rN
~, .
_ ~ \
O N N~--NH O~~ N \/ N~NH O N Nj~_NH
i/
O
// ~
a p ~N F F F
F
\ ~
J F F
O N NH N~ O I/ N NH
NH
O I/ N NH N'H " ~ ~

a F F
F F
\
f i N NH H
Np O ~ ~/ N NH
1 O /l 6 Oy v O
OH O OH

0 N N~.NH O N N~NH O I / N\ NH_ NH
J b /1 b b /J
~

D--NH H
O ~--N O
ON NH NH
~-N" N\ NH
O O 6 O~
1998 a O

O
O
\ N\ ~
l NH NH
O N\ NH O(/ ~-NH
O
~'~j /~~/ .
O
O

p~J-p p`~ p NH
~ --- ~
O+ NH NH p l/ N N O
N ~--NH I\~ ~ -/
NH
O p ~ 'N c p/j- /--NH
b 0 NH ~
p1s~ O N NH ~ p,/ N ~ I NH
NH
p p~NH ~
NH NH
~ p~ 2008 p O

o =~' N/-N ~` - NH NH
~t, ~NH ~-$ N ~j -NH
N N =~p N o g ~ o N ~ /N
N~N~./~Sp N Nzz O ~N
of / Q \
~ N O N \ / N~NH p ~ ,i N N~NH
NH ffN

NH
O
HN-<>

N N=~ C[NH N~
O N HN
o N NH 1- r N {~ NH
'N ` o O~! ~ ~o i N
b b N"C 2020 N
N N
HN ~
~ HN
O I>N NH O ~o ~ / N O~NH N \N `~O
O 6 `N~O N NH

6 2026 6 .

Op~ r--N l/j HN !-O
O
~O
N I i OO ~y NH
o, N NH
N~
NH ~

N-0 N-N\ ; -N
\
~ \ - ~ \ \
p \ ` / N\ o~--NH 0 ~ N ~~NH O N O~NH
b b b N''-O_ \N--N H O ) ~ N ~ / NH p ~~NH
, / N
NH

\ N-\ p- O
I NH
p NH ~NH
O / N p~--NH
~ I~ N NH
b O(~ N NH
i NH p O p b NN~ NN`~ N~ i~
` TO
p C N NH N"H \= ~ NH P O XCIcNH NN~
O ~ p~~ N NH O~
b ~ b bO O
O

N Pp ` N ~N
~ N O
N N ` O
I \ \ ~ NH NH p \
p IV ~-I~fH O N ~-'NH ~ NH
p 0 : N 11 /~--NH
b o O
p N p O
NY
HN N~ ! O \ ~ ~N ~ / N
~ ~O
`N~.p N NH O ~~dN O N

~ / \ ( d NH ~
NH 0=P-O
2052 p N-,:~>

N 0 Na _ O. Q N- O..-N~l O~~ N /
NHO I~` \ NH p ~~ \ - NH p 6 O O~NH O N O~-NH
b b 2055 ~
O

H
OON N
N~
O I/ N \/ N~NH ~\ \ ~ NH
\ \ ~
b O N ~-NH

O b O

H H
N N N
N; N\ N\ ~

\ \ - ~ =` \ - ~ \ \ - ~
N N~NH O N N~
O! ~ -NH O ( / N NjH_NH
~ ~ // 0 O//
b N N
ON
~ I
N N
\ ~
NH Q CN NH O I / N ~ f N~-.NH
O ~ O~ -NH O O~- NH O/~
~ O
O O

p I F F F F
fN ~F O N F
NH
P
\N
p N~
N ~NH p I / NH 'H ~ / N\ NH
~ b J N~ 0~'-p 2073 2074 a N N S ~~,r fN
N
p IV\ NH N'M N ~NH O'N NH p6 0 p ~ -NH

a =
O p F F F F
S~F S~F
p N O~NH O N N~NH

N/`p \ N-5 N'O

NH
\
0 N ~~NH NH 0 N ~NH
N ~-NH
o o F F N

S F N -/~ vN~~ S I N \/ NPO

N NH
\
~ O :/>- NH
o N ~--NH 2093 ~ O
O

N N N N O
NS0 \ - O '~
NH
O ~ ~ ~N O ~/ N NP.O
O O
N1O ffN

NH

~ `0 ;F':O~

/N \ F F F
O~a~
O~ c N NH O
O

F Y O N2097 O /-NH J~ O/j`
xx-~ 0 v b 2099 O

F CI Cl 0 l/ N O~NH O ~ N Nj.H,-NH O I/ N Nj_.NH
Oi~ \ Oii 2100 = 2102 Ij /J

! \ -. n ~
O OH NlHO I/ N OI.~.NH
J b // //
bp N N~ f N
p NH o X -o -p { NH P 0 { N ~ / NH NN

O / N / ~-NH O

b O

N
0\\_o `N N, N O T
N N N ~ I NH %) O N
p O \\
{ , N NH O { / N NH

~N o / ~N ~~
~--o N~ ~
Oo ~ ~ / NH _ 0 ~ ~ / Ni--0=S=0 I N
~ \ / S T' /
2112 ~ ` 6 ,,.N

d /~
_ p HN--~

N p N
p N
p /-O p `~ - -p N~ O ej O-1~ NH NH NH p N N^o ~ N N~N I/ N \~ NH
b /,- . b b N F N~~
N N

p F
-p f/ N ~/ NH O
NH Q~~j NH
=~ N ~ ~ 1 ~ p N
b b N /
. ~ N N~
O O
~ ~S~O p \ O~S` N

C N N ~ N ~ r N NH O // N
OD
~ 0 ~~!
S~~o \J / N NH
2121 2122 b N N
~ ~
HN O ~
O N~ N
N NH N` ~ N N O NH

O NH
2125 N o~--NH

N
o jN - ~--NN =~ ~- - \iN ~ / N ~ ~ NH
N
pap N NH
lio \ \ ~ 2186 N NP.O
b O' 0 2150 ~

N N
~. %~ a /N / N / NH o I \ - 0 O NJ

2194 ~--N 2250 ll~
O-/N
`~ - N
O p`\
~ / \ / p ~
( H N NH ~ / N \ / NH

2251 p ArN
\\ N _ H `
N NT
%, H
p ~ N I e N \/ ~I ~N I/ N \/ NH

N
N O /( ( ~ - T01 F ~
NH ~ ~ ~--N ,N ~ i N \ / NH
O O (/ N ~ ~ N}-~ H j ~
2276 ~ 229~~3//

N (~
N
// o ~ \
N

O ~ N N \/ H O
O ~

N
/
N
%
O
O _ p ~N I/ N \ I Fi N I~ N H

N N p 00-O N 0 ~ ~ - 7 NH o 0 o ~\O N
W
b bo N p /N p ~ ll O
_ =N O
",p cN NH N~/N NH p NvN~/~o ~/ N \ J NH
O d ~p ~N ,N N
5- /N p\\
\ 0 ~~--0 \ N~`~O \ 0 I-O
N NH ~/ N \ J ~ 4 I/ \ I N
N H

N
0`\-p /N ~p~j \ lI N
Y H
`O N h NW O ~ ~ \ I N ~ ~~~` ~O ~ ~ N` ~ -O
H p I! 1I N
!/ O
~N j~-o .- \ / N o p ~ p ~ jH

H H H
p~, N ~p () ~ I H
6 O p N O O p N
r O
~ O

~ b fN !N N
NH ~, \ t NH ~\ NH
bp N` N ~p p / N >=O
O
p ., ~

!J 1{ N
H H
l~p ~ ~ N ~p b ( iy ~p ~ ~ NH p /`.,,, J'- ~
--~ b ~N 1N N
O `~ H p ~, H p ~ H
14 O ~ ~ N ~O bp ~ ~ N ~ f N p I / N / ~O
b H-N ~p b H-N
b ( O\ N
\\ ~
Sb I~ ~ N o N.N~~O O-a ~N~\/~p N ~ ~ FI N~_N~~~N~~\~ ~NJ N
H
`~ H V . b N N CI O
~N NT
N NH N~ N NH

NH ~~ NH r j! p T o NH
N

/% N 0 N
p H \ ~FI " j-p N O~jO F F C~iX-\/ NH p~p N NH
O b F \ F - OO F ONH

cc-o: /\0 N N

< ~

N /=N F F F
~N N N= N N
~ O\\F /~IV
\I` ~-d N,,,- N. N
N N
'H O
p N
/v~ b `O N H

~ (1 /N
O~F H F Cc ~f oH
o b ~~

% p\\ /N - p_ ~.._CFF 1 O ' TO O O / F ` O^~ ~~ _ NTO
p N NH p N N'H LvlOr N \ / H
b b N _ F F F 1N F
~ \ 1 ~ _ N r+ N O F \ 1 ~ O\\ N \ / o N \ / F o ~ - o N ri IT

N NH

CI p- ~ jN No \/ F // a F~ 'H N \ / NH
N
cc-o-/ N F ~F F [F 1N 0 N
O
O~p/ F F O N N O
~0 N N N
N \ / 'M ~O'1`~ N
Cb o o 6 N N N

- ~-o -o N
,-IN M O-ND Ck(Gc-o-O O

N
o. N N
ol 0.
ON S- ~N C/ N NHb ~~ I \ + '~~Q
N H ~N i N \/ NM
o b 6 N Q N O N
7'-0 ~ - ~-O O C H NNH ~NN~O

N_N~ 6 N-N 6 N \ N - ~
N f cro0 NT o .10-~ ~O ` N NH ,p ----0 N NH

N ,--q N O ,- Q N
D
O N N I\ - O~
N~N' \ N O NN~ '\
~ s N H e N \ B ~ ~J e N H
b b b N
N~N ~/O \ // N/~O /f O~ ~ N,NiV0 ~--0 NJ l e N \/ H "~~ I e N "H jN J j e N NH
b b ri r N
~N~o \ - ~ \ B , "~ J ^
" "=H N J ~ ~ " \ B "=H \;J ~ r N NH
b b b N
/
N.N~u \ 1~ _ ~o \ // - o~ NyN~o \ B
~/ N \/ "=H NJ NH
b b b N /N
No ~N~\i0 \ O~ -N N, OTN 0O
~, N NH ~ NH H NH
b b 0~.oj F N o p /
SN' N F p /N
NH I\ - N O
O N
H

2687 ~~~///

N Br 0 Br 0 H
o -N
I NH H
N
N
a \ o-H

)", Br O~/ 0 ~ N ~ , ~-o ~ N H N ep H Uo1S~ Q N H

0 /% Y %
~-o o o N NH S~ I/ NH S~ ~/ NH
o O>-O~

N~ I N /N

N H
S cLI-c/~0 N N
0` N o//-p ~--b N
N p N o \ ~o /
p ~-- /~ -- o O N ~ / \ / N
p ~, N NH O NM O~ N 'H
r F
\ !N Zp p AN // 0 ti cc-o- 4 / NM c NH
O N

N I~ // _ ~\` \ f F % OF F F e // _ o N \/ F
TO
~~.0 ~ N\ \ J H c0co-N f~ \, H H

2708 v 2710 N N
N O\\
0 N p T- ~
N
M o i N 'H
o ~ b S
l NM

O o N
o N N
(~ NH a ~ ji~ N'Lo~~ N\f i~o \/ F
i /N
-NH F N
~p N ~O

N N N 0 / p o~\, j-Q
",/`~
~Q
- ~ - T-p /=~S I i N NH 16; N ~ f NH N ii b . b b N , Q b N~ip - 7~ '~ ~N /~ i0 - d`p ~N~/ ~p - O
N \/ NH ~ o N \ f ~ ~, \/ N
b b ~ "

1 /~ - o~ N- /% - N N \ N O O
y O ~~ ~N/~i0~~ ~'-N N~N~/~O ~ - l`O
~/'~i I / N \ ! NN ` N NH N

N N N
N IV /1 p\\~~ ~ N p 'N O
- NuN~/`~ip O
N \ NH N//\ / N N N
b b 1~

N
N
/ p ~ /=N //
~-o \ < N~N~-,,,,,p N
'H

1 ~F
N N N O ~ N O /-Q N
F
~-N./UO NH ~i ~O N'~`p ~ i N NH O o O N NH F
b b b N
^~ O 1/ Ob `! - o !N CS
I.OJ NH ~O NO N NH ol I i N NH
= b b b N N o N

,O ~ ~ N \ t NH o ~=.,,0 l )~N " aO 0 N \ / NH O H 1-b b 2741 2742 2743 N >/ N N
H Nz~ H
p N P~ O j ~ p N H NS'O
~./~ ~-- ~/~ b ~ `~`

N N N

H H N l~ NS. ~J
o N p- o N o'~ p p%S
b rj J~~/ b N N
// O < ~~ \ !' _ ~\\ 0 \ / F F /!
NH NH Tl~~~// ~ i \ / N7H- ~ -N

// N
I ~.
o N N "o.~o N N
N ~-~? b N N N
~. 0 =, - a ~ -~o~.,o { ~N N N N N

N N N O
{ \ N/ { { ~ _ N N`H
p\~o N-< o N H

lN
CI N / N

N cN { p N NH H ~ N ;S~ (~i 'o'~`o ' N NH N H

N ~ 0 %~ 0 ~ OLoOI>Oo o J N . NH
b ~- b N
~

NH
OO LoJ \/ 0 ~~ b b !N F ~ N / N 0 -o NH F ~ NH ~
oJ N ~oJ / N o N NH
b b b N N
!N o P~ N fl0.4~\& NH `OJ N NH
b b b \ N N
~ / O !N 0 ~ - O
N ~ ~
/ N I / N ji H1O ~ / N \ / NH ~O~^o ~y NH
ISJ 0 b b N
/%' p / O ~ ll - OT Nr~ N
O
p O NH \/ O H
O / N O

% p p I~ p NN p / N \/ O I.~ oy- NH

N
N
O~ O
S ~ O
`~ - N ` ~ - ~ -O ~
~/ N H H ~ ON N NH CN ~/ N NH
O

N N
~, ~ i--Q
~\ J OL0)i-/

o o c ~y \ / o 2789 2790 2791 N
rN // o~-Ol-Q % o 0 - S~ ~ o N "H vN ` / !J \ / N Q~~iN I N NH ~
b 0 F 0 ~-- N
o~ ~-,.N O - C~O
~ NH NM H
~`- ~ J I~ N \l r,H
b N
N "O !! \ F N
/ v~ O\\ )., F I/ O
NH F O I/ N \ f N!H-O j/ ~ N O
b b ~N N `~.i J

N
N
O f' O, N -~ NH cO-0 ~. ` 0~ N N H ~ ~ ~ N H

0,-) O,) b b " N
CI 0 a~- H
`^p 0 ~ !p N
~O
N / o f ~~ ~ \ / N p F \_-pl ~ O F
O F
-..iF-F -F F
/ F
\

N N N
Q C ~ // p C p I~ N C H O C I i N ~, / C NH p ()N \/ p NH
b ~- b -~- ~
b b b N p p - p `~ oo ~/ N I o H aoJC N \ t p H p~/ N a H
b b b N
/
N p I~
~N~Jp ao ~ ~= - N~
o \ - p~-N QQ 0 p O
N
N / p H b b N N
0 p N
~ I!
O
p ~. p .-. ~--NH
p , / N N \ / NH ~
O
~ N H

N F N
py-o H N_^~~ ~ - ~
~ H H O N <1 NJ ~/ N \ I N

N
O
N ~ >> N
~
IS`
O
p 'SN NH ~ O~~O
a~6~

ON N NH 0 p,=\N NO p 2822 2823 2824 N

ONyO O"S~ J~ `b F O N H S p rO N O
O N NH k\ 'H

N
p~ N N N F F
/% o p F~
.~ - N O ~ / N \ / N p\ / F `~ - ~~
i N \/ ,H t p~ ~ 0 ~ O N
. U O . p ,H

F N F
ON ---~-~ N f p' F F N O r0 p\\ p N NH O o,~ NS

p ~ N N

N
N
N O `~ '- o S~N p~ ,O
p pN p I/ N NH H p I~ - NS` N~
N H H
V"O~ , N .H b b , N `HJ / yHN
O N O
N Fl p ~ - ,5ap ~O N ~H N NH ~ - N$`O
p~0~ ,N 'H

- 299 '-O N ,' \ - ~O
N!~-N~\i {\ N IJ O } l ~ J~~ {/ \/ N
~ N \ - ~~ \ ~ C7 N H
{ i N `

N
N
p N--H N
O
N NH N b S C \ - ~
~ N NH
~_.?

N
// ti p cc-o-'H A p /~
N NH N p p ' O ' N I~ N 'H I N I~ N \/ NH

N N
N O O. N O - / O~~~ JN
~. N ~./~. O ,--~ iN ~/ N H I iN N \ NH N O
Y \ ~
I/ N H
N
'H

N F
~ I F N F
(i~ N O F !J 0 F N .
N H O~{\ J\ N O~ p ` \/F
p / { a { \ ~ \ N
N 'H

`\~~~~ ( N
o - T~NH Q o N N H ~N NH N NI-..,, ,) i~j H

N (N N

\ N ~ ~o ^N~ / N ~ ~ p~ NH ~~ NH
( H p N N
1 J \ ~/~

N N N
O
\ NH N
p ~
O p iN\ NH H ^ N ~/ N \~ NH H

N F

\ (( - N~ ~F /N p-õ \ 0 F (N Q ~ , N I ~ N H gN N \ / H N a N ~ 6 6 \ ~

~

N
O~O \ / N

OI_ pa p N NH p ~ // - Oj-O \/ F
p ~ / N \ / NH

N
N p ~-p r To NH \/ F :1 b ~7 0'~ N N"

N N p \\ N

p I ~ // - NN, p~p (/ N / NTH- cc b N
~ \ / H

N
o p I \ - I- ~ N N F
i~N N =H - p,~p I - ~ ~F
N \ / = F
( v N ~ /N H
vv I ~ ~ H

N
/ F p N >4-F p // F N I ) N
N \ j =H F \
F ~ NN
N
~ ~
F p / N \ / `H

N
O
~ \ ~Ny N
p N
O
O , / N NH qCMO N~ NH ~F
O
1 ~ i N F
v ~-O

N
1j F N
H cl N
~o~F F N N O ~ H
p p N
~O ~ N NH 0 N O ~
Q

N

F~I~
W F NH fi / ~--O N O O ONS`~O
~ O b }-- ^ N H
N N0~ b O / O( ,-,J

N
O\\
\ T-o / O /
~ ~ i \ / N
N N H ~--0 p q J NH `
~ ~

N F
N O ~-----F
p ` _ ~\ p !% ~i INI 7~0 F
N7H- `N~O N NH
Np N H b b b -303-.

N N
1l O. O
~0 _ S~0 N / N ~ / N~ / NH O~ I \ ~ ~p p O vN N
O

N /N O. ~ CLgXX00 N ~S~ ~N ~ ~ ~ 'H
b N N
~~--~ `
N ~ N ~ 0 o (~ .
I ~ NS ~OJ~N~O ~ ~ N ~ ` / \ ~ N ~
N
fJ ~ H ~ N ;~71 N N
0,0 1N / O`

O\ C NHr -J 1 N a N I ~ N H

oJ ~N N H
b b b N N F
N 4 '\ N o O\p~F N
O`~ c0 I- O N
C ~ / N H
N O 0 N ~ N H

N \ /N

a QNO \ - H ~J0ix-c/ NH ~N I ~ N ~ ~ NJ

N
Cf ~.
~S/+
/%~
\ - . N
o`S ~ N O {
~ ~
N ~ N \ ~ H O
N N
b H OO 1iN NH

I% N N

O p O OSO r ;S
Oa H~ O~ I/ / NH
O N

N O. i \ - ;S N ~1 F

o ~N ~ - ~-~
~J~O ~ / N

F F
N O Fx N

N "
CNKo oO
% N .H o ,S

F ~ --0 NJ
F \Np / N NH r--'N N
b oJ ~

N
N
O O
O. rr p O

l N N CIO N NH~ !/ - O~F
~ ~ / N \ F
O, NO 'IH
~

N N

NN CI O~ N O ~ O~. ~ N _ / \ ~%
CJ~ N `J. ~/ N~O _ O ~ N N I{ N
}v, d , ~ ~
u' H

% O
O-~ N~O ~= N ~= S
h N I, N / N
rJ` H O
O F F
F

j' N

N CI (:Q-G I czcc~-oH
~ U b N
/N ~ // p N
_ O~ ri C \~ ~ c S ~ o SO
C N FI ~ N O ~O i N

N
N
I CI I~ - N"p j 0 p /
S
N N N
~-- /

.N
N N
/
_ O'S`r-1 CxOxxc/N0 CI N~
I O,~ N[N~ N }
CI

N H N
cco~-o-? H `
N o ~ ~, = N 0 /N N N F
pt ~ O F
\\ N
` N Nhl ~~ N O F F N l N H
N O ~
N ~ N 'H C/ J`-N
/ O O~S\\ N
h~p JQo Fi N 0 \-J b b b N F
N ld N
0~oF ~r \~..
- O ;50 ! ~ N NH \ O O F
~~\O ! O N \/ NH Ors`b O b ~ '~ N NH
~
~ ,. N

N F
~ ~` ~o~F ; o`~ ~
~o ! ` ~ S~o N ( / \ / NH ~N ~ N H N , N N
N ~ H
b b b N

O\,S~=Q l~ \ O ~5~ //
N
N NF! v Ill:~; N \~ NH O~ NS~O

bN o b 1 N H
<1 O

N
O`\ ~-O N
`~ - I
N p.
N O N~..~ b \ - 'J1O
N~ N N

N NH ~ N H

F
N
// F _ N
O / - O~ j--a N 0.- J F \! ~ I NH Ci N
H
\ ! NH~` ~\o &,N

\ O
~

N
N \ %~ 0`, CI NS`() N/ NH NH~O
'H 0-1-0 N
b -b b N
N 0 ~--~ N
\ y p /1 / / 0\\
)-- ~ -- T
~ "- "S_O ^N I / N \ / NH C NH o I) N N

F F

F
Q
`N
O\
N
N N eNNk0 o'SN HNS~. ~ N \/ NH
~~ bi N
F N oc N D
F F \ /
0, S=
/ f ~ NH ~
~
NH N I N.0 N O N ~ '}-~

(IvJ,N N

J 1N ~ I!~
J O\\
~s/ ~ 7-0 N `O N I ~ N NH ( / N \ h NH

N / N H ~ b ~N ~

.,o o~, --o S,.
/ N O~~ p \--N
H
cco- N NO~O N.
N H
o b ~
o=s=o 2987 2988 ' 2989 \s,,o , ~ ~o n S,o NJ--' O~ \--O
N/E.`
N H /j ll ~ ~

