The derivative 1-phenyl-2,5-dibenzimidazol-5-il-pyrolidine is an antiviral agent.

Abstract

Compounds effective in inhibiting replication of Hepatitis C virus (HCV) are described. This invention also relates to processes of making such compounds, compositions comprising such compounds, and methods of using such compounds to treat HCV infection.

Description

[0001] ANTI-VIRAL COMPOUNDS

[0002] This application claims priority from U.S. Patent Application Serial No. 13 / 100,827 filed May 4, 2011, U.S. Provisional Application Serial No. 61 / 446,800 filed February 25, 2011, U.S. Patent Application Serial No. 12 / 964,027 filed December 9, 2010, and U.S. Patent Application Serial No. 12 / 903,822 filed October 13, 2010, all of which are incorporated herein by reference in their entireties.

[0003] FIELD

[0004] The present invention relates to compounds effective in inhibiting replication of Hepatitis C virus ("HCV"). The present invention also relates to compositions comprising these compounds and methods of using these compounds to treat HCV infection.

[0005] BACKGROUND HCV is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. The enveloped HCV virion contains a positive stranded RNA genome encoding all known virus-specific proteins in a single, uninterrupted, open reading frame. The open reading frame comprises approximately 9500 nucleotides and encodes a single large polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, envelope proteins El and E2, a membrane bound protein p7, and the non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

[0006] The nonstructural protein NS5A is a membrane -associated phosphoprotein present in basally phosphorylated and hyperphosphorylated forms. It is a critical component of HCV replication and is believed to exert multiple functions at various stages of the viral life cycle. A full-length NS5A protein comprises three domains - namely, Domain I, Domain II, and Domain III. Domain I (residues 1 to 213) contains a zinc-binding motif and an amphipathic N-terminal helix which can promote membrane association. Domain II (residues 250 to 342) has regulatory functions, such as interactions with protein kinase PKR and PI3K, as well as NS5B, and also contains the interferon sensitivity- determining region. Domain III (residues 356 to 447) plays a role in infectious virion assembly, and can be modulated by phosphorylation within the domain. NS5A has been identified as a promising therapeutic target for treating HCV.SUMMARY

[0007] The present invention features compounds of Formulae I, IA, ¾, Ic, ID, IE, IF and IGand pharmaceutically acceptable salts thereof. These compounds and salts can inhibit the replication of HCV and therefore are useful for treating HCV infection.

[0008] The present invention also features compositions comprising the compounds or salts of the present invention. The compositions can also include additional therapeutic agents, such as HCV helicase inhibitors, HCV polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, CD81 inhibitors, cyclophilin inhibitors, or internal ribosome entry site (IRES) inhibitors.

[0009] The present invention further features methods of using the compounds or salts of the present invention to inhibit HCV replication. The methods comprise contacting cells infected with HCV virus with a compound or salt of the present invention, thereby inhibiting the replication of HCV virus in the cells.

[0010] In addition, the present invention features methods of using the compounds or salts of the present invention, or compositions comprising the same, to treat HCV infection. The methods comprise administering a compound or salt of the present invention, or a pharmaceutical composition comprising the same, to a patient in need thereof, thereby reducing the blood or tissue level of HCV virus in the patient.

[0011] The present invention also features use of the compounds or salts of the present invention for the manufacture of medicaments for the treatment of HCV infection.

[0012] Furthermore, the present invention features processes of making the compounds or salts of the invention.

[0013] Other features, objects, and advantages of the present invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating preferred embodiments of the invention, are given by way of illustration only, not limitation. Various changes and modifications within the scope of the invention will become apparent to those skilled in the art from the detailed description.

[0014] DETAILED DESCRIPTION

[0015] Tellinghuisen et al, NATURE 435:374-379 (2005), describes a crystal structure of the NS5A protein in which two NS5A monomers are packed as a dimer via contacts near the N-terminal ends of the molecules. WO2006093867 postulates the use of the crystal structure of the NS5A protein in conjunction of computer modeling to design or select NS5A inhibitors.

[0016] To improve interactions with the NS5A protein, many NS5A inhibitors have been designed to have dimeric or dimer-like structures. For instance, WO2006133326 (BMS) describes compoundswith the formula: S)

[0017] depicts compoundswith the formula:

[0018] WO2008021927(BMS) shows compounds with the formula:

[0019] 27 (BMS) describes compounds

[0020] with the formula: ; and US20100068176 (BMS)

[0021] selected from aryls (e.g., aliphatic groups (e.g., mbination thereof (e.g.,Certain modifications to the above formulae have also been provided. For instance,

[0023] WO2010065681 (Presidio) discloses the formula: , wherein B is Q or Q-Q, and each Q is independently selected from cycloalkyl, cycloalkenyl, heterocycle, aryl or heteroaryl, with the proviso that only one Q is a six member aromatic ring when B is Q-Q and with the proviso that if B is Q-Q , any Q is that is polycyclic is connected to the remainder of the molecule through only one cycle of the polycycle; WO2010096777 (Presidio) describes a similar formula:

[0025] , wherein B is W-W or W-X"-W, and wherein each W is optionally substituted aryl or heteroaryl, and X" is selected from -0-, -S(0)k, -N(RN)- and -CR'2-; WO2010091413 Enanta) and US20100266543 (Enanta) show the formula:, wherein A is substituted aryl, heteroaryl, heterocyclic, C3- Cscycloalkyl or C3-C8cycloalkenyl and is optionally substituted with selected substituents; and US20100221215 (Enanta) depicts the formula:

[0027] , wherein A is selected from aryl, heteroaryl, heterocyclic, C3-C8cycloalkyl or C3-C8cycloalkenyl, each optionally substituted, D is absent or an optionally substituted aliphatic group, T is absent or an optionally substituted linear aliphatic group containing zero to eight carbons, E is absent or independently selected from optionally substituted aryl and optionally substituted heteroaryl, and wherein one or two of D, E, and T are absent.

[0028] Tables 1-4 compare the antiviral activities of different NS5A compounds. As demonstrated by these tables, several compounds that are generically covered by WO2010065681 (Presidio) WO2010096777 (Presidio), WO2010096462 (Enanta), US20100266543 (Enanta), WO2010096462(Enanta) and US20100266543 (Enanta) appear to have comparable or worse anti-HCV activities than the corresponding compounds described in the BMS applications. WO2010065681 (Presidio) WO2010096777 (Presidio), WO2010096462 (Enanta), US20100266543 (Enanta), WO2010096462 (Enanta) and US20100266543 (Enanta) also fail to identify any advantage of these compounds over those described in the BMS applications.

[0029] (BMS-790052) employs a biphenyl linker between the imidazole moieties. See WO2008021927(BMS). The EC50values of BMS- 790052 against different HCV genotypes were shown by Nettles et al., "BMS-790052 is a First-in- class Potent Hepatitis C Virus (HCV) NS5A Inhibitor for Patients with Chronic HCV Infection: Results from a Proof-of-concept Study", 59th Annual Meeting of the American Association for the Study of Liver Diseases (Oct 31 -Nov 1 2008, San Francisco, CA; www.natap.org / 2008 / AASLD / AASLD_06.htm). Specifically, Nettles et al, observed that the EC50values of BMS-790052 against HCV genotypes la lb, 3a, 4a and 5a were 0.05, 0.009, 0.127, 0.012, and 0.033 nM, respectively. See also Gao et al., NATURE 465:96-100 (2010). The compounds in Table 1 use different linkers between the imidazole moieties. Table 1 depicts the EC5o values of these compounds when tested using respective replicon assays in the presence of 5% (v / v) fetal bovine serum (FBS). As compared to BMS-790052, the replacement of the biphenyl linker with other linkers can significantly reduce the compounds' activities against various HCV genotypes.

[0030] Table 1. Biphenyl linker versus other linkers

[0032] con gurat on t an somer>10 >100 >10 >10 4.0 >10 >10

[0033] (isomer 2, in which the cyclohexanyl

[0034] moiety has a different cis / trans

[0035] configuration than isomer 1)

[0036] Table 2 compares compounds containing unsubstituted benzimidazole to those containing halo-substituted benzimidazole. Anti-viral activities were assessed using wild-type replicons (e.g., lb WT or la WT) as well as replicons containing specific NS5A mutations (e.g., lb L28T, lb Y93H, la L31V, la Y93C, la M28V, or la Q30E) in the absence of FBS. As compared to the reference compound which contains unsubstituted benzimidazole, compounds containing substituted benzimidazole generally exhibited comparable or worse activities against many of these HCV viruses.

[0037] Table 2. Unsubstituted benzimidazole versus halo-substituted benzimidazole

[0038] 0.007 >10 3.6 0.1 80 141 5.8 52

[0039] The present invention sur risingly discovered that compounds with halo-substituted

[0040] benzimidazole (e.g.,can have better activity against certain

[0041] HCV variants containing NS5A mutations e.g., la L31V). Similar testing also showed that

[0042] and , as compared to the reference compound in Table 2, exhibited significantly improved activity against the HCV la variant containing the NS5A mutation M28T. These improvements have not been described or suggested in any of the above-mentioned BMS, Presidio or Enanta applications. Accordingly, the present invention features methods of using the compounds containing halo-substituted benzimidazole (e.g.,

[0043] or ) to treat HCV variants (e.g., la M28T or la L31V). These methods comprise administering an effective amount of such a compound to a patient infected with such a HCV variant (e.g., la M28T or la L31V).

[0044] It was also found that when the phenyl linker between the benzimidazole moieties was replaced with a pyrrolidinyl link (e.g., \— / ), the process chemistry to introduce halo substitutions to the benzimidazole moieties became extremely difficult. The above-mentioned BMS, Presidio and Enanta applications do not provide any enable disclosure that would allow halosubstitutions on the benzimidazole moieties in a compound in which the phenyl linker is replaced with

[0045] >Ot Scheme XXIV and various Example of the present application (e.g., Examples 2.16, 3.35-3.41, 3.46-3.53, 4.26-4.31, 4.37-4.40, 4.42-4.46, and 4.51-4.57) provide an enabling disclosure that allows such substitutions in compounds with substituted pyrrolidinyl linkers.

[0046] Table 3 compares compounds with different linkers between the benzimidazole moieties. Anti-viral activities were determined using la and lb replicon assays. "HP" refers to human plasma. The compound containing the pyrrolidinyl linker showed significantly worse anti-HCV activities than those containing the pyridinyl linker. As compared to the phenyl linker ( ' — / ¾) used in

[0047] US20100068176 (BMS), the pyridinyl linkeror like 6-membered aromatic linkers are expected to provide similar or comparable anti-HCV activities.

[0048] Table 3. Non-aromatic heteroc clic linker versus aromatic heterocyclic linker

[0049] Table 4 further shows that when the phenyl linker is replaced with a pyrrolidinyl linker, the compound's activity against HCV can be significantly reduced. The compound in Table 4 contains a pyrrolidinyl linker and has EC5o values of over 200 nM. In comparison, BMS-790052, which contains a biphenyl linker, has EC5o values of no more than 0.2 nM. see Nettles et ah, supra. Therefore, Tables 3 and 4 clearly demonstrate that the use of an unsubstituted pyrrolidinyl linker in a dimeric or dimer-like NS5A inhibitor can lead to poor anti-HCV activities.

[0050] Table 4. Non-aromatic heteroc clic linker versus aromatic heterocyclic linker

[0052] It was unexpectedly discovered that when the nitrogen atom in the pyrrolidinyl linker is substituted with carbocycle or heterocycle, the anti-viral activities of the compound can be drastically improved. Table 5 shows the anti-HCV activities of compounds in which the pyrrolidinyl linker is substituted with substituted carbocycle or heterocycle.

[0053] Table 5. Substituted rrolidinyl linker

[0056] It is noted that has not been shown

[0057] to be better than that of

[0058] Table 5 also demonstrates that additional halo substitution(s) on the carbocycle / heterocycle substituents on the pyrrolidinyl linker can significantly improve the compounds' anti-HCV activities (e.g., compare Example 4.25 to Example 3.20 or Example 5.1).

[0059] The present invention features compounds having Formula I, and pharmaceutically acceptable salts thereof,

[0060] D

[0061] Y— A— L-i— X— L2— B— Z

[0062] I

[0063] wherein:

[0064] X is C3-Ci2carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more RA or RF;

[0065] Li and L2are each independently selected from bond; or Ci-Cealkylene, C2-C6alkenylene or C2-C6alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL;

[0066] L3is bond or -Ls-K-Ls'-, wherein K is selected from bond, -0-, -S-, -N(RB)-, -C(O)-, - S(0)2- -S(O)-, -OS(O)-, -OS(0)2- -S(0)20- -S(0)0- -C(0)0- -OC(O)-, - OC(0)0- -C(0)N(RB)-, -N(RB)C(0)-, -N(RB)C(0)0- -OC(0)N(RB)-, -N(RB)S(0)-, -N(RB)S(0)2- -S(0)N(RB)-, -S(0)2N(RB)-, -C(0)N(RB)C(0)-, -N(RB)C(0)N(RB')-, - N(RB)S02N(RB')-, or -N(RB)S(0)N(RB')-;

[0067] A and B are each independently C3-Ci2carbocycle or 3- to 12-membered heterocycle, and are each independently optionally substituted with one or more RA;

[0068] D is C3-Ci2carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more RA; or D is C3-Ci2carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more RA, where J is C3-Cncarbocycle or 3- to 12-membered heterocycle and is optionally substituted with one or more RA, or J is -SF5; or D is hydrogen or RA;

[0069] Y is selected from -T'-C(RiR2)N(R5)-T-RD, -T'-C(R3R4)C(R6R7)-T-RD, -LK-T-RD, or - Ri and R2 are each independently Rc, and R5is RB; or Ri is Rc, and R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA;

[0070] R3, R4, R6, and R7are each independently Rc; or R3and R6are each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 3- to 12- membered carbocycle or heterocycle which is optionally substituted with one or more RA;

[0071] Z is selected from -T'-C(R8R9)N(R12)-T-RD, -T'-C(R10Rn)C(Ri3Ri4)-T-RD, LK— T— RDor

[0072] R8and R9are each independently Rc, and R12 is RB; or R8is Rc, and R9and R12, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA;

[0073] Rio, Rn, Ri3, and RMare each independently Rc; or Ri0and R13 are each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a 3- to 12-membered carbocycle or heterocycle which is optionally substituted with one or more RA;

[0074] T and T' are each independently selected at each occurrence from bond, -Ls- -Ls-M-Ls'-, or -Ls-M-Ls'-M'-Ls"-, wherein M and M' are each independently selected at each occurrence from bond, -0-, -S-, N(RB)— , -C(O)-, -S(0)2- -S(O)-, -OS(O)-, - OS(0)2- -S(0)20- -S(0)0-, -C(0)0- -OC(O)-, -OC(0)0-, -C(0)N(RB)-, - N(RB)C(0)-, -N(RB)C(0)0-, -OC(0)N(RB)-, -N(RB)S(0)-, -N(RB)S(0)2- - S(0)N(RB)-, -S(0)2N(RB)-, -C(0)N(RB)C(0)-, -N(RB)C(0)N(RB')-,

[0075] N(RB)S02N(RB')-, -N(RB)S(0)N(RB')-, C3-Ci2carbocycle or 3- to 12-membered heterocycle, and wherein said C3-Ci2carbocycle and 3- to 12-membered heterocycle are each independently optionally substituted at each occurrence with one or more RA;

[0076] LKis independently selected at each occurrence from bond, -Ls-N(RB)C(0)-Ls'- or -Ls- C(0)N(RB)-Ls'-; or Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL; or C3- Ci2carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more RA;

[0077] E is independently selected at each occurrence from C3-Ci2carbocycle or 3- to 12-membered heterocycle, and is independently optionally substituted at each occurrence with one or more RA;RDis each independently selected at each occurrence from hydrogen or RA;

[0078] RAis independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE, wherein two adjacent RA, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;

[0079] RBand RB' are each independently selected at each occurrence from hydrogen; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6- membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in RBor RB' is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2- Cehaloalkenyl or C2-C6haloalkynyl;

[0080] Rcis independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or Q- Cealkyl, C2-Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rc is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci- Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl;

[0081] REis independently selected at each occurrence from -0-Rs, -S-Rs, -C(0)Rs, -OC(0)Rs, - C(0)ORs, -N(RsRs'), -S(0)Rs, -S02Rs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', - N(Rs)C(0)N(Rs'Rs"), -N(Rs)S02Rs', -S02N(RsRs'), -N(Rs)S02N(Rs'Rs"), - N(Rs)S(0)N(Rs'Rs"), -OS(0)-Rs, -OS(0)2-Rs, -S(0)2ORs, -S(0)ORs, -OC(0)ORs, - N(Rs)C(0)ORs', -OC(0)N(RsRs'), -N(Rs)S(0)-Rs', -S(0)N(RsRs'), -P(0)(ORs)2, or - C(0)N(Rs)C(0)-Rs' ; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrencewith one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORs, or - N(RSRS');

[0082] is independently selected at each occurrence from Ci-Ci0alkyl, C2-Ci0alkenyl or C2- Cioalkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independently optionally substituted with one or more RL; or -(RX-RY)Q-(RX-RY'), wherein Q is 0, 1, 2, 3 or 4, and each Rxis independently O, S or N(RB), wherein each RYis independently Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, and wherein each RY' is independently Ci-C6alkyl, C2-C6alkenyl or C2- Cealkynyl each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano;

[0083] is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-Rs, -S-Rs, -C(0)Rs, -OC(0)Rs, -C(0)ORs, -N(RSRS'), - S(0)Rs, -S02Rs, -C(0)N(RsRs') or -N(Rs)C(0)Rs' ; or C3-C6carbocycle or 3- to 6- membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; wherein two adjacent RL, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;

[0084] Ls' and Ls" are each independently selected at each occurrence from bond; or Ci- C6alkylene, C2-C6alkenylene or C2-C6alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL; and

[0085] Rs' and Rs" are each independently selected at each occurrence from hydrogen; Q- Cealkyl, C2-Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -O-Ci-Cealkyl, -O-Ci-Cealkylene-O-Ci-Cealkyl, or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in Rs, Rs' or Rs' is independently optionally substituted at each occurrence with one or more substituents selected from halogen,hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl or C2- Cehaloalkynyl.

[0086] A and B preferably are independently selected from C5-C6carbocycle (e.g., phenyl), 5- to 6- membered heterocycle (e.g., pyridinyl or thiazolyl), or 8- to 12-membered bicycles such aswhere Zi is independently selected at each occurrence from O, S, NH or CH2, Z2is independently selected at each occurrence from N or CH, Z3is independently selected at each occurrence from N or CH, Z4is independently selected at each occurrence from O, S, NH or CH2, and Wi, W2, W3, W4, W5and W6are each independently selected at each occurrence from CH or N. A and B are each independently optionally substituted with one or more RA.

[0087] More preferably, A is selected from C5-C6carbocycle, 5- to 6-membered heterocycle,and is optionally substituted with one or more RA; B is selected from C5-C6carbocycle, 5- to 6-membered heterocycle,orand is optionally substituted with one or more RA; where Z Z2, Z3, Z4, Wi, W2,

[0088] W3, W4, W5, W6are as defined above. Preferably, Z3is N and Z4is NH. For instance, A can be selected from

[0089] ionally substituted with one or more RA; and B can be

[0090] preferably, both A and B are phenyl (e.g., both A and B are5)).. AAllssoo hhiigghhllyy preferably, A

[0092] substituted with one or more

[0093] Also preferably, A isand A and B are substituted with one or more halogen, such as F or CI. It was surprisingly discovered that when A and / or B were

[0094] halo-substituted benzimidazole (e.g., A isand B is

[0095] compounds of Formula I (as well as compounds of Formula IA, ¾, Ic, ID, IE, IF or IGdescribed below, and compounds of each embodiment described thereunder) unexpectedly showed significantly improved pharmacokinetic properties, as compared to compounds with unsubstituted benzimidazole. The improvements in pharmacokinetics can be observed, for instance, as a greater total plasma level exposure, measured as the area under the curve (AUC) over a 24 hour period following oral dosing in mouse (for examples see infra). It was also surprisingly discovered that these compounds with halo- substituted benzimidazole unexpectedly displayed improved inhibitory activity against certain HCV genotype la variants (e.g., variants containing NS5A mutations L31M, Y93H, or Y93N). Accordingly, the present invention contemplates methods of using such compounds to treat HCV genotype la variant infection (e.g., L31M, Y93H, or Y93N la variant infection). These methods comprise administering such a compound to a patient having HCV genotype la variant (e.g., L31M, Y93H, or Y93N la variant). The present invention also contemplates the use of such compounds for the manufacture of a medicament for the treatment of genotype la variant infection (e.g., L31M, Y93H, or Y93N la variant infection).

[0096] D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or more substituents selected from RL. More preferably, D is C5-C6carbocycle (e.g., phenyl), 5- to 6- membered heterocycle (e.g., pyridinyl, pyrimidinyl, thiazolyl), or 6- to 12-membered bicycles (e.g., indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl),and is substituted with one or more RM, where RMis halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE. Also preferably, D is phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more RM, wherein RMis as defined

[0097] above. Highly preferably, D iswherein RMis as defined above, and each

[0098] RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F.

[0099] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

[0100] more RM. Highly preferably, D iswherein RMis as defined above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, D

[0101] is, and is optionally substituted with one or more RM.

[0102] Preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6aikyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, RMis halogen, hydroxy, mercapto, amino, carboxy; or Ci-C6alkyl, C2-C6alkenyl or C2- Cealkynyl, each of which is independently optionally substituted at each occurrence with one or moresubstituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

[0103] Also preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or RMis -LS-RE, wherein Lsis a bond or Ci-C6alkylene, and REis - N(RSRS'), -O-Rs, -C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)ORs', - N(Rs)S02Rs', -S02Rs, -SRs, or -P(0)(ORs)2, wherein Rsand Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C6alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Q-Cealkyl or 3- to 6-membered heterocycle; or RMis Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORs, or - N(RSRS'). More preferably, RMis halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RMis CF3, - C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RMis -Ls- REwhere Lsis a bond and REis -N(RSRS), -0-Rs, -N(Rs)C(0)ORs', -N(Rs)S02Rs', -S02Rs, or - SRS. For example where Lsis a bond, REis -N(Ci-C6alkyl)2(e.g., -NMe2); -N(Ci-C6alkylene-0-Ci- C6alkyl)2(e.g. -N(CH2CH2OMe)2); -N(Ci-C6alkyl)(Ci-C6alkylene-0-Ci-C6alkyl) (e.g. - N(CH3)(CH2CH2OMe));— O-Ci-Cealkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n- hexyl); -0-C C6haloalkyl (e.g., - OCF3, -OCH2CF3); -0-Ci-C6alkylene-piperidine (e.g., -O- CH2CH2-l-piperidyl); -N(Ci-C6alkyl)C(0)OCi-C6alkyl (e.g., -N(CH3)C(0)0-CH2CH(CH3)2), - N(Ci-C6alkyl)S02Ci-C6alkyl (e.g., -N(CH3)S02CH3); -S02Ci-C6alkyl (e.g., -S02Me); -S02C C6haloalkyl (e.g., -S02CF3); or -S-Ci-C6haloalkyl (e.g., SCF3). Also preferably RMis -LS-REwhere Lsis Ci-C6alkylene (e.g., -CH2- -C(CH3)2-, -C(CH3)2-CH2-) and REis -0-Rs, -C(0)ORs, - N(Rs)C(0)ORs', or -P(0)(ORs)2. For example RMis -Ci-C6alkylene-0-Rs(e.g., -C(CH3)2-CH2- OMe); -Ci-C6alkylene-C(0)ORs (e.g., -C(CH3)2-C(0)OMe); -Ci-C6alkylene-N(Rs)C(0)ORs' (e.g., -C(CH3)2-CH2-NHC(0)OCH3); or -C1-C6alkylene-P(0)(ORs)2(e.g., -CH2-P(0)(OEt)2). Also more preferably RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealk l, C2-C6alkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, - C(0)ORs, or -N(RsRs')- Frexample RMis cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomo holin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxy carbonylpiperazin- 1 -yl, pyrrolidin- 1 - yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).

[0104] More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more RA, wherein J is C3- Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6- membered heterocycle, wherein said C3-C6carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D is C5- C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is C3-Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably, J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RSRS'). Also preferably, D is C5-C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more RA. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more RA, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RSRS'). Highly preferably, D iswherein each RNis independently selected from

[0105] RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C C2-C6haloalkynyl, C(0)ORSor -

[0106] N(RSRS'). Also preferably, D isRNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle or 3- to 6-membered heterocycle and is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -

[0107] N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D isand J is C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl, C2-C6haloalkynyl, C(0)ORSor -N(RSRS').

[0108] It was surprisingly discovered that when D contains a halo-substituted carbocycle or heterocycle (e.g., a halo-substituted 5-6 membered carbocycle or heterocycle directly linked to X), the compound of Formula I (as well as compounds of Formula IA, ¾, Ic, ID, IE, IF or IGdescribed below, and compounds of each embodiment described thereunder) can exhibit significantly improved inhibitory activity against HCV genotypes 2a, 2b, 3a or 4a and / or improved pharmacokinetic properties. Therefore, the present invention contemplates methods of using such compounds to treat HCV genotype 2a, 2b, 3a or 4a infection. These methods comprise administering such a compound toa patient having HCV genotype 2a, 2b, 3a or 4a. The present invention also contemplates the use of such compounds for the manufacture of a medicament for the treatment of HCV genotypes 2a, 2b, 3a

[0109] or 4a. Suitable D for this purpose can be, for instance,as described above, wherein at least one RNis halo such as fluorine. Specific examples of suitable D

[0110] include, but are not limited to,

[0112] X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is optionally substituted with one or more RAor RF. X can also be C5-C6carbocycle or 5- to 6-membered heterocycle which is optionally substituted with one or more RA or RF, wherein two adjacent RAon X, taken together with the ring atoms to which they are attached, optionally form a 5-

[0113] to 6-membered carbocycle or heterocycle. Also preferably, X is, wherein X3is

[0114] C(H) or preferably N and is directly appended to -L3-D; X4 is C2-C4alkylene, C2-C4alkenylene or C2- C4alkynylene, each of which optionally contains one or two heteroatoms selected from O, S or N; and X is optionally substituted with one or more RA or RF, and two adjacent RAon X, taken together with the ring atoms to which they are attached, can optionally form a 5- to 6-membered carbocycle or

[0115] heterocycle. In addition, X can bewherein X3is C and is directly linked to -L3-D, X4 is C2-C4alkylene, C2-C4alkenylene or C2-C4alkynylene each of whichoptionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted with one or more RA or RF, and two adjacent RAon X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. Moreover, X can be

[0116] is directly linked to L3-D, X4 is C2-C4alkylene, C2-C4alkenylene or C2- C4alkynylene each of which optionally contains one or two heteroatoms selected from O, S or N, and X is optionally substituted with one or more RA or RF, and two adjacent RAon X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

[0117] For instance, X can be *xixi , X2X2 ?9is independently selected at each occurrence from CH2, O, S or NH, X2is independently selected at each occurrence from CH or N, X3is N and is directly linked to -L3-D, and X3' is C and is directly linked to -L3-D; and X is optionally substituted with one or more RA or RF, and two adjacent RAon X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered

[0118] carbocycle or heterocycle. For another example, X isχι ,Λ2 ,

[0119] , or wherein Xi is independently selected at each occurrence from CH2, O, S or NH, X2is independently selected at each occurrence from CH or N, X3is N and is directly linked to -L3-D, and X3' is C and is directly linked to -L3-D; and wherein X is optionally substituted with one or more RA or RF, and two adjacent RAon X, taken together withthe ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

[0120] Highly preferably, X iswherein X3is C(H) or N and is directly linked to -L3-D, X3 ' is C and is directly linked to -L3-D, and wherein X is optionally substituted with one or more RAor RF, and two adjacent RAon X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. More preferably, X3is N.

