ANTI- VIRAL COMPOUNDS

FIELD

The present invention relates to anti-HCV compounds, compositions comprising the same and methods of using the same to treat HCV infection.

BACKGROUND

Hepatitis C virus ("HCV") is an RNA virus belonging to the Hepacivirus genus in the Flaviviridae family. The enveloped HCV virion contains a positive stranded RNA genome which 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.

HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. Chronic hepatitis C may be treated with peginterferon-alpha in combination with ribavirin. Substantial limitations to efficacy and tolerability remain as many users suffer from side effects, and viral elimination from the body is often inadequate. Therefore, there is a need for new drugs to treat HCV infection.

SUMMARY

The present invention relates to a compound of Formula (I) or pharmaceutically acceptable salts thereof:

wherein:

A is a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, wherein A preferably is substituted with -L-E or prefereably -L ₃ - D, wherein -L-E or -L3-D are as defined below;

W is (a) absent; or (b) an optionally substituted aliphatic group; wherein W, if present, is substituted with -L-E or -L ₃ -D, wherein -L-E or -L3-D are as defined below; T is (a) absent; or (b) an optionally substituted linear aliphatic group containing zero to eight carbons; wherein T, if present, is substituted with -L-E or -L ₃ -D, wherein -L-E or -L ₃ -D are as defined below;

G is (a) absent; or (b) independently selected from optionally substituted aryl and optionally substituted heteroaryl; wherein G, if present, is substituted with -L-E or -L ₃ -D, wherein -L-E or -L3- D are as defined below;

wherein one or two of W, G, and T can optionally be absent; and wherein at least one of A, W, T or G is substituted with L-E or -L3-D are as defined below;

R ¹ and R ² at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C,-C ₄ alkyl,— O— R ¹¹ — NR^*.— C(0)R ^M ,—

CO ₂ R ^{1 1} , and— C(0)NR ^a R ^b ; wherein at least one of R ¹ and R ² can be optionally substituted with -L-E or -L3-D, wherein -L-E or -L ₃ -D are as defined below;

R ¹¹ at each occurrence is independently hydrogen or optionally substituted C|-C ₈ alkyl;

R" and R* at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C ₈ , alkyl, and optionally substituted C ₂ -C ₈ alkenyl; or R" and R* can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;

u and v at each occurrence are each independently 1 , 2, or 3;

Q and J are each independently selected from:

R ³ and R ⁴ at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted Ci-C ₈ , alkyl, optionally substituted C ₂ -C ₈ , alkenyl, and optionally substituted C ₃ -C ₈ , cycloalkyl; or alternatively, R ³ and R ⁴ can be taken together with the carbon atom to which they are attached to form optionally substituted C ₃ -C ₈ , cycloalkyl or optionally substituted heterocyclic;

R ⁵ at each occurrence is independently hydrogen, optionally substituted C _r C ₈ , alkyl, or optionally substituted C ₃ -C, cycloalkyl;

R ⁶ at each occurrence is independently selected from the group consisting of— C(O)— R ¹² , — C(O)— C(O)— R ¹² ,— S(0) ₂ — R ¹² , and— C(S)— R ¹² ; R ¹² at each occurrence is independently selected from the group consisting of:— O— R ¹¹ ,—

NR¾ ^RF ;

R ¹³ at each occurrence is independently selected from the group consisting of hydrogen, Q- C ₈ , alkyl, C ₂ -C ₈ , alkenyl, C ₂ -C ₈ , alkynyl, C ₃ -C ₈ , cycloalkyi, C ₃ -C ₈ , cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; or

R and R ^RF at each occurrence are each independently selected from the group consisting of hydrogen,— R ¹³ ,— C(O)— R ¹³ ,— C(O)—OR ¹³ ,— S(0) ₂ — R ¹³ ,— C(0)N (R13) ₂ , and—

S(0) ₂ N(R ¹³ ) ₂ ;

m is 0, 1 , or 2;

n is 1 , 2, 3, or 4;

X at each occurrence is independendy selected from O, S, S(O), S0 ₂ , and C(R ⁷ ) ₂ , provided that when m is 0, X is C(R ⁷ ) ₂ ; or

R ⁷ at each occurrence is independently selected from the groiip consisting of hydrogen, halogen,— Ci-C ₄ alkyl, cyano,— O— R ^{1 1} ,— R"R ^FR , optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted with— C C ₄ alkyl; or two vicinal R ⁷ groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C ₃ -C ₈ , cycloalkyi or optionally substituted heterocyclic ring; or alternatively two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C ₃ -C ₈ cycloalkyi or optionally substituted heterocyclic ring;