^ N N,H
~F ~b O N

,O
O' s \-O

CI O j-}-F
H ~ F /~
I~ ~ 0 ~-<
N N \ / N . o ~ - ~'O
0=s=0 N\ H
~ ~ / \ / NH
N /~ N N

o N N

O F O ~-o !"Q F F ~j INNO ~, N\ NH N ~ f H N H
6 ( ~N 6 iN 6 N
O
N
~-o \ N
// -Ol-o N
I N NH C N CI
N \ VVV

N
/N

cccÃoH0 Br -F F
F ` ~ .
O N

N
O-N
o N / N

N ~, o N ~ ~ ~ f H-N
~N Q N
H

F F
F
O N
N

- ~\

N F
N
H-N Ci 0~+F
1=0 ~ - -C F CI O
O~ H I~ _ N O
OJ ~N / N \ / H
O

N N
~ !/ ci o~ ~ /( N o O`S O
~ ~-C N
~N I~ N H N Fi J ~N N H C~

/j~
H

F ~ "p pNN H
H p iN

N H N H ~cx:cdo0 NH Np 'H = =
Q0ccOTc0 F F
F
N
= \\
N

Q030H F HN~ ~0 IJ^~ I i N ~/ IH Sp \ ~p p'p \ N
F
N F /N u // <)~ F-1 _N~ " N o N O~ N' N C ~ NNH N
`o O N ~ ~

Oos~ \S,lO
\,lo O
O ~ \--0 o'/ N) N
l ~
_ N 1` H
N N' JI ~ I N,H
I H O~O N
N, I O~O F
OJ=O ~--F
F

3026 = 3027 3028 N N
O.a O N
Br F O
/
~N ` O N NH =N I , N NH NH }--~I
N,_~ N

F\/
N rN FO
/N ~
I/ N ' NO
O0 N \~ H
O~^/\ NH 0 ~ O
J\. .,.~. `O O ~ \/ =

F F

/N F~ r/ N
F O ~--_ N
NH ca ' ~ N o f / F O\\-~ ~~
p N ~--0 N O N H - 7~
N~N 0 F NO N ~/ NH
F

/N \\ / / N N
l1 F O 0 \1 cO N \ F OI-NH -F OTo T
~
/ N H F\0~O l/ N ~/ NH N \ / NH
F F F

F F

F

%

/ F \\ ~--{-/N O
I\ - N NH T'O^ F
N H H-N'O F` O N NH
F
F T ~
fs N N
N
~ / - O / O O
HOe,, ^ l/N ~ ~ H \ ~ ;'~/\ ~~
HOJ( HO>,,^O N NH ~H
HO N-N

N
p\\ N
F
\ - TO ~ O ~F
\ - O
F
N N NH I \ _ ~-O F - O N N
'H
O N \ ! H TF

\S~O
O~ \-O

N 0 ~F ZY p / /~F ~ \ N~
FC c N \/ ~ O F F O N ~ o F
TF F ~ ~ CI
,,.H' N
O~=O

\ o .,o o ~o o \--o NJ~ N

~/ \ I iiN'H _ N' \ I N~H H F

o~O o~oCNI N ~~
F F O O//
.3053 3054 3055 N
/ O
\ ~0 ~ N

O I~ N \/ NH ~ \ / _ O\\ o I~ - N O
N~N ~ 0 + ~ N \ ! "I'~ p ~ N \ / =H

N~N NIN ~
\ ~ ~ I

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

~ ~
/ N H ~O NJN ~CI I \ N N N
O~ H /'~
O
N~N ~Ct F F O~
F

H F H ~
N Fi ~ N~J o~o~F 0N o~j-~ a~ N
F F F F \-<
F
F F F

s"o o \So /0 t \ ~ o - ~ J \ N
H N H

N \ ~ \ N ii N N O ~ N a~T O--O N NH

F
F F

\ ~O
~~ o--o J \ N~

NI NH
O-~-,-O

Exemplary compounds include the following:

I

o o ,S
N O 0 ; ~
N
O
/ N p ~ Or N O
i~ ~ / \ ~ NH /\o ( o N NH o b b .
3070 ~

O N N pl N N 0>=o ~N N NH
N 0 ~NJ
H N O O
~ \ - ~-o 3074 ---p N NH
b I/ \\ ~ lN
~N Ol'H N \/\M--N O' N'NV v0 ~- ~ N,,),p ( 0 N \/ NH NH N

N N /N O
O-/
OS
H ~ o O
I \ I N O ~ ~ ~ N~O I /N H
N So b // ~/ O
`\
ON - To N~ - ~~S~ ~p N / NH ~N N \ / N ~
p O
x NsN
"

N p !!~ !1~

/. Np S-N ~\ r g-N~
n u N_ p ~ N H O O'ti p / N p O-H
JN\ y'0 1 !O

H 0 / i--4 N )-O N O
ON}-N N \/ H
N 'M
~. i~ N H
N O ` 3088 N N N ' O \,r // / p Q Ii NH p N
r o~ xx-o:.O 'SJ~.N.p I i N MH
b õ v ON~~p O ~ o N Q N
~-O H
N~ N /~ SO J ~ N \ f o~'0 b 3093 3 3095 N O N N
H N FI
)/Ho O~S'O O~ N
~~ ~

/N ; \ / F H
o` `N_}i / / ~c-c NH

N p N
O
N \/ NH 0 N" O p N oJ
~'N O_gJ
.oS
J b ~ v p~-N`-% N~ \ /N p\\ a)-- p~ \ /N p`\
N o~ I N o " ~N NHT N I~N _ b N
p\\ N /N
1~0 /
-Ir N ~ ~ NH p / p ~
N
p b b " b N- N
p J N N ~ ~-N
I I N
oL\" o ~~00 0 p / N
~ Jt~J
~ N
O 'H

N
HN vo N " p ~ NS\ o o p~ p O / N
N H NH
O N

/N H ~\ " li _ N-( O
~ ~ ,So \ J 0 ~ - \ / O \ /
O N o O I "> N \ / }{ p I N .H
( /b '" b b N F N
!/
H ~ O N
pt~ ~ \ ~ / O O N (/ N ~ N
'H
~/\.o / N NH
,b b b N
- p I ~ ao'O'N NH~ 0 pp / N \/ H
( NH
O N

F
O // N p ~ - o - p - ~
p n!H o ~ N NH
p 6 N H

F F /N N
%, o F / O
p N N aN N-H
o N H O'N
O / \

/N

N_H /C~~p ' / N \ / N ^ ~Q/`p ' N \ / N
b b " Lj H / \
F

/N / \ p /1 p ,.._ ~j N
~. p ~'N p.
^p (/ N NH H p N \ /- H
3135 3136 ~2 N N ~
N // o\S/-\ / H-N IC I%, H-N
~ O
O N ~ / NH ~ ~ N NH O ~ N
N - H

N N
N \N / H-FV H-N
N H-N O N 0 N NN~
O N o N H
N H

H-O,\ ' N N N
N H-N N~&tNi O ~N~ I1 p O ~
o \ ~ N NH O N 0 I N O
H ~ N H

N~ /N 0 N /N p Co~ N N ~

O N o NH N O
N H N N H
b /V~ b N N s N
H }-N p \
p0 N N S po ~ i N "N O ~ i N NH
b /' b b H, H
OH
F F

F F F
A N S~ l p - }-N N
H 1\ \~
0 ~ N N N N N' H
b _ \ N
N p /
N~Nf 3153 ~N~ ~

F N N
/ \ F
F
p - F H H N H p. I ~ N ~s OO ! ~ N \ / >=s b b H-N H-N
/}-O- N Cf N CI /%~ -p Q I \ N / Q \ \ /
O j N NH p ~ -~ 'H N NH
b b b N N - N
QI'N
\ ~ 'O N
O O O a 0 I / N 'H O N NH O N
b b "

/ N N N~\ N~''~ N
p \ ~ / O I ~. N~Ni) p ~ \ _ ~N
p / N N O / N " O / N
b " b b ~\ - /% Q
O N O I\ _ N~ / 0 p \ I / N O N p N 0 N H
b b " b N a\\ N ~\\ N
o '~Q
0 ~ - 7-o /I~~ o ~ - T-" ~ ~ ~ ~ ~ N
\/~N~~ I i N ~~ NH \/-N~o I i C. NH ~ N O ~N ' H
H H
\ H ~/

\\ O Q

Np N Nj~ O N I / N ~ / NH`H~0 ~ ( / / NH
H O N` -N
l~ H-N \N
3174 3175 v b N N ~F N
O
H F . p :~~ F CNOO
N
Fo N ri}- S
FN/ f 1 6 N i F

N /N O N
N
\ H ~ ~ ~ ;S~ 0=~ N O
~ I/ ~/ N I/ N NH p O I N \/ H
N O N >-S ~
N_~~

O N N
N
F \ o~5 'l NS
F~O f / N N ~ H~ O H Lap N H

N - /p N
p\ O~O~ F F
N k-O
- =s ~ -O N ~ tVH ~O I ~ ! ~ c N
p ~--S
i FN F

F

N N F ~N
// // (\! N
H {N
~~
N` F ~ / ~ ~ N `N" O N k N O //--S `~ O N ~ S 6 H
N ~
F F
F~

F

N N N
/ p N p N b ~ ob3o0 b N
N /N
i NII
N (cX-o p ~ I I/ O

N
N S /N
~ ` ~
o \ ON `O o ~ e ~/ NH 0S`~
~~ N H R((1~ N N N H
N

N N

O
O~! O~ Q q N \ / NH\/~ NH~/~ ~ -p N N N NH
F$F /~ p ~ N-N~
F ~~//

N ~ /N N
O. ~ H - H
~ I~ - NS.,0 F\/-O I,~ N N F_-O ~, N N
N N N H N/~- NS
H J
. ~. `/ +

F

N _ N N N - (-~' <
~/ N Hp O O N(/
~ FN/F

// k- N N
N i N r~ p. 'N //
cxo\7H0 CN N \/ H N~ N NH
b b b N N N

/ N N`S
N O N H O~ ~N O~
O./I OJ 0 N N N

\e ccc-\/0p ccccc0~ ~ I / N~
p ~S
O

N N N
~ cx0c(o0:p X-QD ~ NH

`/

N N /N
0 N iN ~ / - Oe ~
O N CNi~O I/ N N O
N \
~ H
i N
~\ N
b ~. >
N" 3224 ~ 3223 N
/ N ~--~ N H-(Hr ~ N H
~H O
N ~NH Q N
N 6 o//

/N 1 N o p N
y-p N \ - p~~ o H I~ - N -0 pA p pN,O Ji N \ / NH b ~p N ~ I
b ~ >
3228 3229 3230 N _O /N p\ O ~~' 0~~ N
0\~ ,-a ~~ p p=s p~, \ p O N NI~ N H pr~p ~ N N p O

N p N p\\ p %I p ~ O -O
o=~^ ~p I/ \/ N pr o I~ N NH p +/ N Ny O
~ =H ~ ~

N N N
N O
O ccJ/ooJJ N -llz:

/ ~ C/~N N 3238 3239 N // N /~ p`
N
N .~ ~ --' N \/ NH~/
NH p~~p N \ I NH

N /N
N \ // - 0 \ N N ~~ ( N~ ~--Q
N 7H- NS=O N \ e ~ ts N N

N N N
// \~~ )-- Q //
=S \ - TO O:N.O' 0 !~O ~ / - p~r3 /\
`~0 I~ N \ f NH ~ N tvH ~~ ~ N \/ NH
N O
N

N N N
~N~rP0 O N
N 0 ~ F~~~p \ N \~

N N
N
/ -N ~ N o ~ ~-4 / ~ - /-N N~ NH ~\ I / N NH

NH N N b N ~

=~
J) O~\, -O ~=~-~ (/ O NH

\ - ~ / l N N N
Xo-><

N N
o O ~"=o/-a \i "~ ~N ~N "H
~` N 'H ~~ N N O N li C,N // b ~

N
N O ~- Q i ~ cx-o-N N
/N 0 o~r j-Q
o H \ ~Nv^. N
F~o I/ N NH ~

-NN
1~2 o H
NH O
N N
o C-N - N.
~Q Xc-o13 ~ N
N 0 N N~
e N N . /~ o .
~-- ~
XFOJH ~~O N~O ~ i N \ ! =H
tf b b N O N

/N N o N
N ~N O~~
i N O iP ~
/ I / NH ` NH~~ .S-o ~N O N N 0 N N 0 ~H

N /~
N H Fo` ~O
iJ H rN
N NH~./\
C~~ N `

N 0 N ,H

N N N
iN / F Q ~ iN F 0 i i i Fo a'p CN I N NH~ N o~ N NH N \ l NH
N O ~ ` ~ =
\!~ 3281 iN iN N
CN~ e N NH O p F
N O o~-- p N N N
/
iN
/ N \ ~ H N i~ H
N \Nl p N N \ f N_}
N O N ~ ~
N
' N Nj~.
NN

3285 3286 3287 N /N p l /N o (<icc,0~
"H
N N N N N
N O

6 //j6 \

N N N

bo0i, F~ C N \/ NH F c0ck N Jk-~ b b a?

N F N N
/ -/
~ F H N
tib ~ \/ N
F NH~ N H
o1j p sp 0 O
p ~ N )_ p C~~ \N"`p N
b ~ =

/N N

b ~ \ N O ~ s N
N\~ e N H O
N~~
~ N ~

N p`\ 0 CI
o`
O NTO -p-N \
So I ~ - N N 5H ( N
N \~N O
NJ, N 3301 N

HN'O

O
fs .

N N N
N zp- 0 o:/b0 / - NH ~ ~ N =H CN~ N H
~ b b N N ~
N // Ci O` 0 N /N CI o0 O
i 'NIO N h NH N^p 1 N NH
0 I\
O N
3306 3307 i I

N
O-- \~
N
H-N
S
O
~\\

N O O
xxbci0 +
N oNH 0 N 0 O ~ N
\ I \ I

N N
H-N H-N
S'O fO JS0 INI \ - ~ N ` s N ` -~ N O, N-H
N O N N H N O N N H \ .S-O
J`1/ I/ N \/ NH
J ~ .

N N N
// O ~-Q
~-H c-oc0 / N Noi C~ 0 b~0 b O b F

~N p ~ -a N N CJ p` Q iN "CI 0 , JO

O,S ` / N ~ ~ N p N ~ / NH CNb ~. N ~H
~N b b b N p 0 FF !i ~%
/ N I \ -e N o` IF Cc H
N 1 N H I/ N ~---p b b b I

/j N '` N ,N
N H H N ;1~O N \ \ / oN
\~ I\ - N ~S
NO 1~. i N Nj_p N a / N ~ I o1-N~ ~ O
o~i b Qj 3326 '3324 N N N
/ N ccc- \ H N N H N~O / N N H
b b b N ~cc-c>-2 ,NNH M -O \ N N
~ ~

N N N
N / O iN 0 ~
N
N O (Xp 0 ` H 6 b J~~, N N p` ,O -N+ N
~i - ~p~ N
C~N0 ~. I N \ f NH /~ ~I/ \ e~ N
O N N >=O

\ ~...
O-N

N

. / H-N

IN N N
,H Ft N
o ~
N N ~o ~o O. F ~ ...,~~
FF

N N !/
N 0 0,o {dH N
/ N N 0 N 'H
N ~=o ~ H-N O

o N
F o 0 N ~. -pl O N N QN ~~ O N
10, \ \ ~

N FN

H-N H-N
o S' Jo ~\O

N ~J.. 1::CN N 'H
b \\
- ~ ~ I-O ~ ~ - `O
pDp e N NH ~N / N N'H

~ p b b N N N

~ - p p 0 N N
O
b ..,mp. H

N N N
/ > H // - \\
p N
-N N `~ N
N I / \ / NH
p iv b J b N N
N
p - 0 -o N I ~ N \ / NH N NH

F O /%1 /D / O\
~ - N "O
NH H /\iN I/ N ~ I NH "NIff" N H
C

o N N
N

H \ OII ON~
N N ~i / N / N ~ H
O O
N H H o N
'~-/=N O
NvN ~ .~ N N
'H

B. Preparation of Comuounds of the Invention Indole compounds of the present invention can be obtained via standard, well-known synthetic methodology. Many of the indole starting materials can be prepared 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 nitromethane, 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 Al. 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 U.

I. Scheme A

Compounds of formula I, represented by structure II can be prepared as shown in Scheme A below:
Treatment of nitromethane with base followed by reaction with an activated carboxylic acid, e.g., au imidazolide, such as compound Al gives compounds of type A2.
Treatment of compounds of type A2 with an amine of structure A3 gives the compound A4.
Reaction of compound A4 with quinine in the presence of acid, e.g., acetic acid gives the hydroxyindoles of stxucture II.

NN~ 5 base RS~NOx R ~N 2 (A3) Al A2 A4 O~O ~N
~ , R5 (AS) HO R4 HOAc ~l Compounds of formula I, represented by structure ITI can be prepared as shown in Scheme B below:
Treatment of B1 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 III. Examples of leaving groups include but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates.
U. Scheme B

\ R5 R6-L R5 MO I~ N R60 N

Compounds of formula I, represented by structure IV can be prepared as shown in Scheme C below:
Compounds of structure IV can be obtained by nitrating an indole of structure C 1, to give the 3-nitroindole C2. The nitration can be carried out by treatment of Cl 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 dichloromethane. The reaction can be carried out a temperature of -30 C to +50 C.
Treatment of C2 with a reactive functional group Rg 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 carried out in a polar or nonpolar solvent at a temperature from ambient to 200 C in the presence of a copper catalyst, e.g., CuI, a base such as Cs2CO3 or K3P04, and optionally an amine ligand such as 1,2-bis(methylamino)ethane or 1,2-cyclohexanediamine.
An alternative pathway is to convert C1 into C4 in similar fashion as described above and then carry out the nitration reaction to afford compounds of structure IV.

III. Scheme C

R HNO3 :4rEo2R5 I R9-L (C3) I R9-L (C3) Ri I~ R$ HNO3 Rl I~` \ R5 Ra ~ N R2 N

Compounds of forrnula I, represented by structure V can be prepared as shown in Scheme D.
Treatment of (3-ketoesters of structure Dl 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.
IV. Scheme D

C02-alkyl ~O R NH NHR4 O~O \
C02-alkyl 4 - ~C02-alkyl Rs R5 (D2) R5~ (D4) HO Ra D4 D3 HOAc v 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 E1 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 trimethylsilyl 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 treat-nent 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 bytreatinent of the amine E3. Compounds E4 can be converted to compounds of structure VI by treatment of E4 with a reactive functional 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 COa-alkyl i` C02H R CONR7R8 R, !`~ R5 :z: R, I1. acva S -R2 2. HR7n R3 H (E3) R3 H

~ R9-L (H5) (ES) R C02-alkyl R
R COzI=i R CONR, ~ ~ R5 hydrolysis Ri I~ R5 1. activation :.xc7R8 ~. ~ R
R2 N or R2 N 2. HNRp 8R ~ N 5 Ra Rg dealkylation R3 Ry (E3) R3 Rs E6 E7 Vt Compou.nds of the present invention, represented by structure VII compounds can be prepared by the chemistry described in scheme F below.
Indoles F 1 can be formylated with reagents such as phosphorous oxychloride in the presence of DMF to give the indole-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 F1 can first be converted to F4 and then be formylated to compounds of structure VII.

VI. Scheme F

R R CHO
Rl I% \ R5 POCI RI N R5 iR9-L (F3) R9-L (F3) Rl R R CHO
~ \ R5 POCI3 Rl I~

X
R3 f`9 R3 R9 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 KMn04 RI I~ N 5 R2 N Hz0 R2 ~ % R3 R4 R3 R4 Compounds of formula 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 Hl with a nitroalkane, e.g., nitropropane, in the presence of an amine source, e.g., ammonium hydrogen phosphate gives the indole-3-carbonitrile 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 containi.ng a suitable leaving group L (H4) as described previously to afford compounds of structure IX.
Alternatively, H1 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

R2 H \-,H201 HzNOH

R R CN
CHO /~ ~N02 R(NH4)2HP04 H

R3 Rs R9-L I (H4) R9-L (H4) R CHO R CN
R, ^_,NO2 Rl RS ---~ ~ ~ R5 R R9 (NH4)2HP04 R2 3 Rs H5 ~ IX
H2NOH R ~-NOH O -j11201 Ri I Rs Compounds of the present invention, represented by structure X can also be prepared as described in scheme I below.

Indoles Il 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.
DIvIF, CH3CN or dioxane, to afford compounds of sttucture B. 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 Il can be reacted with a reactive functional group R9 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, CIS02NCO R, R2 N\ (12) R2 H

R9-L 1 (14) R9-L (14) R R CN
Ri R5 ClSO2NCO R, R5 \ I \
X (12) R2 RZ N
R3 Rg R3 R9 ,15 x Compounds of formula J, represented by structure XI can be prepared as shown in Scheme J.
Amino crotonates J1 can be reacted with amines J2 to give B. Reaction of J3 with quinone in the presence of a polar, protic solvent, e.g., acetic acid, gives the compound of structure XI.
X. Scheme J

CN
NHRa O~O

CN R ~iCN (J4) HO

d1 () J3 HOAc Ra XI

Compounds of the present invention, represented by structure XII. and XIII can be prepared as described in scheme K below.
Aldehydes of structure 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 fanctionality 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 in 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.
Altennatively, a source of copper can be added, for example, copper bronze, to facilitate decarboxylation.
Reaction of K9 with a reactive functional 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 functional group Rg containing a suitable leaving group L (K6) as described in previously, affords the compound XIII.

XI. Scheme K

R N3,-,C02-alkyt R
R1 ~ CHO RI CO2 aikyl R2 ( (K2) R2 ~ N3 R3 base R3 A =

R R R
Rl [H) Rl H+or OH- R, ( ,----- ~ \ CO2-alkyl -----_ ~ / \
R2 N R2 N A 2 ~

KS CIS02NCO K4 CiSO2NC0 KO
R CN R CN
R9 L (K6) ::1Ii:Ir:r- ::xIiI Rg-L (KS) K8 \ \ Rs-L K11 ~ R9-L
RI CN
Rrt R
~ CISO2NCO R2 R CN
I ~ \ CIS O~NCOR' \
R ~/ N N R / N R2 R
Rs R9 R2 R3 R9 2 R3 R9 R3 9 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 chloromethyl 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, CH2Cl2 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.

MI. Scheme L

X R X R X
Rl NBS R, R5W Rj I~ \
R2 I N or NCS R2 ` iV Br or C1 (L~) R2 N WRs %
R3 Ry R3 Ra R3 R4 Compounds of the present invention, represented by structure XV can be prepared as described in scheme M below.
Anilines of structure Ml 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., CH2CI2 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.