[0121] Non-limiting examples of X include:

[0124] wherein "—► " indicates the covalent attachment to -L3-D. Each X can be optionally substituted with one or more RA or RF, and two adjacent RAon X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

[0125] Non-limiting examples of preferred X include the following pyrrolidine rings, each of which is optionally substituted with one or more RAor RF:

[0127] As shown, the relative stereochemistry at the 2- and 5-positions of the above pyrrolidine ring may be either cis or trans. The stereochemistries of optional substituents RA at the 3- or 4-positions of the pyrrolidine may vary relative to any substituent at any other position on the pyrrolidine ring. Depending on the particular substituents attached to the pyrrolidine, the stereochemistry at any carbon may be either (R) or (S).

[0128] Non-limiting examples of preferred X also include the following pyrrole, triazole or thiomorpholine rings, each of which is optionally substituted with one or more RAor RF:

[0129] As shown, the relative stereochemistry at the 3- and 5 -positions of the thiomorpholine ring may be either cis or trans. Depending on the particular substituents attached to the thiomorpholine, the stereochemistry at any carbo be either (R) or (S).

[0130] Also preferably, X isor wherein X3is N and is directly linked to -L3-D, and X is optionally substituted with one or more RAor RF. Preferably, RFis Ci-Ci0alkyl, C2-Ci0alkenyl or C2-Cioalkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Also preferably, RFis Ci-Cioalkyl, C2-Cioalkenyl or C2-Cioalkynyl, each of which contains 0, 1, 2, 3, 4 or 5 O and is independently optionally substituted with one or more RL. Also preferably, RFis -(RX-RY)Q-(RX-RY'), wherein Q is 0, 1, 2, 3 or 4; each RXis independently O, S or N(RB); each RYis independently Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; and each RY' is independently Ci-Cealkyl, C2-C6alkenyl or C2-C6alkynyl each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Preferably, each RXis O. More preferably, X is optionally substituted with one or more RAor RF, each RFis independently selected from Ci-Cioalkyl, C2-Ci0alkenyl or C2-Cioalkynyl, each of which contains 0, 1, 2 or 3 O and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Also preferably, X is optionally substituted with one or more RAor RF, each RFis independently selected from -(0-Ci-C6alkylene)Q-(0-Ci-C6alkyl), wherein Q preferably is 0, 1, 2 or 3.

[0131] Li and L2are preferably independently bond or Ci-C6alkylene, L3is preferably selected from bond, Ci-C6alkylene or -C(O)-, and Li, L2, and L3are each independently optionally substituted with one or more RL. More preferably, Li, L2and L3are each independently bond or Ci-C6alkylene (e.g., -CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly preferably, L L2and L3are bond.

[0132] Y is preferably selected from -LS-C(RiR2)N(R5)-T-RD;-LS-C(R3R4)C(R6R7)-T-RD, -G- C(RIR2)N(R5)-T-RD>-G-C(R3R4)C(R6R7)-T-RD, -N(RB)C(0)C(R1R2)N(R5)-T-RD;N(RB)C(0)C(R3R4)C(R6R7)-T-RD, -C(0)N(RB)C(R1R2)N(R5)-T-RD;-C(0)N(RB)C(R3R4)C(R6R7)- T-RD, -N(RB)C(0)-Ls-E, or -C(0)N(RB)-Ls- C5-C6carbocycle or 5- to 6-membered

[0133] heterocycle, such as, and is optionally substituted with one or more RA (e.g., one or more chloro or bromo). E preferably is a 7- to 12-

[0134] membered bicycle (such aswherein U is independently selected at each occurrence from -(CH2)- or -(NH)-; V and Z2o are each independently selected from Ci-C4alkylene, C2-C4alkenylene or C2-C4alkynylene, in which at least one carbon atom can be independently optionally replaced with O, S or N), and is independently optionally substituted with one or more RA. More preferably, Ri is Rc, and R2and R5, taken together with the atoms to which they are attached, form a 5- to 6-membered

[0136] is optionally substituted with one or more RA(such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C6alkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)); and R3and R6are each independently Rc, and R4and R7, taken together with the atoms to which they are attached, form a 5-

[0137] to 6-membered carbocycle / heterocycle or 6- to 12-membered bicycle (e.g.,

[0138] which is optionally substituted with one or more RA(such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C6alkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)).Y can also be selected from -M-C(RiR2)N(R5)-C(0)-LY'-M'-RD, -M-C(RIR2)N(R5)-LY'- M'-RD, -Ls-C(R1R2)N(R5)-C(0)-LY'-M'-RD, -LS-C(R1R2)N(R5)-LY'-M'-RD, -M- C(R3R4)C(R6R7)-C(0)-LY'-M'-RD, -M-C(R3R4)C(R6R7)-LY'-M'-RD, -LS-C(R3R4)C(R6R7)-C(0)- LY'-M'-Rd, or -LS-C(R3R4)C(R6R7)-LY'-M'-Rd, wherein M preferably is bond, -C(0)N(RB)- or - N(RB)C(0)-, M' preferably is bond, -C(0)N(RB)-, -N(RB)C(0)-, -N(RB)C(0)0-, N(RB)C(0)N(RB')-, -N(RB)S(0)- or -N(RB)S(0)2- and LY' preferably is C C6alkylene which is optionally substituted with one or more RL. LY', for exampl is a Ci-C6alkylene such as, but not

[0139] limited to,and the optional RLis a substituent such as, but not limited to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon within the group LY' can be either (R) or (S). More preferably, Ri is Rc, and R2and R5, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-

[0140] membered bicycle (e.g.,which is optionally substituted with one or more RA(e.g., one or more hydroxy); and R3 and R6 are each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle / heterocycle

[0141] or 6- to 12-membered bicycle (e.g.,is optionally substituted with one or more RA.

[0142] Also preferably, Y is selected from -N(RB)CO-C(RiR2)N(R5)-C(0)-LY'-N(RB)C(0)0-RD, - N(RB)CO-C(R1R2)N(R5)-C(0)-LY'-N(RB)C(0)-RD, -N(RB)CO-C(R1R2)N(R5)-C(0)-LY'- N(RB)S(0)2-RD, -N(RB)CO-C(R1R2)N(R5)-C(0)-LY'-N(RBRB')-RD, -N(RB)CO-C(R!R2)N(R5)- C(0)-LY'-0-RD, -N(RB)CO-C(RIR2)N(R5)-C(0)-LY'-RD, -N(RB)CO-C(RIR2)N(R5)-RD, -LS- C(R1R2)N(R5)-C(0)-LY'-N(RB)C(0)0-RD, -LS-C(R1R2)N(R5)-C(0)-LY'-N(RB)C(0)-RD, -LS- C(R1R2)N(R5)-C(0)-LY'-N(RB)S(0)2-RD, -LS-C(R1R2)N(R5)-C(0)-LY'-N(RBRB')-RD, -LS- C(R1R2)N(R5)-C(0)-LY'-0-RD, — LS-C(RIR2)N(R5)-C(0)— LY'— RD, -LS-C(R!R2)N(R5)-RD, - N(RB)CO-C(R3R4)C(R6R7)-C(0)-LY'-N(RB)C(0)0-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(0)-LY'- N(RB)C(0)-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(0)-LY'-N(RB)S(0)2-RD, -N(RB)CO-

[0143] C(R3R4)C(R6R7)-C(0)-LY'-N(RBRB')-RD, -N(RB)CO-C(R3R4)C(R6R7)-C(0)-LY'-0-RD, N(RB)CO-C(R3R4)C(R6R7)-C(0)-LY'-RD, -N(RB)CO-C(R3R4)C(R6R7)-RD, -LS-C(R3R4)C(R6R7)- C(0)-LY'-N(RB)C(0)0-RD, -LS-C(R3R4)C(R6R7)-C(0)-LY'-N(RB)C(0)-RD, -LS-

[0144] C(R3R4)C(R6R7)-C(0)-LY'-N(RB)S(0)2-RD, -LS-C(R3R4)C(R6R7)-C(0)-LY'-N(RBRB')-RD, -LS-C(R3R4)C(R6R7)-C(0)-LY'-0-RD, -LS-C(R3R4)C(R6R7)-C(0)-LY'-Rd, or -LS-C(R3R4)C(R6R7)- RD, wherein LY' preferably is Ci-C6alkylene which is optionally substituted with one or more RL. Ri may be Rc, and R2 and R5, taken together with the atoms to which they are attached, may form a 5- to

[0145] 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA; and R3 and R6 may be each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, may form a 5- to 6-membered

[0146] carbocycle / heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA.

[0147] Highly preferably, Y is selected from -N(RB")CO-C(RIR2)N(R5)-C(0)-LY-N(RB")C(0)- LS-REor -C(R1R2)N(R5)-C(0)-LY-N(RB")C(0)-LS-Re, or Y is -G-C(RiR2)N(R5)-C(0)-LY- N(RB")C(0)-Ls-RE, wherein LYis Ci-C6alkylene optionally substituted with one or more RL, and RB" is each independently RB. RB" and Ri are each preferably hydrogen or Ci-C6alkyl, and R2and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered

[0148] heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA(such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C6alkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)). Preferably, LYis Ci-C6alkylene substituted with one or more RLsuch as a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. Hig preferably, i-C6alkylene such as, but not limited to,, or(stereochemistry at a carbon within the group LYcan be either (R) or (S)), LYis independently optionally substituted with one or more RL(e.g., one or more phenyl or methoxy), Gpreferably is; Lsis a bond; and REis methoxy.

[0151] wherein T and RDare as defined herein. T, for example, can be -Ls-M-Ls'-M'-Ls"- w Lsis a bond; M is C( ' is Ci-C6alkylene such as, but not limited to, ,, or , where Ls' is independently optionally substituted with one or more RL; RL is a substituent such as, but not limited to phenyl or methoxy; M' is -NHC(O)- or -NMeC(O)-; and Ls" is a bond. Any stereochemistry at a carbon within the grou Ls' can be either (R) or (S). RD, for

[0152] example is methoxy. T-RDincludes, but is not limited to:

[0153] T-RDmay also include certain stereochemical configurations; thus T-RD includes, but is not limited

[0155] Non-limiting examples of preferred Y also include:

[0157] Z is preferably selected from -LS-C(R8R9)N(R12)-T-RD, -LS-C(R10Rn)C(Ri3Ri4)-T-RD, - G-C(R8R9)N(R12)-T-RD, -G-C(R10R„)C(R13R14)-T-RD, -N(RB)C(0)C(R8R9)N(R12)-T-RD, -N(RB)C(O)C(R10Rn)C(R13R14)-T-RD, -C(0)N(RB)C(R8R9)N(R12)-T-RD,

[0158] C(0)N(RB)C(R1oRn)C(R13R14)-T-RD, -N(RB)C(0)-Ls-E, or -C(0)N(RB)-Ls- G is C5-

[0159] or, and is optionally substituted with one or more RA(e.g., one or more chloro or bromo).

[0160] E preferably is a 8- to 12-membered bicycle (such aswherein U is independently selected at each occurrence from -(CH2)- or -(NH)-; and V and Z20are each independently selected from Ci-C4alkylene, C2-C4alkenylene or C2-C4alkynylene, in which at least one carbon atom is independently optionally replaced with O, S or N), and is independently optionally substituted with one or more RA. More preferably, R8is Rc, and R9and R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-membered bic cle (e.g.,

[0161] ) which is optionally substituted with one or more RA(such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C6alkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)); and Rio and R13 are each independently Rc, and Rn and RM, taken together with the atoms to which th

[0162] or 6- to 12-membered bicycle (e.g.,

[0163] one or more RA (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-Cealkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)).

[0164] Z can also be selected from -M-C(R8R9)N(R12)-C(0)-LY'-M'-RD, -M-C(R8R9)N(R12)-LY'- M'-RD, -Ls-C(R8R9)N(R12)-C(0)-LY'-M'-RD, -LS-C(R8R9)N(R12)-LY'-M'-RD, -M- C(R10Rn)C(R13R14)-C(O)-LY'-M'-RD, -M-C(R10R„)C(R13R14)-LY'-M'-RD, -Ls-C(RIORII)C(RI3RI4)-C(0)-LY'-M'-Rd, or -LS-C(RIORII)C(RI3RI4)-LY'-M'-RD, wherein M preferably is bond, -C(0)N(RB)- or -N(RB)C(0)-, M' preferably is bond, -C(0)N(RB)-, - N(RB)C(0)-, -N(RB)C(0)0-, N(RB)C(0)N(RB')- -N(RB)S(0)- or -N(RB)S(0)2- and LY' preferably is Ci-C6alkylene which is independently optionally substituted wit one or more RL. LY', for example,6alkylene such as, but not limited to, ,, or ; and the optional RLis a substituent such as, but not limited to phenyl, -

[0165] SMe, or methoxy. Any stereochemistry at a carbon within the group LY' can be either (R) or (S). More preferably, R8is Rc, and R9 and R12, taken together with the atoms to which they are attached,

[0166] 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,orwhich is optionally substituted with one or more RA(e.g., one or more hydroxy); and Rio and R13 are each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle / heterocycle or 6- to 12-membered bicycle (e.g.,is optionally substituted with one or more RA.

[0167] Also preferably, Z is selected from -N(RB)CO-C(R8R9)N(R12)-C(0)-LY'-N(RB)C(0)0-RD, -N(RB)CO-C(R8R9)N(R12)-C(0)-LY'-N(RB)C(0)-RD, -N(RB)CO-C(R8R9)N(R12)-C(0)-LY'- N(RB)S(0)2-RD, -N(RB)CO-C(R8R9)N(R12)-C(0)-LY'-N(RBRB')-RD, -N(RB)CO-C(R8R9)N(R12)- C(0)-LY'-0-RD, -N(RB)CO-C(R8R9)N(R12)-C(0)-LY'-RD, -N(RB)CO-C(R8R9)N(R12)-RD, -Ls- C(R8R9)N(R12)-C(0)-LY'-N(RB)C(0)0-RD, -Ls-C(R8R9)N(R12)-C(0)-LY'-N(RB)C(0)-RD, -Ls- C(R8R9)N(R12)-C(0)-LY'-N(RB)S(0)2-RD, -LS-C(R8R9)N(R12)-C(0)-LY'-N(RBRB')-RD, -LS- C(R8R9)N(R12)-C(0)-LY'-0-RD, -Ls-C(R8R9)N(R12)-C(0)-LY'-RD, -LS-C(R8R9)N(R12)-RD, - N(RB)CO-C(R10Rn)C(R13R14)-C(O)-LY'-N(RB)C(O)O-RD, -N(RB)CO-C(R10Rn)C(R13R14)-C(O)- LY'-N(RB)C(0)-RD, -N(RB)CO-C(R1oRn)C(R13R14)-C(0)-LY'-N(RB)S(0)2-RD, -N(RB)CO- C(RioRn)C(Ri3Ri4)-C(0)— LY'— N(RBRB')—¾, -NiRB^O-CiR!oRi CiR^RM^CiO^W-O-RD, - N(RB)CO-C(R10Rn)C(R13R14)-C(O)-LY'-RD, -N(RB)CO-C(R10Rn)C(R13R14)-RD, -Ls- C(R10Rn)C(R13R14)-C(O)-LY'-N(RB)C(O)O-RD, -Ls-C(R10Rn)C(R13R14)-C(O)-LY'-N(RB)C(O)-RD, -LS-C(RIORI I)C(RI3RI4)-C(0)-LY'-N(RB)S(0)2-RD, -LS-C(RIORH)C(RI3RI4)-C(0)-LY'- N(RBRB')-RD, -LS-C(R10R„)C(R13R14)-C(O)-LY'-O-RD, -Ls-C(R10Rn)C(R13R14)-C(O)-LY'-RD, or -Ls-C(Ri0Rn)C(Ri3Ri4)-RD, wherein LY' preferably is Ci-C6alkylene which is independently optionally substituted with one or more RL. R8may be Rc, and R9and R12, taken together with the atoms to which they are attached, may form a 5- to 6-membered heterocycle or 6- to 12-membered

[0168] bicycle (e.g.,which is optionally substituted with one or more RA; and

[0169] Rio and R13 may be each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, may form a 5- to 6-membered carbocycle / heterocycle or 6- to 12-membered bicycleis optionally substituted with one or more RA.

[0170] Highly preferably, Z is selected from -N(RB")CO-C(R8R9)N(RI2)-C(0)-LY-N(RB")C(0)- LS-REor -C(R8R9)N(R12)-C(0)-LY-N(RB")C(0)-LS-Re, or Z is -G-C(R8R9)N(R12)-C(0)-LY- N(RB")C(0)-LS-RE, wherein LYis Ci-C6alkylene optionally substituted with one or more RL, and RB" is each independently RB. RB" and R8are each preferably hydrogen or Ci-C6alkyl, and R9and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered

[0171] heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA(such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C6alkyl (e.g., methyl), or C2-C6alkenyl (e.g., allyl)). Preferably, LYis Ci-C6alkylene substituted with one or more RLsuch as a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- Cealkenyl, C2-C6alk nyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. Hig preferably, i-C6alkylene such as, but not limited to,, or(stereochemistry at a carbon within the group LYcan be either (R) or (S)); LYis independently optionally substituted with one or more RL(e.g., one or more phenyl or methoxy); G

[0172] methoxy.

[0173] Non-limiting examples of preferred Z include:

[0174] V Y-NHQ I.J V-NHQ I- V-NHQ I V v-NHtf | V γ-NH-Φ |

[0175] ¾T-^R ¾ T-^R ¾ T-^R ¾ T-^R ¾ T-^R

[0176] D DDD KD

[0177] wherein T and RDare as defined herein. T, for example, can be -Ls-M-Ls'-M'-Ls"- w Lsis a bond; M is C( ' is Ci-C6alkylene such as, but not limited to, ,

[0178] , or , where Ls' is independently optionally substituted with one or more RL; the optional RLis a substituent such as, but not limited to phenyl or methoxy; M' is -NHC(O)- or - NMeC(O)-; and Ls" is a bond. Any stereochemistry at a carbon within the group Ls' can be either

[0179] (R) or (S). RD, for example is methoxy. T-RDincludes, but is not limited to:,. T-RDmay also include certain stereochemical configurations; thus T-RD includes,Non-limitin examples of preferred Z also include:

[0182] T can be, without limitation, independently selected at each occurrence from -C(0)-Ls'-, - C(0)0-LS'-, -C(0)-LS'-N(RB)C(0)-LS"-, -C(0)-LS'-N(RB)C(0)0-LS"-, -N(RB)C(0)-LS'- N(RB)C(0)-LS"-, -N(RB)C(0)-LS'— N(RB)C(0)0-Ls"-, or -N(RB)C(0)-LS'— N(RB)-LS"-. Preferably, T is independently selected at each occurrence from -C(0)-Ls'-M'-Ls"- or - N(RB)C(0)-Ls'-M'-Ls"-. More preferably, T is independently selected at each occurrence from - C(0)-LS'-N(RB)C(0)-Ls"- or -C(0)-LS'-N(RB)C(0)0-LS"-.

[0183] example, -Ls-M-Ls'-M'-Ls"- where Lsis a bond; M is C(O); Ls' is Ci-where Ls' is independently optionally substituted with RT; the optional

[0184] RTis a substituent selected from -Ci-C6alkyl, -C2-C6alkenyl, -Ci-C6alkyl-OH, -Ci-C6alkyl-0-Ci- C6alkyl, 3- to 6-membered heterocycle (e.g., tetrahydrofuranyl), or C3-C6carbocyclyl (e.g., phenyl, cyclohexyl); M' is -NHC(O)-, -N(Et)C(0)- or -N(Me)C(0)-; and Ls" is a bond. RDpreferably is hydrogen, -Ci-C6alkyl (e.g., methyl), -0-Ci-C6alkyl (e.g., methoxy, tert-butoxy), methoxymethyl, or -Nid-Cealkyfh (e.g., -NMe2).

[0185] , or , wherein the stereochemistry at a carbon within the group T-

[0186] RDcan be either (R) or (S).

[0187] T can also be, without limitation, -Ls-M-Ls'- where Lsis a bond; M is C(O); Ls' is d-

[0188] Cealkylene (e.g., ) where Ls' is independently optionally substituted with RT; the optional

[0189] RTis a substituent selected from -Ci-C6alkyl, -Ci-C6alkyl-OH, -Ci-C6alkyl-0-Ci-C6alkyl, or a C3- C6carbocyclyl (e.g., phenyl, cyclohexyl). RD, for example is -OH; -OC(0)Me; -NH(Ci-C6alkyl) (e.g., -NHMe, -NHEt); -N(Ci-C6alkyl)2(e.g., -NMe2, -NEt2); a 3- to 10-membered heterocyclyl (e.g., pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, mo holinyl, piperidinyl) optionally substituted with one or more halogen, oxo; C3-Ci0carbocycle (e.g., cyclopentyl) optionally substituted with -OH; -Ci-C6alkyl (e.g., isopropyl, 3-pentyl) optionally substituted with -OH; or NHRTwhere RTis a 3- to 6-membered heterocyclyl (e.g., thiazolyl, pyrimidinyl). T-RDincludes, but is not limited to:

[0190] , wherein the stereochemistry at a carbon within the group T-RD can be either (R) or (S).

[0191] For each compound of Formula I, LKcan also be independently selected at each occurrence from a bond; -Ls'-N(RB)C(0)-Ls-; -Ls'-C(0)N(RB)-Ls-; or C C6alkylene, C2-C6alkenylene, C2- C6alkynylene, C3-Ci0carbocycle or 3- to 10-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, RT>- 0-Rs, -S-Rs, -N(RSRS'), -OC(0)Rs, -C(0)ORs, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, wherein RT, RB, Rs, Rs', Lsand Ls' are as defined above.

[0192] For Formula I as well as Formulae IA, ¾, Ic, ID, IE, IF or IGdescribed below, including each and every embodiment described thereunder, RApreferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-Cealkyl, C2-C6alkenyl or C2- Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl; or -LA-0-Rs, -LA-S-RS, -LA-C(0)Rs, -LA-OC(0)Rs, -LA-C(0)ORs, — LA— N(RSRS'), -LA-S(0)Rs, -LA-S02Rs, -LA-C(0)N(RsRs'), -LA-N(Rs)C(0)Rs', -LA- N(Rs)C(0)N(Rs'Rs"), -LA-N(Rs)S02Rs', -LA-S02N(RsRs'), -LA-N(Rs)S02N(Rs'Rs"), -LA- N(Rs)S(0)N(Rs'Rs"), -LA-OS(0)-Rs, -LA-OS(0)2-Rs, -LA-S(0)2ORs, -LA-S(0)ORs, — LA— OC(0)ORs, -LA-N(Rs)C(0)ORs', -LA-OC(0)N(RsRs'), -LA-N(Rs)S(0)-Rs', -LA-S(0)N(RsRs') or -LA-C(0)N(Rs)C(0)-Rs', wherein LAis bond, Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0193] More preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0194] Highly preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of whichis independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

[0195] Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0196] A and B can be the same or different. Likewise, Li and L2, or Y and Z, or Y-A- and Z-B-, or -A-Li- and -B-L2-, can be the same or different. In some instances, Y-A-Li- is identical to Z- B-L2-. In some other instances, Y-A-Li- is different from Z-B-L2-.

[0197] In one embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as \== / ¾), and are each independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle

[0198] (e.g.,wherein X3is N and is directly linked to -L3-D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D is C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6- membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2- C6haloalkynyl, C(0)ORsor -N(RSRS'), J can also be optionally substituted with one or more RA.

[0199] Preferably, D isor , wherein RMand RNare as defined above. Also

[0200] preferably, D iswherein J and RNare as defined above. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and LuL2, and L3are each independently optionally substituted with one or more RL. Preferably, Li, L2, and L3are bond.

[0201] Y is -N(RB)C(0)C(RiR2)N(R5)-T-RD, or -N(RB)C(0)C(R3R4)C(R6R7)-T-RD, and Z is -

[0202] N(RB)C(0)C(R8R9)N(R12)-T-RD, or -N(RB)C(0)C(R1oRn)C(R13R14)-T-RD. Ri is Rc, and R2and R5,taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring

[0203] (e.g.,which is optionally substituted with one or more RA; R3 and R6are each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 5-

[0204] to 6-membered carbocyclic or heterocyclic ring (e.g.,which is optionally substituted with one or more RA. RS is Rc, and R9 and R12, taken together with the atoms to which they are

[0205] attached, form a 5- to 6-membered heterocyclic ring (e.g.,which is optionally substituted with one or more RA; and Rio and R13 are each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

[0206] heterocyclic ring (ch is optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"- or -C(O)- LY'-N(RB)C(0)0-Ls"-. L ' is each independently Ls' and, preferably, is each independently Ci-

[0207] C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(0)-LY'-Ls"-, -C(0)-LY'-0- Ls"- -C(0)-LY'-N(RB)-Ls"-, or -C(0)-LY'-N(RB)S(0)2-Ls"-. In some cases, at least one of Y

[0208] and Z is, or both Y and Z are independently,, wherein non-limiting examples of RDinclude (1) -0-Ci-C6alkyl, -0-C2-C6alkenyl, -0-C2-C6alkynyl, Ci-C6alkyl, C2- Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle; or (2) C3-C6carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-Cehaloalkynyl; and non-limiting examples of LY' include Ci-Cealkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -0-Ci-C6alkyl, -0-C2-C6alkenyl, -0-C2-C6alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl,

[0209] In another embodiment, A is nd is optionally substituted with one or more RA; B isor and is optionally substituted with one or more RA. Zi is independently selected at each occurrence from O, S, NH dependently selected at each occurrence from N or CH. Preferably, AA and B are substituted with one or more halogen, such as F A and / or B are halo-substituted benzimidazole (e.g., A is

[0210] and B is), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. X is 5- or 6-

[0211] membered carbocycle or heterocycle or 6- to 12-membered bicycle (e.g.,orX3is N and is directly linked to -L3-D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D is C5-C6carbocycle or 5- to 6- membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Preferably, D iswherein RMand RNare as defined above. Also preferably, D is

[0212] erein J and RNare as defined above. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, LuL2, and L3are bond. Y is - LS-C(R1R2)N(R5)-T-RDor -LS-C(R3R4)C(R6R7)-T-RD, and Z is -LS-C(R8R9)N(R12)-T-RDor -Ls- C(RioRn)C(Ri3Ri4)-T-RD. Ri is Rc, and R2and R5, taken together with the atoms to which they are

[0213] attached, form a 5- to 6-membered heterocyclic ring (e.g.,which is optionally substituted with one or more RA; R3 and R6 are each independently Rc, and R4 and R7, taken together with the atoms to which the are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring

[0214] (e.g.,optionally substituted with one or more RA. RS is Rc, and R9 and Ri2, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ringwhich is optionally substituted with one or more RA; and Rio and Ri3are each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a

[0215] 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,which is optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-LY'- N(RB)C(0)-Ls"- or -C(0)-LY'-N(RB)C(0)0-Ls"-. LY' is each independently Ls' and, preferably, is independently Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(0)-LY'-Ls"-, -C(0)-LY'-0- Ls"-, -C(0)-LY'-N(RB)-Ls"-, or -C(0)-LY'-N(RB)S(0)2-Ls"-. In some cases, at least one of Yand Z is, or both Y and Z are independently,, wherein non-limiting examples of RDinclude (1) -O-Ci-Cealkyl, -(XVCealkenyl, -0-C2-C6alkynyl, Ci-Cealkyl, C2- Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle; or (2) C3-C6carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-Cehaloalkynyl; and non-limiting examples of LY' include Ci-C6alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -0-Ci-C6alkyl, -0-C2-C6alkenyl, -0-C2-C6alkynyl, or 3- to 6- membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0216] are each independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle

[0217] or heterocycle or 6- to 12-membered bicycle (e.g.,wherein X3is N and is directly linked to -L3-D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D can be, for example, C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor - N(RSRS'), and J can also be optionally substituted with one or more RA. Preferably, D iswherein RMand RNare as defined above. Also preferably, D is

[0218] erein J and RNare as defined above. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, LuL2, and L3are bond. Y is - G-C(RiR2)N(R5)-T-RDor -G-C(R3R4)C(R6R7)-T-RD, and Z is -G-C(R8R9)N(R12)-T-RDor -G- C(RioRn)C(Ri3Ri4)-T-RD. G is independently C5-C6carbocycle or 5- to 6-membered heterocycle, such as, and is independently optionally substituted with one or more RA. Ri is Rc, and R2and R5, taken together with the atoms to which they are attached, form a 5- to 6-

[0219] membered heterocyclic ring (e.g.,which is optionally substituted with one or more RA;

[0220] R3and R6 are each independently RC, and R4 and R7, taken together with the atoms to which they are

[0221] attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,which is optionally substituted with one or more RA. RSis Rc, and R9 and Ri2, taken together with the atoms to

[0222] which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,which is optionally substituted with one or more RA; and Rio and Ri3are each independently Rc, and Rn and Ri4, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

[0223] heterocyclic ring (e.g.,ch is optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"- or -C(O)- LY'-N(RB)C(0)0-Ls"-. LY' is each independently Ls' and, preferably, is each independently Ci-Cealkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(0)-LY'-Ls"-, -C(0)-LY'-0- Ls"- -C(0)-LY'-N(RB)-Ls"-, or -C(0)-LY'-N(RB)S(0)2-Ls" one of Y

[0224] and Z are independently,or, wherein non-limiting examples of RDinclude (1) -0-Ci-C6alkyl, -O- C2-C6alkenyl, -0-C2-C6alkynyl, Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle; or (2) C3-C6carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- Cehaloalkenyl or C2-Cehaloalkynyl; and non-limiting examples of LY' include Ci-Cealkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Q- C6alkyl, -0-C2-C6alkenyl, -0-C2-C6alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.