XIII. Scheme M

R R
RT NaNO2 R~ I \
R NH2 SnCiz RZ NHNH2 O
[H+] R5'~' (M3) R. R
Rt R9 L Ri ~ R5 X Rs R2 ( ~ N (M5) R2 N
R3 R3 Rg R CN R CN
~
Ri R5 ~ ~, \ ~ Rg-L Ri R5 ~ ~
R2 N (M5) Rz N

M7 xy Compounds of formula I, represented by structure XVI can be prepared as shown in Scheme N.
Compounds of formula Ni can be reacted with a dialleylformamide 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 palladiu.m, 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 structure 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 with 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 R O~OR,, R
RI ` H NR7R8 R1 \ NR7R$
, R2 ` ~ N02 (N2) RZ ( NOz [Hl R R
R1 I~ \ R9 L R, I \
Rz / N (N5) 'R2 N

R CN R CN
R, 6 R9`L Rl I~ \
R2 H (N5) R2 R3 . R3. R9 Compounds of formula I, represented by structure XVII can be prepared as shown in Scheme O.
Compounds of structure 01 can be converted to 2-iodo- or bromoindoles 02.
Typically, a strong base, such as n-butyllithium or s-butyllithium 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 limited 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., DMF, toluene, dimethoxy ethane or dioxane at a temperature range of ambient to 150 C. For the Suzuki 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 form compounds of structure XVII.
XV. Scheme 0 R E R E

R1 '\ \ :i::ation R, 1(or Br) R3 R4 or bromination R3 R4 1.base R12-B(OH)2 2. B(OR9)3 Pd or or R12-Sn(R11)3 CtSn(Rs)3 R E R E
R, ~ R12-L R~
i ~ B(QH)2 orSn(Ry1)3 N R12 RZ ~ N Pd R2 R3 R4 Rs R4 03 xvii Compounds of formula I, represented by structure XVIII can be prepared as shown in Scheme P.
Compounds of structure P1 can be converted to compounds P3 by treatment of P 1 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 tb.e presence of a base, e.g., cesium carbonate_ The reaction can be carried out within a temperature range of ambient temperature to 150 C.
X'VI. Scheme P

R1 (P2) R1 CISO2NCO R1 ~
~ N I \ R12 R12 R2 Pd(OAc)2 2 DMSO {~2 N
R3 R4 Cul R3 R4 R3 R4 Pi Cs2CO3 P3 XVIII
, ' .
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 Q1 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.

XVIT. Scheme Q

R R R
~
Ri (Boc)20 RI 1. base RI B(OH) \ _i -= \
R2 ` N \
R2 N 2. B(OR11)9 R2 (/ N 2 R3 H R3 BOc R3 Boc Q1 (Q2) R R
L-R12 R' I~ R12 [H+ R1 ~ \ R12 L R9 (Q4) RZ N R2 H
Pd R3 Boc R3 R R CN
R ~ I \ R12 CISO2NCO Ri R12 R3 9 R3 Rs Compounds of formula I, represented by structure XX can be prepared as shown in Scheme R.
Compounds of structure Rl 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 formarion 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 with R6 with a reactive functional group R9 containing a suitable leaving group L as described above can give compounds of structure XX.
XVITI. Scheme R

R E R E R E
R1 I \ \ (Boc)20 Rt 1. base R1 (H
)+
R2 N N 2. iod(nation or )~N R3 R R2 R3 Boc bromination R2 Boc R1 (R2) R E R42-B(OR11)3 R E R E
R1 (R5) R1 ~ Rs R1 \ --= \ R

R2 N Pd RZ N R2 R4 R6 )0( Compounds of the present invention, represented by structure XXI can be prepared as described in scheme S below.
2-iodo- or bromoindoles of structure 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.
XIX. Scheme S

R E ~R13 R E
R1 ~ ~ I(or Br) 121 -'' R1 R~s N N
2 R3 ~
~
2 Rs R4 Pdo 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 T 1 with an acetylene compound T2 in the presence of a source of palladium, a 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 to 150 C.
XX. Scheme T

R E R B
= Rts R
R1 N I (or Br) `T2)_ 1 ~ ~ N = Rti3 R3 R4 Pd R3 Ra TI xx11 Compounds of formula I, represented by structure XXIII can be prepared as shown in Scheme TJ.
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., CHaCI2, ether, THF, methanol or solvent combinations.
XXI. Scheme U

R E R E R B
R, {~ R k3 [H2] R, (~ \ R13 [H2] R, R

2 R3 ~4 R3 R%
2 ~
XXI XXIII )C)fll Compounds of the present invention, represented by structure XXIV can be prepared as described in scheme V below.
Indoles of structure Vl 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 them to give organoz.inc 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 VS 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. Furthermore, the reactions of V2 or V4 can be carried out in the presence of a palladium source, e.g., as tetrakis (triphenylphosphine) palladium (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 Ry R~ :_hide I/ 2 1. Base R~~-.i (V3) 2. lodination or bromination Pd R E Zn-R12 R1 E
1 ~ N I(or Br) (VS) N R12 R2 ~ R2 R3 Ra Pd R3 R4 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 XXV. 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 stcucture 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 I 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 similar to those described previously. Reaction with XXVII with a reactive functional group Rg containing a suitable leaving group L as described above can give compounds of structure XXVIII.
XXYII. Scheme W

R ~ -R1 ~ R13 (W3) R \ (W2) R1 Ra ~ i N ~ 3!(or Br) R1s R3 H Pd R2 H Pd R2 H
R3 Rs xxvn L-Rg L-Rg R E

I ~ R1 I \

JCXVI
Compounds of fortnula I, represented by structure XXIX can be prepared as shown in Scheme X.
Indoles of structure X1 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 CH2Cla, carbon disulfide or dichloroethane and is typically conducted within a temperature range of-20 C to 80 C.
XXI`'. Scheme X

R1 ~ \ () R, RS
~ N R5 AIC13 N
R2 ar R2 R3 R4 Et2AICI R3 Ra X1 XXiX

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. Schenne Y

N;N 0,0 N R13 R, R CN NaN3 R NX NH R13-`(L R N~ o R1 (Y3) R1 RZ N R5 A R5 ~ Rs R3 ~ R2 1 RZ N
R3 ~4 Rs 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 hydroxylamine 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, dichioroethane or dioxane in a temperature range of 30 C to 150 C can give compounds of structure XXXI.

XXVI. Scheme Z

OH
R CN R HN NH
Ri NH2OH R

R2 N R5 I/ \ Rs %
R R N

O
R13--~

(Z3) O
Np~R13 0~--~
R N R HN NH1s RI ~ \ ` Q R~
~ R5 X Rs R2 '~ IV R2 Ra R4 R3 R4 xxxi Z4 Compounds of the present invention, represented by structure XXXII can be prepared as described in scheme AA below.
Ketoindoles of type AA1 can be converted to oximes of structure AA2 by heating the ketoindoles with hydroxylamine (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 XXXII.
XXVII. Scheme AA

OH ,o R O R N R
R, NH2OH R' n-BuLi Ri Rz ~ i N Rs Rs DMF I/ N Rs %

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. Treatment of AB3 with hydroxylamine (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.
XX'VIII. Scheme AB

N

R1 I~ \ R5 HXNR7R8 :zTII 1 \ NR7R$ NHOH R1 R14 (AB2) I R5 I R5 RZ 2N R2 N %
R3 R4 Rg R4 R3 R4 Compounds of formula I, represented by structure XXXIV can be prepared as shown in Scheme AC.
Vinylogous amides of structure AC1 (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

R R ~ NR7RB R N~
1~~ NH2NHR1 ; Ri R14 RZ N (AC2) N Rs R3 R4 R2 %
R3 F'`4 ACI XX)aY
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 canied out in a suitable organic solvent from ambient temperature to 150 C.

XXX. Scheme AI) OõO
~ SNCO o~N
R CHO Me ~ i R
R~
\ R5 (AD2) R, Ra I N Base Rs R3 ~ A Ra N
%

ADI xxxv Compounds of formula I, represented by structures XXXVI and XXXVII can be prepared as shown in Scheme AE.
3-Indolecarboxylic acids of structure AE1 (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 AE1 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 can be performed with or without added base to afford oxazoles of structure XXXVI.
The indole-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 or ketones 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 thiazoles of structure xxxVII.

XXXI. Scheme AE

R CN R CONH R

:xco25 1 . Lawesson's z 2. NH3 N R5 0 R2 , 2 t % R3 ~ R3 Ra R3 R4 O O
L ~

(AE3) (AE3) R N R S N
R1 I ~. \ R1 R5 \ p5 R3 R4 R3 Ra xxxvi xxxvii Compounds of the present invention, represented by structure XXXVIII and XXXIX
can be prepared as described in scheme AF below.
3-Ketoindoles of structure AF1 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 can give oxazoles of structure XXXVIII.
Treatment of compounds AF3 with 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 structure XXXIX.

XXXII. Scheme AF

PhNMe3Br3 R p R14 1 R p Br R
R5 (AF2) R1 ~\ \ Rs N

R3 4 R3 R%

AFi AF3 ~/S
R134 NH2 (AF4) (AF5) R13 ~NH

N~p N~S

XXXVIII XXXIX

Compounds of formula I, represented by structure XL can be prepared as shown in Scheme AG.
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-bromosucciuimide and iodinating 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 (TI) dichloride or palladium acetate with added phosphine ligand. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, diinethoxy 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 AGS
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 R Br or I R B(OH)2 Rl ~ halogenation Ri ~ Base R, \ R I \
R2 I~ N 5 R /' N R5 13(OR11)3 R2 N
R3 R4 2 R3 R4 (AG4) R3 Ra Pd Pd R12-B(OH)2 R12-L
(AG3) (AG6) R R, Rg Rn 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 AHl 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.
XXXIV. Scheme AH

R Br or l R
R, R
#N~ ~R13 R, C
R
RZ 5 (AH2) R2 N 5 Rs R4 Pd Rs 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 of palladium, a copper co-catalyst and an amine source and carrying out the reaction at a temperature range of ambient to 150 C.
30cw. Scheme AI

RIg ~ Rl 3 + N Rs R::

Rs Ra Pd R2 R3 R4 Compounds of the present invention, represented by structure XLIII and XLIV
can be prepared as described in scheme AJ below.
Nitroanilines of structure AJ1 can be converted to indoles of structure XLIII
by condensation and cyclization with nitrites of stracture 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 02N (/NRa (AJ2) 02N ~ / N NH2 Rg L OzN NH2 base H Ry AJI XLIII XLIV

Compounds of formula I, represented by structure XI.V-XLVIII can be prepared as shown in Scheme AK.

2-aminoindoles of structure XLV can be allcylated with a reactive functional group Rl$
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 stracture XLVI. A
second alkylation utilizing a reactive functional group R' 1 S containing a suitable leaving group L similarly can give compounds of structure XLVIII.
Acylation of compounds of structure XLV with acyl chlorides of structure AKI
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.
XCKVII. Scheme AK

E o 0 E E
~ \ \ NH R5 R A
Cv \ ~ Base &N"
N4i R
ozN ~ N (AIC1) Q N I/ N NHz RI Lo M1I 95 Rq 2 Ra 2 R4 XLVIII base XLV XLVI
Base E

NR15R'15 XLVII
Compounds of the present invention, represented by structure XLTX can be prepared as described in scheme AL below.
Indole-3-carboxylic acids of structure ALl 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 carbodiimide. Reaction of compounds of structure AL2 with hydroxyamidines of structure AL3 can give O-acylhydroxyamidines AI,4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine. Heating compounds of structure AL4 in a non-reactive organic solvent, e.g., toluene, dichloroetbane or dioxane in a temperature range of 30 C to 150 C can give compounds of structure XLIX.

XXXVIII. Scheme AL

RI 3--/<
Ri I~ \ activation Rti HN-OH
Rs Rs RZ N Ra N (AL3) R 0 O~R13 R N~p ' R, Rs Ri R
2 N N s %

(AL4) XLIX
Compounds of fonnula I, represented by structure L can be prepared as shown in Scheme AM.
3-Cyanoindoles of structure AM1 can be converted to tetrazoles of structure AM2 by treatment with, e.g., sodium azide. Heating a mixture of AM2 and the reagent AM3 can give the 3-(1,2,4-oxadiazolyl)indole compound L. The reagent AM3 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 AM2 and AM3 at a temperature range of 30 to 130 C.
XXXIX. Scheme AM

NIN 0 N.R,3 R CN R NN fVH R13R N ~p R, f \ \ R5 NaN3 X R5 (AM3) RI , R5 R3 z R3 R3 Z

Compounds of formula I, represented by structure LI can be prepared as shown in Scheme AN.

3-Cyanoindoles of structure AN1 can be treated with hydroxylamine to give hydroxyamidine compounds of formula AN2. Reaction of hydroxyamidines of structure AN2 with compounds of structure AN3 can give O-acylhydroxyamidines AN4. Compounds can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compounds of structure AN4.
in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30 C to 150 C can give compounds of structure LI.
XL. Scheme AN

OH
R CN R HN NH
RNHz H R

N R5 Rs Rz Z

O
R18-\
L
(AN3) O
o0R13 ,0 R NX N R HN NH1s 1 ~
N p z I RZ
R3 z R3 k Ll AN4 Compounds of the present invention, represented by structure LII can be prepared as described in scheme AO below.
Ketoindoles of type AO1 can be converted to oximes of structure A02 by heating the ketoindoles with hydroxylamine (free base or acid salt) in a suitable solvent.
Bis-deprotonation of compounds of type A02 with a strong organic base (e.g., n-butyllithium or sec-butyllithium or tert-butyllithium) followed by reaction with DMF can give compounds of formula LII.

XLI. Scheme AO

OH

R R NA R N~
R1 ~ ~ NHzOH Ri n-BuLi Ri R2 i~ N R5 +~ +/ \ R5 DMF Rs 3 z RZ Z R2 Z

Compounds of formula I, represented by structure LIII can be prepared as shown in Scheme AP.
3-Ketoindoles of structure AP 1 can be homologated to vinylogous amides of structure AP3 by reaction with dialkyl amide dialkyl acetals AP2. 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 AP1 and AP2 with or without additional solvent at a temperature from ambient to 150 C. Treatment of AP3 with hydroxylamine (free base or acid salt) in a suitable solvent can give compounds of structure LIII. The reaction is typically conducted within a temperature range from ambient to 120 C.
XI,II. Scheme AP

R14 R8R7N _ R14 N
R ~ R11~~/~R11 R R p R1 H/~NR~R8 R' O NHOHy Ri Ri4 R5 ~' ~\ \ Rs R
Z i N (2) z / RZ

3 Z z Compounds of formula I, represented by structure LIV can be prepared as shown in Scheme AQ.
Vinylogous amides of structure AQ1 (as prepared above) can be treated with hydrazines AQ2 in a suitable organic solvent (DMF, alcohol or acetic acid) at temperatures ranging from ambient temperature to 150 C to give compounds of structure LIV.

XLIII. Scheme AQ

R8R7N Rl4 RN
R p R N~
R~ I~ \ R5 NHZNHRIS RI I~ \ RRta R2 (AQ2) RZ N
%
3 Z 3 z Compounds of the present invention, represented by structure LV can be prepared as described in scheme AR below.
Indole-3-carboxaldehydes of structure AR1 (as prepared in Scheme F) can be reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC, AR2) in the presence of a base to give compounds of structure LV. 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.
XLIV. Scheme AR

o, ,o NCO ~N
S
c R CHO M8 R C~=
R~ I \ \ R5 (AR2) R, RZ / N Base Rs R3 Z 0 2 z ARI LV
Compounds of formula I, represented by structures LVI and LVII can be prepared as shown in Scheme AS_ 3-Indolecarboxylic acids of structure AS 1(from Scheme F) can be converted to amides of structure AS2. Compounds of structure AS 1 can be activated by any of the standard methods. For example, the acid AS 1 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 AS2 can be reacted with substituted aldehydes or ketones (AS3) contai.ning a suitable leaving group L, in a suitable solvent at temperatures above ambient and up to 200 C. The reaction can be performed with or without added base to afford oxazoles of structure LVI.
The indole-3-carboxamides of structure AS2 can also be converted to thioamides of structure AS4 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 AS4 can be reacted with substituted aldehydes or ketones containing a suitable leaving group L (AS3), 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 thiazoles of structure LVII.
XLV. Scheme AS

Ry 1. ::' 2 N

0 \Rea wesson's L ge nt R/(AS3) R14 R13 R 1 Rs ~ ~ /
/`-~ R2 N
Z

::lIlNR5 R3 Z L R13 LVI R1a (AS3) R N

LVII
Compounds of the present invention, represented by structure LVIII and LIX can be prepared as described in scheme AT below.

3-Ketoindoles of structure AT1 can be halogenated (e.g., brominated) to give compounds of structure AT3. Suitable brominating agents can include but are not limited to phenyltrimethylammonium tribromide (AT2), N-bromosuccinimide or bromine and can be carried out in a variety of organic solvents.
Treatment of compounds AT3 with amides of type AT4 in a=suitable solvent at temperatures above ambient and up to 200 C with or without added base can give oxazoles of structure LVIII.
Treat.ment of compounds AT3 with thioamides of type AT5 in a suitable solvent at temperatures above ambient and up to 150 C with or without added base can give thiazoles of structure LIX.
XLVI. Scheme AT

R O R14 Br R14 R7 \ PhNMe3Br3 R O
R, R2 N R5 (AT2) ~~ R5 %
/

O g Rts-- ~ (AT4) (AT5) R73~ 11 NO N
R1 R R1 R R1a ~, ~RU Rs , R5 RZ / Rz ~
R3 a R3 LVIII LIX

Compounds of the present invention, represented by structure LX can be prepared as described in scheme AU below.
Indole-3-carboxylic acids of structure AU1 can be activated to give compounds of structure AU2. Compounds of structure AU2 can represent, for example, acyl halides or carboxylic acids activated with a reagent such as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reaction of compounds of structure AU2 with hydroxyamidines of structure AU3 can give O-acylhydroxyamidines AU4. Hydroxyamidines may be obtained commercially or by treatment of nitrile compounds with hydroxylamine. Heating compounds of structure AU4 in a non-reactive organic solvent, e.g., toluene, dichloroethane or dioxane in a temperature range of 30 C to 150 C can give compounds of structure LX.
XLVII. Scheme AU

R CH R O L R NH
::.Ix1IcIco2& 13~
activation N N (AU3) % R2 , HN-J~ N
R 0 p R1s R Nx R, I~ Rb R' ~ 1\1 R5 (AU4) LX
Compounds of formula I, represented by structure LXI can be prepared as shown in Scheme AV.
Reaction of 3-iodo- or bromoindoles AV 1 with a boronic acid AV2 (commonly referred to as a Suzuki reaction) can give the compounds of structure LXI. 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 AVl can be converted to the indole-3-boronic acid derivative AV3 by reacting the 3-haloindole AV I with a strong organic base (alkyllithium or Grignard reagent) and reacting the resultant anion with a trialkylborate reagent AV4. Compounds of type AV3 can be reacted with aryl and heteroaryl bromides and iodides AV6 under sirnilar conditions to those described above to form compounds of structure LXI.

XLVIII. Scheme AV

R Br or 1. R B(OH)2 R, Base R1 R5 ^- ~ \
RZ B(ORIa)s RZ N R5 %
R3 z (AV4) R3 Z

Pd pdo R12-B(OH)2 R12-L
(AV2) (AV6) Rs RZ N

LXI
Compounds of forrnula I, represented by structure LXII, can be prepared as shown in Scheme AW.
Compounds of formula AW 1 can be reacted with a protecting group, e.g., di-tert-butyl dicarbonate, to form the boc-protected indole, in the presence of a suitable base and solvent at ambient temperature to give compounds of structure AW2. Treatment of compounds of structure AW2 with base in a polar aprotic solvent at tempe.ratures from -78 C to ambient temperature, followed by addition of a trialkyl borate would yield compounds of type AW3 upon hydrolytic workup. Reaction of reactive aryl halides or triflates (of the type AW4) with compounds of formula AW3 at or around ambient temperature, in a suitable solvent system containing base and catalytic amounts of palladium catalyst, can give compounds of formula AW5. Removal of the protecting group in compounds of structure AW5, e.g., acid treatment to remove the Boc group would yield compounds of structure AW6. Compounds of type can be alkylated at the indole nitrogen to give compounds of structure LXII.
The allcylation can be carried out in the presence of a suitable alkylating agent and base in a polar solvent at temperatures ranging from ambient temperature to 150 C to yield compounds of formuia LXII.

XLIX. Scheme AW

R E R E R E
R7 Boc20 R, base, 13(OR71)3 R~ \ )2 ~ I , ---.
R2 ~ N R2 N R2 N B(OH
R3 H R3 Boc R3 Boc L-R12 , Pd R E R E R E
R1 H+ R1 \ ~_L R1 (AW4) Rz R3 Boc R2 R R2 Compou.nds of formula I, represented by structure LXIII, 'can be prepared as shown in Scheme AX.
Compounds of formula AX1 can be fluorinated at the 3-position with an electrophilic fluorinating agent, e.g., N-fluorocollidine tetrafluoroborate, in a suitable non-polar solvent at temperatures ranging from -78 C to 100 C to yield compounds of structure LXIII.
L. Scheme AX

R electrophilic R F
R1 fluodnating R
~ \ R5 agent 1 R2 ~ I , Rs AM LXtII
Compounds of formula I, represented by structure LN, can be prepared as shown in Scheme AY.
Compounds of formula AY1 can be chlorinated at the 3-position with an electrophilic chlorinating agent, e.g., N-chlorosuccinimide or chlorine, in a suitable solvent at temperatures ranging from -78 C to 100 C to yield products of structure LXIV.
LI. Scheme AY

R R CI
R, ~
Rs \ R5 #N, I ~' NC3 R, R2 , AY LXIV

Compounds of formula I, represented by structure LXV, can be prepared as shown in scheme AZ.
Compounds of formula AZ1 can be brominated at the 3-position with an electrophilic brominating agent, e.g., N-bromosuccinimide or bromine) in a suitable solvent at temperatures ranging from -78 C to 100 C to yield products of structure LXV.
LII. Scheme AZ
R

I ~ \ R5 NBS RI R Br Rs AZI LXV
Compounds of formula I, represented by structure LXVI, can be prepared as shown in Scheme BA.
Compounds of formula BA1 can be iodinated at the 3-position with an electrophilic iodinating agent, e.g., N-iodosuccinimide, (bis-trifluoroacetoxy)iodobenzene, or ICl, in a suitable solvent at temperatures ranging from -78 C to 100 C to yield products of structure LXVI.
LIYI. Scheme BA

R R
R

I~
I i \ R5 NIS R1 R5 Rg Z R3 Z
BAI LXVI
Compounds of formula I, represented by structure LXVII can be prepared as shown in Scheme BB.
3-lodo- or bromoindoles of structure BB 1 can be reacted with acetylenes BB2 in the presence of a palladium catalyst (commonly referred to as the Sonagashira reaction) to give compounds of type LXVII. 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 BB 1 with an acetylene compound BB2 in the presence of a source of palladium, a copper co-catalyst and an amine and canying out the reaction at a temperature range of ambient to 150 C.

LIV. Scheme BB

Rja R Brorl R
Rl Rl I/ R5 (BB2) X N Rs R2 , 2 Rg Z Pd R3 Z

Compounds of formula I, represented by structure LXVIII, can be prepared as shown in S Scheme BC.
Compounds of formula BCI can react with a mixture of POC13 and DMF at temperatures ranging from ambient to 140 C to yield 3-carboxaldehydes of structure LXVIII
after hydrolysis of the intermediate irnminium salt with aqueous NaOH.
LV. Scheme BC

R R
R CHO
~ I \ R5 POCI3, DMF R~
R2 N N Rs Compounds of formula I, represented by structure LXIX, can be prepared as shown in Scheme BD.
Carboxaldehydes of formula BD1 can be treated with a fluorinating reagent, e.g., (diethylammonium sulfur trifluoride) in a suitable solvent at temperatures ranging from 0 C to $0 C to yield compounds of formula LXIX.
LVI. Scheme BD

Ri R~
N R$ DAST R1 R5 BD1 i.XIX

Compounds of formula I, represented by structure LXX, can be prepared as shown in Scheme BE.
Carboxaldehydes of formula BEl can react with hydroxylamines of structure BE2 in the presence of a suitable polar solvent system and base at temperatures ranging from ambient to100 C to yield compounds of formula LXX.
LVII. Scheme BE

R CHO R N H

(~ \ R5 NH2ORI3 R1 I~ R5 ~
2 R3 Z (BE2) R2 R ~

BEI LXX
Compounds of formula I, represented by structure LXXI, can be prepared as shown in Scheme BF.

Carboxaldehydes of formula BF1 can react with hydrazines of structure BF2, in the presence of a suitable solvent and base at temperatures ranging from ambient to 100 C to yield, compounds of formula LXXI.
LVIII. Scheme BF

~R13R14 R CHO R N H

X*N
R2 R3 (BF2) R2 Z

Compounds of formula I, represented by structure LXXII, can be prepared as shown in Scheme BG.
Indolecarboxaldehydes of formula BG1 can be oxidized to carboxylic acids of formula LXXII, using reagents known to those skilled in the art, e.g., KMnO4 or chromic acid. The oxidation can usually be carried out in aqueous or mixed-aqueous/organic solvent systems and carried out at ambient or elevated temperature.

LIX. Scheme BG

( \ \ R5 E01 R1 ~N
\

R3 z R3 BGI LXXII

Compounds of formula I, represented by structure LXXIII, can be prepared as shown in Scheme BH.
Carboxylic acids of formula BHI can be converted to amides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treated with amines of formula BH2 to give compounds of formula LXXIII.
LX. Scheme BH

R COOH 1. activation R CONR13R14 ~
(~
~ 2. HNRj3R14 R, R5 Rs ~ ~ N
R2 R3 Z (BH2) 2 Z

BHI LXXIII

Compounds of formula I, represented by structure LXXIV, can be prepared as shown in Scheme BI.
Carboxylic acids of formula BI1 can be converted to hydrazides and N-alkoxyamides by treatment of the carboxylic acid with a suitable activating reagent (thionyl chloride, oxalyl chloride or carbonyldiimidazole) and then treating the activated carboxylic acids with hydrazines and alkoxylamines of formula B12 to give compounds of formula-LXXIV.
LXI. Scheme BI

R COOH 1. activation R

C
R5 2. HNR13W R, I\ \
Rg 2 N (B12) R2 N %
Rs Z R3 Z

Compounds of formula I, represented by structure LXXV, can be prepared as shown in Scheme BJ.
Carboxaldehydes of formula BJ 1 can be treated with the appropriate alkyllithium or Grignard reagent of formula BJ2 at temperatures between -78 C to ambient temperature in a suitable aprotic solvent to produce secondary alcohols of formula LXXV. An alternative reduction of the carboxaldehydes with an appropriate hydride reducing agent at -78 C to ambient temperatures can produce primary alcohols of formula LXXV.
LXII. Scheme BJ

R CHO Ri3M HO
R1 R Ris (BJ2) Rti ~
N Re I / \N
Rs R3 or[H] R3 Z

Compounds of formula I, represented by structure LXXVI, can be prepared as shown in Scheme BK.
Compounds of structure BK1 can be sulfonated at the 3-position with sulfur trioxide or some similar sulfuric acid equivalent to produce compounds of formula BK2_ Compounds of formula BK2 can be treated with reagents such as, but not limited to, POC13 at temperatures from 500 C to 100 C to convert them into sulfonyl chlorides of formula BK3.
Alternatively, treatment of compounds of structure BKI with reagents such as chlorosulfonic acid can directly afford compounds of structure BK3. Compounds BK3 can react with amines of formula BK4 at ambient temperature in the presence of a suitable base and solvent to produce sulfonamides of formula LXXVI.

LXIII. Scheme BK

r SOgH
~ POCI3 I \ R5 SOg R1 Rs ~ -- I
R2 N ~ N

R SOzC! HNR13R14 R S02NR N

\ (BK4) R1 R5 ( \
R2 ~ N base R2 N
R3 z R3 Z

Compounds of formula I, represented by structure LXXVII, can be prepared as shown in Scheme BL.
Iodides or bromides of structure BL1 can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., CuI, and a suitable thiol or disulfide.
The reaction can generally be carried out at temperatures between ambient and 150 C to yield compounds of structure BL2. Compounds of structure BL2 can be oxidized to sulfones of formula LXXVII, using oxidizing agents such as, but not limited to, m-CPBA in chloroform at ambient or elevated temperatures.
LXIV. Scheme BL

R (I or Br) R12SH or R
R SR1z R2 N F'`5 Cu (I) R2 N Rs [ol R S02F?12 LXXVII

Compounds of formula I, represented by structure LXXVIII, can be prepared as shown in Scheme BM.
Iodides or bromides of structure BMl can be transformed into 3-thioalkyl indoles using an appropriate copper catalyst, e.g., Cul, and a suitable thiol or disulfide.
The reaction can generally be cazried out at temperatures between ambient and 150 C to yield compounds of structure BM2. Compounds of structure BM2 can be selectively oxidized to sulfoxides of formula LXXVIII, using oxidizing agents such as, but not limited to, sodium periodate in methanol at ambient temperature.
LXV. Scheme BM

R (I or Brj R12SH or R SR12 R R
R2 N s Cu (i) R2 5 R3 ~ R3 Z

1 [Ql R, Rs ucxvm Compounds of formula I, represented by structure LXXIX, can be prepared as shown in Scheme BN.
Compounds of structure BN1 can be converted to ketones of formula LXXIX via a Friedel-Crafts reaction using an acid chloride of formula BN2. The reaction can typically be carried out in a non-polar solvent such as dichloromethane or CS2 in the presence of a suitable Lewis acid, e.g., A1C13 or FeC13 and carried out in a temperature range of 0 C to 100 C.
LXVI. Scheme BN

R R12COCf R O R12 Ry ( ~ \ Rs (BN2) Ri ~= \
RS
2 Lewis acid 2 N
R N
R3 z R3 Compounds of formula I, represented by structure LXXX, can be prepared as shown in Scheme BO.
Compounds of structure B01 can be selectively nitrated at the 3-position using stoichi.ometric amounts of nitric acid under mild reaction conditions to produce compounds of formula LXXX. These conditions may include, but are not limited to, the use of nitric acid in acetic anhydride at a temperature range of -40 C to =room temperature.
LXVII. Scheme BO

R R
NOZ
~
Ri I~ R5 HN03 RI
N I / ~
R2 ~ ~ R~ N

Compounds of formula I, represented by structure LXXXI, can be prepared in several ways, as shown in Scheme BP.
3-Nitroindoles of structure BP 1 can be reduced to 3-anzinoindoles of st.ructure BP2 using any number of standard conditions familiar to chemist skilled in the art, such as hydrogenation or iron reduction. Compounds of formula BP2 can be further elaborated by mono- or di-alkylation of the amino group, using the appropriate alkylating agent, solvent, and base at temperatures ranging from ambient to 150 C to yield compounds of formula LXXXI.
Alternatively, 3-haloindoles of structure BP3 can undergo Buchwald coupling with mono- or di-alkylamines of formula BP4 in the presence of copper or palladium catalysts, using conditions familiar to chemists skilled in the art, to produce compounds of formula LXXXI.

LXVIII. Scheme BP

::c02R5 [H] I i N R5 R2 , base R (Br, I) HNR12R,3 R1,11 (BP4) R N-(H, or R13) Rs R, R2 N Buchwaid Rs R3 coupiing R2 R3 z LXXXt Compounds of formula I, represented by structure LXXXII, can be prepared as shown in BQ.

3-Axninoindoles of structure BQ 1 can be reacted with acyl halides or anhydrides of formula BQ2 in the presence of a suitable base and solvent at ambient temperature to yield amides of structure LXXXII.
LIIX. Scheme BQ

R Rt2 O

~ I R5 (BQ2) R~
N I Rs 2 % 2 N
R3 Z Rs BQI LXXXII
Compounds of formula I, represented by structure LXXXIII, can be prepared as shown in Scheme BR.
3-Aminoindoles of structure BR1 can react with chloroformates or carbonates or dicarbonates of formula BR2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield carbamates of structure LXXXIII. Alternative conditions involve the synthesis of a reactive carbamoyl intermediate of compounds BRl, e.g., by treatment of the amine BRI with p-nitrophenyl chloroform.ate or phosgene, followed by reaction of the activated carbamoyl intermediate with alcohols of formula BR3 at temperatures ranging from ambient to 100 C in a suitable solvent to form earbarnates of formula LXXXYII.
LXX. Scheme BR

R120--~ 0 R
R1 NHZ R120(CO)CI R R NH
I~ \ R5 (BR2) 1 I~ ~ R5 2 ~ or, R2 ~ N
%
R3 1. activation R3 Z
BRI 2. R120H LXXXIII
(BR3) Compounds of formula I, represented by structure LXXXIV, can be prepared as shown in Scheme BS.
3-AYninoindoles of structure BS 1 can react with isocyanates of formula BS2 in the presence of a suitable base and solvent at ambient or elevated temperature to yield ureas of structure LXXXN. Altemative conditions involve the synthesis of a reactive carbamoyl intermediate of compounds BS1, e.g., by treatment of the amine BS1 with p-nitrophenyl chloroformate or phosgene, followed by reaction of the activated carbamoyl intermediate with amines of formula BS3 at ambient temperature to form ureas of structure LXXX.N.
LXXI. Scheme BS

R13R12N --~%O
R
R, NH2 R12NCO R R NH
, R5 (BS2) 1 2 N or, R2 N
Z
R3 1. activation R3 Z
BSI 2. NHR12R13 LXXXIV
(BS3) , Compounds of formula I, represented by structure LXXXV, can be prepared as shown in Scheme BT.

3-Aminoindoles of structure BT1 can be reacted with sulfonyl chlorides of formula BT2 in the presence of a suitable base and solvent and reacted at temperatures in the range of -20 C
to 50 C to yield sulfonamides of structure LXXXV.
LXXII. Scheme BT
R NH~
R~ R12SOaCl R R

R3 z R3 Compounds of formula I, represented by structure LXXXVI can be prepared as shown in Scheme BU.
3-lodo- or bromoindoles of structure BU1 can be reacted with alkenes BU2 in the presence of a palladium catalyst (commonly referred to as the Heck reaction) to give compounds of structure LXXXVI. 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.
LXXIII. Scheme BU

R (f, Br) R12~ R
RY
I ~ \ R5 (BU2) R1 ~ Re N
2 , Pdo R2 N
R3 ~ R3 z BUI LXXXVI
Compounds of formula I, represented by structure LXXX-VII can be prepared as shown in Scheme BV.
Hydrazines of structure BV 1 can react with 3,3,3-trifluoropropanal to form hydrazone intermediates. Heating the hycirazone interniediates in a suitable solvent and at temperatures from ambient to 150 C can form indoles of formula BV2. Typically, a Lewis acid catalyst is used, e.g., A1C13, TiCla or ZnCla. Compounds of formula BV2 can be reacted with a protecting group, e.g., di-tert-butyl dicarbonate, to prepare the Boc derivative BV3.
Treatment of compounds of structure BV3 with a strong base, e.g., lithium diisopropyl amide, in an aprotic solvent, e.g., TIHF or DME at temperatures from -78 C to ambient temperature, followed by addition of a trialkyl borate can yield compounds BV4 upon hydrolytic workup.
Reaction of compounds BV4 with reactive aryl halides or triflates, e.g., BV5 at temperatures in the range of 20 C to 100 C, in a suitable solvent system containing base and sub-stoichiometric amounts of a palladium catalyst, can give compounds of formula BV6. Proteolytic cleavage of the Boc group of compounds of type BV6 can give compounds of structure BV7. The indole BV7 can be alkylated in the presence of a suitable alkylating agent and base in a suitable solvent at temperatures ranging from 0 C to 150 C to yield indoles of formula LXXXVII.
LXXIV. Scheme BV

R~ F3C_~,CHO R R CF3= Bo O R"VN
1 ~ \ ~ R
z NHNH2 protic or R ~ N RR3 Lewis acid 2 R H OC

base, B(qRII)3 R1 I-R12 1 --= 1 ~ \ B(OH)2 ~ \ \ R12 BV4 Pd , base BV6 + R CFg H Rj~ Z-L Rt2 :$$F3R12 base H Z
B~ R3 LXXlCViI
Compounds of formula I, represented by structure LYXXVIII can be prepared as shown in Scheme BW.
Compounds of structure BWI are commercially available, or can be prepared by well-known methodology, e.g., from the hydrolysis of substituted phenylacetonitriles. BWI can then be activated, e.g., using peptide coupling reagents, or converted to an acid halide, and then reacted with amines (BW2) to provide substituted acetamides BW3. Compounds of type BW3 can undergo cyclization in the presence of a base, such as potassium carbonate or sodium hydride, and a catalyst, such as CuI or CuBr to form compounds of structure BW4. Reduction of compounds BW4 with a reducing agent, such as DIBALH or lithium aluminum hydride can furnish indoles of type BW5. Compounds of type BW5 can then be cyanated with a reagent such as chlorosulfonyl isocyanate (BW6) to afford compounds of type BW7.
Treatment of compounds BW7 with a base, e.g., lithium diisopropyl amide in a solvent such as THF or DME
and a trialkyl borate can give a 2-indolylboronic acid intermediate. Reaction of the 2-indolylboronic acid intermediate with a group L-R12 in the presence of a palladium catalyst can afford compounds of structure LXXXVIII.
LXXV. Scheme BW

R R H R
Rq OH 1)Activation R' .~ N,z Bas e Rl O [H]
R2 I~ Br0 2)Z-NH2 RZ I~ Br0 Catalyst RZ N
Z

BWI (BW2) BW3 BW4 R R CN R CN
R CIS ZNCO Rl 1). B(OR11)31base Rj~
\ R12 Ra I~ N (BW6) R2 ~ 2).Pd~/ L-R12 RZ N

BW5 BW7 L)OOCYIII

Compounds of formula I, represented by structure LXXXIX can be prepared as shown in Scheme BX.
Indoles BXl can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (BX2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH3CN or dioxane, and carrying out the reaction at or above ambient temperature to afford compounds of structure BX3. Treatment of BX3 with a reactive fanctional group Z
containing a suitable leaving group L (BX4) can give compounds of structure BX5. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate.
The reaction between BX3 and BX4 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 trialkylanmine.
to afford compounds of formula BX5.
Compounds of structure BX5 can be converted to indolyl-2-boronic acids BX6.
Typically, a strong base, such as lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed 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. Quenching with a trialkylborate derivative can give the indolyl-2-boronic acid BX6. Reaction of the indolyl-2-boronic acid BX6 with an aryl or heteroaryl halide BX7 (conunonly referred to as a Suzuki reaction) can give the compounds of structure BX8. 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 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex. The reactions are carried out in a suitable solvent, e.g., DMF, toluene, dirnethoxy ethane or dioxane at a temperature range of ambient to 150 C in the presence of a base. 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.
Compounds BX8 can be de-methylated to give compounds of structure BX9.
Suitable de-methylating reagents can include, but are not limited to boron tribromide, boron trichloride or iodotrimeth.ylsilane in a variety of organic solvents, such as methylene chloride. Indoles of structure BX9 can be alkylated with an electrophile, L(CHa)õOP (BX10), to give compounds of structure BX11. L can represent a halide, particularly chloro, bromo or iodo or an alkylsulfonate. N can be equa12,3 or 4. P can represent any acid-labile protecting group, such as tert-butyldimethylsilyl, triethylsilyl or tetrahydropyranyl. The reaction can be conducted in a suitable solvent, e.g., THF, CH2C12 or DMF, within a temperature range of 20 C to 100 C.
A base, e.g., an inorganic base, such as potassium or cesium carbonate or an organic base, such as a trialkylamine can be used to remove the acid formed in the reaction.
Compounds BX11 can be deprotected to give compounds of structure BX12. Suitable deprotecting reagents can include, but are not limited to any mild organic acid, such as para-toluenesulfonic acid or pyridinium para-toluenesulfonate or an inorganic acid, subh as acetic or hydrochloric acid in a variety of organic solvents, such as methylene chloride, THF or methanol.
Oxidation of compounds BX12 to carboxylic acids with structure BX13 can be accomplished with various oxidating reagents such as potassium pennanganate or pyridinium dichromate. Compounds of type BX13 can then be activated and treated with amines of type BX14 to form compounds of structure LXXXIX. Activation of the carboxylic acid can be carried out by any of the standard methods. For example, the acid BX13 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine BX14, 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 BX14.

LXXVI. Scheme BX

~ Ci302NC0 ~ Z-~. ~ base ~ \ ---~ I \
Me01 M (BX2) Me0/ H BX4 Me0// N 2. B(ORe)s axi BX3 BX5 (BX7) demethylation ~
g(OH)z ` -~ ~/ \ R~2 ---- ---= ~, N Rti2 Med Z Pd MeO Z HO ~

l-OlP
%
n=2.3.4 \ R1Z deprotection R12 _ ~ N ~/~~~
(BXIO) PO'~'C z HOO z n=2,3,4 n=2.3,4 oxidation R12 1. activation I \ R12 HO` ~OS N 2. HNR7R8 R$R7N` ~0~~
~O`Jn_=1,2,3 Z (BX14) ~O( `Jn-1,2,3 Compounds of the present invention represented by structure XC and XCI can be prepared by the methodology depicted in Scheme BY below, wherein p is an integer between 2 and 6.
A compound of formula BYI is treated with a reagent of structure BY2, wherein L and L' represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or difFerent. If different, the more reactive of the two will be displaced by the phenol oxygen atom to give compound BY3. Conditions for this reaction include solvents such as, but not limited to, acetonitrile, acetone, 2-butanone or dimethylformamide; bases such as sodium carbonate, potassium carbonate, cesium carbonate, tertiary amine bases or sodium hydride;
and reaction temperatures from ambient to the reflux temperature of the chosen solvent. The remaining leaving group in this molecule may be displaced by a reagent of formula RI8SH
(BY4), wherein Rl$ may be alkyl, aryl or heteroaryl to give compounds of structure XC. The conditions for this reaction may be similar but not necessarily the same as used for the transformation of BY 1 to BY3.

Oxides of the resulting sulfide group in compound XC may be prepared, utilizing oxidizing reagents, such as'ri.-chloroperbenzoic acid, potassium permanganate, potassium peroxyrnonosulfate or dimethyldioxirane, in stoichiometries chosen to optimize the particular oxidation state, using solvents such as dichloromethane, ethanol, methanol or acetone, and at temperatures ranging from -30 C to 120 C to afford compounds of structure XCI.
LXXVII. Scheme BY

L-(CH2)P L' HO r ~ Rs L--(CH2-O - R5 N (BY2) / N
z z Rta-SH
(BY4) (O) RiI 7 CN

R18 S-(CH2)p-O r 5 N
R~T CN xc Z
\
R18 S(0r(CH2)p O r`~

~
xcl Compounds of this invention represented by structure XCII can be prepared by the methodology depicted in Scheme BZ below, wherein p is 1-6:
A compound of formula BZ1 is treated with a reagent of structure BZ2, wherein L and L' represent leaving groups (halogen, arylsulfonate, etc.) and can be the same or different. The resulting compounds of formula BZ3 may be alkylated by an amine of formula R,$R, 9NH to prepare compounds of formula XCII. Conditions for this alkylation reaction may include solvents such as ethanol, tetrahydrofuran or dimethylformamide. The presence of a basic reagent, such as pyridine, diisopropylethylamine or potassium carbonate, may be utilized.

LXXVIII. Scheme BZ

Rtt CN R17 CN
\.~ L---(CHz)P L \\
HO -/ ~ Rs L(CHZ)p-O r, R
N (BZ2) s Z

NHRIsR1s i19 R17 CN
~R
R,$-N-(CH2)a ~ - N s Z
xclr Compounds of this invention represented by structure XCIII can be prepared by the methodology depicted in Scheme CA below.
A phenol compound, CA1, can be reacted with an alkylating agent CA3, which can be derived from a compound of structure CA2. Compounds of structure CA2, wherein R19 taken together with the hydroxyl-bearing carbon atom to which Ri9 is attached, represent a 4-7 membered ring. Such atoms may be all carbon, but may also include up to two heteroatoms, chosen from N, 0, S or SO2. A reagent of the formula CA2 may be purchased from commercial sources or be prepared by means familiar to those skilled in the art of organic synthesis and is then converted to compounds of structure CA3, wherein L
represents a leaving group. Compound CA3 is then used in an alkylation reaction with the phenol compound CAl, employing the usual alkylation reaction conditions discussed above, to give the compound of formula XCIII.
LXXIX. Scheme CA

(CA2) HO (\` Rs R (\~~ ~ s ls ( ) XCIII

Compounds of this invention represented by structure XCN and XCV can be prepared by the methodology depicted in Scheme CB below.
Compounds of structure CB 1 can be prepared starting from bromo-substituted indoles using the methodology discussed elsewhere in this invention (introduction of the Z group, installation of the cyano group at C-3 of the indole ring, and cross-coupling of the indole with an aryl reagent to give the corresponding 2-aryl group). Alternatively, the bromide may be introduced at a later stage by bromination of the indole ring, employing brominating reagents such as bromine, N=bromosuccinimide or HOBr. The bromide compound can be then subjected to a metal-halogen exchange reaction to generate an organometallic compound CB2, which is not isolated but taken on directly to the next reaction, wherein M is a metal atom such as magnesium or lithium. Organomagnesium reagents may be prepared from aryl bromides by treating with magnesium metal in refluxing ether-like solvents, or treatment with other organomagnesium reagents such as isopropyl magnesium chloride. Organolithium reagents may be prepared from aryl bromides by treating with lithium metal in refluxing solvents, or by treatment with other organolithium reagents such as sec- or tert-butyllithium.
The metallated indole may then be treated in situ with a thionating reagent to afford compounds such as XCIV
or CB3. If the group R,$-(CH2)P is relatively simple, it may prove convenient to employ a reagent of the structure R18-(CH2)p S-S-(CH2)P R,8a which will give sulfide compound XCN
directly. Otherwise, it may be more efficient to react compound CB2 with a reagent such as atomic sulfur (Ss), which will afford a thiol compound CB3. The thiol group may be alkylated with a reagent of structure CB4, where L represents a suitable leaving group.
Typical alkylation conditions known to those skilled in the art can be employed.
Oxides of the resulting sulfide group in compound XCV can be prepared using oxidizing reagents, such as m-chloroperbenzoic acid, potassium permanganate, potassium peroxymonosulfate or dimethyldioxirane in stoichiometries chosen to optimize the particular oxidation state desired, in solvents such as dichloromethane, ethanol, methanol or acetone, and ' at temperatures ranging from -30 C to 120 C.