[0225] In yet another embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as \== / ¾), and are each independently optionally substituted with one or more RA. X is 5- or 6-membered carbocycle or

[0226] heterocycle or 6- to 12-membered bicycle (e.g.,or , wherein X3is N and is directly linked to -L3-D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D can be, for example, C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with Jand optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Preferably, D is

[0227] , wherein RMand RNare as defined above. Also preferably, D is

[0228] swherein J and RNare as defined above. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, LuL2, and L3are bond. Y is - N(RB)C(0)C(RIR2)N(R5)-T-Rdor -N(Rb)C(0)C(R3R4)C(R6R7)-T-RD, and Z is -G-C(R8R9)N(Ri2)- T-RDor -G-C(RioRn)C(Ri3Ri4)-T-RD; or Y is -G-C(RiR2)N(R5)-T-RDor -G-C(R3R4)C(R6R7)-T- RD, and Z is -N(RB)C(0)C(R8R9)N(R12)-T-RDor -N(RB)C(O)C(R10Rn)C(R13R14)-T-RD. Ri is Rc, and R2and R5, taken together with the atoms to which they are attached, form a 5- to 6-membered

[0229] eterocyc c r ng e.g., w c s opt ona y su st tute w t one or more RA;

[0230] are each independently Rc, and R4and R7, taken together with the atoms to which they are attached,

[0231] form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,which is optionally substituted with one or more RA. RS is Rc, and R9 and Ri2, taken together with the atoms to which

[0232] they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,which is optionally substituted with one or more RA; and Rio and Ri3are each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic orheterocyclic ring (e.g.,which is optionally substituted with one or more RA. independently C5-C6carbocycle or 5- to 6-membered heterocycle, such as

[0233] and is independently optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"- or -C(0)-LY'-N(RB)C(0)0-Ls"-.

[0234] ' is each independently Ls' and, preferably, is each independently Ci-C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(0)-LY'-Ls"-, -C(0)-LY'-0-Ls"-, -C(0)-LY'-N(RB)-Ls"-, '-N(RB)S(0)2-Ls"-. In some cases, Y isas described above,

[0236] In still another embodiment, A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl

[0237] is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as¾\= / ¾). A and B are each independently optionally substituted with one or more RA. Zi is independently selected at each occurrence from O, S, NH or CH2; and Z2is independently selected at each occurrence from N or CH.

[0238] X is 5- or 6-membered carbocycle or heterocycle or 6- to 12-membered bicycle (e.g.,

[0239] or, wherein X3is N and is directly linked to -L3-D) and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. D is C5-C6carbocycle or 5- to 6- membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Preferably, D is

[0240] s wherein RMand RNare as defined above. Also preferably, D is

[0241] herein J and RNare as defined above. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, LuL2, and L3are bond. When

[0242] A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as \== / ¾), Y is N(RB)C(0)C(R!R2)N(R5)-T-RD, -N(RB)C(0)C(R3R4)C(R6R7)-T-RD, -G-C(R!R2)N(R5)-T-Rdor - G-C(R3R4)C(R6R7)-T-RD, and Z is -LS-C(R8R9)N(R12)-T-RDor

[0243] When B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl

[0244] C(RiR2)N(R5)-T-RDor -LS-C(R3R4)C(R6R7)-T-RD, and Z is -N(RB)C(0)C(R8R9)N(R12)-T-RD,N(RB)C(0)C(RioRn)C(Ri3Ri4)-T-RD, -G-C(R8R9)N(R12)-T-RDor -G-C(R10RH)C(RI3RI4)-T-RD. Ri is Rc, and R2 and R5, taken together with the atoms to which they are attached, form a 5- to 6-

[0245] membered heterocyclic ring (e.g.,which is optionally substituted with one or more RA;

[0246] R3and R6 are each independently RC, and R4 and R7, taken together with the atoms to which they are

[0247] attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,which is optionally substituted with one or more RA. RS is Rc, and R9 and R12, taken together with the atoms to

[0248] which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,which is optionally substituted with one or more RA; and Rio and R13 are each independently Rc, and Rn and Ri4, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

[0249] heterocyclic ring (e.g.,is optionally substituted with one or more RA. G is independently C5-C6carbocycle or 5- to 6-membered heterocycle, such as

[0250] and is independently optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"- or -C(0)-LY'-N(RB)C(0)0-Ls"-. ' is each independently Ls' and, preferably, is each independently Ci-Cealkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(0)-LY'-Ls"-, -C(0)-LY'-0-Ls"-, -C(0)-LY'-N(RB)-Ls"-, or -C(0)-LY'-N(RB)S(0)2-Ls"-. In some cases when A is 5- or 6-membered carbocycle or

[0252] as described above, and Z isas described above. In some other cases when B is 5- or 6-membered

[0253] carbocycle or heterocycle (e.g., phenyl such as

[0254] described above, and Z isoras described above.

[0255] The present invention also features compounds of Formulae I, IA, ¾, Ic and IDas described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:

[0256] D is C3-Ci2carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more RA; or D is C3-Ci2carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more RA, where J is C3- Ci5carbocycle or 3- to 15-membered heterocycle (e.g., a 3- to 6-membered monocycle, a 6- to 12-membered fused, bridged or spiro bicycle, a 10- to 15-memberd tricycle containing fused, bridged or spiro rings, or a 13- to 15-membered carbocycle or heterocycle) and is optionally substituted with one or more RA, or J is -SF5; or D is hydrogen or RA;

[0257] RAis independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LB-RE; wherein two adjacent RA, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle;

[0258] LBis independently selected at each occurrence from Ls; or Ci-Ci0alkylene, C2-Ci0alkenylene or C2-Cioalkynylene, each of which optionally has 1 , 2, 3, 4 or 5 carbon atoms independently replaced with O, S or N(RB), and each of said Ci-Cioalkylene, C2- Ci0alkenylene or C2-Cioalkynylene being independently optionally substituted with one or more RL;

[0259] REis independently selected at each occurrence from -0-Rs, -S-Rs, -C(0)Rs, -OC(0)Rs, - C(0)ORs, -N(RsRs'), -S(0)Rs, -S02Rs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)N(Rs'Rs"), -N(Rs)S02Rs', -S02N(RsRs'), -N(Rs)S02N(Rs'Rs"), - N(Rs)S(0)N(Rs'Rs"), -OS(0)-Rs, -OS(0)2-Rs, -S(0)2ORs, -S(0)ORs, -OC(0)ORs, - N(Rs)C(0)ORs', -OC(0)N(RsRs'), -N(Rs)S(0)-Rs', -S(0)N(RsRs'), -P(0)(ORs)2, =C(RSRS'), or -C(0)N(Rs)C(0)-Rs'; or C C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-Ci2carbocycle or 3- to 12-membered heterocycle; or C3-Ci2carbocycle or 3- to 12-membered heterocycle (e.g., 7- to 12- membered carbocycle or heterocycle), each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, trimethylsilyl, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- Cghaloalkenyl, C2-C6haloalkynyl, -0-Rs, -S-Rs, -C(0)Rs, -C(0)ORs, or -N(RsRs').

[0260] RLis independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-Rs, -S-Rs, -C(0)Rs, -OC(0)Rs, -C(0)ORs, -N(RSRS'), - S(0)Rs, -S02Rs, -C(0)N(RsRs') or -N(Rs)C(0)Rs' ; or C3-Ci2carbocycle or 3- to 12- membered heterocycle (e.g., C3-C6carbocycle or 3- to 6-membered heterocycle), each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; wherein two adjacent RL, taken together with the atoms to which they are attached and any atoms between the atoms to which they are attached, can optionally form carbocycle or heterocycle.

[0261] In one embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (preferably, A and B are each independently phenyl such asand are each independently optionally substituted with one or more RA (preferably, A and B are each independently substituted with at least one halo such as F). X is 5- or 6-membered carbocycle or heterocycle or 6- to

[0262] 12-membered bicycle (preferably, X iswherein X3is N and is directly linked to -L3-

[0263] D), and is optionally substituted with one or more RA. D is a C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is substituted with J and optionally substituted with one or more RA. J is C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle, or 13- to 15-membered carbocycle / heterocycle, and J is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle / heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORsor -N(RSRS'), or (2) trimethylsilyl, -0-Rs, -S-Rs, -C(0)Rs; and J can also be optionally substituted with one or more RA.

[0264] Preferably, D isor•nbv, wherein J is as defined above, and each RNis independently selected from RDand preferably is hydrogen or halo such as F. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and LuL2, and L3are each independently optionally substituted with one or more RL. Preferably, Li, L2, and L3are bond. Y is -N(RB)C(0)C(R!R2)N(R5)-T-RD, -N(RB)C(0)C(R3R4)C(R6R7)-T-RD, -G-C(R!R2)N(R5)-T-RDor -G-C(R3R4)C(R6R7)-T-RD. Z is -N(RB)C(0)C(R8R9)N(R12)-T-RD,

[0265] N(RB)C(0)C(RioRn)C(Ri3Ri4)-T-RD, -G-C(R8R9)N(R12)-T-RDor -G-C(RioRn)C(Ri3Ri4)-T-RD. Ri is Rc; and R2and R5, taken together with the atoms to which they are attached, form a 5- to 6-

[0266] membered heterocyclic ring (e.g.,or 6- to 12-membered bicycle (e.g.,

[0267] which is optionally substituted with one or more RA; R3and R6 are each independently RC, and R4 and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

[0268] heterocyclic ring (e.g.,- to 12-membered bicycle which is optionally substituted with one or more RA. RS is Rc; and R9 and Ri2, taken together with the atoms to which they are

[0269] attached, form a 5- to 6-membered heterocyclic ring (e.g., to 12-membered bicycle

[0270] (e.g.,which is optionally substituted with one or more RA; and Rio and Ri3are each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a5- to 6-membered carbocyclic or heterocyclic ring (e.g.,or 6- to 12-membered bicycle which is optionally substituted with one or more R . G is independently C5-C6carbocycle or 5- to 6- membered heterocycle, such asand is independently optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-LY'- N(RB)C(0)-LS"- or -C(0)-LY'-N(RB)C(0)0-LS"- ' is each independently LS' and, preferably, is each independently Ci-C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(0)-LY'-Ls"- '-0-Ls"-, -C(0)- '-N(RB)-Ls"-, or -C(0)-LY'-N(RB)S(0)2-Ls"-. In some cases, Y

[0271] as described above.

[0272] In another embodiment, A is and is optionally substituted with one or more RA; B isor , and is optionally substituted with one or more RA. Zi is independently selected at each occurrence from O, S, NH or CH2; and Z2is independently selected at each occurrence from N or CH. Preferably, A and B are each independently substituted with at least one halo such as F. Also preferably, A isB isand A and B are substituted with one or more halogen, such as F or CI. When

[0273] halo-substituted benzimidazole (e.g., A isand B is), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. X is 5- or 6-

[0274] membered carbocycle or heterocycle or 6- to 12-membered bicycle (preferably, X is

[0275] wherein X3is N and is directly linked to -L3-D), and is optionally substituted with one or more RA. D is a C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is substituted with J and optionally substituted with one or more RA. J is C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle / heterocycle, and J is optionally substituted with one or more RA. Preferably, J is substituted with a C3- Cecarbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle / heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2- Cehaloalkynyl, -C(0)ORSor -N(RSRS'), or (2) trimethylsilyl, -0-RS, -S-RS, or -C(0)RS; and J can

[0276] also be optionally substituted with one or more RA. Preferably, D is

[0277] wherein J is as defined above, and each RNis independently selected from RDand preferably is hydrogen or halo such as F. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and LuL2, and L3are each independently optionally substituted with one or more RL. Preferably, LuL2, and L3are bond. Y is -Ls-C(RiR2)N(R5)-T-RDor -Ls- C(R3R4)C(R6R7)-T-RD. Z is¾ is Rc; and R2and R5, taken together with the atoms to which they are attached, form a 5- to 6-memberedheterocyclic ring (e.g.,or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA; R3 and R6 are each independently RC, and R4 and R7, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

[0278] heterocyclic ring (e.g.,or 6- to 12-membered bicycle which is optionally substituted with one or more RA. RS is Rc; and R9 and R12, taken together with the atoms to which they are

[0279] attached, form a 5- to 6-membered heterocyclic ring (e.g., to 12-membered bicycle

[0280] (e.g.,which is optionally substituted with one or more RA; and Rio and R13 are each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, form a

[0281] 5- to 6-membered carbocyclic or heterocyclic ring (e.g.,or 6- to 12-membered bicycle which is optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"- or -C(0)-LY'-N(RB)C(0)0-Ls"-. LY' is each independently Ls' and, preferably, is each independently Ci-C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. T can also be, without limitation, selected from -C(0)-LY'-Ls"-, -C(0)-LY'-0-Ls"-, -C( -LY'-N(RB)-Ls"-, or -

[0282] C(0)-LY'-N(RB)S(0)2-LS"-. In some cases, Y and Z are independently

[0283] or, wherein non-limiting examples of RDinclude (1) -0-Ci-C6alkyl, -0-C2-

[0284] C6alkenyl, -0-C2-C6alkynyl, Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which isindependently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle; or (2) C3-C6carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- Cehaloalkenyl or C2-C6haloalkynyl; and non-limiting examples of LY' include Ci-Cealkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -O-Q- C6alkyl, -0-C2-C6alkenyl, -0-C2-C6alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl or C2-C6haloalkynyl.

[0285] In another aspect, the present invention features compounds of Formula IA and pharmaceutically acceptable salts thereof.

[0287] IA

[0288] wherein:

[0289] RNB is each independently selected from RB;

[0290] Rc' is each independently selected from Rc;

[0291] RD' is each independently selected from RD;

[0292] R2and R5, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA;

[0293] R9and Ri2, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA;

[0294] A, B, D, X, Li, L2, L3, T, RA, RB, RC, and RDare as described above in Formula I.

[0295] In this aspect, A and B preferably are independently selected from C5-C6carbocycle or 5- to 6- membered heterocycle, and are each independently optionally substituted with one or more RA. More preferably, at least one of A and B is phenyl (e.g.,and is optionally substituted withone or more RA. Highly preferably, both A and B are each independently phenyl (e.g., \= / ¾), and are each independently optionally substituted with one or more RA.

[0296] D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 8- to 12- membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or more RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is substituted with one or more RM, where RMis halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE. Also preferably, D is phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more

[0297] RM, wherein RMis as defined above. Highly preferably, D iswherein RMis as defined above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F.

[0298] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

[0299] more RM. Highly preferably, D is, wherein RMis as defined above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, D

[0300] iss an(j jsoptionally substituted with one or more RM.

[0301] Preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl orcyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, RMis halogen, hydroxy, mercapto, amino, carboxy; or Ci-C6alkyl, C2-C6alkenyl or C2- Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RMis Ci-C6alkyl which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

[0302] Also preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or RMis -LS-RE, wherein Lsis a bond or Ci-C6alkylene, and REis - N(RSRS'), -O-Rs, -C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)ORs', - N(Rs)S02Rs', -S02Rs, -SRs, or -P(0)(ORs)2, wherein Rsand Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-Cealkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Q-Cealkyl or 3- to 6-membered heterocycle; or RMis Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORs, or - N(RSRS'). More preferably, RMis halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RMis CF3, - C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RMis -Ls- REwhere Lsis a bond and REis -N(RSRS), -0-Rs, -N(Rs)C(0)ORs', -N(Rs)S02Rs', -S02Rs, or - SRS. For example where Lsis a bond, REis -N(Ci-C6alkyl)2(e.g., -NMe2); -N(Ci-C6alkylene-0-Ci- C6alkyl)2(e.g. -N(CH2CH2OMe)2); -N(Ci-C6alkyl)(Ci-C6alkylene-0-Ci-C6alkyl) (e.g. - N(CH3)(CH2CH2OMe));— 0-Ci-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n- hexyl); -0-C C6haloalkyl (e.g., - OCF3, -OCH2CF3); -0-Ci-C6alkylene-piperidine (e.g., -O- CH2CH2-l-piperidyl); -N(Ci-C6alkyl)C(0)OCi-C6alkyl (e.g., -N(CH3)C(0)0-CH2CH(CH3)2), - N(Ci-C6alkyl)S02Ci-C6alkyl (e.g., -N(CH3)S02CH3); -S02Ci-C6alkyl (e.g., -S02Me); -S02C Cehaloalkyl (e.g., -S02CF3); or -S-Ci-Cehaloalkyl (e.g., SCF3). Also preferably RMis -LS-REwhere Lsis Ci-C6alkylene (e.g., -CH2- -C(CH3)2-, -C(CH3)2-CH2-) and REis -0-Rs, -C(0)ORs, -N(Rs)C(0)ORs', or -P(0)(ORs)2. For example RMis -Ci-C6alkylene-0-Rs(e.g., -C(CH3)2-CH2- OMe); -Ci-C6alkylene-C(0)ORs(e.g., -C(CH3)2-C(0)OMe); -Ci-C6alkylene-N(Rs)C(0)ORs' (e.g., -C(CH3)2-CH2-NHC(0)OCH3); or -C1-C6alkylene-P(0)(ORs)2(e.g., -CH2-P(0)(OEt)2). Also more preferably RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, - C(0)ORs, or -N(RSRS'). For example RMis cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4-methoxycarbonylpiperazin-l -yl, pyrrolidin-1- yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RMis Ci-C6alkyl which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).

[0303] More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more RA, wherein J is C3- Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6- membered heterocycle, wherein said C3-C6carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D is C5- C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably, J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RSRS'). Also preferably, D is C5-C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more RA. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more RA, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is atleast substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6ha C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -

[0304] N(RSRS'). Highly preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor -

[0305] N(RSRS'). Also preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle or 3- to 6-membered heterocycle and is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -

[0306] N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D isand J is C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RsRs').X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered

[0307] bicycles (e.g.,, wherein X3is N and is directly linked to -L3-D), and is optionally substituted with one or more RA or RF. Non-limiting examples of X are described hereinabove.

[0308] Li and L2are preferably independently bond or Ci-C6alkylene, L3is preferably selected from bond, Ci-C6alkylene or -C(O)-, and LuL2, and L3are each independently optionally substituted with one or more RL. More preferably, LuL2and L3are each independently bond or Ci-C6alkylene (e.g., - CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly preferably, L L2and L3are bond.

[0309] R2and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-

[0310] membered heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA.

[0311] R9and Ri2, taken together with the atoms to which they are attached, preferably form a 5- to

[0312] 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA.

[0313] -T-RD' can be, without limitation, independently selected at each occurrence from -C(O)- LY'-, -C(0)0-LY'-RD', -C(0)-LY'-N(RB)C(0)-LS"-RD' , -C(0)-LY'-N(RB)C(0)0-LS"-RD', - N(RB)C(0)-LY'-N(RB)C(0)-LS"-RD', -N(RB)C(0)-LY'— N(RB)C(0)0-LS"-Rd', or -N(RB)C(0)- LY'— N(RB)-LS"-RD', wherei ' is each independently LS' and, preferably, is each independently Ci-C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. Preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'- M'-LS"-RD' or -N(RB)C(0)-LY'-M'-LS"-Rd' . More preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(0)-LY'-N(RB)C(0)0-LS"-RD' . Highly preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)- RD' or -C(0)- '-N(RB)C(0)0-RD' , wherein LY' preferably is each independently Ci-C6alkylene

[0314] (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL.RNB and Rc' are preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from Ci- Cealkyl, C2-Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0315] RApreferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; or -LA- 0-Rs, -LA-S-RS, -LA-C(0)Rs, -LA-OC(0)Rs, -LA-C(0)ORs, -LA-N(RSRS'), -LA-S(0)Rs,— LA— S02Rs, -LA-C(0)N(RsRs'), -LA-N(Rs)C(0)Rs', -LA-N(Rs)C(0)N(Rs'Rs"), -LA-N(Rs)S02Rs', - LA-S02N(RsRs'), -LA-N(Rs)S02N(Rs'Rs"), -LA-N(Rs)S(0)N(Rs'Rs"), -LA-OS(0)-Rs, — LA— OS(0)2-Rs, -LA-S(0)2ORs, -LA-S(0)ORs, -LA-OC(0)ORs, -LA-N(Rs)C(0)ORs', — LA— OC(0)N(RsRs'), -LA-N(Rs)S(0)-Rs', -LA-S(0)N(RsRs') or -LA-C(0)N(Rs)C(0)-Rs', wherein LAis bond, Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0316] More preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-Cealkyl, C2-Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0317] Highly preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0318] A and B can be the same or different. Likewise, Li and L2can be the same or different.

[0319] In one embodiment of this aspect, A and B are each independently phenyl, and are each independently optionally substituted with one or more RA; D is phenyl, and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6- membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2- C6haloalkynyl, C(0)ORsor -N(RSRS'), J can also be optionally substituted with one or more RA.

[0320] Preferably, D isor , wherein RMand RNare as defined above. Also

[0321] preferably, D iswherein J and RNare as defined above. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and LuL2, and L3are each independently optionally substituted with one or more RL. Preferably, Li, L2, and L3are bond. - T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(O)- LY'-N(RB)C(0)0-LS"-RD' , wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-LY'-LS"-RD', -C(0)-Ly'-0-LS"-RD', -C(0)-LY'-N(RB)- LS"-RD', or -C(0)-LY'-N(RB)S "-RD' . Preferably, R2and R5, taken together with the atoms

[0322] to which they are attached, formwhich is optionally substituted with one or more RA; Rg

[0323] and Ri2, taken together with the atoms to which they are attached, form

[0324] optionally substituted with one or more RA.ther embodiment of this aspect, A and B are each independently phenyl (e.g.,and are each independently optionally substituted with one or more RA(preferably, A

[0325] and B are each independently substituted with at least one halo such as F). X is

[0326] wherein X3is N and is directly linked to -L3-D, and X is optionally substituted with one or more RAor RF. D is phenyl, and is substituted with J and optionally substituted with one or more RA. J is C3- C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle / heterocycle, and J is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12- membered bicycle or 7- to 12-membered carbocycle / heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2- Cgalkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORsor -N(RSRS'), or (2) trimethylsilyl, -0-Rs, -S-R or -C 0 R and J can also be optionally substituted with one or more

[0327] RA. Preferably, D isin J is as defined above, and each RNis independently selected from RDand preferably is hydrogen or halo such as F. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and LuL2, and L3are each independently optionally substituted with one or more RL. Preferably, Li, L2, and L3are bond. - T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"-RD' or -C(O)- LY'-N(RB)C(0)0-Ls"-RD', wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-LY'-Ls"-RD', -C(0)-LY'-0-Ls"-RD', -C(0)-LY'-N(RB)- LS"-RD', or -C(0)-LY'-N(RB)S(0)2-Ls"-RD'. R2and R5, taken together with the atoms to which

[0328] they are attached, for 6-membered heterocyclic ring (e.g.,or 6- to 12-

[0329] membered bicycle (e.g.,which is optionally substituted with one or more RA; and R9and

[0330] Ri2, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclicring (e.g.,which is optionally substituted with one or more RA.

[0331] In still another aspect, the present invention features compounds of Formula IBand pharmaceutically acceptable salts thereof:

[0332] wherein:

[0333] Rc' is each independently selected from Rc;

[0334] RD' is each independently selected from RD;

[0335] R2and R5, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA;

[0336] R9and R12, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA;

[0337] A, B, D, X, Li, L2, L3, T, RA, Rc, and RDare as described above in Formula I.

[0338] In this aspect, A and B preferably are independently selected from 8- to 12-membered

[0339] bicycles such asorwhere Zi is independently selected at each occurrence from O, S, NH or CH2, Z2is independently selected at each occurrence from N or CH, Z3is independently selected at each occurrence from N or CH, Z4is independently selected at each occurrence from O, S, NH or CH2, and Wi, W2, W3, W4, W5and W6are each independently selected at each occurrence from CH or N. A and B are each independently optionally substituted with one or more RA.More preferably, A is selected from is

[0340] optionally substituted with one or moreRA; B is selected from orand is optionally substituted with one or more RA, where Zi, Z2, Z3, Z4, Wi, W2,

[0341] W3, W4, W5, W6are as defined above. Preferably, Z3is N and Z4is NH. For instance, A can be

[0343] e.g., , an swherein A' and B' are independently selected from

[0344] C5-C6carbocycle or 5- to 6-membered heterocycle, and A and B are independently optionally substituted with one or more RA.

[0345] More preferably, A isand A and B are substituted with one or more halogen, such as F or CI. When A and / or B are halo -substituted benzimidazole

[0346] (e.g., A isand B is ), the compounds of Formula IBcan have significantly improved pharmacokinetic properties as well as improved inhibitory activity againstcertain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole.