LXXX. Scheme CB

1~ CN R17 CN
= \~ ~
Br N Rs Z Z

\\
R18 (CHa)R S~, \ R5 R 8--(CH2)p -L H~S ~\~ \ R5 N (CB4) ~ N
Z z XClV CB3 F21a-(CHz tS0)~ N Rs D
n t z xcv Compounds of this invention represented by structures XCVI and XCVII can be prepared by the methodology depicted in Scheme CC below.
A compound of formula CCl may be nitrated at the indole C-5 position with reagents such as concentrated nitric acid optionally with solvents such as acetic acid or sulfuric acid.
The resulting nitro group in compound CC2 may be reduced to the amino compounds of structure CC3 with the use of reducing reagents such as hydrogen (with a catalyst such as palladium on carbon), tin dichloride (in the presence of HCI), sodium thiosulfate (in the presence of ammonia) or iron powder. The amino and hydroxyl groups of compound CC3 may be used to construct a ring; for example, cyclocondensation of CC3 with a reagent CC4, such as phosgene, carbonyldiimidazole or trichloromethyl chloroformate in the presence of a basic reagent to afford compounds of structure CC5. Alternatively, reacting compounds of structure CC3 with compounds of structure CC6 in the presence of a base gives compounds of structure CC7. Compounds CC5 and CC7 can be alkylated with groups of structure L-R21 to give compounds XCVI and XCVII.

LXXXI. Scheme CC

R CN R CN

( \ \ s ----- ~ \ \ Rs HQ 3 ~ HO 3 N

R
O N R CN R2o(R20-)(Br)CC(=0)CI H2N N
\ ~ ^ ~ \ S
Rzo ' 5 (CC6) HO N

O
J L-R21 (CC4) L,"KL
O Nzt R N H R CN

R20 O' N 5 O=0 N a R201 3 z 3 Z
?tCvII CC5 %

Compounds of this invention represented by structures CXVIII, XCIX and C can be prepared by the methodology depicted in Scheme CD, below.
Commercially available 5,6-dihydroxyindole may be protected on the phenol groups with group P to give compound CDl. Suitable protecting groups include e.g., tert-butyldimethylsilyl, benzyl, or tetrahydropyranyl, and their synthesis and subsequent removal are well known to those skilled in the art. Functionalization of the indole nitrogen to give compound CD2, followed by cyanation of CD2 to give CD3, and aryl cross-coupling of CD3 to give CD4 have been discussed elsewhere in this invention. The protecting groups on the phenol oxygen atoms may then be removed, and the oxygens used in various cyclocondensation reactions. For example, reaction with a reagent of structure CD6 in the presence of a suitable base can afford the dioxanyl-fused ring system of compound XCIX.

Treatment of CD5 with phosgene or a phosgene equivalent (CD7) can give compounds of structure XCVIII. Condensation of CD5 with ketones of fonnula CD8 or ketal derivatives of the ketone CD8 can afford the cyclic ketal compounds of structure C.
LXXXII. Scheme CD

F R R R CN
O
O
\ \ \
PlO I NP- N p~
H O k O N

HO R CN ~ R CN
I D

CD5 L"IkL (CD6) R

\:N
N Ri2 R CN ~ R Z
O \ R2o R2o XCVIiI
R20~0 I/ N 12 (CD8) XCIX R CN
R20 ( /N 12 ~

C

Compounds of formula I, represented by structure CI can be prepared by the methodology depicted in Scheme CE below.
Treatment of CE 1 with a reactive heteroaryl 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., a trialkylamine, can afford the compound of structure CI. The leaving group L can be a halide, particularly choro, bromo or iodo. R18 can be an alkyl, aryl or heteroaryl group.

LXXXIII. Scheme CE

~ \ R18-'L
HO r/ N Rs (CE2 R180 r N Rs ) CEI CI
Compounds of formula I, represented by structure CII can be prepared by the methodology depicted in Scheme CF below.
Treatment of CF1 with the compound CF2 containing leaving groups L and 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 CF3. L and L' independently represent a leaving group, including but are not limited to halogens (e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates, and p is an integer between 1 and 6. The reactive heterocycle or heteroaryl compound CF4 can be reacted with the compound CF3 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, diisopropylamine, to afford the compound of structure CII.
Alternatively, the compound CF1 can be treated with a reactive compound CF5 containing a suitable leaving group L as described above to afford the compound of structure CII.
L,NXXIV. Scheme CF

r~ \ \ L-(CH2)p L' rl \
HO ~/ N Rs (CF2) L-(CH2)p N Rs Z

(CF4) R18-H

R18-(CH2)p L r~ ~ \
(CF5) R1s (CH2)p O t/ R5 Z
CII

Compounds of formula I, represented by structure CIII can be prepared by the methodology depicted in Scheme CG below:
Indoles CG1 can be cyanated with an appropriate cyanating agent, e.g., chlorosulfonyl isocyanate (CG2) or a dialkyl phosphoryl isocyanate in a suitable solvent or solvent mixture, e.g. DMF, CH3CN or dioxane, car:rying out the reaction at a temperature between -20 C and 80 C to afford compounds of structure CG3. The compounds CG3 can then be reacted with a reactive functional group Z containing a suitable leaving group L (CG4) as described previously to afford the compound CG6. Alternatively, compound CG1 can be reacted with a reactive functional group Z containing a suitable leaving group L to give compounds of structure CGS, which can then be cyanated as above to give compounds of formula CG6.
Compounds of structure CG6 can be converted to indolyl-2-boronic acid CG7.
Typically, a strong base, such as lithium diisopropylamide or lithium or potassium hexamethyldisilazide is employed in a suitable unreactive solvent, e.g., ether or THF, or solvent mixtures containing them. The reaction is typically camed out in the range of -78 C
to ambient temperature. Quenching with a trialkylborate derivative can give the indolyl-2-boronic acid CG7. Reaction of indolyl-2-boronic acid C07 with aryl or heteroaryl halide CG8 (commonly referred to as a Suzuki reaction) can give the compounds of structure CG9. 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 1,1'-bis(diphenylphosphino) ferrocene palladium (II) dichloride dichloromethane complex. 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 in the presence of a base. 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.
Indole-carboxylic esters CG9 can be converted to indole-carboxylic acids CG10 by treatment of compounds of structure CG9 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 trimethylsilyl iodide, in a suitable solvent. Compounds of type CG10 can then be activated and treated with amines of type CG11 to form compounds of structure CIII. Activation of the carboxylic acid can be carried out by any of the standard methods. For example, the acid CG10 can be activated with coupling reagents such as EDCI or DCC with or without HOBt in the presence of the amine CGi l, 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 with amines CG11.
LXXXV. Scheme CG

Rt7 R17 CN
CISOZNCO
MeO I~ N (CG2) MeO~' H
O CGI H p CG3 Z-L I (CG4) Z-L (CG4) C1S02NCO 1.base --.. -_- `~ ~ --B(OH)2 MeO z (CG2) Me0 0 2. g(OR9~ MeO O ~

(CG8) L-R72 Pd - 1\ R12 , hydrolysis ~ \ R
HO ~ N or Me0 ~2 ~ Z dealkylation Z

1. activation 2. HNR7RB
(CGII) R8R7N~ N
O Z
CIII
Compounds of formula I, represented by structure C1V can be prepared as shown in Scheme CH.
Compounds of formula CH1 can be reduced at the 6-ester group to give 6-hydroxymethyl indoles CH2. The reduction reaction can be carried out using a hydride regent such as lithium borohydride, in an ethereal solvent such as THF, ethyl ether or DME at temperatures ranging from ambient to reflux to give the alcohol CH2. The benzylic alcohol group in CH2 can be converted to a leaving group L (halogen, aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula CH3 can= be displaced by a reagent of formula R, 8H to afford compounds of formula CIV, wherein Rl $ maybe a heterocycle or a heteroaryl compound. Conditions for this reaction include solvents such as but not limited to aceton.itrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride;
and reaction temperatures ranging from ambient to reflux.
LXXXVI. Scheme CH

/I N N
R'7 Rt7 ~/
\~ \ R [H] l~ \ R activatiort - ---O z z N
N R17 f0 Rl$-H ~
R17 \

\ R5 R18 N
~ 2 Compounds of formula I, represented by structure CV can be prepared as shown in Scheme Cl Compounds of formula CII in which V represents bromide or iodide, can undergo reaction with alkyl vinyl ethers such as ethyl vinyl ether in the presence of palladium catalysts such as but not limited to palladium acetate, palladium (tetra[cis)tr.iphenylphosphine, in solvents such as but not limited to dimethyl formamide or dimethoxyethane to give the addition products of formula C12. Vinyl ethers of formula CI2 can be hydrolyzed to aldehydes of formula C13 using aqueous acids, such as but not limited to, hydrochloric acid, sulfiu-ic acid or acetic acid. Compounds of formula C13 can be reduced to the alcohol using hydrides such as lithium borohydride or sodium borohydride, in solvents such as methanol or tetrahydrofuran to give primary alcohols C14.

The alcohol group in C14 can be converted to a leaving group L (halogen or aryl sulfonate or alkyl sulfonate) by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichioroethane or chloroform.
The leaving group L in compounds of formula C15 can be displaced by a reagent of formula Rl$H to afford compounds of formula CV, wherein Ri$ maybe a heterocycle or a heteroaryl group. Conditions for this reaction include using solvents such as but not limited to acetonitrile, tetrahydrofuran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride; and reaction temperatures ranging from ambient to reflux.
LXXXVII. Scheme CI

N N
R~7 jR17 *
~H V IN Rs Pdo lQ N Rs Z

N /N
Ri~ // R17 /
R5 ` I \ \ R5 ac6vation O ~ \ \ (H]

H H-O N
z z N ~N

X\ R18H
RS Rs R78 ~
~

Compounds of formula I, represented by structure CVI can be prepared as shown in Scheme CJ.
Compounds of formula CJl in which V represents iodine or bromine, can undergo reaction with acrylic esters in the presence of palladium catalysts such as palladium acetate, palladium (tetrakis)triphenylphosphine or palladium (bis)-triphenylphosphinedichloride, and ligands such as triphenylphosphine or tri-ortho-tolylphosphine, in solvents such as but not limited to, dimethyl formamide, dimethoxyethane or toluene to give compounds of structure CJ2. Hydrogenation of compounds of type CJ2 can give products of type CJ3 by addition of hydrogen in the presence of a catalyst such a palladium or platinum in a solvent such as, but not limited to, methanol, ethanol or acetic acid at pressures ranging from 1-5 atmospheres.
Reduction of the ester group in compounds CJ3 can be accomplished using hydride reagents such as lithium borohydride to give the alcohols CJ4. Conversion of the alcohol in CJ4 to a leaving group L (halogen or aryl sulfonate or alkyl sulfonate) can be accomplished by treatment with reagents such as thionyl chloride, phosphorous trichloride, thionyl bromide, methane sulfonyl chloride or toluenesulfonyl chloride in a solvent such as but not limited to dichloromethane, 1,2-dichloroethane or chloroform. The leaving group L in compounds of formula 05 can be displaced by a reagent of formula RI$H to afford compounds of formula CVI, wherein R18 maybe a heterocycle or a heteroaryl group. Conditions for this reaction include solvents such, as but not limited to, acetonitrile, tetrahydrofu.ran, dimethylformamide or dimethyl sulfoxide; bases such as potassium carbonate, cesium carbonate or sodium hydride;
and reaction temperatures ranging from ambient to reflux.
LXXXVIII. Scheme CJ

N
R~y /~ O R
CHI
R
\= \ Ra /O N s Pd v N Pd Z
z N N
R17 Rr7 `\ ~ LiBH4 i Rs H-O N Rs Z
O

N
N R. 0 1\

activation RI8H \1 Rs N Z

Cvl Compounds of formula 1, represented by structure CVII can be prepared as shown in Scheme CK.
Compounds of formula CKl (in which L is a leaving group such as chloride, bromide, iodide or sulfonate and n is 0 or 1) can undergo reaction with triphenylphosphine in a solvent such as but not limited to tetrahydrofu.ran, toluene or dichloromethane; at a temperature ranging from ambient or to reflux to give the phosphonium salt CK2. Phosphonium salt CK2 can be converted to olefm compounds of type CK3 by treatment with a base such as butyllithium, sodium hydride, sodium amide or potassium t-butoxide in a solvent such as tetrahydrofuran, ethyl ether or DME followed by addition of an aldehyde Ri 8CHO (in which RI $
is an aryl, heterocycle or heteroaryl) at temperatures ranging from ambient to reflux.
Hydrogenation of compounds of type CK3 can be accomplished in the presence of a catalyst such a palladium or platinum in a solvent such as but not limited to methanol, ethanol or acetic acid at pressures ranging from ambient to 100 C under a hydrogen atmosphere to give compounds of formula CVII.
LXXX.IX. Scheme CK

N N
R// Ri7 ~ R5 PPh3 ~\ base ~ (Ph3)P^ (n) ~ Z RIg-CHO

~N
RiT ~!~ Rt7 /
\ \ ~ [H]
\ \ ~
N
(n) R5 Pd RYe R5 z CK3 CWii Compounds of formula 1, represented by st.ructure CVIII can be prepared as shown in Scheme CL.
Compounds of formula CL1 (in which L represents iodide, bromide or chloride or methanesulfonate) can undergo reaction with boronic acids of structure R1$B(OH)2 (in which Rl s is an aryl or heteroaryl) in the presence of palladium catalysts such as palladium acetate, palladium tetralcis triphenylphosphine or palladium diohloride; and ligands such as triphenylphosphine or tri-ortho-tolylphosphine in solvents such as but not limited to acetone, dimethyl formamide or toluene at temperatures from ambient to reflux to give the addition product CVIII.
XC. Scheme CL

N N

ft18-8(OH)2 R5 R5 L i N Pd F / N

Compounds of formula T, represented by structure CIX can be prepared as shown in Scheme CM.
Compounds of formula CM1 (in which L represents iodide, bromide or chloride or methanesulfonate) can undergo reaction with metal sulfinates (in which Ri $ is an alkyl, aryl or heteroaryl) in solvents such as but not limited to acetone, dimethylformaniide or toluene at temperatures from ambient to reflux to give the addition product CIX.
XCI. Scheme CM

R17 E R18-S O Na} R17 E
( \ ~ Rg b ~18~cy'Q ? r~~ ~ R 5 L 0~ N O~n N
n Q jR4 R4 CM1 CiX
Compounds of formula I, represented by structure CX can be prepared as shown in Scheme CN.
Compounds of formula CLl (in which R17, defined above, is 1-3 substituents placed on the indole ring) when treated with a base such as potassium hydride, sodium hydride or the like, and then an alkyl lithium such as tert-butyl lithium form a carbanion that reacts with disulfide R18SS R,$ (in which R18 is an alkyl, aryl or heteroaryl) in solvents such as but not limited to THF, diethyl ether, or toluene at temperatures from -78 C to ambient to provide intermediate. Cyanation (CN3), alkylation of the indole nitfogen (CN4) and metal coupling to form product CX are described above.
XCII. Scheme CN

1. base`~ CSI ~ Z-L -a-BrH 2. BuLi R18gX H R188~~ ~ base CNI Rj6 SS'R18 CN2 CN3 ~N
R17 s N 1) B(OR11)3 / base R\
N 2) Pda , base R12L Zs N R12 Z
CN4 Cx Compounds of formula I, represented by structure CXI, can be prepared as shown in Scheme CO.
Compounds of formula COI (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 fonnula C02. 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 C03 which is subsequently cyclized to form compounds of structure C04 employing palladium (II) acetate as catalyst, a phosphine ligand and a base such as triethylamine in solvents such as but not limited to tetrahydrofuran, dimethylformamide 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 CO5. The subsequent steps leading to product CXI
are described above.
XCIII. Scheme CO

Z-NH2 jc1 CICOCH2CI KgPO4/ CUI NH base o N O
Z
z Pdo, R3P X H" 1. CSI
base ~ O!~ -, ~ N 2. B HO ~
z 1) B(OR11)s / base ~ R12 R18L R
~~ -- ~ 12 2) Pd , base R12L HD N base Compounds of formula I, represented by structure CXII can be prepared as shown in Scheme CP.
Compounds of formula CP1 was elaborated using conditions as described above provide CP3 which can be subsequently hydrogenated using a metal such as palladium on carbon and a source of hydrogen such as hydrogen gas or ammonium formate to provide the aniline intermediate CP4. Bis-alkylation using CP5 where X can be CH2, S, SO, SOZ, 0, C=O, etc.
and n = 0 to 3, with two leaving groups (L), as described above, and an appropriate base such as triethylamine or potassium hydroxide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux will provide interrnediate CP6. Employing conditions described above then provides product CXII.
XCIV. Scheme CP

R17 R17 CN R\DI- CN [H]

~ N base N

L L

R17 CN n(iX' 'n R17 CN R17 CN
CP5 ~ ~ 1) B(OR11)3 / base_ H N/~ N /~ N 2) Pdo base R12L N
2 base ~~
z .( z n( CP4 x n CP6 X ~ CXII
Compounds of formula I, represented by structure CXHI, can be prepared as shown in Scheme CQ.
Compounds of formuia CQ1 can be elaborated using conditions described above to provide product CXIII.
XCV. Scheme CQ

1) 8(OR11)3 ! base H R

N 2) Pd base R12L N 12 2. Z-L
Boc Boc base o Z

1. BBr3 ~
c~~ N R12 2.R18L R380 base cxlll Compounds of formula I, represented by structure CXIV, can be prepared as shown in Scheme CR.

Compounds of formula CR1 can be elaborated using conditions described above to provide intermediate CR4. Treatment of indole CR4 with a halogen source, such as halogen substituted succinimides, in, solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux provide halogen substituted product CXIV.
XCVI. Scheme CR

R R R
R~ =, \ 1) B(ORII)3 / base R1 .~ \ H+ R' \
R2 I N 2) Pdo , base R12L R I N R12 -- R I~ N R~2 Boc z Boc 2 R R
or Cl Z-L R1 halogenation ::
base R12 R2 2 Compounds of formula I, represented by structure CXV, can be prepared as shown in Scheme CS.
Compounds of formula CS1 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 tetrahydrofiu-an, dichloromethane or toluene at temperatures from ambient to reflux to provide intermediate CS2.
CS2 can either be directly reacted with palladium (0) and a R, a substituted trialkyl tin compound in the presence of cesium fluoride and copper (1) iodide in solvents such as but not limited to tetrahydrofuran, dimethylformamide or toluene at temperatures from ambient to reflux to provide product CXV 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 and then a second palladium coupling with palladium (0), 20. cesium fluoride and an appropriate Rl ZL compound in solvents such as but not limited to tetrahydrofuran, dimethoxy ethane or toluene at temperatures from ambient to reflux to provide CXV.

XCVII. Scheme CS

R17 E R17 E (R11o)2B-L R17 E
N R5 Tf--T- N R5 f N R5 HO R4 base Tf0 R4 Pd (II) (R110)2B R4 Pdo R12SnBu3 R\ E

Pd R12 IR4 cxv 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 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.
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 marnmal or a waim-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 TR.ES 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 phartnaceutically 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 flavivirus 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 and/or translation in a subject in need thereof, 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.
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) hepatoceilular 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 marmosets and tarmarins. 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., ED50 (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, ED502D50= 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 ED50 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 1 g/mL to approximately 50 g/mL, from approximately 5 g/mL to approximately 50 g/mL, or from approximately 10 g/mL to approximately 25 gg/mL. To achieve such plasma concentrations, the compounds of the invention may be administered at doses that vary from 0.1 jig 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 0.1g 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, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, 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, transdercnal, and puhnonary routes of administration.

D. Metabolites of the Compounds of the Invention Also failing 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, atnidation, 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 H3) 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 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.
A pharmaceutical composition of the present invention 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 pharmaceutical composition is formulated to achieve a pH of about 5 to a pH of about 8.
The pharmaceutical composition may comprise 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; a glucosidase inhibitor; 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 MerimepadibTm (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha 1(ZADAXINTm, SciClone Pharmaceuticals Inc.); a glycosidase inhibitor; therapeutic viral vaccines, such as those produced by Chiron and Immunogenics; and immunomodulators, such as histamine.
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 pharmaceutical excipient that may be administered without undue toxicity.
Pharmaceutically acceptable excipients may be determined in part by the particular composition being administered, as well as by the particular mode of administration and/or dosage form. Nonlimiting examples of pharmaceutically acceptable excipients include carriers;
solvents, stabilizers, adjuvants, diluents, etc. Accordingly, there exist 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 include 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 emulsifying 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 formulations 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 pharmaceutical 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 ceiluloses, 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, pharmaceutical 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 coinpositions 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-occurring 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 flavoring 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, palatabilit),, 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 genera.lly 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 pharmmaceutically .
acceptable surfactants, such as polyoxyl 40 hydrogenated castor oil.
In alternative embodiments, the pharmaceutical composition may further comprise-one or more aqueous solubility enhancer(s), such as a cyclodextrin. Nonlimitin.g examples of cyclodextrin include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of a-, J3-, and y-cyclodextrin, and hydroxypropyl-(3-cyclodextrin (HPBC). In some embodiments, the pharmaceutical composition further comprises about 0.1 % to about 20%
hydroxypropyl-(3-cyclodextrin, about 1% to about 15% hydroxypropyl-(I-cyclodextrin, 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 useful in the treatment of HCV infection, including compounds, in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequetttial 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 immunomodulatory 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; a glucosidase inhibitor, protease inhibitors, polymerase inhibitors, helicase inhibitors, a Toll-like receptor agonist, a caspase inhibitor and a glycosidase inhibitor. Furthermore, the compounds of the invention may also be admin.istered 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 or in vivo or both in vitro and 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 IA: Preparation of 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (compound 5):
CN CN
j:):::~ ~ CISa2NC0 ~ NaH + ~ ~
MelJ
{+! DMF Me0l N Ett Me0 ~ 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 lh. 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-lH-indole-3-carb6nitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 rnmol).
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 Ha0 (3X) and .
saturated NaC1 and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2C12/hexanes (50-100%) as eluent to yield 6-methoxy-l-ethyl-lH-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 113: Preparation of 6-ethoxy-1-ethyl-1lY-indole-3-carbonitrile (compound 9).
CN CN CN

~ BBr3 WN
CO3 N CH2C12 HO Etl N

Step A: To a solution of 1-ethyl-6-methoxy-lH-indole-3-carbonitrile (2.85 g, 14.2 mmol), prepared by example 1A, 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 1M NaOH
is added until the pH is 8-9. The product is extracted with CHaC12 (3X) and the combined organic phases are washed with saturated NaHCO3, H20 and saturated NaCI. After drying over MgSO4, the solution is concentrated and the product is purified by chromatography (EtOAc/CH2Cl2, 0-10%) to afford 2.15 g (82%) of 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.
Step B: To a solution 6-hydoxy-l-ethyl-1H=indole-3-carbonitrile (80 mg, 0.43 mmol) in.
5 mL of methyl ethyl ketone is added anhydrous K2C03 (71 mg, 0.52 mmol) and iodomethane (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 (CHZCIZ) gives 94 mg (100~ of 6-ethoxy-l-ethyI-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
K2PO4 ~
O CH I~ Q
Q~5 MeO'v v .Cul /o toluene, reflux A mixture of p-iodoanisole (85 mg, 0.36 mnnol), anhydrous K3P04 (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-f]indole-7-carbonitrile (45 mg, 0.24 mmol), prepared as described by the method of example lA, 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 CH2Clz (5 mL) and the mixture is filtered. The filtrate is concentrated to afford crude product, which is purified by silica gel chromatography using EtOAc/petroleum ether (1:4) as eluent to yield 5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-ff indole-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 1D: Preparation of 1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile (compound 13).

CN CN

\ ~ \
-----HO N ~N~ -N N
`-- N C1 DMF, 110 C

To a solution of 1-ethyl-6-hydroxy-lH-indo.te-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 mmal) 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 NaCI, dried and concentrated. The product is isolated by chromatography (EtOAc/CH2C12, 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 IE: Preparation of 3-cyano-l-ethyl-lH-indole-6-carboxylic acid phenylamide (compound 15).

CN CN
` ~ IN NaOH (COCI)z MeO ~ N THF HO / N DMF
X reflux CHaC12 CN CN
\ N

H2 H CI N THF N ylc)~ Step A: A solution of methyl 3-cyano-l-ethyl-lH-indole-6-carboxylate (1.60g, 7.02 mmol), prepared by the method described in example lA from methyl 1.H-indole-6-ca.rboxylate, in THF (35 mL) is treated with IN 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 solution is diluted with H20 and extracted with ether (2X). The ether extracts are discarded. The aqueous phase is then acidified with 6N HCl to pH 2 and then extracted with EtOAc (3X). The EtOAc layers are combined, washed with saturated NaCI and then dried and concentrated to afford 1.43 g (95%) of 3-cyano-l-ethyl-1.H-indole-6-carboxylic acid as a white solid.
Step B: A suspension of 3-cyano-l-ethyl-lH-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CH2C12 (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 became 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-l-ethyl-lH-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/CHZCIa, 2/98) over silica gel gives 44 mg (51 910) of 3-cyano-l-ethyl-l-indole-6-carboxylic acid phenylamide.
Utilizing essentially the procedure above gives the following compound:
Compound 89.

Example 1F: Preparation of t-butyl (3-cyano-l-ethyl-l.H-indol-6-yl)-carbamate (compound 16).

CN CN
~
\' DPPA ~ %N

HOzC Et3N H
t-BuOH O

A solution of 3-cyano-l-ethyl-lFl-indole-6-carboxylic acid (0.60 g, 2.80 mmol) from Example 1E, step A, in t-butanol (20 mL) is treated with Et3N (0.46 mL, 3.36 mmol) and diphenylphosphoryl azide (0.73 mL, 3.36mmo1) 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 HZO, 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/CH2CI2 (0-1%) to afford 0.52 g (65%) of t-butyl (3-cyano-l-ethyl-lf7-indol-6-yl)-carbatnate as a white solid.
The following compound is made in similar fashion: Compound 90.

Example 1Ga: Preparation of 2-(4-aminophenyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile via Suzuki route (compound 55).

~ NHZ
CN CN o=B ~ / CN
~ ~ LDA o I \ \ /
Me0 ~ 12 MeO N PdCIZ(PPh3)3 Meo I N NH2 THF ~'-CsF
-70 C - rt DME
reflux Step A: A 2M solution of lithium diisopropyl amide in THF/hexanes (Acros) (3.9 mL, 7.8 mmol) 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 additional 30 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 with 1M sodium thiosulfate and saturated NaCI and then concentrated to a brown solid. Chromatography (CHZC12/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-indole-3-carbonitrile (1.25 g, 3.83 mmol), 4-(4,4,5,5-tetrarnethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90 rnmol), CsF
(1.46 g, 9.58 rnmol) and Pd(PPh3)2C12 (110 mg, 0.15 mmol) in DME (20 mL) is added to a flask and alternatively 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 NaCI and then dried over MgSO4 and concentrated. The crude reaction mix is purified by flash chromatography on silica gel using EtOAc/CH2Cla (5/95) as eluent to afford 765 mg (69%) of 2-(4-anainophenyl)-1-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-lFl-indole-3-carbonitrile via alternative Suzuki route.

CN 1. iPr2NH, n-BuLI, THF CN
2. B(OMe)3 MeO N 3. K3PO4 (3M, aq.) MeO _N

1 l / 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 farther for 40 min. 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. Tri.methyl borate (1.0 mL, 8.77 mxnol) 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 fiufiher 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 mL, 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-->60% 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 lGc: Preparation of 2-(4-aminophenyl)-6-methoxy-l-propyl-lH-indole-3-carbonitrile via Negishi route.

CN 1. LDA, ZnClz CN
THF
Hz N 2. ilo j Pd2dba3 PPh3 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 gel 60). 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 1Gd: Preparation of I-ethyl-2-(3-hydroxyphenyl)-6-methoxy-iH-indole-3-carbonitrile (Compound 288).

OH
CN CN
, 1. LDA, THF ,. CN OH
Me0' I ry 2. Bu3Snl N SnBus ---~ = ~ ~ \ \/
~ Me0 ~ THF C12, Me0 -`?
Cul, 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 1A, 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 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 25 minutes. The reaction mixture is absorbed onto silica gel and concentrated.
Purification by chromatography (CH2CI2) yields 1-ethyl-6-methoxy-2-tributylstannanyl-lH-indole-carbonitrile (12.05 g, 98%).
Step B: I-Ethyl-6-methoxy-2-tributylstannanyl-lH-indole-3-earbonitrile (1.0 g, 2.05 mmol), prepared in step A, is combined with 3-iodophenol (474 mg, 2.15 mmol), Pd(PPh3)2C12 (67 mg, 0.102 mmol), CuI (75 mg, 0.39 mmol) and THF (4.0 mL). This nwcture 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 (4:1, CH2CI2/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 conimercially 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 IGe: Preparation of ethanesulfonic acid [4-(3-cyano-6-difluoromethoxy-l-ethyl-1HHindol-2-yl)-phenyI]-amide via Heck route (compound 519).

I ~ 0 F I\ \ I f . C~ F ONIi~O
F~O~ F~O N
~ Cul, CsCO3, Pd(OAC)p DMF, 135 C

F O'/-NH
DMF, r.t. F-'-Q I N

Step A: A solution of 6-difluoromethoxy-l-ethyl-1F1' 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 DMA (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 chromatography on silica gel (25 g) using EtOAc/Hexanes (10-20%) as eluent to afford 298.2 mg (37.1% yield) of ethanesulfonic acid [4-(6-difluoromethoxy-l-ethyl-lH-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-l-ethyl-IH-iodo-2-yl)-phenyl]-amide is converted to ethanesulfonic acid [4-(3-cyano-6-difluorornethoxy-l-ethyl-1H=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
O \
Me0 N PdCI2(PPh3)3 Me0 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 iGa, step A, 4-fluorophenylacetylene (80 mg, 0Ø69 mmol), bis(triphenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and CuI
(4 mg, 0.0 18 mmol) is added to a sealable tube and alternatively 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 1I: Preparation of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-lH-in.dole (compound 28).

OH O
HN NH
NH20H EtCOCI N~ N
~ \ H o~ OH \ --- ~ \
MeO ~ N 2 MeO ~ / N I/
A ~N Me0 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 hydroxylamine (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 mmol/g loading) and propionyl chloride (0.03 mL, 0.32 mmol) in CH2C1-2, (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/CH2Cla, 2/98) to afford 27 mg (46%) of 1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-lH-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).

NzN
N N~ N N
H O
~ NaN3 ~ ~ \ EtCOCI I ~
MeO I~ N Et3N HCI MeO ~ N DCE Me0 ~ N
toluene A

Step A: A mixture of 1-ethyl-6-methoxy-IH 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 sodium azide (0.49 g, 7.50 mmol) and is heated at refiux 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 NaCI and dried and concentrated to give 0.55 g (45%) of 1-ethyl-6-rnethoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.
Step B: A suspension of the tetrazole above (50 mg, 0.21 mmol) 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/CH2Cl2, 5-10rb} 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-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (compound 49).

C02Et C02Et HO HCF2C1 F o ~' ~ ty CH2Clg F

NaOH

OMe OMe Freon-22 (HCF2CI) gas is bubbled into a solution of ethyl5-hydroxy-l-(4-methoxyphenyl)-2-metliyl-IH-indole-3-carboxylate (250 mg, 0.77 mmol) 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-rnethoxy-l-(4-methoxyphenyl)-1-H-indol-3-yl]-ethanone (compound 42).

O
~ I \ Et3AICl O ~' \
+ N
\ N CH3COC ~
I
~ ~. CH2CI2 0 O- O_..

5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared by the method of example 1 C, is dissolved in 1 mL of CH2C12 at 0 C. Et2A1C1(300 L, 1M in hexanes, 0.3 mmol) is then added. After stirring at 0 C for 30 min, a solution of acetyl chloride (22 L, 0.3 mmol) in 1 mL of CHaCI2 is added dropwise. This is stirred at 0 C
for a further 90 min. The reaction mixture is quenched with H20 and is extracted with CH2CI2 and concentrated in vacuo. Purification by column chromatography on silica gel EtOAc/CHaC12 (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-l-Fl-indole (compound 57).

OH
O N~ N~ ~
( ~ \ NH2OH HCI I ~ \ n-BuLi + ~ \
Me0 N NaOAc Me0 N THF Me0 ~ N
EtOH
~

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-lH-indole by the procedure described in example 1L, hydroxylamine hydrochloride (128 mg, 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 column chromatography using EtOAc/CH2ClZ (1/9) yields 1-(1-ethyl-6-methoxy-1-H-indole-yl)ethanone oxime as a white solid (189 mg, 92%).
Step B: 1-(1-Ethyl-6-methoxy-l-lY-indole-3-yl)ethanone oxitne (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 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 lh and then is partitioned between H20 and EtOAc. The organic phase is dried and concentrated. Purification by column chromatography (CH2Cl2) yields 1-ethyl-3-isoxazol-3-yl-6-methoxy-l-H-indole product as a white solid (13 mg, 12%).

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

N
O pO~

CI
M e0 ~ MeO N

1-(1-Ethyl-6-methoxy-lH-indol-3-yl)ethanone (100 mg, 0.46 mmol), prepared from ethyl-6-methoxy-lH-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 hydroxylamine 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, 5/95) 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)-IH-indole (compound 59).

1. DMF DMA

2. NH2NH2 H2O +~ \
MeO ~ MeO N
1-(1-Ethyl-6-methoxy-1H-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-I.H-indole by the procedure described in example 1L, is heated with 1.5 mL
of dimethylformamide dimethyl acetal and 100 L pyrrolidine at I 10 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 EtaO 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 ON
POCI3 'f03MIC
MeO2C N DMF MeOpC K2CO
MeOH MeOZC N
Step A: 1-Ethyl-lH-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) is dissolved in DMF (3.3 mL), This is added dropwise to an ice-cold solution of POC13 (430 pL, 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/CH2C12) yields 1-ethyl-3-formyl-lH-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
Step B: 1-Ethyl-3-formyl-IH-indole-6-carboxylic acid methyl ester (100 mg, 0.42 mmol), TOSIVIIC (100 mg, 0.52 mmol), K2C03 (178 mg, 1.29 mmol), and MeOH (800 L) 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-lH-indole-6-carboxylate (26 mg, 23%) as an off-white solid.

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

I~ \ KMnO4 \ 1. (COCI)2 DMF
MeO2C acetone MeOZC N 2- NH4OH

CONH OMe O !
a Br~OMe N
\ _ Me0 C N diglyme z Me02C ~
Step A: 1-Ethyl-3-formyl-llY-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 KMnO4 (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 Ha (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 HCl, 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 L, 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-l-ethyl-1HHindole-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/CHZCl2 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-1FI-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).

I~ ~ POCI3 I~ \ KMnO4 I~ \ 1. (COCI)2 DMF

M eO ~ N acetone Me0 ~ N 2. NH4OH
MeO. N DMF

CONH2 CSNH2 OMe N
\ Lawesson's ~ Br-J.OMe ~
Me0 ` toluene Meo diglyeme Me0 I~ N
A

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 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 H20. Purification by silica gel chromatography (EtOAc/CH2CIa, 5/95) yields 1-ethyl-6-methoxy-lH-indole-3-carbaldehyde (849 mg, 81%) as a yellow solid.
Step B: 1-Ethyl-6-methoxy-lH-indole-3-carbaldehyde (600 mg, 2.95 mmol) is dissolved in acetone (85 mL). A.solution of KMnO4 (450 mg, 2.85 mmol) 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 Jo) 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 CHaCIa (12.5 mL) and DMF (10 uL). Oxalyl chloride (230 L, 2.64 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 (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-lFl-indole-3-thiocarboxamide (83 mg, 0.36 mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 L, 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 dimethyl 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-indole 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
LiAIHa ~ CIS02NCO CO2Me ~
Me0 ~ N dloxane Me0 ~ N\ DMF Me0 ~ H

CN CN
NaH D`~ benzoyl peroxide (~ \ NaH
DMF N NBS Me0 ~ Br I~ QH
Me0I ~
Et- benzene ~
DMF
CN

a \ -MeO N O ~ ~

Step A: To a suspension of LiA1H4 (7.6 g, 0.2 mol) in dioxane (100 mL) is added dropwise a solution of inethyl6-methoxy-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 ih 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 (115) as eluent to yield 61 %
of 6-methoxy-2-methyl-lS-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 rnL, 1.3eq.) in acetonitrile (31 mL) at 0 C. After the addition, the rnixture 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 CH2Cl2 and then evapora.ted. The residue is purified with flash column chromatography on silica gel using EtOAc/petroleum ether (115) 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 the mixture is extracted 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 (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 rnmol) in benzene (130 mL) is added benzoyl peroxide (226 mg) and NBS
(1.21 g, 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-1-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 extracted with CH202. 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 1-ethyl-6-methoxy-2-phenoxymethyl-lH-indole-3-carbonitrile, compound 99.

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

CN CN
F K2CO3 Meo p oMe ~
~ ~
NHZ NC DMF CN , NH2 ACOH p N' ~ N
O2N O2N a A

Step A: A solution of 2-fluoro-5-nitroaniline (11.7 g, 74.9 mmol) in dimethylformamide (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 gives a second crop. The two crops are combined and dried under vacuum to give 2-amino-l-ethyl-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 COZ
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, 1/4) to afford 6-nitro-2-pyrrol- 1 -yl-1H-indole-3 -carbonitrile, compound 5, as a yellow solid (232 mg, 51%).

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

CN NaH CN NaH CN 0 ~ ~ I ~
NH
\
I i NH2 DMSO ( ~ \ NH2 acetyl chloride OZN ~ N
OZN H Etl 02N ; 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 1T) 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-1H-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 MgSO4a filtered and evaporated. The resulting solid is triturated with EtzO, collected by filtration and dried under vacuum to afford N-(3-cyano-l-ethyl-6-nitro-lH-indol-Z-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 IV: Preparation of N-ethyl-3-phenyl-5-nitroindole (compound 41).
pyr+dinium bromide Br I i B OH2 OZN \ ~ ~ perbrom ide 02N \ ! ~

N pyridine N Pd(OAc)2 H H PPh3 OME
Na2CC13 ~- _ 02N NaH 02N
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 mmol) 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 reaction mixture is degassed again. To the reaction is added palladium (II) acetate (23.4mg, 0104 mmol), and the reaction is refluxed under dry nitrogen with stirring for 8 hours.
The reaction mixture is then diluted with 1 M HCl (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 puurified 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 rnL) is added dropwise a solution of 3-phenyl-5-nitroindole (40.0 mg, 2.1 mmo]) in DMF (0.75 mL). The reaction nzixture is stirred for 20 min at 0 C under N2. Ethyl iodide (14.8 gL, 0.185 rnmol) 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-1-(4-methoxyphenyl)-1H-indol-6-yl]-carbamic acid propyl ester (compound 97).

%t N
~ \ /~OCOCI 0 ~ N
H2N ~
Et3N
f / N `/\O~H
EtOH

/p /O
6-Amino-l-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), is suspended in EtOH (300 L). Propyl chloroformate (168 L, 1.5 mmol) is added, and this mixture is stirred at room temperature ovemight. The addition of triethylamine (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)-1Fl-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.

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

N /N
O\
~ \ - MeSOaCI

~ -p N pyridine O N
~ 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 L, 0.21 mmol) is added dropwise. This i 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, CH2CI2/EtOAc) yields N-[4-(3-cyano-l-ethyl-6-methoxy-1H-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 IY: Preparation ofN-[4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-methanesulfonamide (compound 129).

/!~ ~N
/
~ \ - MeSO2CI NH~\o O N NHZ E~N ~0 N \ . /

~ THF ~
rt A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H=indole-3-carbonitrile (70 mg, 0.24 n3mo1), prepared as described in. Example 1 Ga, 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 H20 and saturated NaC1, dried and concentrated and purified by flash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%) of N-[4-(3-Cyano-l-ethyl-6-methoxy-lH-i.n.dol-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, l 155, 1160, 1161, 1170, 1175, 1181, 1182, 1188, 1189, 1228, 1229, 1230, 1231, 1280.

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

% O
~ \ ~ - - Acetyl chloride NH2 ~ _ - N~
Me0 ~ N E~N Me0 N
THF
2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (95 mg, 0.29 nunol), prepared as described in Example 1H, is dissolved in THF (1.4 mL).
Triethylamine (84 L, 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 mixture is partitioned between H20 and EtOAc. The organic layer is dried and concentrated. Purification by silica chromatography (9/1, CH2Cla/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
_ - Ac20, HCOOH NHCHO
/ ~ ~ NH2 Me0 THF Me0 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 mmoi), 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 NaHCO3a followed by saturated brine. The organic layer is dried and concentrated.
Purification by silica gel chromatogra.phy (4/1, CH2C12/EtOAc) yields N-[4-(3-cyano-l-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 1AA: Preparation of I,T-[4-(3-Cyano-l-ethyl-6-methoxy-lH-indol-2-yl)-phenyl]-acetamide (compound 128).

N N
O
) \ NH2 AcCI ~ NH
I
~O / N Et3N ~ 0 / N
THF
A solution of 2-(4-aminophenyl)-1-ethyl-6-methoxy-l.H-indole-3-carbonitrile (70 mg, 0.24 miuol), 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%) of N-[4-(3-cyano-l-ethyl-6-methoxy-1H=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 lAB: Preparation of 1-[3-(3-cyano-l-ethyl-6-methoxy-IH-indoI-2-ylethynyl)phenyl]-3-ethyl urea (compoun.d 220).

N N
EtNCO
N + \ f Pyridine N -- \ /
H2 ~ HN-~
H

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 (670 L).
Ethyl isocyanate (62 L, 0.75 mmol) is added. The reaction mixture is then heated at 100 C for 2h.
The rnixture is then diluted in EtOAc, and is washed with aqueous HCI, followed by brine.
The organic layer is dried and concentrated. Purification by silica chromatography (4/1, CHaCIa/EtOAc), followed by trituration with hexanes/acetone (1/1), yields 1-[3-(3-cyano-1-ethyl-6-methoxy-lH-indol-2-ylethynyl)-phenyl]-3-ethyl urea (44 mg, 36%) as a white solid.

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

ii N
CICHaCH2NCO O NH
\ --~ ~ \ - H
N NH~ toluene N N

~ o 2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-lH-indole-3-carbonitrile (100 mg, 0.32 mmol), prepared as described in Example 1H, is suspended in toluene (600 L).
2-Chloroethyl isocyanate (32 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 CH2C12) 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)-phenyl]methyl amide (compound 157).

N \ /N
O~ / NaH \ - - O `U
~~ \ - - NH O ~
O Mel ~O N
~ DMF

N-[4-(3-cyano-l-ethyl-6-methoxy-lH-indol-2-ylethynyl)phenyl] ethanesulfonamide (70 mg, 0.17 mmol), prepared as in Example IX, is combined with K2C03 (49 mg, 0.35 mmol), and DMF (1.0 mL). lodomethane (16 L, 0.26mmo1) 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 IAE: Preparation of 1-ethyl-5-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile (compound 245).

N N
MeO NaOH Me0 1)~ N COZMe H20/THF I I/ N C02H

IN
1. (COCI)2/DMF O
2. morpholine I~ N \/ N
~ ~_O

Step A: Methyl4-(3-cyano-l-ethyl-5-methoxy-lH-indol-2-yl)-benzoate (350 mg, 1.05 mmol), prepared as described in Example 1 Ga step B, is combined-with NaOH (40 mg, 1 mmol), H20 (0.8 mL), 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-l-ethyl-6-methoxy-lH-indol-2-yl)-benzoic acid (50 mg, 0.16 mmol) is suspended in CH2Cl2 (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 occurs. This reaction mixture is pipetted dropwise into a vigorously stirring solution of morpholine (1.0 mL) in CHaCl2 (5m1). After addition is complete, the reaction mixture is washed with aqueous HCI solution. The organic layer is dried and concentrated.
Purification by silica column (1:1 CH2C12/EtOAc) yields 1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1Fl-indole-3-carbonitrile (56 mg, 90%) as a white solid.

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PLUS D'UN TOME.