[0347] D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or more substituents selected from RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more RM, where RMis halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE. Also preferably, D is phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more R wherein R is as defined above. Highly preferably, D is

[0348] above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F.

[0349] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

[0350] more RM. Highly preferably, D is, wherein RMis as defined above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, D

[0351] is? an(j jg optionally substituted with one or more RM.

[0352] Preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independentlyoptionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, RMis halogen, hydroxy, mercapto, amino, carboxy; or Ci-C6alkyl, C2-C6alkenyl or C2- Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

[0353] Also preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or RMis -LS-RE, wherein Lsis a bond or Ci-C6alkylene, and REis - N(RSRS'), -O-Rs, -C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)ORs', - N(Rs)S02Rs', -S02Rs, -SRs, or -P(0)(ORs)2, wherein Rsand Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C6alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Ci-Cealkyl or 3- to 6-membered heterocycle; or RMis Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORs, or - N(RSRS'). More preferably, RMis halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RMis CF3, - C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RMis -Ls- REwhere Lsis a bond and REis -N(RSRS), -0-Rs, -N(Rs)C(0)ORs', -N(Rs)S02Rs', -S02Rs, or - SRS. For example where Lsis a bond, REis -N(Ci-C6alkyl)2(e.g., -NMe2); -N(Ci-C6alkylene-0-Ci- C6alkyl)2(e.g. -N(CH2CH2OMe)2); -N(Ci-C6alkyl)(Ci-C6alkylene-0-Ci-C6alkyl) (e.g. - N(CH3)(CH2CH2OMe));— 0-Ci-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n- hexyl); -0-C C6haloalkyl (e.g., - OCF3, -OCH2CF3); -0-Ci-C6alkylene-piperidine (e.g., -O- CH2CH2-l-piperidyl); -N(Ci-C6alkyl)C(0)OCi-C6alkyl (e.g., -N(CH3)C(0)0-CH2CH(CH3)2), - N(Ci-C6alkyl)S02Ci-C6alkyl (e.g., -N(CH3)S02CH3); -S02Ci-C6alkyl (e.g., -S02Me); -S02C C6haloalkyl (e.g., -S02CF3); or -S-Ci-C6haloalkyl (e.g., SCF3). Also preferably RMis -LS-REwhere Ls is Ci-Cealkylene (e.g., -CH2- -C(CH3)2-, -C(CH3)2-CH2-) and REis -O-Rs, -C(0)ORs, - N(Rs)C(0)ORs', or -P(0)(ORs)2. For example RMis -Ci-C6alkylene-0-Rs(e.g., -C(CH3)2-CH2-OMe); -Ci-C6alkylene-C(0)ORs(e.g., -C(CH3)2-C(0)OMe); -Ci-C6alkylene-N(Rs)C(0)ORs' (e.g., -C(CH3)2-CH2-NHC(0)OCH3); or -C1-C6alkylene-P(0)(ORs)2(e.g., -CH2-P(0)(OEt)2). Also more preferably RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, - C(0)ORs, or -N(RSRS'). For example RMis cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomo holin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxy carbonylpiperazin- 1 -yl, pyrrolidin- 1 - yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).

[0354] More preferably, D is Cs-Cecarbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more RA, wherein J is C3- Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6- membered heterocycle, wherein said C3-C6carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D is C5- C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is C3-Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably, J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RSRS'). Also preferably, D is C5-C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more RA. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more RA, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independentlyoptionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6ha C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor -

[0355] N(RSRS'). Highly preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor -

[0356] N(RSRS'). Also preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle or 3- to 6-membered heterocycle and is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor -

[0357] N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D isand J is C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RsRs').

[0358] X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered

[0359] bicycles (e.g.,, wherein X3is N and is directly linked to -L3-D), andis optionally substituted with one or more RA or RF. Non-limiting examples of X are described hereinabove.

[0360] Li and L2are preferably independently bond or Ci-C6alkylene, L3is preferably selected from bond, Ci-C6alkylene or -C(O)-, and LuL2, and L3are each independently optionally substituted with one or more RL. More preferably, LuL2and L3are each independently bond or Ci-C6alkylene (e.g., - CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly preferably, L L2and L3are bond.

[0361] R2and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-

[0362] membered heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA. R9 and Ri2, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA.

[0363] -T-RD' can be, without limitation, independently selected at each occurrence from -C(O)- LY'-RD', -C(0)0-LY'-RD', -C(0)-LY'-N(RB)C(0)-LS"-RD', -C(0)-LY'-N(RB)C(0)0-LS"-RD', - N(RB)C(0)-LY'-N(RB)C(0)-LS"-RD', -N(RB)C(0)-LY'— N(RB)C(0)0-LS"-Rd', or -N(RB)C(0)- LY'— (RB)-LS"-RD', wherei ' is each independently LS' and, preferably, is each independently

[0364] Ci-C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. Preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'- M'-LS"-RD' or -N(RB)C(0)-LY'-M'-LS"-Rd' . More preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(0)-LY'-N(RB)C(0)0-LS"-RD' . Highly preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)- RD' or -C(0)- '-N(RB)C(0)0-RD' , wherein LY' preferably is each independently Ci-C6alkylene

[0365] (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL.

[0366] RC' is preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from Ci-C6alkyl, C2- Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle;or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0367] RApreferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; or -LA- 0-Rs, -LA-S-RS, -LA-C(0)Rs, -LA-OC(0)Rs, -LA-C(0)ORs, -LA-N(RSRS'), -LA-S(0)Rs,— LA— S02Rs, -LA-C(0)N(RsRs'), -LA-N(Rs)C(0)Rs', -LA-N(Rs)C(0)N(Rs'Rs"), -LA-N(Rs)S02Rs', - LA-S02N(RsRs'), -LA-N(Rs)S02N(Rs'Rs"), -LA-N(Rs)S(0)N(Rs'Rs"), -LA-OS(0)-Rs, — LA— OS(0)2-Rs, -LA-S(0)2ORs, -LA-S(0)ORs, -LA-OC(0)ORs, -LA-N(Rs)C(0)ORs', — LA— OC(0)N(RsRs'), -LA-N(Rs)S(0)-Rs', -LA-S(0)N(RsRs') or -LA-C(0)N(Rs)C(0)-Rs', wherein LAis bond, Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0368] More preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0369] Highly preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

[0370] Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0371] A and B can be the same or different. Likewise, Li and L2can be the same or different.In one embodiment of this aspect, A is

[0372] optionally substituted with one o more RA>B isis optionally substituted with one or more RA; and D is C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor - '), and J ca be optionally substituted with one or more RA. Preferably, D is

[0373] s wherein RMand RNare as defined above. Also preferably, D is

[0374] or swherein J and RNare as defined above. Zi is independently selected at each occurrence from O, S, NH or CH2; and Z2is independently selected at each occurrence from Nand A and B are substituted with and / or B are halo-substituted benzimidazole (e.g., A isand B is ), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. Li and L2are each independently bond or Ci-Cealkylene, and L3is bond, Ci- C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, L L2, and L3are bond. -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"-RD' or -C(0)-LY'-N(RB)C(0)0-Ls"-RD', wherein LY' is CCealkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-LY'-Ls"- RD', -C(0)-LY'-0-LS"-RD', -C(0)-LY'-N(RB)-LS"-Rd', or -C(0)-LY'-N(RB)S(0)2-LS"-RD'.

[0375] In another embodiment of this aspect, A isand optionally substituted

[0376] with one or more RA(e.g., halogen); B isand is optionally substituted with one or more RA(e.g., halogen); and D is C5-C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12- membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci- C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor -N(RSRS'), and J can also be

[0377] optionally substituted with one or more RA. Preferably, D isor , wherein RM

[0378] and RNare as defined above. Also preferably, D iswherein J and RNare as defined above. When A and / or B are halo-substituted benzimidazole (e.g., A is

[0379] and B is), the compounds of this embodiment can have significantly improved pharmacokinetic properties as well as improved inhibitory activity against certain HCV genotype la mutants, as compared to the same compounds but with unsubstituted benzimidazole. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, Li, L2, and L3are bond. -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-Ls"-RD' or-C(0)-LY'-N(RB)C(0)0-LS"-RD', wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and LS" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-LY'-LS"-RD' , -C(0)-LY'-0-LS"-RD' , -C(0)-LY'- N(RB)-LS"-RD' , or -C(0)-LY'-N(RB)S(0)2-LS"-RD' . R2and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered

[0380] bicycle (e.g.,which is optionally substituted with one or more RA. R9 and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered

[0381] heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA. More preferably, R2 and R5, taken together with the atoms to which

[0382] they are attached, formwhich is optionally substituted with one or more R R9 and R12,

[0383] taken together with the atoms to which they are attached, forms optionally substituted with one or more RA.

[0384] In still another embodiment of this aspect, A isand optionally substituted ferably, A is substituted with at least one halogen such as F); B isoptionally substituted with one or more RA(preferably, B is substituted

[0385] with at least one halogen such as F). X is, wherein X3is N and is directly linked to -

[0386] L3-D, and X is optionally substituted with one or more RAor RF. D is phenyl, and is substituted with J and optionally substituted with one or more RA. J is C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle / heterocycle, and J is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to12-membered carbocycle / heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORsor -N(RSRS'), or (2) trimethylsilyl, -0-Rs, -S-Rsor - C(0)Rs; and J can also be optionally substituted with one or more RA. Preferably, D is

[0387] wherein J is as defined above, and each RNis independently selected from RDand preferably is hydrogen or halo such as F. Li and L2are each independently bond or Ci- C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, L L2, and L3are bond. -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(0)-LY'- N(RB)C(0)0-LS"-RD' , wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and LS" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-LY'-LS"-RD' , -C(0)-LY'-0-LS"-RD', -C(0)-LY'-N(RB)-LS"- RD', or -C(0)-LY'-N(RB)S(0)2-LS"-RD' . R2and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

[0388] which is optionally substituted with one or more RA. R9 and Ri2, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or

[0389] 6- to 12-membered bicycle (e.g.,is optionally substituted with one or m e preferably, R2and R5, taken together with the atoms to which they are attached,

[0390] formwhich is optionally substitut one or more RA; R9 and Ri2, taken together

[0391] with the atoms to which they are attached, formwhich is optionally substituted with one or more RA.The present invention unexpectedly found that a compound according to this aspect of the invention (preferably a compound of Formula IBor a pharmaceutically acceptable salt thereof, wherein A isand A and B are independently optionally substituted with one or more RAsuch as one or more halo) showed significantly improved activities against different HCV genotypes and variants. For instance, when tested against HCV replicons of different genotypes in stable cell lines (in the presence of 5% FBS), and as compared to Example 37 of U.S. Patent Application Publication No. 2010 / 0317568, the EC5o values of the compounds of Examples 3.48, 3.52, 4.38, and 5.1 were at least about 6-fold less than that of Example 37 against genotype la, at least about 3-fold less against genotype 3a, at least about 50-fold less against genotype 6a, and significantly less against genotype 2a. In addition, when tested against HCV genotype la replicons containing certain NS5A mutations in transient transfection assays, and as compared to Example 37 of U.S. Patent Application Publication No. 2010 / 0317568, the EC5o values of the compounds of Examples 3.48, 3.52, 4.38, and 5.1 were at least about 130-fold less than that of Example 37 against the L31V variant, at least about 7,500 fold less against the M28T variant, at least about 80-fold less against the M28V variant, at least about 500-fold less against the Q30E variant, at least about 300-fold less against the Q30R variant, at least about 800-fold less against the Y93C variant, at least about 1,500-fold less against the Y93H variant, and significantly less against the Q30H variant. Likewise, when tested against HCV genotype lb replicons containing certain NS5A mutations in transient transfection assays, and as compared to Example 37 of U.S. Patent Application Publication No. 2010 / 0317568, the EC5o value of the compound of Example 5.1 was at least about 10- fold less than that of Example 37 against the Y93H variant.

[0392] Accordingly, the present invention features methods of treating different HCV genotype or variant infection. The methods comprise administering a compound of Formula IB, or a pharmaceutically acceptable salt thereof, to a patient infected with HCV genotype la, lb, 2a, 2b, 3a, 4a, 5a or 6a, or infected with one of the variants described above. Preferably, A is

[0393] B isand A and B are independently optionally substituted with one or more RA such as one or more halo. Other compounds described in this aspect of the invention or any embodiment thereunder, as well as the title compounds in the Examples described below, may also be used. In one embodiment, the patient being treated is infected with HCV genotype 1, such as la. In another embodiment, the patient being treated is infected with HCV genotype 2, such as 2a. In still another embodiment, the patient being treated is infected with HCV genotype 3, such as 3a. In another embodiment, the patient being treated is infected with HCV genotype 4, such as 4a. In afurther embodiment, the patient being treated is infected with HCV genotype 5, such as 5 a. In another embodiment, the patient being treated is infected with HCV genotype 6, such as 6a.

[0394] In yet another aspect, the present invention further features compounds of Formula Icpharmaceutically acceptable salts thereof.

[0395] wherein:

[0396] RC' is each independently selected from RC;

[0397] RD' is each independently selected from RD;

[0398] R2and R5, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA;

[0399] R9and R12, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA;

[0400] A, B, D, X, Li, L2, L3, T, RA, RB, RC, and RDare as described above in Formula I.

[0401] In this aspect, A preferably is C5-C6carbocycle or 5- to 6-membered heterocycle, and is optionally substituted with one or more RA; and B preferably is 8- to 12-membered bicycle (such asor and is optionally substituted with one or more

[0402] RA. Zi is O, S, NH or CH2; Z2is N or CH; Z3is N or CH; Z4is O, S, NH or CH2; and Wi, W2, W3, W4, W5and W6are each independently selected from CH or N.

[0403] More preferably, A is phenyl (e.g.,and is optionally substituted with one or

[0404] more RA; and B isis optionally substituted with one or more RA, where Zi, Z2, Z3, Z4, Wi, W2, W3, W , W5, W6are as defined above. Preferably, Z3is N and Z4is NH. For instance, B can beorand is optionally substituted with one or more R A-

[0405] Also preferably, A is C

[0406] membered heterocycle; and B is' is selected from C5-C6carbocycle or 5- to 6-membered heterocycle. A and B are independently optionally substituted with one or more RA.

[0407] D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or more substituents selected from RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more RM, where RMis halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE. Also preferably, D is phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more RM, wherein RMis as defined above. Highly preferably, D is

[0408] above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F.

[0409] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

[0410] more RM. Highly preferably, D is, wherein RMis as defined above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, Dis, or , and is optionally substituted with one or more RM.

[0411] Preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, RMis halogen, hydroxy, mercapto, amino, carboxy; or Ci-C6alkyl, C2-C6alkenyl or C2- Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

[0412] Also preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or RMis -LS-RE, wherein Lsis a bond or Ci-C6alkylene, and REis - N(RSRS'), -O-Rs, -C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)ORs', - N(Rs)S02Rs', -S02Rs, -SRs, or -P(0)(ORs)2, wherein Rsand Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C6alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Ci-Cealkyl or 3- to 6-membered heterocycle; or RMis Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORs, or - N(RSRS'). More preferably, RMis halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RMis CF3, - C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RMis -Ls-RE where Lsis a bond and REis -N(RSRS), -O-Rs, -N(Rs)C(0)ORs', -N(Rs)S02Rs', -S02Rs, or - SRS. For example where Lsis a bond, REis -N(Ci-C6alkyl)2(e.g., -NMe2); -N(Ci-C6alkylene-0-Ci- C6alkyl)2(e.g. -N(CH2CH2OMe)2); -N(Ci-C6alkyl)(Ci-C6alkylene-0-C C6alkyl) (e.g. - N(CH3)(CH2CH2OMe));— 0-Ci-C6alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n- hexyl); -0-C C6haloalkyl (e.g., - OCF3, -OCH2CF3); -0-Ci-C6alkylene-piperidine (e.g., -O- CH2CH2-l-piperidyl); -N(Ci-C6alkyl)C(0)OCi-C6alkyl (e.g., -N(CH3)C(0)0-CH2CH(CH3)2), - N(Ci-C6alkyl)S02Ci-C6alkyl (e.g., -N(CH3)S02CH3); -S02Ci-C6alkyl (e.g., -S02Me); -S02C C6haloalkyl (e.g., -S02CF3); or -S-Ci-C6haloalkyl (e.g., SCF3). Also preferably RMis -LS-REwhere Lsis Ci-C6alkylene (e.g., -CH2- -C(CH3)2-, -C(CH3)2-CH2-) and REis -0-Rs, -C(0)ORs, - N(Rs)C(0)ORs', or -P(0)(ORs)2. For example RMis -Ci-C6alkylene-0-Rs(e.g., -C(CH3)2-CH2- OMe); -Ci-C6alkylene-C(0)ORs (e.g., -C(CH3)2-C(0)OMe); -Ci-C6alkylene-N(Rs)C(0)ORs' (e.g., -C(CH3)2-CH2-NHC(0)OCH3); or -C1-C6alkylene-P(0)(ORs)2(e.g., -CH2-P(0)(OEt)2). Also more preferably RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, - C(0)ORs, or -N(RSRS'). For example RMis cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., mo holin-4-yl, 1 , 1 - dioxidothiomo holin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxy carbonylpiperazin- 1 -yl, pyrrolidin- 1 - yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).

[0413] More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more RA, wherein J is C3- Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6- membered heterocycle, wherein said C3-C6carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D is C5- C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is C3-Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably, J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or moresubstituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RSRS'). Also preferably, D is C5-C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more RA. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more RA, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6ha C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -

[0414] N(RSRS'). Highly preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -

[0415] N(RSRS'). Also preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle or 3- to 6-membered heterocycle and is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl, C2-Cehaloalkynyl, C(0)ORs or -

[0416] N(RsRs')>and J can also be optionally substituted with one or more RA. Also preferably, D isand J is C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RsRs').

[0417] X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered

[0418] bicycles (e.g.,and is directly linked to -L3-D), and is optionally substituted with one or more RA or RF. Non-limiting examples of X are described hereinabove.

[0419] Li and L2are preferably independently bond or Ci-C6alkylene, L3is preferably selected from bond, Ci-C6alkylene or -C(O)-, and Li, L2, and L3are each independently optionally substituted with one or more RL. More preferably, Li, L2and L3are each independently bond or Ci-C6alkylene (e.g., - CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly preferably, Li, L2and L3are bond. Li and L2can be the same or different.

[0420] R2and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-

[0421] membered heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA. R9 and Ri2, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,which is optionally substituted with one or more RA.

[0422] -T-RD' can be, without limitation, independently selected at each occurrence from -C(O)- LY'-RD', -C(0)0-LY'-RD', -C(0)-LY'-N(RB)C(0)-LS"-RD', -C(0)-LY'-N(RB)C(0)0-LS"-RD', - N(RB)C(0)-LY'-N(RB)C(0)-LS"-RD', -N(RB)C(0)-LY'— N(RB)C(0)0-LS"-Rd', or -N(RB)C(0)- LY'— (RB)-LS"-RD', wherei ' is each independently LS' and, preferably, is each independently

[0423] Ci-C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. Preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'- M'-LS"-RD' or -N(RB)C(0)-LY'-M'-LS"-Rd' . More preferably, -T-RD' is independently selectedat each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(0)-LY'-N(RB)C(0)0-LS"-RD' . Highly preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)- RD' or -C(0)- '-N(RB)C(0)0-RD', wherein LY' preferably is each independently Ci-C6alkylene

[0424] (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL.

[0425] RNB and Rc' are preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from Ci- Cealkyl, C2-Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0426] RA preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; or -LA- O-Rs, -LA-S-RS, -LA-C(0)RS, -LA-OC(0)RS, -LA-C(0)ORS, -LA-N(RSRS'), -LA-S(0)RS, -LA- S02Rs, -LA-C(0)N(RSRS'), -LA-N(RS)C(0)RS', -LA-N(RS)C(0)N(RS'RS"), -LA-N(RS)S02RS' , - LA-S02N(RSRS'), -LA-N(RS)S02N(RS'RS"), -LA-N(RS)S(0)N(RS'RS"), -LA-OS(0)-RS, -LA- OS(0)2-Rs, -LA-S(0)2ORs, -LA-S(0)ORs, -LA-OC(0)ORs, -LA-N(Rs)C(0)ORs', -LA- OC(0)N(RsRs'), -LA-N(RS)S(0)-RS' , -LA-S(0)N(RSRs') or -LA-C(0)N(Rs)C(0)-Rs', wherein LAis bond, Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0427] More preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.Highly preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

[0428] Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0429] In one embodiment of this as ect A is hen l and is optionally substituted with one or more

[0430] RA; and Band is optionally substituted with one or more RA, wherein Zi is O, S, NH or CH2; and Z2is N or CH. D is C5-C6carbocycle or 5- to 6- membered heterocycle (e.g., phenyl), and is optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor - '), and J ca be optionally substituted with one or more RA. Preferably, D is

[0431] s wherein RMand RNare as defined above. Also preferably, D is

[0432] or , wherein J and RNare as defined above. Li and L2are each independently bond or Ci-C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, L L2, and L3are bond. -T- RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(O)- LY'-N(RB)C(0)0-LS"-RD', wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-LY'-LS"-RD', -C(0)-LY'-0-LS"-RD', -C(0)-LY'-N(RB)- Ls"-RD', or -C(0)-LY'-N(RB)S(0)2-LS"-RD'. Preferably, R2and R5, taken together with the atomsto which they are attached, formwhich is optionally substituted with one or more RA; R9

[0433] and R12, taken together with the atoms to which they are attached, formwhich is optionally substituted with one or more RA.

[0434] In another embodiment of this aspect, A is phenyl (e.g., \= / ?), and is optionally substituted with one or more RA(preferably, A is substituted with at least one halogen such as F); and

[0435] B is, and is optionally substituted with one or more RA (preferably, B is

[0436] substituted with at least one halogen such as F). X is , wherein X3is N and is directly linked to -L3-D, and X is optionally substituted with one or more RA or RF. D is phenyl, and is substituted with J and optionally substituted with one or more RA. J is C3-C6carbocycle, 3- to 6- membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15- membered carbocycle / heterocycle, and J is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to 12-membered carbocycle / heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci- Cehaloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORsor -N(RSRS'), or (2) trimethylsilyl, -O- and J can also be optionally substituted with one or more RA. Preferably, D is

[0437] wherein J is as defined above, and each RNis independently selected from RD and preferably is hydrogen or halo such as F. Li and L2are each independently bond or Q- C6alkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, L L2, and L3are bond. -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(0)-LY'- N(RB)C(0)0-LS"-RD' , wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, withoutlimitation, selected from -C(0)-LY'-LS"-RD', -C(0)-LY'-0-LS"-RD', -C(0)-LY'-N(RB)-LS"- RD', or -C(0)-LY'-N(RB)S(0)2-LS"-Rd'. Preferably, R2and R5, taken together with the atoms to

[0438] which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., or 6- to 12-

[0439] membered bicycle (e.g.,which is optionally substituted with one or more RA; R9 and

[0440] R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic

[0441] ring (e.g.,or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA.

[0442] In yet another aspect, the present invention features compounds of Formula IDand pharmaceutically acceptable salts thereof.

[0444] wherein:

[0445] Gi and G2are each independently selected from Cs-Cecarbocycle or 5- to 6-membered heterocycle, and are each independently optionally substituted with one or more RA; Rc' is each independently selected from Rc;

[0446] RD' is each independently selected from RD;

[0447] R2and R5, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA; R9and R12, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA; A, B, D, X, Li, L2, L3, T, RA, Rc, and RDare as described above in Formula I.

[0448] In this aspect, A and B preferably are independently selected from C5-C6carbocycle or 5- to 6- membered heterocycle, and are each independently optionally substituted with one or more RA. MoreI

[0449] preferably, at least one of A and B is phenyl (e.g., \= / ¾), and is optionally substituted with

[0450] I

[0451] one or more RA. Highly preferably, both A and B are each independently phenyl (e.g., \= / ¾), and are each independently optionally substituted with one or more RA.

[0452] D preferably is selected from C5-C6carbocycle, 5- to 6-membered heterocycle, or 8- to 12- membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, and is optionally substituted with one or more RL. More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is substituted with one or more RM, where RMis halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE. Also preferably, D is phenyl, and is optionally substituted with one or more RA. More preferably, D is phenyl, and is substituted with one or more

[0453] RM, wherein RMis as defined above, Highly preferably, D isor, wherein RMis as defined above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F.

[0454] D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more RA. More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

[0455] more RM. Highly preferably, D is, wherein RMis as defined above, and each RNis independently selected from RDand preferably is hydrogen. One or more RNcan also preferably be halo such as F. D is also preferably indanyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, or indazolyl, and is optionally substituted with one or more RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more RM. Highly preferably, D

[0456] is^ jg optionally substituted with one or more RM.Preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, RMis halogen, hydroxy, mercapto, amino, carboxy; or Ci-C6alkyl, C2-C6alkenyl or C2- Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

[0457] Also preferably, RMis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or RMis -LS-RE, wherein Lsis a bond or Ci-C6alkylene, and REis - N(RSRS'), -O-Rs, -C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)ORs', - N(Rs)S02Rs', -S02Rs, -SRs, or -P(0)(ORs)2, wherein Rsand Rs' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) Ci-C6alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Q-Cealkyl or 3- to 6-membered heterocycle; or RMis Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORs, or - N(RSRS'). More preferably, RMis halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-C6alkyl (e.g., methyl, isopropyl, tert-butyl), C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, cyano, or carboxy. For example RMis CF3, - C(CF3)2-OH, -C(CH3)2-CN, -C(CH3)2-CH2OH, or -C(CH3)2-CH2NH2. Also preferably RMis -Ls- REwhere Lsis a bond and REis -N(RSRS), -0-Rs, -N(Rs)C(0)ORs', -N(Rs)S02Rs', -S02Rs, or - SRS. For example where Lsis a bond, REis -N(Ci-C6alkyl)2(e.g., -NMe2); -N(Ci-C6alkylene-0-Ci- C6alkyl)2(e.g. -N(CH2CH2OMe)2); -N(Ci-C6alkyl)(Ci-C6alkylene-0-Ci-C6alkyl) (e.g. - N(CH3)(CH2CH2OMe));— O-Ci-Cealkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n- hexyl); -0-C C6haloalkyl (e.g., - OCF3, -OCH2CF3); -0-Ci-C6alkylene-piperidine (e.g., -O-CH2CH2-l-piperidyl); -N(Ci-C6alkyl)C(0)OCi-C6alkyl (e.g., -N(CH3)C(0)0-CH2CH(CH3)2), - N(Ci-C6alkyl)S02Ci-C6alkyl (e.g., -N(CH3)S02CH3); -S02Ci-C6alkyl (e.g., -S02Me); -S02C C6haloalkyl (e.g., -S02CF3); or -S-Ci-C6haloalkyl (e.g., SCF3). Also preferably RMis -LS-REwhere Lsis C C6alkylene (e.g., -CH2- -C(CH3)2-, -C(CH3)2-CH2-) and REis -0-Rs, -C(0)ORs, - N(Rs)C(0)ORs', or -P(0)(ORs)2. For example RMis -Ci-C6alkylene-0-Rs(e.g., -C(CH3)2-CH2- OMe); -Ci-C6alkylene-C(0)ORs(e.g., -C(CH3)2-C(0)OMe); -Ci-C6alkylene-N(Rs)C(0)ORs' (e.g., -C(CH3)2-CH2-NHC(0)OCH3); or -C1-C6alkylene-P(0)(ORs)2(e.g., -CH2-P(0)(OEt)2). Also more preferably RMis C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, - C(0)ORs, or -N(RSRS'). For example RMis cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l- methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1,1 - dioxidothiomo holin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxy carbonylpiperazin- 1 -yl, pyrrolidin- 1 - yl, piperidin-l -yl, 4-methylpiperidin-l-yl, 3,5-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l-yl, tetrahydropyran-4-yl, pyridinyl, pyridin-3-yl, 6-(dimethylamino)pyridin-3-yl). Highly preferably, RMis Ci-C6alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF3).