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Claims (119)

1. A compound of formula IIa or a pharmaceutically acceptable salt thereof, wherein:
X is:
-cyano;
-nitro;
-formyl;
-COOH;
-COR x, wherein R x is C1 to C6 alkyl;
-CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C1 to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more independently selected halos or cyanos;
-oximyl;
-SO2R x;
-SO2NH2;
-SO2NH(R x);
-SO2N(R x)2;
-amino optionally substituted with one or more C1 to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;
Y is:
-benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
-indolyl optionally substituted on the nitrogen with -SO2R x;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-halos;
-C1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-one or more halos; and -5 or 6 membered heterocyclo;
-hydroxy;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x;
-C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls; and -PO2R x;
-OC(O)NHR x;
-OC(O)N(R x)2;
-OC(O)NH(OR x);
-OC(O)NR x(OR x);
-OC(O)N(OR x)2;
-OC(O)R ab, wherein R ab is 5 or 6 membered heterocyclo;
NR o COR p, wherein R p is:
-C1 to C6 alkyl;

-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
and wherein R o is:
-hydrogen; or -C1 to C6 alkyl;
NR q CONR q R r, wherein R q is hydrogen;
and wherein R r is:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl optionally substituted with one or more halos;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-C1 to C6 alkoxy; or -5 or 6 membered heterocyclo;
-SO2R aa, wherein R aa is:
-5 or 6 heterocyclo optionally substituted with hydroxy;
-C1 to C6 alkoxy; or -C1 to C6 alkyl;
-COR m, wherein R m is:
-amino optionally substituted with one or more C1 to C6 alkyls, wherein the C1 to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is:
-C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:

a aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-halo;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;
-C2 to C6 alkenyl; or -C6 to C8 aryl optionally substituted with halo;
-NHR bb, wherein R bb is:
-C(=S)NH2; or -PO(OR x)2;
-NR v SO2R w, wherein R v is hydrogen, and wherein R w is:
-C1 to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo;

Z is:
-C1 to C6 alkyl;
R is hydrogen;
R1 is:
-hydrogen;
-5 or 6 membered heterocyclo;
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with heterocyclo;

-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-C1 to C6 alkoxy optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl;
-SO2R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl;
R2 is:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with C1 to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;

-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo;
-alkylthio optionally substituted with C6 to C8 aryl;
-alkylthio optionally substituted with C1 to C6 alkyl;
-SO2R x optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C1 to C6 alkyls;
-SO2R x optionally substituted with 5 or 6 membered heterocyclo;
-SO2R x optionally substituted with C6 to C8 aryl;
-SO2R x optionally substituted with C1 to C6 alkyl;
-S(O)R x optionally substituted with 5 or 6 membered heteroaryl;
-S(O)R x optionally substituted with 5 or 6 membered heterocyclo;
-S(O)R x optionally substituted with C6 to C8 aryl;
-S(O)R x optionally substituted with C1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido optionally substituted with C1 to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-S-C1 to C6 alkyl;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl;
-sulfinyl-C6 to C8 aryl;

-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-sulfonyl-C1 to C6 alkyl;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls; and -C6 to C8 aryl;
-C6 to C8 aryl;
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
-C(O)-C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from;
-hydroxy;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl; and -C(O)OR x; or -OR kk, wherein R kk is:
-C6 to C8 aryl;
-5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
-SO2R x; or -Si(R x)3; and R3 is hydrogen;

with the proviso that at least one of X, Y, Z, R1, and R2 is selected from the following:
X is:
-COOH;
-CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C1 to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2R x;
-SO2NH2;
-SO2NH(R x);
-SO2N(R x)2;
-amino optionally substituted with one or more C1 to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;

Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
-indolyl substituted on the nitrogen with SO2R x; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x, and -C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryls;
-OC(O)NHR x;
-OC(O)N(R x)2;
-OC(O)NH(OR x);
-OC(O)NR x(OR x);
-OC(O)N(OR x)2;
-OC(O)R ab, wherein R ab is 5 or 6 membered heterocyclo;
-NR o COR p, wherein R p is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys, or -5 or 6 membered heterocyclo substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls, -NR q CONR q R r, wherein R r is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with one or more halos;
-C2 to C6 alkenyl;
-C1 to C6 alkoxy; or -5 or 6 membered heterocyclo;
-NR1COOR u, wherein R u is:

substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
and -5 or 6 membered heteroaryl; or -C2 to C6 alkenyl; and R1 is:
-C1 to C6 alkyl substituted with:
-amido optionally substituted with C1 to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-C1 to C6 alkoxy substituted with:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo substituted with C1 to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl;
-SO2R x optionally substituted with:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and/or -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and/or -5 or 6 membered heteroaryl;
R2 is:

-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with C1 to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo;
-alkylthio optionally substituted with C6 to C8 aryl;
-alkylthio optionally substituted with C1 to C6 alkyl;
-SO2R x optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C1 to C6 alkyls;
-SO2R x optionally substituted with 5 or 6 membered heterocyclo;
-SO2R x optionally substituted with C6 to C8 aryl;
-SO2R x optionally substituted with C1 to C6 alkyl;
-S(O)R x optionally substituted with 5 or 6 membered heteroaryl;
-S(O)R x optionally substituted with 5 or 6 membered heterocyclo;
-S(O)R x optionally substituted with C6 to C8 aryl;
-S(O)R x optionally substituted with C1 to C6 alkyl;
-alkoxy substituted with:
-alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclos; and -amino optionally substituted with one or more alkyls;
-amido optionally substituted with C1 to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-S-C1 to C6 alkyl;

-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-sulfonyl-C1 to C6 alkyl;

-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is substituted with one or more C1 to C6 alkoxys;
-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls; or -C6 to C8 aryl;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
-C(O)-C6 to C8 aryl;

-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl; and -C(O)OR x;
-OR kk wherein R kk is:
-C6 to C8 aryl;
-5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl and/or C6 to C8 aryl; or -Si(R x)3;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more independently selected C1 to C6 alkyls; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls.

2. The compound of claim 1, wherein:
X is:
-COOH;
-CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C1 to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2R x;
-SO2NH2;
-SO2NH(R x);
-SO2N(R x)2;
-amino optionally substituted with one or more C1 to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano.

3. The compound of claim 2, wherein X is cyano, halo, or alkyl substituted with one or more halos.

4. The compound of claim 3, wherein X is cyano.

5. The compound of claim 3, wherein X is fluoro, bromo, chloro, or iodo.

6. The compound of claim 3, wherein X is trifluoromethyl.

7. The compound of claim 1, wherein:

Y is C6 to C8 aryl substituted with one or more of the following:
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x; and -C1 to C6 alkyl substituted with one or more 5 or 6 membered heteroaryls;
-OC(O)NHR x;
-OC(O)N(R x)2;
-OC(O)NH(OR x);
-OC(O)NR x(OR x);
-OC(O)N(OR x)2;
-OC(O)R ab, wherein R ab is 5 or 6 membered heterocyclo;
NR o COR p, wherein R p is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
-NR q CONR q R r, wherein R r is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl;
-C1 to C6 alkoxy; or -5 or 6 membered heterocyclo;
-NR t COOR u wherein R u is:
-C1 to C12 alkyl substituted with one or more substituents independently selected from the following:
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls; and -5 or 6 membered heteroaryl;

8. The compound of claim 7, wherein C6 to C8 aryl is phenyl.

9. The compound of claim 8, wherein phenyl has at least one substituent at the para position.

10. The compound of claim 1, wherein Z is:
cyclobutyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl.

11. The compound of claim 1, wherein Z is C1 to C6 alkyl.

12. The compound of claim 11, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.

13. The compound of claim 1, wherein:
R1 is:
-C1 to C6 alkyl substituted with:
-amido optionally substituted with C1 to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-C1 to C6 alkoxy substituted with:
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo substituted with C1 to C6 alkyl; and/or -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl;
-SO2R x optionally substituted with:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and/or -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with:
-5 or 6 membered heterocyclo;

-C6 to C8 aryl; and/or -5 or 6 membered heteroaryl.

14. The compound of claim 1, wherein:
R2 is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with C1 to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-alkylthio optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with alkyl;
-alkylthio optionally substituted with 5 or 6 membered heterocyclo;
-alkylthio optionally substituted with C6 to C8 aryl;
-alkylthio optionally substituted with C1 to C6 alkyl;
-SO2R x optionally substituted with 5 or 6 membered heteroaryl, which heteroaryl is optionally substituted with one or more C1 to C6 alkyls;
-SO2R x optionally substituted with 5 or 6 membered heterocyclo;
-SO2R x optionally substituted with C6 to C8 aryl;
-SO2R x optionally substituted with C1 to C6 alkyl;
-S(O)R x optionally substituted with 5 or 6 membered heteroaryl;
-S(O)R x optionally substituted with 5 or 6 membered heterocyclo;
-S(O)R x optionally substituted with C6 to C8 aryl;
-S(O)R x optionally substituted with C1 to C6 alkyl;
-alkoxy substituted with:
-alkoxy;
-amino substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclos; and -amino optionally substituted with one or more alkyls;

-amido optionally substituted with C1 to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-S-C1 to C6 alkyl;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-sulfonyl-C1 to C6 alkyl;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is substituted with C1 to C6 alkoxy;
-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls; or -C6 to C8 aryl;

-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;

-C(O)-C6 to C8 aryl;

-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl;
-SO2R x, -C(O)-C6 to C8 aryl; and -C(O)OR x;

-OR kk wherein R kk is:
-C6 to C8 aryl;

-5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl and/or C6 to C8 aryl; or -Si(R x)3;
-(O)-5 or 6 membered heterocyclo; or -(O)-S or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls.

15. The compound of claim 1, wherein:
X is:
-cyano;
-halo; or -alkynyl optionally substituted with C1 to C6 alkyl;
Y is:
-C6 to C8 aryl substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-alkoxy optionally substituted with:
-one or more halos; or -5 or 6 membered heterocyclo;
-C1 to C6 alkyl;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x; and -C1 to C6 alkyl optionally and independently substituted with one or more 5 or 6 membered heteroaryls;
-OC(O)NHR x;
-NR o COR p, wherein R p is:
-C1 to C6 alkyl; or -amino optionally substituted with one or more C1 to C6 alkyls;
and wherein R o is hydrogen;
-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is:
-C1 to C6 alkyl optionally substituted with one or more halos; or -C6 to C8 aryl optionally substituted with halo;
-SO2R aa wherein R aa is:
-5 or 6 heterocyclo optionally substituted with hydroxy;

y; or -C1 to C6 alkyl;
-COR m, wherein R m is:
-amino optionally substituted with one or more C1 to C6 alkyls, wherein the C1 to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
NR t COOR u, wherein R t is hydrogen, and wherein R u is:
-C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-halo; and -5 or 6 membered heteroaryl;
-C6 to C8 aryl optionally substituted with halo; or -5 or 6 membered heterocyclo;

-NHR bb, wherein R bb is:
-C(=S)NH2; or -PO(OR x)2;
-NR v SO2R w, wherein R v is hydrogen, and wherein R w is:
-C1 to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; or Z is:
-C1 to C6 alkyl;
R is hydrogen;
R1 is:
-hydrogen;
-C1 to C6 alkoxy substituted with one or more substituents independently selected from:

-5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl; or -5 or 6 membered heterocyclo;
R2 is:
-alkoxy substituted with one or more substituents independently selected from:

-halo;
-hydroxy;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amido optionally substituted with C1 to C6 alkyl;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-S-C1 to C6 alkyl;
-sulfinyl-C1 to C6 alkyl;
-sulfonyl-C1 to C6 alkyl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more independently selected C1 to C6 alkoxys; and -5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
-SO2R x optionally substituted with C1 to C6 alkyl;
-S(O)R x optionally substituted with C1 to C6 alkyl;
-(O)-5 or 6 membered heteroaryl optionally substituted with one or more independently selected C1 to C6 alkyls;
-C(O)-5 or 6 membered heterocyclo optionally substituted with one or more C6 to C8 aryls;
-C(O)-C6 to C8 aryl;

ptionally substituted with one or more substituents independently selected from;
-C1 to C6 alkyl; and;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-one or more halos;
-C1 to C6 alkyl; and -SO2R x;
-OR kk, wherein R kk is:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl; or -5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; and R3 is hydrogen.

16. The compound of claim 15, wherein:
X is:
-cyano; or -halo;
Y is:
-phenyl substituted with one or more substituents independently selected from:

-halo; and -NR t COOR u, wherein R t is hydrogen, and wherein R u is:
-C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos;

-halo; and -5 or 6 membered heteroaryl;
-C6 to C8 aryl optionally substituted with halo; or -5 or 6 membered heterocyclo;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is:
-alkoxy substituted with one or more substituents independently selected from:

-halo; and -alkoxy optionally substituted with alkoxy;
-(0)-5 or 6 membered heterocyclo;
-amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more C1 to C6 alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-one or more halos;
-C1 to C6 alkyl; and -SO2R x; and R3 is hydrogen.

17. The compound of claim 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from NR t COOR u, wherein is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more C6 to C8 aryls;
Z is 5 or 6 membered heterocyclo;
R is hydrogen;
R1 is hydrogen;
R2 is alkoxy; and R3 is hydrogen.

18. The compound of claim 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with C1 to C6 alkyl;

-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C1 to C6 alkyl;
-COR m, wherein R m is:
-amino optionally substituted with one or more C1 to C6 alkyls, wherein the C1 to C6 alkyls are optionally substituted with a 5 or 6 membered heterocyclo; or -3 to 7 membered heterocyclo; and -NR t COOR u, wherein R t is hydrogen, and wherein R u is:
-C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more haloalkyls; and -halo; or -5 or 6 membered heterocyclo;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is alkoxy substituted with alkoxy; and R3 is hydrogen.

19. The compound of claim 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more halos; and -NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is amido optionally substituted with one or more C1 to C6 alkyls, which alkyls are substituted with one or more C1 to C6 alkoxys; and R3 is hydrogen.

20. The compound of claim 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more C1 to C6 alkyls;

-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more halos;
-NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl; and Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is alkoxy substituted with sulfonyl-C1 to C6 alkyl; and R3 is hydrogen.

21. The compound of claim 15, wherein Y is C6 to C8 aryl substituted with one or more substituents independently selected from NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more halos.

22. The compound of claim 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl;
-amino optionally substituted with one or more C1 to C6 alkyls;
-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C1 to C6 alkyl;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
-NR v SO2R w, wherein R v is hydrogen and wherein R w is:
-C1 to C6 alkyl; or -alkyl- or dialkyl-amino;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl; and R3 is hydrogen.

23. The compound of claim 22, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl; and -NR v SO2R w, wherein R v is hydrogen, and wherein R w is:
-C1 to C6 alkyl; or -alkyl- or dialkyl-amino;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl; and R3 is hydrogen.

24. The compound of claim 22, wherein R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl substituted with one or more C1 to C6 haloalkyls.

25. The compound of claim 22, wherein R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls.

26. The compound of claim 1, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl; and -NR v SO2R w, wherein R u is hydrogen, and wherein R w, is C1 to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is C(O)-5 or 6 membered heterocyclo; and R3 is hydrogen.

27. The compound of claim 1, wherein:
X is halo;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-amino;
-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C1 to C6 alkyl;
and -NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is alkoxy; and R3 is hydrogen.

28 The compound of claim 15 wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-halo;
-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C1 to C6 alkyl;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos; and -halo;
-NR v SO2R w, wherein R v is hydrogen, and wherein R w is:
-C1 to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; and Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is 5 or 6 membered heterocyclo; and R3 is hydrogen.

29. The compound of claim 28, wherein Y is C6 to C8 aryl substituted with NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl.

30. The compound of claim 28 wherein Y is C6 to C8 aryl substituted with

31. The compound of claim 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-halo;
-amino optionally substituted with one or more C1 to C6 alkyls;
-OC(O)NHR x;
-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C1 to C6 alkyl;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls; and -halo;
-NHR bb, wherein R bb is -C(=S)NH2;
-NR v SO2R w, wherein R v is hydrogen, and wherein R w is:
-C1 to C6 alkyl; or -alkyl- or dialkyl-amino optionally substituted with halo; and Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is (O)-5 or 6 membered heterocyclo; and R3 is hydrogen.

32. The compound of claim 31, wherein Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls.

33. The compound of claim 15, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with one or more halos;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is -hydrogen;
-(O)-5 or 6 membered heterocyclo; or -5 or 6 membered heterocyclo;
R2 is:
-alkoxy substituted with one or more substituents independently selected from:

-halo;
-alkoxy;
-sulfonyl-C1 to C6 alkyl;
-5 to 7 membered heterocyclo;
-5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl;
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo; or -OR kk, wherein R kk is 5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkoxys; and R3 is hydrogen.

34. The compound of claim 33, wherein R1 is hydrogen, and R2 is alkoxy substituted with one or more halos.

35. The compound of claim 33, wherein R t is hydrogen; and R2 is alkoxy substituted with one or more alkoxys.

36. The compound of claim 15, wherein:
X is cyano;

Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR q CONR q R r, wherein R q is hydrogen; and wherein R r is C6 to C8 aryl substituted with halo; and -NR t COOR u, wherein, R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more halos and/or haloalkyls;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is:
-alkoxy substituted with one or more substituents independently selected from:

-alkoxy; and -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo; or -(O)-5 or 6 membered heteroaryl; and R3 is hydrogen.

37. The compound of claim 36, wherein Y is C6 to C8 aryl substituted with NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C6 to C8 aryl substituted with halo.

38. The compound of claim 36, wherein Y is C6 to C8 aryl substituted with one or more substituents independently selected from NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more halos and/or haloalkyls.

39. A compound of formula IIb or a pharmaceutically acceptable salt thereof, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl;

-amino substituted with C1 to C6 alkyl -NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more halos;
-NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is:
-alkoxy substituted with one or more halos;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and -NO2;
-C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and -OR kk, wherein R kk is:
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from cyano, and C1 to C6 alkyl; or -5 or 6 membered heterocyclo optionally substituted with one or more =O; and R3 is hydrogen.

40. The compound of claim 39, wherein:
X is a cyano group;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with one or more halos;
Z is C1 to C6 alkyl;
R is a hydrogen, R1 is a hydrogen;
R2 is alkoxy substituted with one or more halos; and R3 is a hydrogen.

41. The compound of claim 40, wherein the C6 to C8 aryl is phenyl.

42. The compound of claim 41, wherein the phenyl is substituted at the para position.

43. The compound of claim 41, wherein R u is C1 to C12 alkyl substituted with fluoro.

44. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl;
-amino substituted with C1 to C6 alkyl; and -NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl substituted with cyano; and R3 is hydrogen.

45. The compound of claim 44, wherein Y is C6 to C8 aryl para substituted with NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl.

46. The compound of claim 44, wherein Y is C6 to C8 aryl para substituted with C1 to C6 alkyl and NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl.

47. The compound of claim 44, wherein Y is C6 to C8 aryl para substituted with amino substituted with C1 to C6 alkyl.

48. The compound of claim 44, wherein R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl substituted with cyano at the ortho position.

49. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl; and -NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl substituted with C1 to C6 alkyl; and R3 is hydrogen.

50. The compound of claim 49, wherein the C6 to C8 aryl is phenyl.

51. The compound of claim 50, wherein Y is phenyl substituted at the para position with NR v SO2R w wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl.

52. The compound of claim 50, wherein Y is phenyl substituted at the para position with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl.

53. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with one or more halos;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl; and R3 is hydrogen.

54. The compound of claim 53, wherein the C6 to C8 aryl is phenyl.

55. The compound of claim 54, wherein the phenyl is substituted at the para position.

56. The compound of claim 55, wherein R u is C1 to C12 alkyl substituted with fluoro.

57. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more halos;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is 5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
and R3 is hydrogen.

58. The compound of claim 57, wherein the C6 to C8 aryl is phenyl.

59. The compound of claim 58, wherein Y is phenyl substituted at the para position with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl.

60. The compound of claim 58, wherein Y is phenyl substituted at the para position with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with one or more halos.

61. The compound of claim 60, wherein R u is C1 to C12 alkyl substituted with fluoro.

62. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is 5 or 6 membered heterocyclo; and R3 is hydrogen.

63. The compound of claim 62, wherein the C6 to C8 aryl is phenyl.

64. The compound of claim 63, wherein the phenyl is substituted at the para position.

65. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is 5 or 6 membered heterocyclo; and R3 is hydrogen.

66. The compound of claim 65, wherein the C6 to C8 aryl is phenyl.

67. The compound of claim 66, wherein the phenyl is substituted at the para position.

68. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is 5 or 6 membered heteroaryl substituted with NO2; and R3 is hydrogen.

69. The compound of claim 68, wherein the C6 to C8 aryl is phenyl.

70. The compound of claim 69, wherein the phenyl is substituted at the para position.

71. The compound of claim 39, wherein:

X is cyano;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is -C(O)-3 to 7 membered heterocyclo or -C(O)-5 membered heterocyclo; and R3 is hydrogen.

72. The compound of claim 71, wherein the C6 to C8 aryl is phenyl.

73. The compound of claim 72, wherein the phenyl is substituted at the para position.

74. The compound of claim 39, wherein:
X is cyano;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is -5 or 6 membered heterocycle substituted with one or more =O; and R3 is hydrogen.

75. The compound of claim 74, wherein the C6 to C8 aryl is phenyl.

76. The compound of claim 75, wherein the phenyl is substituted at the para position.

77. A compound of formula IIc or a pharmaceutically acceptable salt thereof, wherein:

X is cyano;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C1 to C6 alkyl;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos;
-halo; and -5 or 6 membered heteroaryl; and -NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl;
Z is:
-C1 to C6 alkyl; or -5 or 6 membered heterocyclo;
R is hydrogen;
R1 is:
-C1 to C6 alkoxy substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -5 or 6 membered heteroaryl;
-(O)-5 or 6 membered heterocyclo;
-(O)-5 or 6 membered heteroaryl; or -5 or 6 membered heterocyclo;
R2 is hydrogen; and R3 is hydrogen;

with the proviso that when R1 is C1 to C6 alkoxy substituted with a 5 or 6 membered heterocyclo or when R1 is a 5 or 6 membered heterocyclo, Y is a C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is:

C1 to C12 alkyl substituted with one or more halos; or aryl substituted with one or more halos.

78. The compound of claim 77, wherein:
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is C1 to C6 alkyl; and R1 is C1 to C6 alkoxy substituted with 5 or 6 membered heteroaryl.

79. The compound of claim 77, wherein R1 is C1 to C6 alkoxy substituted with 5 or 6 membered heteroaryl.

80. The compound of claim 77, wherein R1 is (O)-5 or 6 membered heterocyclo.

81. The compound of claim 77, wherein R1 is (O)-5 or 6 membered heteroaryl.

82. The compound of claim 77, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, or cyclopentyl.

83. A compound of formula IId or a pharmaceutically acceptable salt thereof, wherein:
X is hydrogen;
Y is C6 to C8 aryl substituted with one or more substituents independently selected from:
NR q CONR q R r, wherein R q is hydrogen, and wherein R r is C1 to C6 alkyl;
and -NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more halos;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo; or -5 or 6 membered heteroaryl optionally substituted with one or more independently selected halos; and R3 is hydrogen.

84. The compound of claim 83, wherein:
X is hydrogen;
Y is C6 to C8 aryl substituted with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with one or more halos;

Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is OR kk, wherein R kk is 5 or 6 membered heteroaryl; and R3 is hydrogen.

85. The compound of claim 84, wherein the C6 to C8 aryl is phenyl.

86. The compound of claim 84, wherein Y is phenyl substituted at the para position with NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl substituted with fluoro.

87. The compound of claim 84, wherein Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl.

88. The compound of claim 83, wherein R2 is (O)-5 or 6 membered heterocyclo.

89. A compound of formula IIe or a pharmaceutically acceptable salt thereof, wherein:
X is:
-hydrogen;
-cyano;
-nitro;
-formyl;
-COOH;
-COR x, wherein R x is C1 to C6 alkyl;
-CH=N-(C1 to C6 alkoxy);
-CH-N-(amino optionally substituted with one or more C1 to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;

-alkynyl optionally substituted with cyano or C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos;
-oximyl;
-SO2R x;
-SO2NH2;
-SO2NH(R x);
-SO2N(R x)2;
-amino optionally substituted with one or more independently selected C1 to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;
Y is:
-benzothiazolyl optionally substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
-indolyl optionally substituted on the nitrogen with -SO2R x;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-halo;
-C1 to C6 alkyl;
-alkoxy, optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo;
-C(O)NH2 optionally substituted with C6 to C8 alkyl;
-C(O)NH-(C1 to C6)-alkyl;
-hydroxy;
-haloalkyl;

-cyano;
-nitro;
-COOH;
-N=CHN(R x)2;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
-alkoxy; and -halo; and -PO2R x;
-OC(O)NHR x wherein R x is optionally substituted with vinyl;
-OC(O)N(R u)2, wherein R u is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino;
-OC(O)NH(OR uu), wherein R uu is -C6 to C8 aryl optionally substituted with dialkylamino;
-OC(O)NR x(OR x);

-OC(O)N(OR x)2;
-OC(O)R ab, wherein R ab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
-NR o C(O)R p, wherein R p is:
-C1 to C6 alkyl;
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or -5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from C1 to C6 alkyl and C6 to C8 aryl;
and wherein R o is:
-hydrogen; or -C1 to C6 alkyl;
-NR q CONR q R r, wherein R q is hydrogen, and wherein R r is:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
- halo;
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl optionally substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-C1 to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-SO2R aa, wherein R aa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkoxy; and -C1 to C6 alkyl;

-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy;
-hydroxy;
-halo;
-COR m, wherein R m is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo or aryl is optionally substituted one or more substituents independently selected from halo and alkoxy;
-heterocyclo optionally substituted with hydroxy;
-3 to 7 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with dialkyl-amino;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is:
-C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-halo;
-SO2R w;
-SO2R x;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo;
-C2 to C6 alkenyl;
-C6 to C8 aryl optionally substituted with halo;
-4 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=O;
-SO2R w;
-COR p; and -(CO)O-(C1 to C4 alkyl)-O-(C1 to C4 alkyl);
-NHR bb, wherein R bb is:
-C(=S)NH2;
-C(=S)NHR x;
-C(=S)NR x R x;
-C(=N-CN)NHR x; or -PO(OR x)2;
-N(CONHR w)2;
NH(SOR w);
-N(SO2R w)2;
-NR v SO2R w, wherein R v is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo;
and wherein R w is:
-C1 to C6 alkyl optionally substituted with C6 to C8 aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to C8 aryl;
-C6 to C8 heteroaryl; or -amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C2 to C6 alkoxy, alkoxycarbonyl, (CO)O-(C1 to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-halo;
-C1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to C8 alkyl;
-hydroxy;
-haloalkyl;
-cyano;

-nitro;
-COOH;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
- C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and -C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-NR o COR p, wherein R p is:
-C1 to C6 alkyl;
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
and wherein R o is:
-hydrogen; or -C1 to C6 alkyl;

NR q CONR q R r, wherein R q is hydrogen, and wherein R r is:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
- halo;
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl optionally substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-C1 to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is:
-C1 to C12 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more halos and/or haloalkyls;
-alkoxy optionally substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-halo;
-SO2R w;
-SO2R x;
-5 or 6 membered heteroaryl; and -5 or 6 membered heterocyclo; and -NR v SO2R w, wherein R v is hydrogen or alkyl optionally substituted with 4 to 7 membered heterocyclo;
and wherein R w is:
-C1 to C6 alkyl optionally substituted with C6 to C8 aryl, which aryl is optionally substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to C8 aryl;
-C6 to C8 heteroaryl;

-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

Z is:
-C1 to C6 alkyl;
R is hydrogen;

R1 is:
-hydrogen;
-a 5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;

-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -5 or 6 membered heteroaryl optionally substituted with one or more independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2 R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;

-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxys;
-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-SO2 R x;
-C2 to C6 alkenyl optionally substituted with -SO2 R x;
-C1 to C6 alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C1 to C6 alkyl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkoxy; and -C6 to C8 alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and -4 to 7 membered heterocyclo;
-alkoxy; and -C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:

-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl;
-5 or 6 membered heteroaryl; and -C1 to C6 alky further optionally substituted with one or more substituted with hydroxys;
-SO2R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;

-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C8 aryl;
-COOH; or -OR kk, wherein R kk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;

-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;

R2 is:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with C1 to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and -S02 R x;
-C2 to C6 alkenyl optionally substituted with SO2R x;

-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-SO2R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-S(O)R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more substituents independently selected from -SO2-C1 to C4 alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido optionally substituted with C1 to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;

-S-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-sulfonyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, heterocyclo, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkoxy; and -C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more alkoxys;

-4 to 7 membered heterocyclo; and -allcoxy; and -C6 to C8 aryl;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substitated with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;

=O;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;

-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl;
-5 or 6 membered heteroaryl; and -C1 to C6 alkyl optionally substituted with one or more hydroxys;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C8 aryl;
-amino optionally substituted with one or more substituents independently selected from:

-SO2R x;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;

-C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;

-C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and halolkyl;

-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=O;
-C1 to C6 alkyl;
-SO2R x;

-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x;
-OR kk, wherein R kk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;

-5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
-SO2R x; or -Si(R x)3;
-OC(O)NHR x wherein R x is optionally substituted with -C6 to C8 aryl;
-OC(O)N(R x)2; or R3 is hydrogen; or -nitro, with the proviso that at least one of X, Y, Z, R1, R2 and R3 is selected from the following:
X is:
-CH=N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C1 to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;

-oximyl;
-SO2R x ;

-SO2NH(R x);
-SO2N(R x)2, -amino optionally substituted with one or more independently selected C1 to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected C1 to C6 alkyls;
-5 or 6 membered heterocyclo;

-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano;
Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
-indolyl substituted on the nitrogen with -SO2R x;
-C6 to C8 aryl substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more substituents independently selected from:

-C(O)NH2 optionally substituted with C6 to C8 alkyl; and -C(O)NH-(C1 to C6)-alkyl;
-haloalkyl;
-cyano;
-COOH;
-N=CHN(R x)2;
-amino substituted with one or more substituents independently selected from:
-SO2R x;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-C1 to C7 alkyl substituted with one or more substituents independently selected from:

-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
-alkoxy; and -halo; and -PO2R x;
-OC(O)NHR x wherein R x is optionally substituted with vinyl;
-OC(O)N(R u)2, wherein R u is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino;
-OC(O)NH(OR uu), wherein R uu is -C6 to C8 aryl optionally substituted with dialkylamino;
-OC(O)NR x(OR x);
-OC(O)N(OR x)2;
-OC(O)R ab, wherein R ab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
NR o C(O)R p, wherein R p is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from C1 to C6 alkyl and C6 to C8 aryl;
NR q CONR q R r, wherein R r is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;

-C1 to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-SO2R aa, wherein R aa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkoxy; and -C1 to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy;
-hydroxy;
-halo;
-COR m, wherein R m is:
-amino substituted with one or more C1 to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys;
-heterocyclo substituted with hydroxy;
-NR t COOR u, wherein R u is:
-C1 to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-SO2R w;
-SO2R x; and -5 or 6 membered heteroaryl;
-C2 to C6 alkenyl;

-4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
=O;
-SO2R w;
-COR p; and -(CO)O-(C1 to C4 alkyl)-O-(C1 to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=O;
-SO2R w;
-COR p; and -(CO)O-(C1 to C4 alkyl)-O-(C1 to C4 alkyl);
-NHR bb, wherein R bb is:
-C(=S)NHR x;
-C(=S)NR x R x; or -C(=N-CN)NHR x;
-N(CONHR w)2;
-NH(SOR w);
-N(SO2R w)2;
-NR v SO2R w, wherein R v is alkyl substituted with 4 or 7 membered heterocyclo;
or wherein R w is:
-C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, (CO)O-(C1 to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-halo;
-C1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to C8 alkyl;
-hydroxy;
-haloalkyl;
-cyano;
-nitro;
-COOH;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x;

-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
-C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and -C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-NR o COR p, wherein R p is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
-NR q CONR q R r, wherein R r is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;

-C1 to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-NR t COOR u, wherein R u is:
-C1 to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-SO2R w;
-SO2R w; and -5 or 6 membered heteroaryl;
-NR v SO2R w, wherein R v is alkyl substituted with 4 to 7 membered heterocyclo;
or wherein R w is:
-C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to C8 aryl;
-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
Z is;
-C1 to C6 alkyl;
R1 is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -5 or 6 membered heteroaryl substituted with one or more independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;

-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo substituted with C1 to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;
-SO2R x;
-C2 to C6 alkenyl optionally substituted with -SO2R x;
-C1 to C6 alkoxy substituted with one or more substituents independently selected from:
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;

-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C1 to C6 alkyl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkoxy; and -C6 to C8 alkyl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and -4 to 7 membered heterocyclo; and -alkoxy;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;

-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl;
-5 or 6 membered heteroaryl; and -C1 to C6 alky further optionally substituted with one or more substituted with hydroxys;

-SO2R, optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C8 aryl;
-COOH;
-OR kk, wherein R kk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;

R2 is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with C1 to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and -SO2R x;
-C2 to C6 alkenyl optionally substituted with SO2R x;
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;

-SO2R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-S(O)R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-alkoxy substituted with one or more substituents independently selected from:

-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino substituted with one or more substituents independently selected from -SO2-C1 to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido substituted with C1 to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-S-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;

-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-sulfonyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, heterocyclo, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkoxy; and -C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more alkoxys;
-4 to 7 membered heterocyclo; and -alkoxy; and -C6 to C8 aryl;
-C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
=O;

-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -(O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;

-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:

-C6 to C8 aryl;

-5 or 6 membered heteroaryl; and -C1 to C6 alkyl optionally substituted with one or more hydroxys;
-C(O)-5 or 6 membered heteroaryl;

-C(O)-C6 to C8 aryl;

-amino substituted with one or more substituents independently selected from:
-SO2R x;

-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;

-C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;

-C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;

-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;

-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
=O;
-C1 to C6 alkyl;
-SO2R x;

-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x;
-OR kk, wherein R kk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
-5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
-SO2R x; or -Si(R x)3;
-OC(O)NHR x wherein R x is optionally substituted with -C6 to C8 aryl;
-OC(O)N(R x)2; or R3 is nitro.

90. The compound of claim 89, wherein:

X is:
-CH-N-(C1 to C6 alkoxy);
-CH=N-(amino optionally substituted with one or more C1 to C6 alkyls);
-halo;
-alkyl optionally substituted with one or more halos;
-alkynyl optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with one or more halos and/or cyanos;
-oximyl;
-SO2R x;
-SO2NH2;
-SO2NH(R x);

-SO2N(R x)2;
-amino optionally substituted with one or more independently selected C1 to C6 alkyls and/or -C(O)-C1 to C6 alkyls;
-amido optionally substituted with one or more independently selected C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more halos; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more halos;
-halo; and -cyano.

91. The compound of claim 89, wherein:
Y is:
-benzothiazolyl substituted with amino, which amino is optionally substituted with one or more C1 to C6 alkyls;
-indolyl substituted on the nitrogen with -SO2R x; or -C6 to C8 aryl substituted with one or more substituents independently selected from:
-alkoxy substituted with one or more substituents independently selected from:

-C(O)NH2 optionally substituted with C6 to C8 alkyl; and -C(O)NH-(C1 to C6)-alkyl;
-haloalkyl;
-cyano;
-COOH;
-N=CHN(R x)2;
-amino substituted with one or more substituents independently selected from:
-SO2R x;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and C6 to C8 aryl optionally substituted with halo;

-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, alkyl and haloalkyl;
-C1 to C7 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one more substituents independently selected from alkyl, halo, and haloalkyl;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo, and haloalkyl;
-alkoxy; and -halo; and -PO2R x;
-OC(O)NHR x wherein R x is optionally substituted with vinyl;
-OC(O)N(R u)2, wherein R u is alkyl or C6 to C8 aryl, which alkyl or aryl is optionally substituted with dialkylamino;
-OC(O)NH(OR uu), wherein R uu is -C6 to C8 aryl optionally substituted with dialkylamino;
-OC(O)NR x(OR x);
-OC(O)N(OR x)2;
-OC(O)R ab, wherein R ab is 5 or 6 membered heterocyclo optionally substituted with heteroaryl, which heteroaryl is optionally substituted with alkyl or haloalkyl;
NR o C(O)R p, wherein R p is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from C6 to C8 aryl and alkoxy; or -5 or 6 membered heterocyclo substituted with one or more substituents independently selected from C1 to C6 alkyl and C6 to C8 aryl;
-NR q CONR q R r, wherein R r is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;

-alkoxy;
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-C1 to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-SO2R aa, wherein R aa is:
-5 or 6 heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkoxy; and -C1 to C6 alkyl;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-alkoxy;
-hydroxy;
-halo;
-COR m, wherein R m is:
-amino substituted with one or more C1 to C6 alkyls, which alkyls are substituted with 5 or 6 membered heterocyclo or C6 to C8 aryl, which heterocyclo is substituted with one or more halos and/or alkoxys, and which aryl is optionally substituted with one or more halos and/or alkoxys;
-heterocyclo substituted with hydroxy;
-NR t COOR u, wherein R u is:
-C1 to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;

-SO2R w;
-SO2R x; and -5 or 6 membered heteroaryl;
-C2 to C6 alkenyl;
-4 to 7 membered heterocyclo substituted with one or more substituents independently selected from:
=O;
-SO2R w;
-COR p; and -(CO)O-(C1 to C4 alkyl)-O-(C1 to C4 alkyl);
-4 or 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
=O;
-SO2R w;
-COR p; and -(CO)O-(C1 to C4 alkyl)-O-(C1 to C4 alkyl);
-NHR bb, wherein R bb is:
-C(=S)NHR x;
-C(=S)NR x R x; or -C(=N-CN)NHR x;
-N(CONHR w)2;
-NH(SOR w);
-N(SO2R w)2;
-NR v SO2R w, wherein R v is alkyl substituted with 4 or 7 membered heterocyclo;
or wherein R w is:
-C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-amino optionally substituted with heterocyclo or alkyl, which heterocyclo or alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, (CO)O-(C1 to C6) alkyl), hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;

-5 to 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-halo;
-C1 to C6 alkyl;
-alkoxy optionally substituted with one or more substituents independently selected from:
-halo;
-5 or 6 membered heterocyclo; and -C(O)NH2 optionally substituted with C6 to C8 alkyl;
-hydroxy;
-haloalkyl;
-cyano;
-nitro;

-COOH;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x;
-6 to 8 memebered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
- C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl; and -C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more alkyls, halos, and/or haloalkyls;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-NR o COR p, wherein R p is:
-amino optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally and independently substituted with one or more C6 to C8 aryls and/or alkoxys; or -5 or 6 membered heterocyclo optionally substituted with one or more C1 to C6 alkyls and/or C6 to C8 aryls;
-NR q CONR q R r, wherein R r is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-hydroxy;
-alkoxy;

-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl substituted with halo;
-C2 to C6 alkenyl optionally substituted with one or more halos;
-C1 to C6 alkoxy;
-5 or 6 membered heterocyclo; or -5 to 6 membered heteroaryl optionally substituted with alkyl;
-NR t COOR u wherein R u is:
-C1 to C12 alkyl substituted with one or more substituents independently selected from:
-C6 to C8 aryl substituted with one or more halos and/or haloalkyls;
-alkoxy substituted with one or more alkoxys;
-amino optionally substituted with one or more C1 to C6 alkyls;
-SO2R w;
-SO2R x; and -5 or 6 membered heteroaryl; and -NR v SO2R w, wherein R v is alkyl substituted with 4 to 7 membered heterocyclo;
or wherein R w is:
-C1 to C6 alkyl substituted with C6 to C8 aryl, which aryl is substituted with one or more substituents independently selected from haloalkyl, halo, alkoxy, and alkyl;
-C6 to C8 aryl;
-amino substituted with heterocyclo or alkyl, which heterocyclo is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl, and which alkyl is substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, alkoxycarbonyl, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;

92. The compound of claim 89, wherein Z is:
-C1 to C6 alkyl.

93. The compound of claim 89, wherein:
R1 is:
-a 5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -5 or 6 membered heteroaryl substituted with one or more independently selected from:

-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is substituted with one or more alkoxys;
-amido optionally substituted with C1 to C6 alkyl;
-5 or 6 membered heterocyclo substituted with C1 to C6 alkyl;
-5 or 6 membered heteroaryl; and -C6 to C8 aryl;

-SO2R x;
-C2 to C6 alkenyl optionally substituted with -SO2R x;
-C1 to C6 alkoxy substituted with one or more substituents independently selected from:
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino optionally substituted with one or more independently selected from 5 or 6 membered heteroaryl, 5 or 6 membered heterocyclo and alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyl;
-amino optionally substituted with heterocyclo;
-amido optionally substituted with C1 to C6 alkyl;
-5 to 7 membered heterocyclo substituted with one or more substituents independently selected from hydroxy and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkoxy; and -C6 to C8 alryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl; and -4 to 7 membered heterocyclo; and -alkoxy;
-(O)-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-hydroxy;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -(O)-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
C-OR x;
-C(O)NH2 optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl; and -amido optionally substituted with one or more or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;

-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl;
-5 or 6 membered heteroaryl; and -C1 to C6 alky further optionally substituted with one or more substituted with hydroxys;
-SO2R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl; or -alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -5 or 6 membered heteroaryl;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C8 aryl;
or -OR kk, wherein R kk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl.

94. The compound of claim 89, wherein:
R2 is:
-C1 to C6 alkyl substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo;
-5 or 6 membered heteroaryl;
-C6 to C8 aryl;
-amido optionally substituted with C1 to C6 alkyl; and -amino optionally substituted with one or more substituents independently selected from heterocyclo, alkoxy and alkyl, which alkyl is optionally substituted with one or more alkoxy; and -SO2 R x;
-C2 to C6 alkenyl optionally substituted with SO2R x;
-alkylthio optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with alkyl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-SO2R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl optionally substituted with one or more C1 to C6 alkyls;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-S(O)R x optionally substituted with one or more substituents independently selected from:
-5 or 6 membered heteroaryl;
-5 or 6 membered heterocyclo;
-C6 to C8 aryl; and -C1 to C6 alkyl;
-alkoxy substituted with one or more substituents independently selected from:

-halo;
-hydroxy;
-cyano;
-alkoxy optionally substituted with alkoxy;
-amino substituted with one or more substituents independently selected from -SO2-C1 to C4 alkyl and alkyl, which alkyl is substituted with one or more substituents independently selected from:
-5 or 6 membered heterocyclo; and -amino optionally substituted with one or more alkyls;
-amido substituted with C1 to C6 alkyl;
-S-5 or 6 membered heterocyclo;
-S-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;

-S-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-S-C6 to C8 aryl;
-sulfinyl-5 or 6 membered heterocyclo;
-sulfinyl-5 or 6 membered heteroaryl;
-sulfinyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfinyl-C6 to C8 aryl;
-sulfonyl-5 or 6 membered heterocyclo;
-sulfonyl-5 or 6 membered heteroaryl optionally substituted with C1 to C6 alkyl;
-sulfonyl-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo; and -C5 to C6 heteroaryl optionally substituted with one or more substituents independently selected from alkyl, haloakyl and halo;
-sulfonyl-C6 to C8 aryl;
-5 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, =O, heterocyclo, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkoxy; and -C6 to C8 aryl;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more alkoxys;

-4 to 7 membered heterocyclo; and -alkoxy; and -C6 to C8 aryl;
-C6 to C8 aryl;
-(O)-5 or 6 membered heterocyclo substituted with one or more substituents independently selected from:
-hydroxy;
=O;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x; or -(O)-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with alkyl, which alkyl is optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;

-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;
-C(O)-3 to 7 membered heterocyclo optionally substituted with one or more substituents independently selected from;
-C6 to C8 aryl, -5 or 6 membered heteroaryl; and -C1 to C6 alkyl optionally substituted with one or more hydroxys;
-C(O)-5 or 6 membered heteroaryl;
-C(O)-C6 to C8 aryl;
-amino substituted with one or more substituents independently selected from:
-SO2R x;
-6 to 8 membered aryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, COR x and haloalkoxy;
-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo, haloalkyl, cyano, alkoxy, haloalkoxy and -C6 to C8 aryl optionally substituted with halo;
-C5 to C6 heterocyclo optionally substituted with one or more substituents independently selected from hydroxy, alkyl and haloalkyl;
-C1 to C7 alkyl optionally substituted with one or more substituents independently selected from:

-5 or 6 membered heteroaryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from alkyl, halo and haloalkyl;
-alkoxy; and -halo;
-5 or 6 membered heteroaryl substituted with one or more substituents independently selected from:
-C1 to C6 alkyl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-alkoxy;
-halo;
-alkylthio;
-haloalkyl;
-cyano;
-amino optionally substituted with one more alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, cyano, 5 or 6 membered heterocyclo and or 6 membered heteroaryl;
-heterocyclo;
-nitro;
-hydroxy;
-COOH;
-CO2R x;
-COR x;
-C(O)NH2 optionally substituted with one or more C1 to C6 alkyls, which alkyls are optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo and 5 or 6 membered heteroaryl;
-amido optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkoxy, hydroxy, 5 or 6 membered heterocyclo, 5 or 6 membered heteroaryl, and C1 to C6 alkyl, which alkyl is optionally substituted with one or more C1 to C6 alkoxys;

-5 or 6 membered heterocyclo optionally substituted with one or more substituents independently selected from;
-hydroxy;
=O;
-C1 to C6 alkyl;
-SO2R x;
-C(O)-C6 to C8 aryl;
-COR p; and -C(O)OR x;
-OR kk, wherein R kk is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C4 alkoxy, and C1 to C6 haloalkyl;
-5 to 6 membered heterocyclo optionally substituted with C1 to C6 alkyl, which alkyl is optionally substituted with C6 to C8 aryl; or -5 to 6 membered heteroaryl substituted with one or more substituents independently selected from halo, C1 to C6 alkyl, C1 to C6 alkoxy, and C1 to C6 haloalkyl;
-SO2R x; or -Si(R x)3; or

95. The compound of claim 89, wherein R3 is nitro.

96. The compound of claim 89, wherein:
X is cyano or hydrogen;
Y is:

-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
-halo;
-C1 to C6 alkyl;
-amino optionally substituted with one or more substituents independently selected from:
-SO2R x;
-5 or 6 membered heteroaryl optionally substituted with one or more alkyl;
-C1 to C7 alkyl;
-NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
-NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl or amino optionally substituted withalkyl;

Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano; and R3 is hydrogen.

97. The compound of claim 96, wherein the C6 to C8 aryl is phenyl.

98. The compound of claim 97,wherein:
X is cyano;
Y is phenyl para substituted with NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.

99. The compound of claim 97, wherein:
X is cyano;
Y is phenyl substituted with C1 to C6 alkyl and NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.

100. The compound of claim 97, wherein:
X is cyano;
Y is phenyl substituted with halo and NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.

101. The compound of claim 97, wherein:
X is hydrogen;
Y is phenyl is para substituted with -NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl;
Z is cyclobutyl, cyclopropyl, cyclopropylmethyl, ethyl or cyclopentyl; and R2 is -(O)-5 or 6 membered heteroaryl substituted with cyano at the ortho position.

102. The compound of claim 89, wherein:
X is cyano;
Y is:
-C6 to C8 aryl optionally substituted with one or more substituents independently selected from:
NR t COOR u, wherein R t is hydrogen, and wherein R u is C1 to C12 alkyl optionally substituted with one or more halo; or -NR v SO2R w, wherein R v is hydrogen, and wherein R w is C1 to C6 alkyl;
Z is C1 to C6 alkyl;
R is hydrogen;
R1 is hydrogen;
R2 is -(O)-5 or 6 membered heterocyclo substituted with one or more =O; and R3 is hydrogen.

103. A compound which is selected from the compound range: 1330-2128 and 2600-3348.

104. The compound of claim 103 selected from:

105. A composition comprising the compound of claim 1 and one or more pharmaceutically acceptable excipient(s).

106. A composition comprising the compound of claim 39 and one or more pharmaceutically acceptable excipient(s).

107. A composition comprising the compound of claim 77 and one or more pharmaceutically acceptable excipient(s).

108. A composition comprising the compound of claim 83 and one or more pharmaceutically acceptable excipient(s).

109. A composition comprising the compound of claim 89 and one or more pharmaceutically acceptable excipient(s).

110. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 1.

111. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 39.

112. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 77.

113. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 83.

114. A method for treating Hepatitis C viral infection in a subject in need thereof, comprising administering to the subject an effective amount of one or more compound(s) according to claim 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 89.

115. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 1 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 1.

116. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 39 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 39.

117. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 77 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 77.

118. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 83 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 83.

119. A method for treating an infection by a virus in a subject in need thereof, wherein the virus comprises an internal ribosome entry site, comprising administering to the subject an effective amount of one or more compound(s) according to claim 89 or a pharmaceutical composition comprising an effective amount of one of more compound(s) according to claim 89.