[0458] More preferably, D is C5-C6carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more RA, wherein J is C3- Cecarbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle or 3- to 6- membered heterocycle, wherein said C3-C6carbocycle or 3- to 6-membered heterocycle is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor - N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D is C5- C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is C3-Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably, J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2- C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RSRS'). Also preferably, D is C5-C6carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more RA, and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or spiro bicyclecomprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more RA. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more RA, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6ha C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor -

[0459] N(RSRS'). Highly preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORSor -

[0460] N(RSRS'). Also preferably, D is, wherein each RNis independently selected from RDand preferably is hydrogen or halogen, and J is C3-C6carbocycle or 3- to 6-membered heterocycle and is substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -

[0461] N(RSRS'), and J can also be optionally substituted with one or more RA. Also preferably, D isand J is C3-C6carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a C3-C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl,cyano, Q-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RsRs').

[0462] X preferably is C5-C6carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered

[0463] bicycles (e.g.,, wherein X3is N and is directly linked to -L3-D), and is optionally substituted with one or more RA or RF. Non-limiting examples of X are described hereinabove.

[0464] Li and L2are preferably independently bond or Ci-C6alkylene, L3is preferably selected from bond, Ci-C6alkylene or -C(O)-, and Li, L2, and L3are each independently optionally substituted with one or more RL. More preferably, Li, L2and L3are each independently bond or Ci-C6alkylene (e.g., - CH2- or -CH2CH2-), and are each independently optionally substituted with one or more RL. Highly preferably, Li, L2and L3are bond.

[0465] R2and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-

[0466] membered heterocycle or 6- to 12-membered bicycle (e.g.,which optionally substituted with one or more RA.

[0467] Rg and R12, taken together with the atoms to which they are attached, preferably form a 5-

[0468] 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

[0469] optionally substituted with one or more RA.

[0470] H are each independently selected from —N , N-, and are each independently optionally substituted with one or more

[0471] RA (e.g., one or more chloro or bromo). More preferably, Gi is(including any tautomer thereof), and G2is ^ (including any tautomer thereof), and each Gi and G2is independently optionally substituted with one or more RA (e.g., one or more chloro or bromo).-T-RD' can be, without limitation, independently selected at each occurrence from -C(O)- LY'-, -C(0)0-LY'-RD', -C(0)-LY'-N(RB)C(0)-LS"-RD', -C(0)-LY'-N(RB)C(0)0-LS"-RD', - N(RB)C(0)-LY'-N(RB)C(0)-LS"-RD', -N(RB)C(0)-LY'— N(RB)C(0)0-LS"-Rd', or -N(RB)C(0)- LY'— N(RB)-LS"-RD', wherei ' is each independently LS' and, preferably, is each independently Ci-C6alkylene (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL. Preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'- M'-LS"-RD' or -N(RB)C(0)-LY'-M'-LS"-Rd'. More preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(0)-LY'-N(RB)C(0)0-LS"-RD'. Highly preferably, -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)- RD' or -C(0)- '-N(RB)C(0)0-RD', wherein LY' preferably is each independently Ci-C6alkylene

[0472] (e.g., -CH2- or) and optionally substituted with one or more substituents selected from RL.

[0473] Rc' is preferably hydrogen, and RD' preferably is independently selected at each occurrence from RE. More preferably, RD' is independently selected at each occurrence from Ci-C6alkyl, C2- Cealkenyl or C2-Cealkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C3-C6carbocycle or 3- to 6-membered heterocycle; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-C6alkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0474] RApreferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; or -LA- 0-Rs, -LA-S-RS, -LA-C(0)Rs, -LA-OC(0)Rs, -LA-C(0)ORs, -LA-N(RSRS'), -LA-S(0)Rs,— LA— S02Rs, -LA-C(0)N(RsRs'), -LA-N(Rs)C(0)Rs', -LA-N(Rs)C(0)N(Rs'Rs"), -LA-N(Rs)S02Rs', - LA-S02N(RsRs'), -LA-N(Rs)S02N(Rs'Rs"), -LA-N(Rs)S(0)N(Rs'Rs"), -LA-OS(0)-Rs, — LA— OS(0)2-Rs, -LA-S(0)2ORs, -LA-S(0)ORs, -LA-OC(0)ORs, -LA-N(Rs)C(0)ORs', — LA—OC(0)N(RsRs'), -LA-N(RS)S(0)-RS' , -LA-S(0)N(RSRs') or -LA-C(0)N(Rs)C(0)-Rs', wherein LAis bond, Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0475] More preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

[0476] Highly preferably, RAis halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

[0477] Ls, Ls' and Ls" preferably are each independently selected at each occurrence from bond; or Ci-C6alkylene, C2-C6alkenylene or C2-C6alkynylene.

[0478] A and B can be the same or different. Likewise, Li and L2can be the same or different. In one embodiment of this aspect, A and B are each independently phenyl, and are each independently optionally substituted with one or more RA; D is phenyl, and is independently optionally substituted with one or more RA, or is substituted with J and optionally substituted with one or more RA, wherein J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA. Preferably, J is substituted with a C3- C6carbocycle or 3- to 6-membered heterocycle which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci- C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORsor -N(RSRS'), and J can also be optionally substituted with one or more RA; and Gi is, and each Gi and G2is independently optionally substituted with one or more RA(e.g., one or more chloro or bromo).

[0479] preferably, D isor , wherein J and RNare as defined above. Li and L2are each independently bond or Ci-Cealkylene, and L3is bond, Ci-Cealkylene or -C(O)-, and Li, L2, and L3are each independently optionally substituted with one or more RL. Preferably, Li, L2, and L3are bond. - T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(O)- LY'-N(RB)C(0)0-LS"-RD', wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-LY'-LS"-RD', -C(0)-LY'-0-LS"-RD', -C(0)-LY'-N(RB)- LS"-RD', or -C(0)-LY'-N(RB)S "-Rd'. Preferably, R2and R5, taken together with the atoms

[0480] to which they are attached,which is optionally substituted with one or more RA; R9

[0481] and Ri2, taken together with the atoms to which they are attached, formwhich is optionally substituted with one or more RA.

[0482] ther embodiment of this aspect, A and B are each independently phenyl (e.g.,and are each independently optionally substituted with one or more RA(preferably, A

[0483] and B are each independently substituted with at least one halogen such as F). X is

[0484] wherein X3is N and is directly linked to -L3-D, and X is optionally substituted with one or more RAor RF. D is phenyl, and is substituted with J and optionally substituted with one or more RA. J is C3- C6carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle / heterocycle, and J is optionally substituted with one or more RA. Preferably, J is substituted with a C3-C6carbocycle, 3- to 6-membered heterocycle, 6- to 12- membered bicycle or 7- to 12-membered carbocycle / heterocycle, which is independently optionally substituted with one or more substituents selected from (1) halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2- Cgalkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -C(0)ORSor -N(RSRS'), or (2) trimethylsilyl, -0-RS, -S-RSor -C(0)RS; and J can also be optionally substituted with one or moreRA. Preferably, D iswherein J is as defined above, and each RNis

[0485] H independently selected from RDand preferably is hydrogen or halo such as F. Gi is N , G2isand each Gi and G2is independently optionally substituted with one or more RA(e.g., one or more chloro or bromo). Li and L2are each independently bond or Ci-Cealkylene, and L3is bond, Ci-C6alkylene or -C(O)-, and L L2, and L3are each independently optionally substituted with one or more RL. Preferably, Li, L2, and L3are bond. -T-RD' is independently selected at each occurrence from -C(0)-LY'-N(RB)C(0)-LS"-RD' or -C(0)-LY'-N(RB)C(0)0-LS"-RD', wherein LY' is Ci-C6alkylene (e.g., -CH2-) and optionally substituted with one or more substituents selected from RL, and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(O)- LY'-LS"-RD', -C(0)-LY'-0-LS"-RD', -C(0)-LY'-N(RB)-LS"-RD', or -C(0)-LY'-N(RB)S(0)2- LS"-RD'. Preferably, R2and R5, taken together with the atoms to which they are attached, form a 5-

[0486] to 6-membered heterocyclic ring (e.g.,6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA; R9 and Ri2, taken together with the atoms to

[0487] which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

[0488] membered bicycle (e.g.,one or more RA.

[0489] In another aspect, the present invention features compounds having Formula IEand pharmaceutically acceptable salts thereof,

[0490] D I

[0491] L3

[0492] I

[0493] Y— A— L— X— L2— B— Z

[0494] IF,wherein:

[0495] X is 4- to 8-membered heterocycle, and is optionally substituted with one or more RA;

[0496] Li and L2are each independently selected from bond or Ci-Cealkylene which is independently optionally substituted at each occurrence with one or more halo, hydroxy, -0-Ci-C6alkyl, or -0-Ci-C6haloalkyl;

[0497] L3is bond or Ci-C6alkylene;

[0498] A and B are each independently phenyl, pyridinyl, thiazolyl,

[0499] is independently selected at each occurrence from O, S, NH or CH2, Z3is independently selected at each occurrence from N or CH, and Wi, W2, and W3are each independently selected at each occurrence from CH or N; A and B are each independently optionally substituted with one or more RA.

[0500] D is C6-Ciocarbocycle or 5- to 12-membered heterocycle, each of which is optionally substituted with one or more RM5

[0501] Y is -T'-C(R1R2)N(R5)-T-RD;

[0502] Z is -T'-C(R8R9)N(R12)-T-RD;

[0503] Ri is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, -0-Ci-C6alkyl or -0-Ci-C6haloalkyl;

[0504] R2and R5are each independently hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, -0-Ci-C6alkyl or -0-Ci-C6haloalkyl; or R2and R5, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more RA(e.g., 1 , 2, 3, or 4 RA);

[0505] R8is hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C6alkyl, Ci-C6haloalkyl, -0-Ci-C6alkyl or -0-Ci-C6haloalkyl;

[0506] R9and Ri2are each independently hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, or 3- to 6- membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-Cealkyl, Ci-Cehaloalkyl, -O-Ci-Cealkyl or -O-Ci-Cehaloalkyl; or Rg and R12, taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more RA (e.g., l, 2, 3, or 4 RA);

[0507] T is independently selected at each occurrence from bond or -C(0)-Ls'-;

[0508] T' is independently selected at each occurrence from bond, -C(0)N(RB)-, -N(RB)C(0)-, or

[0509] 3- to 12-membered heterocycle, wherein said 3- to 12-membered heterocycle is independently optionally substituted at each occurrence with one or more RA;

[0510] RDis each independently selected at each occurrence from hydrogen or RA;

[0511] RAis independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -LS-RE;

[0512] RBand RB' are each independently selected at each occurrence from hydrogen; or Ci-C6alkyl which is independently optionally substituted at each occurrence with one or more substituents selected from halogen or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in RBor RB' is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, Ci-C6alkyl, Ci-C6haloalkyl, - 0-Ci-C6alkyl, or -0-C C6haloalkyl;

[0513] REis independently selected at each occurrence from -0-Rs, -S-Rs, -C(0)Rs, -OC(0)Rs, - C(0)ORs, -N(RsRs'), -S(0)Rs, -S02Rs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', - N(Rs)C(0)N(Rs'Rs"), -N(Rs)S02Rs', -S02N(RsRs'), -N(Rs)S02N(Rs'Rs"), -

[0514] N(Rs)S(0)N(Rs'Rs"), -OS(0)-Rs, -OS(0)2-Rs, -S(0)2ORs, -S(0)ORs, -OC(0)ORs, - N(Rs)C(0)ORs', -OC(0)N(RsRs'), -N(Rs)S(0)-Rs', -S(0)N(RsRs'), -C(0)N(Rs)C(0)- Rs', or =C(RsRs');orCi-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-Ci2carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl;

[0515] RLis independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-Rs, -S-Rs, -C(0)Rs, -OC(0)Rs, -C(0)ORs, -N(RSRS'), - S(0)Rs, -S02Rs, -C(0)N(RsRs'), or -N(Rs)C(0)Rs'; or C3-Ci2carbocycle or 3- to 12- membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto,amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl; is independently selected at each occurrence from bond; or Ci-C6alkylene, C2- C6alkenylene or C2-C6alkynylene, each independently optionally substituted with halogen;

[0516] is independently selected at each occurrence from bond; or Ci-C6alkylene, C2- C6alkenylene or C2-C6alkynylene, each of which is independently optionally substituted at each occurrence with one or more RL;

[0517] Rs' and Rs" are each independently selected at each occurrence from hydrogen; Q- Cealkyl, C2-Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -0-Ci-C6alkyl, -0-Ci-C6haloalkyl, or 3- to 12-membered carbocycle or heterocycle; or 3- to 12-membered carbocycle or heterocycle; wherein each 3- to 12- membered carbocycle or heterocycle in Rs, Rs' or Rs" is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl or C2- Cehaloalkynyl;

[0518] s independently selected at each occurrence from:

[0519] halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, SF5, -N(RSRS'), -0-Rs, -OC(0)Rs, -OC(0)ORs, -OC(0)N(RsRs'), - C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)ORs', - N(Rs)S02Rs', -S(0)Rs, -S02Rs, -S(0)N(RsRs'), -SRS, -Si(Rs)3, or -P(0)(ORs)2;

[0520] Ci-C6alkyl, C2-Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, -N(RSRS'), -0-Rs, -OC(0)Rs, -OC(0)ORs, -OC(0)N(RsRs'), - C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)ORs', - N(Rs)S02Rs', -S(0)Rs, -S02Rs, -S(0)N(RsRs'), -SRS, or -P(0)(ORs)2; or

[0521] G2, wherein G2is a C3-Ci2carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more RQ2, and each RG2is independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C6alkyl, C2- Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl, C2-C6haloalkynyl, -O- Rs, -C(0)ORs, -C(0)Rs, -N(RSRS'), or -L4-G3;L4is a bond, Ci-Cealkylene, C2-C6alkenylene, C2-C6alkynylene, -0-, -S-, -N(RB)-, -C(O)-, -S(0)2- -S(O)-, -C(0)0-, -OC(O)-, -OC(0)0- -C(0)N(RB)-, -N(RB)C(0)-, - N(RB)C(0)0-, -OC(0)N(RB)-, -N(RB)S(0)-, -N(RB)S(0)2- -S(0)N(RB)-, - S(0)2N(RB)-, -N(RB)C(0)N(RB')-, -N(RB)S02N(RB')-, or -N(RB)S(0)N(RB')-;

[0522] G3is a C3-Ci2carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more RG3; and

[0523] RG3 is each independently, at each occurrence, halogen, -Ci-C6alkyl, -C(0)Ci-C6alkyl, -Q- C6haloalkyl, -0-Ci-C6alkyl, -0-Ci-C6haloalkyl, C3-C6carbocycle, or 3- to 6-membered heterocycle.

[0524] As described hereinabove for compounds of Formula IEA and B are each phenyl, pyridinyl,each occurrence from O, S,

[0525] NH or CH2, Z3is independently selected at each occurrence from N or CH, and Wi, W2, and W3are each independently selected at each occurrence from CH or N; A and B are each independently optionally substituted with one or more RA.

[0526] Prefera), pyridinyl (e.g., thiazolyl (e.g.,and is optionally substituted with one or more RA.

[0527] thiaz

[0528] is optionally substituted with one or more RA.

[0529] Highly preferably, both A and B are phenyl (e.g., both A and B areor A is

[0530] and B is ; or Aiswherein each A and B is independently optionally substituted with one or more RA.

[0531] In certain embodiments of this aspect of the invention, A and B are substituted by one or more RA, wherein each RAis independently selected from halogen (e.g., fluoro, chloro), LS-RE(where Lsis bond and REis -C C6alkyl (e.g., methyl), -0-RS(e.g., -0-C C6alkyl, -OCH3), or -C C6alkyl optionally substituted with one or more halogen (e.g., -CF3)), or LS-RE (where LSis Ci-Cealkylene

[0533] As described hereinabove for compounds of Formula IED is C6-Ci0carbocycle or 3- to 12- membered heterocycle optionally substituted by one or more RM. Preferably, D is C6-Ci0aryl (e.g., phenyl, naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l ,3]dioxol-5-yl), and D is substituted with one or more RM. For example, in certain embodiments D is preferably phenyl substituted by one or more RM, wherein each RMis independently halogen (e.g., fluoro, chloro, bromo); Ci-C6alkyl (e.g., tert-butyl); Ci-C6alkyl substituted with one or more halogen (e.g., CF3); -O-Rs such as -Ο-Ci-Cealkyl (e.g., -0-CH2CH3); or -O-Ci-Cealkyl substituted at each occurrence with one or more halogen (e.g., -0-CF3, -0-CH2CHF2) or -0-C C6alkyl (e.g., -0-CH2CH2OCH3); -O- Rs(e.g., -0-Ci-C6alkyl, such as -0-CH2) substituted with 3- to 12-membered heterocycle (e.g., 3- ethyloxetan-3-yl, l ,3-dioxolan-4-yl); -O-Rs where Rsis an optionally substituted 3- to 12-membered carbocycle or heterocycle (e.g., cyclopentyl, cyclohexyl, phenyl, l,3-dioxan-5-yl); -N(Rs)C(0)Rs' wherein Rsand Rs' are each independently Ci-C6alkyl (e.g., -N(t-Bu)C(0)Me); SF5; -S02Rswherein Rsis Ci-C6alkyl (e.g., -S02Me); or C3-Ci2carbocycle (e.g., cyclopropyl, cyclohexyl, phenyl).

[0534] In certain embodiments of this aspect of the invention, D is preferably phenyl or pyridyl and is substituted by one or more RMwhere one RMis G2. In certain embodiments where D is phenyl or pyridyl, D is substituted by G2, G2is 3- to 12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) and is optionally substituted with one or more halogen (e.g., fluoro, chloro), hydroxy, oxo, cyano, Ci-C6alkyl (e.g., methyl), C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl (e.g., CF3), C2-C6haloalkenyl, C2-C6haloalkynyl, -0-C C6alkyl (e.g., -0-CH3), -C(0)ORs(e.g., - C(0)OCH3), -C(0)Rs(e.g., -C(0)CH3), or -N(RSRS'); and D is further optionally substituted by one or more RMwhere RMis halogen (e.g., fluoro, chloro), Ci-C6alkyl (e.g., methyl), Ci-C6haloalkyl (e.g., CF3), or -0-Ci-C6alkyl (e.g., -0-CH3). In certain other embodiments D is phenyl or pyridyl and G2is, for example, a monocyclic 3-8 membered carbocycle or monocyclic 4-8 membered heterocycle substituted with L4-G3and optionally substituted with one or more RG2wherein L4, G3and RG2are as defined herein. L4, for example is a bond, a Ci-C6alkylene (e.g., -CH2-, -CH2CH2-, -CH2CH2CH2- etc.), -0-, or -S(0)2- G3is for example a C3-Ci2carbocycle optionally substituted with one or more RG3. RG2 and RG3are each independently at each occurrence halogen, -C(0)Ci-C6alkyl, -Ci-C6alkyl,

[0535] -Ci-Cehaloalkyl, -O-Ci-Cealkyl, or -O-Ci-Cehaloalkyl. In certain embodiments G2is ,

[0536] wherein is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl) attached to the parent molecular moiety through a nitrogen atom and substituted with one or two L4-G3and optionally substituted with one or more RG2. Thus, in

[0537] G3

[0538] certain embodiments where L4is a bond G2is , whereis optionally substituted with

[0539] G3

[0540] RG2and G3is optionally substituted with RG3. Thus, can be, for example, 3-phenylazetidin-1-yl, 3-phenylpyrrolidin-l-yl, 4-phenylpiperazin-l-yl, 4-phenylpiperidin-l-yl, 4-phenyl-3,6- dihydropyridin- 1 (2H)-yl, 4,4-diphenylpiperidin- 1 -yl, 4-acetyl-4-phenylpiperidin- 1 -yl, 4-(4- methoxyphenyl)piperidin-l-yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl, and wherein D can be further optionally substituted with one or more RM(e.g., fluoro, chloro, methyl, methoxy).

[0541] In certain other embodiments of this aspect of the invention, L4is a C1-C6 alkylene, -0-, or -

[0542] S(0)2- and G2is, where is as defined above and is optionally substituted with RG2

[0543] and G3is as defined above and is optionally substituted with RG3. Thus, ^ can be, for example, 4-tosylpiperazin-l-yl, 4-phenoxypiperidin-l-yl, 3-phenoxypyrrolidin-l-yl, 4-benzylpiperidin-l-yl, 4- phenethylpiperidin-l-yl, or 3-phenylpropyl)piperidin-l-yl.

[0544] In certain other embodiments of this aspect of the invention, D is phenyl or pyridyl, D is substituted by G2and G2is a spiro, bridged, or fused bicyclic carbocycle or heterocycle optionally substituted with L4-G3and one or more RG2, wherein D is optionally substituted with one or more RM

[0545] and RMG3, and RG2 are as defined herein. In certain embodiments G2is

[0546] whereinis a spiro, bridged, or fused bicyclic nitrogen-containing heterocycle (e.g., 3- azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2H- isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H-isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec- 8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with G3and one or more RG2- Thus, G2is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6- azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H- isoindol-2-yl, or l,4-dioxa-8-azaspiro[4.5]dec-8-yl; L4is a bond and D is optionally substituted with one or more RM(e.g., fluoro, chloro, methyl, methoxy).In certain embodiments of this aspect of the invention, D iswherein RMis as defined above in connection with Formula IE, and D is optionally substituted by one or more additional RM.

[0547] For instance, where D isΦ■Λ>η' , RMcan be fluoro, chloro, tert-butyl, -0-CH2CH3, -O-CF3, -O- CH2CHF2, -0-CH2CH2OCH3, -0-CH2-(3-ethyloxetan-3-yl), -0-CH2-(l,3-dioxolan-4-yl), -O- cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(l,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF5, -S02Me, or -N(t-Bu)C(0)Me and D can be optionally substituted by one or more additional RMselected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C6alkyl (e.g., methyl).

[0548] In certain embodiments, D iswherein RMis fluoro, chloro, tert-butyl, -0-CH2CH3, - 0-CF3, -0-CH2CHF2, -0-CH2CH2OCH3, SF5, -S02Me, or -N(t-Bu)C(0)Me and D is optionally substituted by one or more additional RMselected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C6alkyl (e.g., methyl).

[0549] In certain embodiments, D iswherein RMis cyclopropyl, cyclohexyl, or phenyl and D is optionally substituted by one or more additional RMselected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C6alkyl (e.g., methyl).

[0550] In certain embodiments, D iswherein RMis -0-CH2-(3-ethyloxetan-3-yl), -0-CH2-

[0551] (l,3-dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, or -0-(l,3-dioxan-5-yl) and D is optionally substituted by one or more additional RMselected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C6alkyl (e.g., methyl).In certain embodiments, D iswherein G2is pyridinyl (e.g., pyridin-2-yl), piperidin-1- yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4-(propan-2- yl)piperidin- 1 -yl, 4-fluoropiperidin- 1 -yl, 3 ,5 -dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin- 1 - yl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l-yl, 2-oxopiperidin-l-yl, 3,3-dimethylazetidin-l-yl, or oxazolyl (e.g., l,3-oxazol-2-yl) and D is optionally substituted by one or more additional RMselected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C6alkyl (e.g., methyl).

[0552] In another embodiment of this as ect of the invention, D iswherein Gi is N,

[0553] C-H, or C-RM; G2wherein is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) attached to the parent molecular moiety through a nitrogen atom and substituted by L4-G3and optionally substituted with one or more RG2; L4 is a bond, Ci-C6alkylene, -0-, or -S(0)2-; G3is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle (e.g., thienyl) wherein each G3 is optionally substituted with one or more RG3; RG2 and RG3at each occurrence are each independently halogen, -C(0)Ci-C6alkyl, -Ci-C6alkyl, -Ci-C6haloalkyl, - 0-Ci-C6alkyl, or -0-Ci-C6haloalkyl; g is 0, 1, 2, or 3; and RMis as defined above in connection with

[0554] Formula IE. In one group of compounds according to this embodiment, D iswherein

[0555] G3is phenyl optionally substituted with one or two RG3; g is 0, 1, or 2; RMis each independently

[0556] fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; andand RG3are asdefined above. In a further subgroup of compounds of this embodiment, D is

[0557] wherein G3is phenyl optionally substituted with one or two RG3; RMI is each independently hydrogen, fluoro, chloro, or methyl; and RG2 is an optional substituent as described herein. In another group of

[0558] compounds according to this embodiment, D iswherein L4is Ci-C6alkylene, -0-, or -

[0559] S(0)2-; G3is phenyl optionally substituted with one or two RG3; g is 0, 1, or 2; RMis each

[0560] independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and

[0561] RG3 are as defined above.

[0562] In yet another embodiment of this aspect of the invention, D iswherein Gi is

[0563] N, C-H, or C-RM; G2 is , wherein ^ is a spiro, bridged, or fused bicyclic nitrogen- containing heterocycle (e.g., 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6- azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l ,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with L4-G3and one or more RG2; L4is a bond, Ci-C6alkylene, -0-, or -S(0)2-; G3is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle (e.g., thienyl) wherein each G3 is optionally substituted with one or more R^; RQ2 and RG3 at each occurrence are each independently halogen, -C(0)Ci-C6alkyl, -Ci-C6alkyl, -Ci-C6haloalkyl, -O-Q- C6alkyl, or -0-Ci-C6haloalkyl; g is 0, 1, 2, or 3; and RMis as defined above in connection withFormula IE. In one group of compounds according to this embodiment, D ISwherein g is 0, 1, or 2; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

[0564] trifluoromethoxy; andas defined above. In a further subgroup of compounds D is

[0565] wherein RM1is each independently hydrogen, fluoro, chloro, or methyl, andis as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2-yl, 2- azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l ,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).

[0566] till another embodiment of this aspect of the invention, D ISwhereinis a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more RG2, wherein RG2at each occurrence is each independently halogen, -C(0)Ci-C6alkyl, -Ci-C6alkyl, -Ci-C6haloalkyl, -0-Ci-C6alkyl, or -O-Ci- C6haloalkyl; and RMis each independently halogen, -Ci-C6alkyl, -Ci-C6haloalkyl, -0-Ci-C6alkyl, or

[0567] G2

[0568] N

[0569] -0-Ci-C6haloalkyl. In one group of compounds according to this embodiment, is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two RG2, wherein RG2 at each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and RMiseach independently fluoro, chloro, or methyl. For exampleis 4,4-dimethylpiperidin-l-yl,

[0570] 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4-(propan-2-yl)piperidin-l-yl, 4- fluoropiperidin- 1 -yl, 3 ,5-dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin- 1 -yl, 4-methylpiperidin- 1-yl, 4-tert-butylpiperidin-l-yl, 2-oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl.

[0571] For compounds of Formula IEattachment of X to the remainder of the molecule can be conveniently depicted by the abbreviated structural Formula X', wherein the groups attached to X maintain the same relative spatial orientation as drawn in Formula IEIt is understood that in subsequent depictions of the variable group X, the substituents of X will retain the same relative positions and orientation as in Formula IEand Formula X'.

[0572] X'

[0573] Compounds of Formula IEinclude those where the variable X is selected from the group consisting of X-1, X-2, X-3, and X-4 wherein X-1, X-2, X-3, and X-4 retain the same orientation as structure X' relative to the remainder of the molecule; wherein the presence of = in X-1, X-2, and X-3 represents single or double bonds, Xi is Ci-C2alkylene or C2alkenylene, X2 and X3 are each Ci- C2alkylene or C2alkenylene, and X4 is C1-C2alkylene.

[0575] X-1 X-2 X-3 X-4

[0576] In accordance with the foregoing description, in certain embodiments of this aspect of the invention, X is pyrrolyl and is attached to the remainder of the molecule as shown in Formula

[0577] ΧΑ: In certain embodiments, X is pyrrolidinyl and is attached to the remainder of themolecule as shown in Formula XB: . Embodiments according to Formula XBmay exist

[0578] in cis (XBI) or trans (XB2) forms: 'm'"u. Chiral carbon atoms in

[0579] XB, XBI, and XB2may have either the (R) or (S) absolute stereochemistry.

[0580] In yet another embodiment of this aspect of the invention, X is pyrrolyl and is attached to the

[0581] remainder of the molecule as shown in Formulae Xci or

[0582] In certain embodiments, X is rrolidinyl and is attached to the remainder of the molecule as shown

[0583] in Formulae XDi or XD2:ζ. Embodiments according to

[0584] Formulae XDi or XD2may exist in cis or trans forms and chiral carbon atoms in XDi and XD2may have either the (R) or (S) absolute stereochemistry. In certain embodiments, X is azetidinyl and is attached to the remainder molecule as shown in Formulae XEi or XE2:

[0586] . Chiral carbon atoms in XEi and XE2may independently have either the (R) or (S) absolute stereochemistry.

[0587] In certain preferred embodiments of this aspect of the invention, X is XA, XB, XBI, XB2, XCI, or XC2and LuL2, and L3are each a bond. In certain other embodiments, X is XDi, XD2, XEI, or XE2and Li, L2, and L3 are each a bond. In another embodiment, X is XEi and Li and L2are each methylene (i.e. -CH2-), and L3is a bond.In compounds of Formula IE, Y is-T'-C(RiR2)N(R5)-T-RD and Z is -T'-C(R8R9)N(Ri2)-T- RD; wherein T', RlsR2, R5, Rs, R9, R12, T, and RDare as defined herein.

[0588] Preferably Ri, R2, R5, Rs, R9, and R12 are each independently hydrogen; Ci-C6alkyl; or 3- to 6- membered carbocycle or heterocycle, wherein each 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen or Ci-Cealkyl; wherein R2and R5, taken together with the atoms to which they are attached, optionally form a 3- to 12-membered heterocycle which is substituted with 0, 1, 2, 3, or 4 RA, and R9and Ri2taken together with the atoms to which they are attached, optionally form a 3- to 12- membered heterocycle which is substituted with 0, 1, 2, 3, or 4 RAwherein RAis as defined herein.

[0589] In certain embodiments of this aspect of the invention, Ri is hydrogen and R2and R5, taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (e.g.,

[0590] 4 RAwherein

[0591] RAis halogen (e.g., fluoro, chloro); cyano; LS-RE where LSis a single bond and REis Ci-Cealkyl (e.g., methyl, ethyl), -0-Ci-C6alkyl (e.g., methoxy), or -0-Ci-C6hal trifluoromethoxy); or Ls-

[0592] REwhere LSis a double bond and REis =C(RSRS') (e.g.,In a preferred embodime R5, taken together with the atoms to which they are attached form a pyrrolidine

[0593] ring (i.e.,substituted with 0 or 1 RAwherein RAis fluoro, methoxy, methyl, ethyl, or cyano. In another preferred embodi and R5, taken together with the atoms to which they are

[0594] attached form a pyrrolidine ring (i.e.,

[0595] In certain other embodiments of this aspect of the invention, R8is hydrogen and R9 and Ri2, taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (e.g.,

[0596] substituted with 0, 1, 2, 3, or 4

[0597] RAwherein RAis halogen (e.g., fluoro, chloro); cyano; LS-REwhere Lsis a single bond and REis Ci- C6alkyl (e.g., methyl, ethyl), -0-Ci-C6alkyl (e.g., methoxy), or -0-Ci- trifluoromethoxy); or LS-RE where LSis a double bond and REis =C(RSRS') (e.g.,

[0598] In a preferred embodime and R12, taken together with the atoms to which they are attached form

[0599] a pyrrolidine ring (i.e.,substituted with 0 or 1 RAwherein RAis fluoro, methoxy, methyl, ethyl, or cyano. In another preferred embodiment R9and R12, taken together with the atoms

[0600] to which they are attached form a pyrrolidine ring (i.e.,

[0601] As used herein, a chiral carbon in any rings formed by joining R2and R5or R9and R12 may

[0602] possess either (R) or (S) stereochemistry. A pyrrolidine ring (i.e.,

[0603] and R5or R9and R12 preferably possesses the (S) stereochemistry

[0604] In this aspect of the invention, is independently selected at each occurrence from a bond,- C(0)N(RB)-, -N(RB)C(0)-, or 3- to 12-membered heterocycle, and wherein said 3- to 12-membered heterocycle is each independently optionally substituted at each occurrence with one or more RA, and RAand RBare as described herein. In particular, where T is -C(0)N(RB)-, RBcan be hydrogen (i.e.,

[0605] H H

[0606] T' is -C(0)N(H)-). In certain embodiments, T' is imidazolyl (i.e., — N , N— ) optionally substituted at each occurrence with one or more RAwherein RAis halogen (e.g., fluoro, chloro), CiCealk l (e.g., methyl, ethyl), or Ci-Cehaloalkyl (e.g., trifluoromethyl). In certain embodiments, T' is imidazolyl (i.e.,

[0607] This aspect of the invention contemplates particular combinations of A with Y and B with Z. Non-limiting examples of preferred Y when A is C5-C6carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) and preferred Z when B is C5-C6carbocycle (e.g., phenyl) or

[0608] wherein T and RDare as defined herein.

[0609] In certain embodiments of this aspect of the invention, A isoptionally substituted with one or more RAas described herein, or Y-A isand non-limitingexamples of preferred Y, where T' is a bond, include:

[0610] wherein T and RDare as defined herein.

[0611] In certain embodiments of this aspect of the inventi optionally substituted with one or more RAas described herein, or B-Z ison-limiting examples of preferred Z, where T' is a bond, include:,

[0612] wherein T and RDare as defined herein.

[0613] T at each occurrence is independently a bond or -C(0)-Ls'-, wherein Ls' is as defined herein. Ls' includes, but is not limited to, ,, or, where Ls' is optionally substituted with one or more RL; and RLis a substituent such as, but not limited to carbocycle (e.g., cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl), methoxy, or heterocycle (e.g., tetrahydrofuranyl, tetrahydropyranyl).

[0614] RDis hydrogen or RAwherein RAis as defined herein. Thus RDincludes, but is not limited to, RAwherein RAis LS-RE, and Lsand REare as defined herein. Thus RDincludes, but is not limited to, LS-RE wherein Lsis a bond and REis-N(RsRs'), -N(Rs)C(0)Rs', -N(Rs)C(0)N(Rs'Rs"), - N(Rs)S02Rs', — N(Rs)S02N(Rs'Rs"), -N(Rs)S(0)N(Rs'Rs"), -N(Rs)C(0)ORs', or -N(Rs)S(0)- Rs'; or C3-Ci2carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or Ci-C6haloalkyl.

[0615] In one embodiment of this aspect of the invention, RDis LS-RE wherein Ls is a bond and RE is -N(Rs)C(0)ORs' or 3- to 12-membered heterocycle (e.g., pyrrolidine, piperidine, azepanyl) wherein Rs and Rs' are as defined herein. For example RDis preferably LS-RE wherein Lsis a bond and REis -N(H)C(0)OMe.

[0616] Thus according to the foregoing description T-RDincludes, but is not limited to:

[0618] etc.

[0619] According to this aspect of the invention, non-limiting examples of preferred Y when A is C5- C6carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) and preferred Z when B is C5-C6carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl) include:

[0623] 121

[0624] In still another aspect, the present invention features compounds of Formula harmaceutically acceptable salts thereof:wherein:

[0625] X is rein X is optionally substituted with one or more RAnally substituted with one or more RA;

[0626] B isor , wherein B is optionally substituted with one or more RA; andY, Z, RA, and D are as described hereinabove (e.g., Y, Z, RA, and D as described for Formula I, IA, IB, IC, ID, or IE, preferably as described for Formula IE).

[0627] In one embodiment of this aspect of the invention, X isA is s, wherein B is optionally substituted with one or more RA; Y is

[0628] ; and D, RA, T and RDare as defined hereinabove (e.g., as described for Formula I, IA, ¾, Ic, ID or IE, preferably as described for Formula IE).

[0629] In another embodiment according to this aspect of the invention, A or B are optionally substituted with one or more substituents selected from: RAwherein RAis each independently halogen (e.g., fluoro, chloro); LS-REwhere Lsis a single bond, and REis -Ci-Cealkyl (e.g., methyl), -O-Rs (e.g., -0-Ci-C6alkyl, -OCH3), or -Ci-C6alkyl optionally substituted with one or more halogen (e.g., - CF3); or LS-REwhere Lsis a Ci-C6alkylene and REis -O-Rs (e.g., -Ci-C6alkyl-0-Ci-C6alkyl, - CH2OCH3). This embodiment includes compounds where A and B are both substituted by one RA; compounds where A and B are both substituted by zero RA; compounds where A is substituted by oneRAand B is substituted by zero RA; and compounds where A is substituted by zero RAand B is

[0631] In a further embodiment of this aspect of the invention, T-RDis independently selected at

[0632] each occurrence from the group consisting of

[0634] preferred and wherein D is as defined hereinabove.

[0635] In another embodiment, this aspect of the invention features compound of Formula IFand pharmaceutically acceptable salts thereof, wherein:X iswherein A is optionally

[0636] substituted with one or more RA; B iswherein B is optionally substituted with one or

[0638] I HN— ,ί I HN— .J

[0639] p — T *R*

[0640] D, orD; and D, RA, T and RDare as defined hereinabove. A particular subgroup according to this embodiment includes compounds where A is

[0641] ; and D is as defined hereinabove.

[0642] In yet another embodiment, this aspect of the invention features compounds of Formula IFand

[0644] are as defined hereinabove. A particular subgroup according to this embodiment includes compounds

[0645] , or ; and D is as defined hereinabove.

[0646] According to each of the foregoing embodiments and description of this aspect of the invention of Formula IFare groups and subgroups of compounds having particular values for D. Included in each of the foregoing embodiments are groups and subgroups of compounds with the following particular values for D:In certain groups of compounds accordin to Formula IFand the foregoing embodiments and

[0647] description of this aspect of the invention, D is, where RMis fluoro, chloro, tert-butyl, -O- CH2CH3, -0-CF3, -0-CH2CHF2, -0-CH2CH2OCH3, -0-CH2-(3-ethyloxetan-3-yl), -0-CH2-(l ,3- dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(l,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF5, -S02Me, or -N(t-Bu)C(0)Me and D is optionally substituted by one or more additional RM, selected from the group consisting of halogen (e.g., fluoro, chloro) or Ci-C6alkyl (e.g., methyl).

[0648] In other groups of compounds accordi Formula IFand the foregoing embodiments and

[0649] description of this aspect of the invention, D iswherein G2is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l -yl, 2,6-dimethylpiperidin-l-yl, 4- (propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin-l-yl, 4-

[0650] (trifluoromethyl)piperidin- 1 -yl, 4-methylpiperidin- 1 -yl, 4-tert-butylpiperidin- 1 -yl, 2-oxopiperidin- 1 - yl, 3,3-dimethylazetidin-l-yl, or oxazolyl (e.g., l ,3-oxazol-2-yl) and D is optionally substituted by one or more additional RMselected from the group consisting of halogen (e.g., fluoro, chloro), or Ci- C6alkyl (e.g., methyl). In particular according to these groups are compounds where D is

[0651] is piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-l -yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin- l -yl, 4-(trifluoromethyl)piperidin-l -yl, 4-methylpiperidin- 1 -yl, 4-tert-butylpiperidin- 1-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l -yl; and RMi is each independently hydrogen, fluoro, chloro, or methyl.

[0652] In other groups of compounds according Formula IFand the foregoing embodiments and

[0653] ucsuipuuii ui mis aspci ui mvciiuuii, uwherein Gi is N, C-H, or C-RM; G2is, wherein , RM, and g are as defined hereinabove. In particular according to these groups, RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

[0654] trifluoromethoxy; g is 0, 1 , or 2; and is as defined hereinabove. In further subgroups L4is a

[0655] ; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

[0656] trifluoromethoxy; and g is 0, 1 , or 2. In particular subgroups,is 3-phenylazetidin-l -yl, 3- phenylpyrrolidin- 1 -yl, 4-phenylpiperazin- 1 -yl, 4-phenylpiperidin- 1 -yl, 4-phenyl-3 ,6-dihydropyridin- 1 (2H)-yl, 4,4-diphenylpiperidin- 1 -yl, 4-acetyl-4-phenylpiperidin- 1 -yl, 4-(4-methoxyphenyl)piperidin- 1 -yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or 2. In other subgroups

[0657] L4is Ci-C6alkylene, -0-, or -S(0)2-; G2is ^ ; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particular subgroups,

[0658] is 4-tosylpiperazin-l -yl, 4-phenoxypiperidin-l-yl, 3-phenoxypyrrolidin-l -yl, 4- benzylpiperidin-l-yl, 4-phenethylpiperidin-l-yl, or 3-phenylpropyl)piperidin-l -yl; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or2. In further subgroups of compounds D iswherein G3is phenyl optionally substituted with one or two RG3; g is 0, 1, or 2; RMis each independently fluoro, chloro, methyl, methoxy,

[0659] trifluoromethyl, or trifluoromethoxy; andand RG3 are as defined above. In other groups of

[0660] compounds D isis Ci-C6alkylene, -0-, or -S(0)2-; G3is phenyl optionally substituted with one or two RG3; g is 0, 1 , or 2; RMis each independently fluoro, chloro, methyl,

[0661] methoxy, trifluoromethyl, or trifluoromethoxy; andand RG3 are as defined above. In further

[0662] subgroups of compounds D iswherein G3is phenyl optionally substituted with one or two RG3 as defined hereinabove; RMi is each independently hydrogen, fluoro, chloro, or methyl; and RG2 is an optional substituent, as described above, selected from the group consisting of -C(0)Ci- C6alkyl, -C C6alkyl, -C C6haloalkyl, -0-C C6alkyl, and -O-d-Cghaloalkyl.

[0663] In other groups of compounds according Formula IFand the foregoing embodiments and

[0664] description of this aspect of the invention, D iswherein Gi is N, C-H, or C-RM; G2is

[0665] subgroups, RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

[0666] N

[0667] trifluoromethoxy; g is 0, 1 , or 2; and is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-

[0668] 2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l ,3-dihydro-2H- isoindol-2-yl, or l ,4-dioxa-8-azaspiro[4.5]dec-8-yl. In further subgroups of compounds D is

[0669] wherein g is 0, 1 , or 2; RMis each independently fluoro, chloro, methyl, methoxy,

[0670] trifluoromethyl, is as defined above. In further subgroups of

[0671] compounds D isis each independently hydrogen, fluoro, chloro, or

[0672] N

[0673] methyl and is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2- yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).

[0674] In other groups of compounds according Formula IFand the foregoing embodiments and

[0675] description of this aspect of the invention, D isis a monocyclic

[0676] 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more RG2, wherein RG2at each occurrence is each independently halogen, -C(0)Cr C6alkyl, -Ci-C6alkyl, -Ci-C6haloalkyl, -0-Ci-C6alkyl, or -0-Ci-C6haloalkyl; and RMis eachindependently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, -O-Ci-Cealkyl, or -O-Ci-Cehaloalkyl. In each

[0677] group of compounds according to the foregoing embodimentsis azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two RG2, wherein RG2at each occurrence is each methyl, ethyl, isopropyl, t trifluoromethyl; and RMis each independently fluoro, chloro,

[0678] or methyl.is 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-1 -yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin-l -yl, 4-methylpiperidin-l -yl, 4-tert-butylpiperidin-l-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl.

[0679] In still another aspect, the present invention features compounds of Formula IGand pharmaceutically acceptable salts thereof,wherein:

[0680] X is , wherein X is optionally substituted with one or more R

[0681] A isor , wherein A is optionally substituted with one or more RA;

[0682] B iswherein B is optionally substituted with one or more RA; and

[0683] Y, Z, RA, and D are as described hereinabove (e.g., as described for Formula I, IA, ¾, Ic, ID, IE or IF, preferably as described for Formula IE).In one embodiment, this aspect of the invention features compounds of Formula IGand

[0685] RAis halogen (e.g., fluoro, chloro); LS-REwhere Lsis a single bond and REis -Ci-C6alkyl (e.g., methyl), -0-Rs(e.g., -0-C]-C6alkyl, -OCH3), or -Ci-C6alkyl optionally substituted with one or more halogen (e.g., -CF3); or LS-REwhere Lsis a Ci-C6alkylene and REis -0-Rs(e.g., -Ci-C6alkyl-

[0686] -Ci-Cealkyl, -CH2OCH3); Y and Z are each independently?

[0687] ; and D is as defined hereinabove.

[0688] In another embodiment, this aspect of the invention features compounds of Formula IGand

[0689] pharmaceutically acceptable salts thereof, wherein X

[0690] wherein A is optionally substituted with one RA; B is, wherein B is optionally substituted with one RA; RA is halogen (e.g., fluoro, chloro); LS-REwhere Lsis a single bond and REis -Ci-C6alkyl (e.g., methyl), -O-Rs (e.g., -0-Ci-C6alkyl, -OCH3), or -Ci-C6alkyl optionally substituted with one or more halogen (e.g., -CF3); or LS-REwhere Lsis a Ci-C6alkylene and REis -

[0691] ., -Ci-C6alkyl-0-Ci-C6alkyl, -CH2OCH3); Y and Z are each independentlyR

[0693] is each independently, wherein compounds having (S) stereochemistry (e.g., ) are particularly contemplated; and D is as defined hereinabove. This subgroup includes compounds where A and B are both substituted by one RA; compounds where A and B are both substituted by zero RA; compounds where A is substituted by one RAand B is substituted by zero RA; and compounds where A is substituted by zero RAand B is substituted by one RA. In particular, according to this subgroup are included compounds where A isand B is

[0695] According to each of the foregoing embodiments and description of this aspect of the invention of Formula IGare groups and subgroups of compounds having particular values for D. Included in each of the foregoing embodiments are groups and subgroups of compounds with the following particular values for D:

[0696] Groups of compounds according to this aspect of the invention include compounds where D is C6-Ci0aryl (e.g., phenyl, naphthyl, indanyl), or 5- to 10-membered heteroaryl (pyridinyl, thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, benzo[d][l,3]dioxol-5-yl), and D is substituted with one or more RM. Particular subgroups according to this aspect and these embodiments include compounds wherein RMis halogen (e.g., fluoro, chloro, bromo); Ci-C6alkyl (e.g., tert-butyl); Ci-C6alkyl substituted with one or more halogen (e.g., CF3); -0-Ci-C6aikyl (e.g., - 0-CH2CH3); -0-Ci-C6alkyl substituted at each occurrence with one or more halogen (e.g., -0-CF3, -0-CH2CHF2) or -0-C C6alkyl (-0-CH2CH2OCH3); -0-C C6alkyl (e.g., -0-CH2) substituted with an optionally substituted 3- to 12-membered heterocycle (e.g., 3-ethyloxetan-3-yl, 1,3-dioxolan- 4-yl); -0-Rswhere Rsis an optionally substituted 3- to 12-membered carbocycle or heterocycle (e.g., cyclopentyl, cyclohexyl, phenyl, l,3-dioxan-5-yl); -N(Rs)C(0)Rs' wherein Rsand Rs' are each independently Ci-C6alkyl (e.g., -N(t-Bu)C(0)Me); SF5; -S02Rswherein Rsis Ci-C6alkyl (e.g., - S02Me); or C3-Ci2carbocycle (e.g., cyclopropyl, cyclohexyl, phenyl). Other subgroups according to this embodiment include compounds wherein D is phenyl substituted by G2and optionally substituted by one or more RM, wherein G2is a 3- to 12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, cyano, Ci-Cealkyl (e.g., methyl), C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl (e.g., CF3), C2-C6haloalkenyl, C2-C6haloalkynyl, -Ο-Ci-Cealkyl (e.g., -O- CH3), -C(0)ORs(e.g., -C(0)OCH3), -C(0)Rs(e.g., -C(0)CH3), -N(RSRS'), or L4-G3; RMis halogen (e.g., fluoro, chloro), alkyl (e.g., methyl), haloalkyl (e.g., CF3), or -0-Ci-C6alkyl (e.g., -0-CH3); and L4, G3, Rs, and Rs' are as defined hereinabove.

[0697] In certain groups of compounds accordin to Formula IGand the foregoing embodiments and

[0698] description of this aspect of the invention, D is, where RMis fluoro, chloro, tert-butyl, -O-

[0699] CH2CH3, -0-CF3, -O-CH2CHF2, -0-CH2CH2OCH3, -0-CH2-(3-ethyloxetan-3-yl), -0-CH2-(l,3- dioxolan-4-yl), -O-cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-(l,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF5, -S02Me, or -N(t-Bu)C(0)Me and D is optionally substituted by one or more additional RM, selected from the group consisting of halogen (e.g., fluoro, chloro) or Ci-C6alkyl (e.g., methyl).

[0700] In other groups of compounds accordin Formula IGand the foregoing embodiments and

[0701] description of this aspect of the invention, D iswherein G2is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4-

[0702] (propan-2-yl)piperidin- 1 -yl, 4-fluoropiperidin- 1 -yl, 3,5 -dimethylpiperidin- 1 -yl, 4-

[0703] (trifluoromethyl)piperidin- 1 -yl, 4-methylpiperidin- 1 -yl, 4-tert-butylpiperidin- 1 -yl, 2-oxopiperidin- 1 - yl, 3,3-dimethylazetidin-l-yl, or oxazolyl (e.g., l,3-oxazol-2-yl) and D is optionally substituted by one or more additional RMselected from the group consisting of halogen (e.g., fluoro, chloro), or Ci- C6alkyl (e.g., methyl). In particular according to these groups are compounds where D is

[0704] ; G2is piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-l-yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin- 1 -yl, 3,5-dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin-l-yl, 4-methylpiperidin- 1-yl, 4-tert-butylpiperidin- 1-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl; and RMi is each independently hydrogen, fluoro, chloro, or methyl.In other groups of compounds according Formula IGand the foregoing embodiments and

[0705] description of this aspect of the invention, Dwherein Gi is N, C-H, or C-RM; G2is

[0706] RM, and g are as defined hereinabove. In particular according to these groups, RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

[0707] L4

[0708] trifluoromethoxy; g is 0, 1 , or 2; and is as defined hereinabove. In further subgroups L4is a

[0709] bond; G2is ^ ; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

[0710] trifluoromethoxy; and g is 0, 1 , or 2. In particular subgroups, ^ is 3-phenylazetidin-l -yl, 3- phenylpyrrolidin- 1 -yl, 4-phenylpiperazin- 1 -yl, 4-phenylpiperidin- 1 -yl, 4-phenyl-3 ,6-dihydropyridin- 1 (2H)-yl, 4,4-diphenylpiperidin- 1 -yl, 4-acetyl-4-phenylpiperidin- 1 -yl, 4-(4-methoxyphenyl)piperidin- 1 -yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or 2. In other subgroups

[0711] L4is Ci-C6alkylene, -0-, or -S(0)2-; G2is; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2. In particular subgroups,

[0712] is 4-tosylpiperazin-l -yl, 4-phenoxypiperidin-l-yl, 3-phenoxypyrrolidin-l -yl, 4-benzylpiperidin-l-yl, 4-phenethylpiperidin-l-yl, or 3-phenylpropyl)piperidin-l -yl; RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or

[0713] 2. In further subgroups of compounds D iswherein G3is phenyl optionally substituted with one or tw is each independently fluoro, chloro, methyl, methoxy,

[0714] trifluoromethyl, and RG3 are as defined above. In other groups of

[0715] compounds D is6alkylene, -0-, or -S(0)2-; G3is phenyl optionally substituted with one or two RG3; g is 0, 1 , or 2; RMis each independently fluoro, chloro, methyl,

[0716] methoxy, trifluoromethyl, or trifluoromethoxy; andand RG3 are as defined above. In further

[0717] subgroups of compounds D iswherein G3is phenyl optionally substituted with one or two RG3 as defined hereinabove; RMi is each independently hydrogen, fluoro, chloro, or methyl; and RG2 is an optional substituent, as described above, selected from the group consisting of -C(0)Ci- C6alkyl, -Ci-C6alkyl, -Ci-C6haloalkyl, -0-Ci-C6alkyl, and -0-Ci-C6haloalkyl.

[0718] In other groups of compounds accord IGand the foregoing embodiments and

[0719] description of this aspect of the invention, D iswherein Gi is N, C-H, or C-RM; G2 is

[0720] subgroups, RMis each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

[0721] N

[0722] trifluoromethoxy; g is 0, 1 , or 2; and is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-

[0723] 2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l ,3-dihydro-2H- isoindol-2-yl, or l ,4-dioxa-8-azaspiro[4.5]dec-8-yl. In further subgroups of compounds D is

[0724] wherein g is 0, 1 , or 2; RMis each independently fluoro, chloro, methyl, methoxy,

[0725] trifluoromethyl, is as defined above. In further subgroups of

[0726] compounds D isis each independently hydrogen, fluoro, chloro, or

[0727] N

[0728] methyl and is as defined above (e.g., 3-azabicyclo[3.2.0]hept-3-yl, octahydro-2H-isoindol-2- yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, 3-azaspiro[5.5]undec-3-yl, l,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl).

[0729] In other groups of compounds according Formula IGand the foregoing embodiments and

[0730] description of this aspect of the invention, D isis a monocyclic

[0731] 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more RG2, wherein RG2at each occurrence is each independently halogen, -C(0)Cr C6alkyl, -Ci-C6alkyl, -Ci-C6haloalkyl, -0-Ci-C6alkyl, or -0-Ci-C6haloalkyl; and RMis eachindependently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, -O-Ci-Cealkyl, or -O-Ci-Cehaloalkyl. In each

[0732] group of compounds according to the foregoing embodimentsis azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two RG2, wherein RG2at each occurrence is each methyl, ethyl, isopropyl, t trifluoromethyl; and RMis each independently fluoro, chloro,

[0733] or methyl.is 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-1 -yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin-l -yl, 4-methylpiperidin-l -yl, 4-tert-butylpiperidin-l-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl.

[0734] The present invention also features compounds of Formulae IE, IF and IG as described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:

[0735] REis independently selected at each occurrence from -0-Rs, -S-Rs, -C(0)Rs, -OC(0)Rs, -

[0736] C(0)ORs, -N(RsRs'), -S(0)Rs, -S02Rs, -C(0)N(RsRs'), -N(Rs)C(0)Rs', - N(Rs)C(0)N(Rs'Rs"), -N(Rs)S02Rs', -S02N(RsRs'), -N(Rs)S02N(Rs'Rs"), - N(Rs)S(0)N(Rs'Rs"), -OS(0)-Rs, -OS(0)2-Rs, -S(0)2ORs, -S(0)ORs, -OC(0)ORs, - N(Rs)C(0)ORs', -OC(0)N(RsRs'), -N(Rs)S(0)-Rs', -S(0)N(RsRs'), -P(0)(ORs)2, =C(RsRs'), or -C(0)N(Rs)C(0)-Rs'; or Ci-C6alkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; or C3-Ci2carbocycle or 3- to 12- membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, trimethylsilyl, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, Ci-C6haloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, -0-Rs, -S-Rs, -C(0)Rs, -C(0)ORs, or -N(RSRS').

[0737] The compounds of the present invention can be used in the form of salts. Depending on the particular compound, a salt of a compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability under certain conditions or desired solubility in water or oil. In some instances, a salt of a compound may be useful for the isolation or purification of the compound.Where a salt is intended to be administered to a patient, the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, base addition salts, and alkali metal salts.

[0738] Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Examples of suitable organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylammosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

[0739] Pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts and organic salts. Non-limiting examples of suitable metallic salts include alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other pharmaceutically acceptable metal salts. Such salts may be made, without limitation, from aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc. Non-limiting examples of suitable organic salts can be made from tertiary amines and quaternary amine, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be quaternized with agents such as alkyl halides (e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides / bromides / iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibuytl, and diamyl sulfates), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.

[0740] The compounds or salts of the present invention may exist in the form of solvates, such as with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to form, respectively, methanolate, ethanolate or acetonitrilate).

[0741] The compounds or salts of the present invention may also be used in the form of prodrugs. Some prodrugs are aliphatic or aromatic esters derived from acidic groups on the compounds of the invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of the invention. Phosphate prodrugs of hydroxyl groups are preferred prodrugs.The compounds of the invention may comprise asymmetrically substituted carbon atoms known as chiral centers. These compounds may exist, without limitation, as single stereoisomers (e.g., single enantiomers or single diastereomer), mixtures of stereoisomers (e.g. a mixture of enantiomers or diastereomers), or racemic mixtures. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that is substantially free from other stereoisomers (e.g., substantially free from other enantiomers or diastereomers). By "substantially free," it means that at least 80% of the compound in a composition is the described stereoisomer; preferably, at least 90%> of the compound in a composition is the described stereoisomer; and more preferably, at least 95%, 96%, 97%>, 98%> or 99%o of the compound in a composition is the described stereoisomer. Where the stereochemistry of a chiral carbon is not specified in the chemical structure of a compound, the chemical structure is intended to encompass compounds containing either stereoisomer of the chiral center.

[0742] Individual stereoisomers of the compounds of this invention can be prepared using a variety of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers followed by chromatographically separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic resolution.

[0743] Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or substantial optically pure materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at the chiral centers. Mixtures of stereoisomers of compounds, including racemic mixtures, resulting from a synthetic reaction may be separated, for example, by chromatographic techniques as appreciated by those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished by using chiral chromatography resins, many of which are commercially available. In a non-limiting example, racemate is placed in solution and loaded onto the column containing a chiral stationary phase. Enantiomers can then be separated by HPLC.

[0744] Resolution of enantiomers can also be accomplished by converting enantiomers in a mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can be separated by column chromatography or crystallization / re-crystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Non-limiting examples of suitable chiral auxiliaries include chirally pure amino acids, organic carboxylic acids or organosulfonic acids. Once the diastereomers are separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.Enzymes, such as esterases, phosphatases or lipases, can be useful for the resolution of derivatives of enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be treated with an enzyme which selectively hydrolyzes only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.

[0745] Alternatively, salts of enantiomers in a mixture can be prepared using any suitable method known in the art, including treatment of the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization / re-crystallization of the enantiomerically pure salts. Methods suitable for the resolution / separation of a mixture of stereoisomers, including racemic mixtures, can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et al, 1981, John Wiley and Sons, New York, NY).

[0746] A compound of this invention may possess one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as the cis (Z) and trans (E) isomers, and mixtures thereof are intended to be encompassed within the scope of a recited compound unless otherwise specified. In addition, where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.

[0747] Certain compounds of the invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotations about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The invention encompasses each conformational isomer of these compounds and mixtures thereof.

[0748] Certain compounds of the invention may also exist in zwitterionic form and the invention encompasses each zwitterionic form of these compounds and mixtures thereof.

[0749] The compounds of the present invention are generally described herein using standard nomenclature. For a recited compound having asymmetric center(s), it should be understood that all of the stereoisomers of the compound and mixtures thereof are encompassed in the present invention unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-transisomers. Where a recited compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms. Certain compounds are described herein using general formulas that include variables (e.g., A, B, D, X, Li, L2, L3, Y, Z, T, RAor RB,). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. If moieties are described as being "independently" selected from a group, each moiety is selected independently from the other. Each moiety therefore can be identical to or different from the other moiety or moieties.

[0750] The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix "Cx-Cy," where x is the minimum and y is the maximum number of carbon atoms in the moiety. Thus, forexample, "Ci-Cealkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C3-Cecycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms. A prefix attached to a multiple-component substituent only applies to the first component that immediately follows the prefix. To illustrate, the term "carbocyclylalkyl" contains two components: carbocyclyl and alkyl. Thus, for example, C3-C6carbocyclylCi-C6alkyl refers to a C3-C6carbocyclyl appended to the parent molecular moiety through a Ci-Cealkyl group.

[0751] Unless otherwise specified, when a linking element links two other elements in a depicted chemical structure, the leftmost-described component of the linking element is bound to the left element in the depicted structure, and the rightmost-described component of the linking element is bound to the right element in the depicted structure. To illustrate, if the chemical structure is -Ls-M- Ls'- and M is -N(RB)S(0)- then the chemical structure is -Ls-N(RB)S(0)-Ls'-.

[0752] If a linking element in a depicted structure is a bond, then the element left to the linking element is joined directly to the element right to the linking element via a covalent bond. For example, if a chemical structure is depicted as -Ls-M-Ls'- and M is selected as bond, then the chemical structure will be -Ls-Ls'-. If two or more adjacent linking elements in a depicted structure are bonds, then the element left to these linking elements is joined directly to the element right to these linking elements via a covalent bond. For instance, if a chemical structure is depicted as -Ls- M-Ls'-M'-Ls"-, and M and Ls' are selected as bonds, then the chemical structure will be -Ls-M'- Ls"-. Likewise, if a chemical structure is depicted as -Ls-M-Ls'-M'-Ls"-, and M, Ls' and M' are bonds, then the chemical structure will be -Ls-Ls"-.

[0753] When a chemical formula is used to describe a moiety, the dash(s) indicates the portion of the moiety that has the free valence(s).

[0754] If a moiety is described as being "optionally substituted", the moiety may be either substituted or unsubstituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either unsubstituted, or substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heterocycle optionally substituted with up to three non-hydrogen radicals, then any heterocycle with less than three substitutable positions will be optionally substituted by up to only as many non- hydrogen radicals as the heterocycle has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) will be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to two non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to two non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only one non-hydrogen radical.Where a moiety is substituted with oxo or thioxo, it means that the moiety contains a carbon atom covalently bonded to at least two hydrogens (e.g., CH2), and the two hydrogen radicals are substituted with oxo or thioxo to form C=0 or C=S, respectively.

[0755] The term "alkenyl" means a straight or branched hydrocarbyl chain containing one or more double bonds. Each carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons. Non-limiting examples of alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.

[0756] The term "alkenylene" refers to a divalent unsaturated hydrocarbyl chain which may be linear or branched and which has at least one carbon-carbon double bond. Non-limiting examples of alkenylene groups include -C(H)=C(H)-, -C(H)=C(H)-CH2- -C(H)=C(H)-CH2-CH2- -CH2-C(H)=C(H)-CH2- -C(H)=C(H)-CH(CH3)-, and -CH2-C(H)=C(H)-CH(CH2CH3)-.

[0757] The term "alkyl" means a straight or branched saturated hydrocarbyl chain. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, pentyl, iso-amyl, and hexyl.

[0758] The term "alkylene" denotes a divalent saturated hydrocarbyl chain which may be linear or branched. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and -CH2CH(CH3)CH2-.

[0759] The term "alkynyl" means a straight or branched hydrocarbyl chain containing one or more triple bonds. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, and 3-butynyl.

[0760] The term "alkynylene" refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon triple bonds. Representative alkynylene groups include, by way of example, — C≡C— , — C≡C— CH2— , — C≡C— CH2— CH2— , -CH2-C≡C-CH2- -C≡C-CH(CH3)-, and -CH2-C≡C-CH(CH2CH3)-.

[0761] The term "carbocycle" or "carbocyclic" or "carbocyclyl" refers to a saturated (e.g., "cycloalkyl"), partially saturated (e.g., "cycloalkenyl" or "cycloalkynyl") or completely unsaturated (e.g., "aryl") ring system containing zero heteroatom ring atom. "Ring atoms" or "ring members" are the atoms bound together to form the ring or rings. A carbocyclyl may be, without limitation, a single ring, two fused rings, or bridged or spiro rings. A substituted carbocyclyl may have either cis or trans geometry. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl, and norpinanyl. A carbocycle group can be attached to the parent molecular moiety through any substitutable carbon ring atom. Where a carbocycle group is a divalent moiety linking two otherelements in a depicted chemical structure (such as A in Formula I), the carbocycle group can be attached to the two other elements through any two substitutable ring atoms. Likewise, where a carbocycle group is a trivalent moiety linking three other elements in a depicted chemical structure (such as X in Formula I), the carbocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.

[0762] The term "carbocyclylalkyl" refers to a carbocyclyl group appended to the parent molecular moiety through an alkylene group. For instance, C3-C6carbocyclylCi-C6alkyl refers to a C3- C6carbocyclyl group appended to the parent molecular moiety through Ci-C6alkylene.

[0763] The term "cycloalkenyl" refers to a non-aromatic, partially unsaturated carbocyclyl moiety having zero heteroatom ring member. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl.

[0764] The term "cycloalkyl" refers to a saturated carbocyclyl group containing zero heteroatom ring member. Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.

[0765] The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, "Ci-Cehaloalkyl" means a Ci-C6alkyl substituent wherein one or more hydrogen atoms are replaced with independently selected halogen radicals. Non-limiting examples of Ci-Cehaloalkyl include chloromethyl, 1-bromoethyl, fluorom ethyl, difluoromethyl, trifluorom ethyl, and 1,1 ,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).

[0766] The term "heterocycle" or "heterocyclo" or "heterocyclyl" refers to a saturated (e.g., "heterocycloalkyl"), partially unsaturated (e.g., "heterocycloalkenyl" or "heterocycloalkynyl") or completely unsaturated (e.g., "heteroaryl") ring system where at least one of the ring atoms is a heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocycle may be, without limitation, a single ring, two fused rings, or bridged or spiro rings. A heterocycle group can be linked to the parent molecular moiety via any substitutable carbon or nitrogen atom(s) in the group. Where a heterocycle group is a divalent moiety that links two other elements in a depicted chemical structure (such as A in Formula I), the heterocycle group can be attached to the two other elements through any two substitutable ring atoms. Likewise, where a heterocycle group is a trivalent moiety that links three other elements in a depicted chemical structure (such as X in Formula I), the heterocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.

[0767] A heterocyclyl may be, without limitation, a monocycle which contains a single ring. Non- limiting examples of monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl,isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as "azoximyl"), 1,2,5-oxadiazolyl (also known as "furazanyl"), and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4- oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2- dioxazolyl, and 1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1,3 -diazinyl"), and pyrazinyl (also known as "1,4-diazinyl")), piperazinyl, triazinyl (including s-triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as "1,2,3-triazinyl), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl, and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2, 5 -oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, thiomorpholinyl, and diazepinyl.

[0768] A heterocyclyl may also be, without limitation, a bicycle containing two fused rings, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl. Other non-limiting examples of fused-ring heterocycles include benzo-fused heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl" or indazolyl), benzazinyl (including quinolinyl (also known as "1- benzazinyl") and isoquinolinyl (also known as "2 -benzazinyl")), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as "1,2-benzodiazinyl") and quinazolinyl (also known as "1,3 -benzodiazinyl")), benzopyranyl (including "chromenyl" and "isochromenyl"), benzothiopyranyl (also known as "thiochromenyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", "thionaphthenyl", and "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl", "isothionaphthenyl", and "isobenzothiofuranyl"), benzothiazolyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1 -benzoxazinyl, and 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl and 1 ,4-benzisoxazinyl), and tetrahydroisoquinolinyl.

[0769] A heterocyclyl may also be, without limitation, a spiro ring system, such as, for example, 1,4- dioxa-8-azaspiro[4.5]decanyl.A heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom(s) is oxidized to SO or SO2. The nitrogen heteroatom(s) in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to N-oxide. In addition, the nitrogen heteroatom(s) may or may not be N-protected.

[0770] A heterocycle or carbocycle may be further substituted. Unless specified, the term

[0771] "substituted" refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -CI, -Br, -I, hydroxy, protected hydroxy, -N02, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-Ci-Ci2-alkyl, -NH-C2-C8-alkenyl, -NH-C2-C8-alkynyl, -NH-C3-Ci2-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocycloalkyl, - dialkylamino, -diarylamino, -diheteroarylamino, -0-Ci-Ci2-alkyl, -0-C2-C8-alkenyl, -0-C2-C8- alkynyl, -0-C3-Ci2-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycloalkyl, -C(0)-Ci-Ci2-alkyl, - C(0)-C2-C8-alkenyl, -C(0)-C2-C8-alkynyl, -C(0)-C3-Ci2-cycloalkyl, -C(0)-aryl, -C(0)-heteroaryl, - C(0)-heterocycloalkyl, -CONH2, -CONH-C Ci2-alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8- alkynyl, -CONH-C3-Ci2-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, - OC02-Ci-Ci2-alkyl, -OC02-C2-C8-alkenyl, -OC02-C2-C8-alkynyl, -OC02-C3-Ci2-cycloalkyl, -OC02- aryl, -OC02-heteroaryl, -OC02-heterocycloalkyl, -OCONH2, -OCONH-C Ci2-alkyl, -OCONH-C2- Cg-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-Ci2-cycloalkyl, -OCONH-aryl, -OCONH- heteroaryl, -OCONH-heterocycloalkyl, -NHC(0)-C Ci2-alkyl, -NHC(0)-C2-C8-alkenyl, -NHC(O)- C2-C8-alkynyl, -NHC(0)-C3-Ci2-cycloalkyl, -NHC(0)-aryl, -NHC(0)-heteroaryl, -NHC(O)- heterocycloalkyl, -NHC02-C Ci2-alkyl, -NHC02-C2-C8-alkenyl, -NHC02-C2-C8-alkynynl, -NHC02- C3-Ci2-cycloalkyl, -NHC02-aryl, -NHC02-heteroaryl, -NHC02-heterocycloalkyl, -NHC(0)NH2, - NHC(0)NH-Ci-Ci2-alkyl, -NHC(0)NH-C2-C8-alkenyl, -NHC(0)NH-C2-C8-alkynyl, -NHC(0)NH- C3-Ci2-cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-heteroaryl, -NHC(0)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-C Ci2-alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8-alkynyl, - NHC(S)NH-C3-Ci2-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH- heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-C Ci2-alkyl, -NHC(NH)NH-C2-C8-alkenyl, - NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-Ci2-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH- heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)-Ci-Ci2-alkyl, -NHC(NH)-C2-C8-alkenyl, - NHC(NH)-C2-C8-alkynyl, -NHC(NH)-C3-Ci2-cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, - NHC(NH)-heterocycloalkyl, -C(NH)NH-Ci-Ci2-alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8- alkynyl, -C(NH)NH-C3-Ci2-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH- heterocycloalkyl, -S(0)-Ci-Ci2-alkyl, -S(0)-C2-C8-alkenyl, -S(0)-C2-C8-alkynyl, -S(0)-C3-Ci2- cycloalkyl, -S(0)-aryl, -S(0)-heteroaryl, -S(0)-heterocycloalkyl, -S02NH2, -S02NH-Ci-Ci2-alkyl, - S02NH-C2-C8-alkenyl, -S02NH-C2-C8-alkynyl, -S02NH-C3-Ci2-cycloalkyl, -S02NH-aryl, -S02NH- heteroaryl, -S02NH-heterocycloalkyl, -NHS02-Ci-Ci2-alkyl, -NHS02-C2-C8-alkenyl, -NHS02-C2-C8- alkynyl, -NHS02-C3-Ci2-cycloalkyl, -NHS02-aryl, -NHS02-heteroaryl, -NHS02-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -C3-C12- cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-Ci-Ci2-alkyl, - S-C2-C8-alkenyl, -S-C2-C8-alkynyl, -S-C3-Ci2-cycloalkyl, -S-aryl, -heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. It is understood that the aryls, heteroaryls, alkyls, and the like can be further substituted.

[0772] An "aliphatic" group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and / or triple bonds. Examples of aliphatic groups are functional groups, such as, O, OH, NH, NH2, C(O), S(0)2, C(0)0, C(0)NH, OC(0)0, OC(0)NH, OC(0)NH2, S(0)2NH, S(0)2NH2, NHC(0)NH2, NHC(0)C(0)NH, NHS(0)2NH, NHS(0)2NH2, C(0)NHS(0)2, C(0)NHS(0)2NH or C(0)NHS(0)2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo-substituted. An aliphatic group may be straight chained, branched or cyclic and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted. A linear aliphatic group is a non-cyclic aliphatic group. It is to be understood that when a linear aliphatic group is said to "contain" or "include" or "comprise" one or more specified functional groups, the linear aliphatic group can be selected from one or more of the specified functional groups or a combination thereof, or a group wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a specified functional group. An exemplary linear aliphatic group is an alkyl, alkenyl or alkynyl, each optionally substituted, which is interrupted or terminated by a functional group.

[0773] in a chemical formula refers to a single or double bond.

[0774] The term "pharmaceutically acceptable" is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.

[0775] The term "therapeutically effective amount" refers to the total amount of each active substance that is sufficient to show a meaningful patient benefit, e.g. a reduction in viral load.

[0776] The term "prodrug" refers to derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. A prodrug of a compound may be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy, carboxy or phosphate group). Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, Bungard, H.,DESIGN OF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amine functional groups within the compounds of the invention, or phosphate esters of the compounds of the invention.

[0777] The term "solvate" refers to the physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, and methanolates.

[0778] The term "N-protecting group" or "N-protected" refers to those groups capable of protecting an amino group against undesirable reactions. Commonly used N-protecting groups are described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3rded., John Wiley & Sons, NY (1999). Non-limiting examples of N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p- methylphenyl-S(O)-) or t-butylsulfinyl (t-Bu-S(O)-); carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, l -(p-biphenylyl)-l-methylethoxycarbonyl, dimethyl-3,5- dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2 -trichloro-ethoxy-carbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbonyl; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl; p- methoxyphenyl; and silyl groups such as trimethylsilyl. Preferred N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0779] Abbreviations which have been used in the descriptions of the Schemes, Intermediates and

[0780] Examples that follow are: Ac for acetyl; APCI for atmospheric pressure chemical ionization; aq oraq. for aqueous; atm for atmosphere; Boc for z-butoxycarbonyl; Bu for butyl; z-Bu or teri-butyl for tertiary-butyl; Cbz for benzyloxycarbonyl; dba for dibenzylidineacetone; DCI for desorption chemical ionization; DDQ for 2,3-dichloro-5,6-dicyano- ?-benzoquinone; DEPBT for 3- (diethoxyphosphoryloxy)-! , 2, 3-benzotriazin-4(3 / )-one; DIBAL for diisobutylalurninum hydride; DMA for AyV-dimethylacetamide; DME for 1 ,2-dimethoxyethane; DMF for Λ^,Λ^-dimethylformamide; DMSO for dimethyl sulfoxide; DMPU for l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone; dppf for l,l '-bis(diphenylphosphino)ferrocene; EDC, EDAC or EDCI for A^3-dimethylaminopropyl)- / V'- ethylcarbodiimide hydrochloride; e.e. for enantiomeric excess; ELSD for evaporative light scattering detector; ESI for electrospray ionization; Et for ethyl; Et3N for triethylamine; EtOAc for ethyl acetate; EtOH for ethanol; Et20 for diethyl ether; eq or equiv for equivalents; Fmoc for 9- fluorenylmethoxycarbonyl; HATU for 0-(7-azabenzotriazol-l-yl)-A^^V,A^',A^'-tetramethyluronium hexafluorophosphate; HOBt for 1 -hydroxybenzotriazole; HPLC for high performance liquid chromatography; HOBt for 1 -hydroxybenzotriazole; LCMS for liquid chromatography / mass spectrometry; mCPBA for wi-chloroperoxybenzoic acid; Me for methyl; MeOH for methanol; OAc for acetate; Ms for methanesulfonyl; OTF for triflate or trifluoromethanesulfonate; PDC for pyridinium dichromate; z'-Pr for isopropyl; Ph for phenyl; PPh3for triphenylphosphine; psi or psig for pounds per square inch (gas); PTFE for polytetrafluoroethylene; PXPd for [(i-Bu^PCl^PdC^, PyBOP for (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate; SEM for 2- (trimethylsilyl)ethoxymethyl; T3P for propane phosphonic acid anhydride; Tf for trifluorosulfonyl; TFA for trifluoroacetic acid; THF for tetrahydrofuran; TLC for thin layer chromatography; Troc for 2,2,2-trichloroethoxycarbonyl; v / v for volume / volume; wt% for weight percent; w / v for weight / volume; w / w for weight / weight; XantPhos for 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene;

[0781] The compounds of the present invention can be prepared using a variety of methods. As a non-limiting example, the compounds of the present invention can be prepared according to Scheme I starting from compounds of Formula II (e.g., n = 0 to 8), Formula V (¾ can be, for example, O or NRA, where RAis as described hereinabove and is preferably H or REas defined above such as Cl- C6alkyl, 3- to 12-membered carbocycle or heterocycle, -C(0)Rs, -C(0)ORs, -C(0)N(RsRs'), - S02N(RsRs'), -S(0)2ORs, -S(0)ORs, -S(0)N(RsRs'), or a suitable protecting group such as Boc or Fmoc), or Formula VIII (E can be, for example, 3- to 7-membered carbocycle or heterocycle and is optionally substituted with one or more RA), wherein A, B, D, Y, Z and RAare as described above. The 1,4-diketones II, V, and VIII can be reduced to the 1,4-diols using the methods described below, and the resultant racemic, enantiomerically enriched, or meso 1,4-diols may be converted to the dimesylates III, VI, or IX, or alternatively to ditriflates, ditosylates, or dihalides by the methods described below. The dimesylates III, VI, and IX, ditriflates, ditosylates, or dihalides may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described below to give the compounds of the invention. Li and L2can be readily introduced to Formulae II, V and VIII, as appreciated by those skilled in the art in light of the present invention. Likewise, D-L3- NH2can be used instead of D-NH2, as appreciated by those skilled in the art.

[0783] Scheme I As another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II and Formula III as shown in Scheme II. The 1,4-diketones such as Formula IV may be prepared using known methods (see Nevar, et al., Synthesis:1259-1262 (2000), such as the reaction of a-bromoketones such as Formula II with methyl ketones such as Formula III in the presence of a suitable Lewis acid such as ZnCl2or Ti(OiPr)4. For example reaction of II (1 equivalent) with III (1.5 equivalents) in the presence of ZnCl2(2 equivalents), diethylamine (1.5 equivalents) and teri-butanol (1.5 equivalents) in a solvent such as benzene at around room temperature can provide the diketones IV. The 1,4-diketones IV may be reduced to the 1,4-diols such as V by the action of NaBH4, LiAlH4, or DIBAL. Alternatively, enantioselective reduction of 1,4- diketones such as Formula IV can be accomplished by analogy with reported methods (see Chong, et al., Tetrahedron: Asymmetry 6:409-418 (1995), Li, et al., Tetrahedron 63:8046-8053 (2007), Aldous, et al., Tetrahedron: Asymmetry 11 :2455-2462 (2000), Masui, et al., Synlett:273-274 (1997), Jing, et al., Adv. Synth. Catal. 347:1193-1197 (2005), Sato, et al., Synthesis:1434-1438 (2004)), such asreduction with (-) or (+)-diisopinocamheylchloroborane (DIP-chloride), with borane and an oxazaborolidine catalyst, or with asymmetric hydrogenation in the presence of a suitable Ruthenium (II) catalyst, such as [RuC12 {(R)-BINAP} {(R,R)-DPEN}] (BINAP=2,2'-bis(diarylphosphino)-l,l '- binaphthyl; DPEN=l ,2-diphenylethylenediamine). The diketones IV (1 equivalent) can be reduced by NaBH4 (3 equivalents) in solvents such as tetrahydrofuran with heating to about 50 °C. The diketones IV (1 equivalent) can be enantioselectively reduced upon addition to a mixture made from AyV-diethylaniline borane (about 2 equivalents), trimethylborate (about 0.2 equivalents) and either (S) or (R) a,a-diphenyl-2-pyrrolidinemethanol (about 0.17 equivalents) in a solvent such as THF at temperatures ranging from about 10 °C to about 30 °C (Synthesis 2507-2510 (2003)). The resultant racemic, enantiomerically enriched, or meso 1 ,4-diols V may be reacted with methanesulfonyl chloride or methanesulfonic anhydride to provide the dimesylate Formula VI. For example, diols V (1 equivalent) can be reacted with methanesulfonic anhydride (about 2.5 equivalents) in the presence of a base such as diisopropylethylamine (about 4 equivalents) in a solvent such as tetrahydrofuran or 2-methyltetrahydrofuran at temperatures starting from about -15 °C to -25 °C and increasing to about room temperature. Alternatively Formula V may be converted to a ditriflate or ditosylate by the action of p-toluenesulfonyl chloride or triflic anhydride, or to a dihalide such as a dibromide or dichloride by the action of PPh3in the presence of CC or CBr4, or by the action of SOCI2, POCI3, or PBr3. The dimesylate, ditriflate, ditosylate, or dihalide may be reacted with an amine, such as 4- fluoroaniline (as shown for illustration in Scheme II), with or without a co-solvent such as DMF at room temperature to 100 °C, to give the pyrrolidines such as Formula VII. The dimesylate VI (1 equivalent) (or in the alternative the ditriflate, ditosylate, or dihalide) may be reacted with between 1 to 20 equiv of an amine D-NH2, such as, for example, a substituted aniline in solvents such as tetrahydrofuran or 2-methyltetrahydrofuran with or without a co-solvent such as DMF, at about room temperature to about 100 °C, to give the pyrrolidines such as Formula VII. Where fewer equivalents of amine D-NH2are employed (i.e., 1 -2 equivalents), a base such as diisopropylethylamine can be added to promote the reaction. In certain cases, the amine can be used in a large excess (i.e., as reaction solvent). For example, the reaction of a dimesylate (1 equivalent) with excess aniline (about 6.5 equivalents) can be conducted by heating to 65 °C in 2-methyltetrahydrofuran until completion of the reaction. Numerous substituted anilines can be reacted with the dimesylate Formula VI, including, but not limited to, 3-fluoro-4-(piperidin-l-yl)aniline, 3,5-difluoro-4-(piperidin-l-yl)aniline, 3 ,5 -difluoro-4-(4-phenylpiperidin- 1 -yl)aniline, 3-difluoro-4-(4-phenylpiperidin- 1 -yl)aniline, 4-(4- phenylpiperidin-1 -yl)aniline, 4-cyclopropylaniline, 4-cyclopropyl-2-fluoroaniline, 4-cyclopropyl-3,5- difluoroaniline, 4-cyclohexyl-3-fluoroaniline, biphenyl-4-amine, 4-(pyridin-2-yl)aniline, 3,5-dichloro- 4-(piperidin- 1 -yl)aniline, 4-(4,4-dimethylpiperidin- 1 -yl)-3,5 -difluoroaniline, 4-(4,4-fluoropiperidin- 1 - yl)-3,5-difluoroaniline, 3-methyl-4-(piperidin-l -yl)aniline, 2,5-difluoro-4-(piperidin-l-yl)aniline, 4- (3,5-dimethylpiperidin-l-yl)-3,5-difluoroaniline, 4-(2,6-dimethylpiperidin-l -yl)-3,5-difluoroaniline,2,3,5-trifluoro-4-(piperidin-l -yl)aniline, 3,5-difluoro-4-(4-isopropylpiperidin-l -yl)aniline, 3,5- difluoro-4-(4-methylpiperidin-l-yl)aniline, 3,5-difluoro-4-(4-(trifluoromethyl)piperidin-l-yl)aniline, 4-(4-?eri-butylpiperidin-l-yl)-3,5-difluoroaniline, 3,5-difluoro-4-(6-azaspiro[2.5]octan-6-yl)aniline, 4- (2-azabicyclo[2.2.2]octan-2-yl)-3,5-difluoroaniline, 4-(3,3-dimethylazetidin-l-yl)-3,5-difluoroaniline, 4-teri-butylaniline, 4-ethoxyaniline, 4-phenoxyaniline, l-(4-aminophenyl)piperidin-2-one, 4- (cyclopentyloxy)-3-fluoroaniline, 3-chloro-4-(trifluoromethoxy)aniline, 2,5-difluoro-4-

[0784] (trifluoromethyl)aniline, 4-(2,2-difluoroethoxy)aniline, 4-chloroaniline, 4-(2-methoxyethoxy)aniline, 4-(oxazol-2-yl)aniline, 4-(2-fluoropyridin-4-yl)aniline, 3,4-difluoroaniline, 4-chloro-3-fluoroaniline, 3-fluoro-4-(methylsulfonyl)aniline, 4-(3-azabicyclo[3.2.0]heptan-3-yl)-3,5-difluoroaniline, 4-((3- ethyloxetan-3-yl)methoxy)aniline, 4-cyclopropyl-3 ,5 -difluoroaniline, 4-( 1 ,3 -dioxan-5-yloxy)aniline, 3,5-difluoro-4-(octahydroisoindol-2-yl)aniline, 4-((l,3-dioxolan-4-yl)methoxy)aniline, 4-((3- ethyloxetan-3-yl)methoxy)-3 ,5 -difluoroaniline, 4-(pentafluorosulfanyl)aniline, -teri-butyl-2- fluorobenzene-l,4-diamine, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, allylamine, or anilines that are listed in or can be made using General Procedures 1, 1.1, or 1.2. The dinitro Formula VII may be reduced to the diamino Formula VIII using Fe in the presence of NH4C1, HCl, or acetic acid, or by treatment with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as BiC¾, SbC¾, NiC¾, Cu2Cl2, or CoCl2) in a solvent such as ethanol or THF. For example compounds VII (1 equivalent) can be reduced to VIII by reaction with iron powder (about 6 equivalents) and ammonium chloride in a 1 :1 mix of THF and ethanol with heating to about 60-80 °C. Alternatively, Formula VII can be reduced to the product Formula VIII by hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney-nickel. For example reduction of VII to VIII can be effected by exposure to 30 psig hydrogen gas in the presence of Raney-nickel Grace 2800 in a solvent such as tetrahydrofuran with shaking. The diamine Formula VIII may be reacted with a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be substituted) in the presence of a peptide coupling reagent, such as EDAC / HOBT, PyBOP, HATU, T3P or DEPBT, in a solvent such as THF, DMF, dichloromethane, ethyl acetate, or DMSO, with or without the addition of an amine base such as A -methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to give Formula IX. For example, reaction of VIII (1 equivalent) with l-(teri-butoxycarbonyl)pyrrolidine-2- carboxylic acid (2.5 equivalents) and HATU (2.5 equivalents) in the presence of diisopropylethylamine (3 equivalents) in DMSO at about room temperature can provide the product IX. Removal of the Boc protecting groups to give X may be accomplished by treatment with an acid, such as TFA, HCl, or formic acid. For example, reaction of IX (1 equivalent) with TFA:CH2Cl2(1 :1) at room temperature can provide compounds X. Compounds XI may be prepared by coupling of Formula X with an acid of choice using the standard peptide coupling reagents and conditions described above. For example, X(l equivalent) can be reacted with acids (2 equivalents) such as, butnot limited to, 2-(methoxycarbonylamino)-3-methylbutanoic acid, 2-(methoxycarbonylamino)-3,3- dimethylbutanoic acid, 2-cyclohexyl-2-(methoxycarbonylamino)acetic acid, 2- (methoxycarbonylamino)-2-(tetrahydro-2 f-pyran-4-yl)acetic acid, or acids listed under General Procedure 19. Alternately, diamine VIII may be reacted directly with an appropriately / V-substituted proline in the presence of a peptide coupling reagent such as EDAC / HOBT, PyBOP, HATU, T3P, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as A -methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to directly give compounds XI. For example, VIII (1 equivalent) can be reacted directly with l-(2- (methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (about 2 equivalents) and T3P (about 2.8 equivalents) in the presence of diisopropylethylamine (about 5.5 equivalents) in a solvent such as ethyl acetate at temperatures from about 0 °C to about room temperature to provide XI. The foregoing sequence illustrates the synthesis of particular compounds of the invention XI having a substituted proline group at Y and Z (i.e., R2 and R5taken together with the atoms to which they are attached, and R9 and R12 taken together with the atoms to which they are attached, each form a 5-membered heterocycle). It is understood that analogous synthetic procedures can be used to make compounds of the invention where Y, Z, R2, R5, R9, and R12 are other than that shown and described

[0785] in Scheme II.in each Formula within Scheme II can be replaced with where D is defined above, and such compounds can be readily prepared according to the process described in Scheme II (including making compound XI directly from compound VIII). Likewise, compounds of Formula XII can be prepared from compounds of Formula X or directly from compounds of Formula VIII.

[0788] XII

[0789] Scheme II

[0790] As yet another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II and Formula III as shown in Scheme III, where A, B, D, Y, and Z are as described above, using conditions similar to those described above for the preparation of IV in Scheme II. Similarly, the resulting 1,4-diketone IV may be reduced to the 1,4-diols V using themethods described above for Scheme II. The resultant racemic, enantiomerically enriched, or meso 1,4-diols V may be converted to the dimesylate VI or alternatively to a ditriflate, ditosylate, or dihalide by the methods described above. The dimesylate VI, ditriflate, ditosylate, or dihalide may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4-difluoroaniline, 4- fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroaryl amines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under the conditions described above the give the compounds of the invention. Alternatively, compounds such as VIII, where R is a group such as allyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl, may be treated with reagents useful for the removal of the R group (rhodium catalyst such as Rh(Ph3P)3Cl for R = allyl, treatment with an acid such as TFA or HC1 for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for R = substituted benzyl) to generate compounds such as IX. Amine IX may be reacted with an aryl halide or triflate such as X (iodide shown for illustration) employing the Buchwald- Hartwig reaction in the presence of a palladium catalyst (such as Pd(OAc)2 or Pd2(dba)3) and a phosphine ligand (such as triphenylphosphine or XantPhos) and a base (such as sodium bis(trimethylsilyl)amide, potassium tert-butoxide, or K3P04) to give the compounds of the present invention. Alternatively, the compounds of the present invention may be obtained by reaction of IX with an aldehyde or ketone through reductive amination in the presence of a hydride reducing agent, such as sodium borohydride or sodium cyanoborohydride (with or without the addition of an acid, such as acetic acid) in a solvent such as ethanol, toluene, THF, or dichloromethane. Alternatively the reductive amination may be conducted through the use of hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. Alternatively, amine IX may react with electrophihc reagents, such as alkyl halides, or with aryl electrophiles (suitably electron deficient aryl and heteroaryl halides and triflates) through nucleophilic aromatic substitution reactions to give the compounds of the present invention.

[0793] R = allyl or substitued benzyl

[0794] Scheme III

[0795] As a further non-limiting example, the compounds of XIII can be prepared starting from compounds of Formula II and Formula III as shown in Scheme IV, where X5in Formula II and Formula III represents a halogen (e.g., CI, Br, or F) or a nitro group. Additionally, each phenyl ring can be substituted with Xi3, wherein X13 is X5, H, alkyl, haloalkyl, alkoxy, or haloalkoxy. The 1 ,4- diketones such as IV may be prepared using known methods described above for the preparation of IV for Scheme II. The 1,4-diketones IV may be reduced to the 1 ,4-diols such as V by the action of NaBH4, L1AIH4, or DIBAL. Alternatively, enantioselective reduction of 1,4-diketone such as IV can be accomplished by the methods described above for the preparation of V in Scheme II. As described for Intermediate 20D, the chiral reduction may proceed with lower stereoselectivity with an additional substituent Xi3on the phenyl ring. The resultant racemic, enantiomerically enriched, or meso 1 ,4- diols V may be reacted with methansulfonyl chloride or methanesulfonic anhydride to provide the dimesylate VI. Alternatively V may be converted to a ditriflate or ditosylate by the methods described above for Scheme II. The dimesylate, ditriflate, ditosylate, or dihalide may be reacted,analogously to Scheme II, with an amine D-NH2including but not limited to those amines described or referred to in Scheme II to give VII. When X5in Formula VII is nitro, the nitro groups may be reduced to the tetraamino product IX using Fe in the presence of NH4C1, HC1, or acetic acid, or with a hydride reducing agent, such as sodium borohydride (with or without the addition of a transition metal salt, such as B1CI3, SbCl3, NiCl2, Cu2Cl2, or CoCl2) in a solvent such as ethanol or THF.

[0796] Alternatively, VII (X5= nitro) can be reduced to the product IX by hydrogenation in the presence of a suitable catalyst, such as a palladium or platinum catalyst or Raney nickel. Alternatively, compounds VII where X5= halogen may be reacted with ammonia (R = H) or an amine bearing a suitable protecting group (R = substituted benzyl such as 4-methoxybenzyl or 2,4 dimethoxybenzyl or R = allyl). The resulting products VIII may be treated with a reagent useful for the removal of the R protecting group (rhodium catalyst such as Rh(Ph3P)3Cl for R = allyl, treatment with an acid such as TFA or HC1 for R = 4-methoxybenzyl or 2,4-dimethoxybenzyl, hydrogenolysis with a Pd catalyst for R = substituted benzyl) to give the product IX. Formula IX may be reacted with a suitably protected proline acid (Boc is shown, although Cbz, Troc, or Fmoc may be substituted) in the presence of a peptide coupling reagent, such as EDAC / HOBT, PyBOP, HATU, T3P, or DEPBT, in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base, such as N- methylmorpholine, Hunig's base, pyridine, 2,6-lutidine, or triethylamine, to give X as a mixture of the amide products. Although formula X depicts reaction taking place on a specific NH2group, the reaction may take place at either NH2. Conversion to the benzimidazole compound XI may be accomplished by heating X in acetic acid (50-100 °C). Alternatively, XI may be prepared by reaction of IX with an aldehyde, followed by treatment with an oxidant, such as Cu(OAc)2or Mn02(see Penning, et al., Bioorg. Med. Chem. 2008, 16, 6965-6975. After removal of the Boc protecting groups from XI (accomplished by treatment with an acid, such as TFA, HC1, or formic acid), the compounds of the present invention may be prepared by coupling of the resulting diamine XII with an acid of choice using the standard peptide coupling reagents and conditions described above for

[0797] Scheme II to give XIII.in each Formula within Scheme IV can be replaced with

[0798] where D is defined above, and such compounds can be readily prepared according to the process described in Scheme IV. Compounds of Formula XIV can be similarly prepared from compounds of Formula XII. When subjected to synthetic processes in Scheme IV, enantiomerically enriched diols V may produce mixtures containing varying amounts of stereoisomeric cis and trans pyrrolidines VII. The stereoisomeric pyrrolidines may be separated according to standard chromatography techniques. Alternatively, such separations may be carried out at a later stage in the synthetic process including the steps of Schemes XIII and XIV, or after the final step.

[0800] Scheme IV

[0801] Alternatively IX in Scheme IV may be prepared from a compound of Formula II as shown in Scheme V. Compound VIII from Scheme II may be treated with an acylating agent such as acetylchloride or acetic anhydride to give compound II (Scheme V). Nitration of compound II to provide III may be accomplished using known methods, such as treatment with nitric acid or potassium nitrate in the presence of an acid such as sulfuric acid or treatment with NO2BF4. Removal of the acetamide protecting group may be accomplished by treatment with Boc anhydride in the presence of DMAP to give IV, followed by sequential treatment of IV with hydroxide (such as NaOH, KOH, or LiOH) to remove the acetyl group and a strong acid such as TFA or HC1 to remove the Boc protecting group to provide V. The nitro groups in V may be reduced to amino groups using the methods described above

[0802] for Scheme IV to provide IX.in each Formula within Scheme V can be replaced with where D is defined above, and such compounds can be readily prepared according to the process described in Scheme V.

[0804] FX in Scheme IV

[0805] Scheme V

[0806] As still another non-limiting example, the compounds of the present invention can be prepared starting from compounds of Formula II as shown in Scheme VI, where A, B, D, Y, and Z are as described above. A 1,4-diketone compound of Formula II (prepared as described in Scheme III) may be reacted with an amine, including but not limited to, aniline, 3,5-difluoroaniline, 3,4- difluoroaniline, 4-fluoroaniline, 3-fluoroaniline, 4-trifluoromethylaniline, 4-chloroaniline, heteroarylamines, alkyl amines, cycloalkyl amines, substituted benzylamines, or allylamine, under acid catalyzed conditions, such as acetic acid, TFA, formic acid or HC1, to give the compounds of the invention.

[0807] Scheme VI

[0808] As a further non-limiting example, the compounds of the present invention can be prepared from a compound of Formula II as shown in Scheme VII. A compound of Formula II, where Rxis a halogen, such as bromo, chloro, or iodo, or a triflate or a nonaflate may be converted to a boronic acid or ester such as Formula III, using the chemistry analogous to that of...

Claims

Revised October 4, 2018. No claims made. ++++++++++++++++++++++------February 16, 2018------(OCR) Page 1 of 1 page. Claims 1. Methyl {(2S,r)-!-[(2r)-2-{5-[(2p,r)-!-{3,r-difluoro-4-[4-(4-fluorophenyl)piperidin-!-il]phenyl}-r-(th-fluoro-2-{(2S)-!-[A / -(methoxycarbonyl)-(v-methyl-threonyl]pyrolidin-2-il}-!p-benzimidazol-r-il)pyrolidin-2-il]-th-fluoro-!p-benzimidazol-2-il} pyrolidin-1-il]-r-methoxy-!-oxobutane-2-il}carbamate (methyl {(2S,RP)-!-[(2S)-2-{5-[(RP,RP)-!-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-l-yl]phenyl}-5-(6-fluoro-2-{(2S)-!-[ / \ / -(methoxycarbonyl)-0-methyl-L-threonyl]pyrrolidin-2-yl}-1 / - / -benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-!พ-benzimidazol-2-yl}pyrrolidin-l-yl]-3-methoxy-!-oxobutan-2-yl}carbamate), or salts of these that are pharmaceutically acceptable.

2. Pharmaceutical compositions containing methyl. {(2S,RP)-!-[(2R)-2-{5-[(RP,RP)-!-{3,3. The compounds of claim 1, or their pharmaceutically acceptable salts, for the treatment of patients infected with HCV, by delivering an effective dose of such compounds, Or salts of these that are pharmaceutically acceptable, give to the said patient------------1. Compound with formula I,Or a pharmaceutically acceptable salt (chemical formula) where X is a C3-C12 carbocycle or heterocycle containing 3- to 12-carbon atoms and is chosen to be replaced by one or more RA or RF; L1 and L2 are independently chosen from each other from the bond or C1-C6 alkylene, C2-C6 alkyneline, or C2-C6 alkyneline, which are independently chosen to be replaced in each case by one or more RL; L3 is the bond or - Ls-K-Ls'-, where K is selected from the bonds -O-,-S-,-S(RB)-,-C(O)-,-S(O)2-,-S(O))-,-OS(O)-,-OS(O)2-,-S(O)2-,-S(O)2O--S(O)o-,-C(O)o,-OC(O)-,-OC(O)O-,-C(O)N(Rb)-,-N(Rb)C(O)-,-N(Rb)C(O)O-,-OC(O)N(Rb)-,-N(Rb)S(O)-,-N (Rb)S(O)2-,-S(O)N(Rb)-,-S(O)2N(Rb)-,-C(O)N(Rb)C(O)-,-N(Rb)C(O)N(RB')-,N(Rb)SO2N(Rb') or -N(RB)S(O)N(R')-;A and B are independent of each other, being C3-C12 carbocycles or heterocycles containing 3- to 12-carbon atoms.And they are each chosen to replace each other independently with one or more RAs; D is a C3-C12 carbocycle or heterocycle with 3- to 12-carbon atoms and is chosen to replace one or more RAs; or D is a C3-C12 carbocycle or heterocycle with 3- to 12-carbon atoms which is replaced by J and is chosen to replace one or more RAs; when J is a C3-C12 carbocycle or heterocycle with 3- to 12-carbon atoms and is chosen to replace one or more RAs. More than one RA, or J is -SF5; or D is hydrogen or RA; Y is chosen from -TC(R1R2)N(R5)-T-RO, -T'-C(R3R4)C(R6R7)-T-Rd, -Lk-T-RD, or -Lk-E; R1 and R2 are independent of each other, i.e. Rc, and R5 is R8; or R1 is Rc, and R2 and R5, together with atoms which are attached to form a heterocycle of 3- to 12-carbon atoms which are chosen to replace one or more RAs; R3, R4, R6, and R7 are independent of each other, i.e. Rc; or R3 and R6 are independent of each other, i.e. Rc, and R4 and R7,These are brought together with atoms which are attached to form a carbocycle or heterocycle with 3- to 12 carbon atoms which are chosen to be replaced by one or more RAs; Z is chosen from -TC(R8R9)N(R12)-T-RD,-T'-c(R10R11)C(R13R14)-T-RD,-LK-T-RD, or -Lk-E; R8 and R are independent of each other, i.e. RcR3 and R12 are R8; or R8 is Rc, and R9 and R12, which are brought together with atoms which are attached to form a heterocycle with 3- to 12 carbon atoms which are chosen to be replaced by one or more RAs; R10, R11, R13, and R14 are independent of each other, i.e. R c; or R10 and R13 are independent of each other, i.e. Rc, and R11 and R14, which are brought together with atoms which are attached to form a carbocycle or heterocycle with 3- to 12-carbon atoms which are chosen to replace one or more RA; T and T are chosen independently of each other in each case from the bonds -Ls-, -Ls-M-Ls'-, or -Ls-M-Ls'-M'-Ls"-, where M and M' are chosen independently of each other in each case from the bonds -O-, -S-, -N(RB)-, -c(O)-, -S(O)2-, -S(O)-, -OS(O)-, -OS(O)2-, -S(O)2O-, -S(O)O-, -C(O)O-, -OC(O)-, -OC(O)O-, -C(O)N(RB)-,-N(RB)C(O)-,-N(RB)C(O)O-,-OC(O)N(RB)-S(O)-,-N(RB)S(O)2-,S(O)N(RB)-,-S(O)2N(RB)-,-C(O)N(RB)C(O)-,-N(RbB)C(O)N(RB')-,-N(RB)SO2N(RB')-,-N(RB)S(O)N(RB')-,-C3-C12 carbocycles or heterocycles with 3 to 12 carbon atoms, where the C3-C12 carbocycles and such heterocycles with 3 to 12 carbon atoms are independently selected to replace each other at each In each case, with one or more RA; Lk is chosen independently of each other in each case from the -Ls-N(RB)C(O)-Ls'- bond, or -Ls-C(O)N(RB)-Ls'-; or C1-6 alkyneline, C2-C6 alkyneline or C2-C6 alkyneline, each chosen to replace each other independently in each case with one or more RL; or C3-C12 carbocycle or heterocycle with 3- to 12 carbon atoms.These are each chosen to replace each other independently in each case with one or more RA; E is chosen independently in each case from C3-C12 carbocycles or heterocycles with 3- to 12 carbon atoms and is chosen to replace each other independently in each case with one or more RA; RD is each chosen independently in each case from hydrogen or RA; RA is each chosen independently in each case from halogen, nitroxo, phosphooxyphosphonothioxocyadon or -Ls-RE, The second adjacent RA, which brings together the atoms to which these are attached, and any atoms between which these are attached can be selected to form a carboxycycle or a heterocycle; RB and RB' are each selected independently of each other in each case from hydrogen; or C1-C6 alkyl, C2-C6 alkynyl, or C2-C6 alkynyl which are each selected to replace each other independently in each case with one or more substitutes which are selected from halogen, hydroxymer, capto, aminocarboxynitrogzo, phosphonoxy, phosphono, thixo, formil.A cyano or carbocycle or heterocycle with 3- to 6 carbon atoms; or a carbocycle or heterocycle with 3- to 6 carbon atoms; where the carbon cycle or heterocycle with 3- to 6 carbon atoms in RB or RB' are independently selected to replace each other in each case with one or more substitutes chosen from halogen hydroxymercapto, aminocarboxynitrogxo, phosphonoxy, phosphono, formil, cyanoC1-C6 alkyl, C2-C6 alkynyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2. -C6 haloalkinil or C2-C6 haloalkinil; RC is independently selected from each other in each case from hydrogen halogen hydroxy, mercapto, aminocarboxynitrogzo, phosphonoxy, phosphono, thioxo, formil or cyano; or C1-C6 alkyl, C2-C6 alkenil or C2-C6 alkenil, each independently selected to be replaced in each case by one or more substitutes which are selected from halogen hydroxy, mercapto, aminocarboxynitrogzo, phosphonoxy, phosphono, thioxo, formil.Cyanos, carboxycycles, or heterocycles with 3- to 6 carbon atoms, or heterocycles with 3- to 6 carbon atoms, Rc are independently selected in each case to replace one or more substitutes chosen from halogen hydroxymer captoaminocarboxynitooxophosphooxyphosphono, thoxoformyl cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, or C2-C6 haloalkenyl; RE are independently selected in each case from -O-Rs, -S-Rs, -C(O)Rs, -OC(O)Rs, -c(O)ORs, -N(RsRs]), -S( O)Rs'-sO2Rs'-C(O)N(RsRs')'-N(Rs)C(O)Rs',-N(Rs)C(O)N(Ra'Rs"),-N (Rs)SO2Rs',-sO2N(RsRs')-N(Rs)SO2N(Rs]Rs",-N(Rs)S(O)N(Rs'R"),-O S(O)-Rs,-OS(O)2-Rs,-S(O)2ORs,-S(O)ORs,-OC(O)OTd,-N(Rs)C(O)ORs',-OC(O)N(RsRs'),-N(Rs)S(O)-Rs',-s(O)N(RsRs'),-O(O)(ORs)2,OR-C (O)N(Rs)C(O)-Rs'; or C1-C6 alkyl, C2-C6 alkynyl or C2-C6 alkynyl, each independently selected to replace each other with one or more substitutes chosen from the halogen hydroxymer captoaminocarboxynitrooxophosphooxyphosphono, thoxo,Formyl or cyano or C3-C6 carboxylate or heterocycle with 3- to 6-carbon atoms each independently selected to replace each other in each case with one or more substitutes which are chosen from halogen hydroxymer captoaminocarboxynitooxophosphooxyphosphono, thoxo, formyl or cyano C1-C6 alkyl C2-C6 alkenyl, C2-C6 alkenyl C1-C6 haloalkyl C2-C6 haloalkinyl C2-C6 haloalkinyl C(O)ORs, or -N(RsRs');RF independently selected in each case from C1-C10 alkyl C2-C10 Alkenyl or C2-C10 alkynyl, each having O, 1, 2, 3, 4, or 5 hetero atoms chosen from O, S, or N and selected to be replaced by one or more RL; or -(Rx-Ry)Q-(Rx-Ry'), where Q is 0, 1, 2, 3, or 4, and reciprocal Rx is O, S, or N (RB), and reciprocally independent Ry is C1-C6 alkylene, C2-C6 alkynylene, or C2-C6 alkynylene, each selected to be independently replaced by one or more substitutes chosen from halogen hydroxymer capto, aminocarboxynitrogzo.Phosphonoxy, phosphonothioxoformyl, or cyano, and where the independent Ry's are C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkenyl, each is independently selected to replace the other with one or more substitutes chosen from halogen hydroxymer captoaminocarboxynitooxo, phosphonoxy, phosphonothioxo, formil, or cyano; RL is independently selected in each case from halogen nitro, oxophosphonoxy, phospho. No,thioxocyano-O-Rs,-S-Rs,-C(O)Rs,-OC(O)Rs,-C(O)ORs,-N(RsRs')-S(O)Rs,-SO2Rs,-C(O)N(RsRs') or-N(Rs)C(O)Rs', or C3-C6 carboxylates or heterocycles with 3- to 6-carbon atoms each independently selected to replace each other in each case with one or more substitutes chosen from halogens, hydroxymer captoaminocarboxynitrooxophosphooxyphosphonothioxofarmylcyanoC1-C6alkylC2-C6alkenylC2-C6alkenyl,C1-C6 haloalkyl, C2-C6 haloalkyl, or C2-C6 haloalkenil, where two adjacent RLs are brought together with the atoms to which they are bonded, and any atoms between these bonded atoms can be selected to form a carbocycle or heterocycle; Ls, Ls', and Ls" are each selected independently of each other in each case from the bonds, or C1-C6 alkylene, C2-C6 alkynelene, or C2-C6 alkynelene, which are each selected to replace each other independently in each case with one or more RLs; and Rs, R', and Rs" are each selected independently of each other in each case. In each case, hydrogen C1-C6 alkyl, C2-C6 alkynyl, or C2-C6 alkynyl are chosen to be independently replaced by one or more substitutes chosen from halogen, hydroxymer, captoaminocarboxynitrogisophosphonoxyphosphonothioxoformylcyano-O-C1-C8 alkyl-O-C1-C6 alkylene-O-C1-C6 alkyl or a carbocycle or heterocycle with 3- to 6 carbon atoms, where the carbocycle or heterocycle with 3- to 6 carbon atoms in Rs.Rs' or Rs' are each chosen to replace the other independently in each case with one or more substitutes which are selected from halogen, hydroxymer, capto, amino, carboxynitrogens, phosphonoxy, phosphono, thioxo, formilcyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkenyl, C1-C6 haloalkyl, C2-C6 haloalkinyl, or C2-C6 haloalkinyl;