-L-E are as follows:

E is (i) C ₃ -Ci ₄ carbocycle or 3- to 14-membered heterocycle, and is optionally substituted with one or more R _A ; or (ii) E is -L _S -RE;

L is -Ls-, -Ls-0-L _s '-, - -C(0)-Ls'-, -L^S(.0) ₂ -W- -Ls-S(0)-Ls'-, -Le-OSiOr-Ls'- , -Ls-S(0) ₂ 0-L _s '-, -Ls-OS(0)-Ls'-, -Ls-S(0)0-L _s '- -Ls-C(0)0-L _s '-, -Ls-OC(0)-L _s '-, -Ly- OC(0)0-Ls'-, -Ls-C(0)N(R _B >-Ls'-, -Le-

N(RB)C(0)0-L _S '-, -L _S -OC(0)N(R _B )-L _S '-,— L$— C(0)N(RB)N(R _b )-Ls'— , -Ls-S-L _s '-, -Ls-C(S)- L _s '-, -L _s -C(S)0-Ls'-, -Ls-OC(S)-Ls'-, -I^(S)N(R _B )-Ls'-, -Ls-NiReH - -Ls-N(R _B )C(S)- Ls'- -L _S -N(R _B )S(0)-L _S '-, -LS-N(RB)S(0) ₂ -LS -, -LS-S(0) ₂ N(R _B )-LS'-, -Ls-S(0)N(R _B )-L _s '-, - Ls-C(S)N(R _B )0-L _s '-, -Ls-C(0)N(RB)C(0)-Ls ^, -, -Ls-N(R _B )C(0)N(R _B ')-Ls'-, -Ls- N(R _B )S0 ₂ N(RB ^, )-LS'-, -L _S -N(R _B )S(0)N(R _B ')-L _s '-, or -Ls— C(S)N(R _B )N(R _B )— Ls'— ;

Ls and L _s ' are each independently selected at each occurrence from bond; or Ci-C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, each of which is independently optionally substituted at each occurrence with one or more R _L ;

R _A is independently selected at each occurrence from halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphonoxy, or phosphono; or -L _S -RE;

R _B and R _B are each independently selected at each occurrence from hydrogen; or C _r C6 alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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-C6 carbocycle or 3- to 6-membered heterocycle; or C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; wherein each C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle in R _B or R _B ' 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-C6 alkyl, C2-C ₆ alkenyl, C ₂ -C ₆ alkynyl, C]-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl;

R _E is independently selected at each occurrence from -O-Rs, -S-R _s , -C(0)R _s , -OC(0)R _s , - C(0)OR _s , -N(RsRs'), -S(0)R _s , -S0 ₂ R _s , -C(0)N(R _s R _s '), -N(R _s )C(0)R _s '. -N(R _s )C(0)N(R _s 'R _s "), - N(R _s )S0 ₂ R _s \ -S0 ₂ N(R _s R _s '), -N(R _s )S0 ₂ N(R _s 'R _s "), -N(R _s )S(0)N(R _s 'Rs"), -OS(0)-R _s , -OS(0) ₂ - Rs, -S(0) ₂ OR _s , -S(0)ORs, -OC(0)OR _s , -N(R _s )C(0)OR _s \ -OC(0)N(R _s R _s '), -N(R _s )S(0)-R _s ', - S(0)N(RsR _s ') or _^ C(0)N(R _s )C(0)-Rs'; or C,-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 Ca-Cecarbocycle 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 C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C,-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl;

R _L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-R _s , -S-R _s , -C(0)R _s , -OC(0)R _s , -C(0)OR _s , -N(R _S R _S '), -S(0)R _s , - S0 ₂ R _s , -C(0)N(R _s R _s ') or -N(R _s )C(0)R _s ' ; or C ₃ -C ₆ carbocycle 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl;

Rs, Rs' and Rs" are each independently selected at each occurrence from hydrogen; Q-Ce alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 R _s , R _s ' or R _s ' 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl;

-L3-D are follows:

L3 is bond or -Ls-K-Ls'-, wherein is selected from bond, -0-, -S-, -N(R _B )-, -C(O)-, - S(0) ₂ - -S(O)-, -OSCO)-, -OS(O -, -S(0) ₂ 0-, -S(0)0-, -C(0)0-, -OC(O)-, -OC(0)0-, - C(0)N(R _B )- ₎ -N(R _B )C(0)- -N(R _B )C(0)0-, -OC(0)N(R _B )-, -N(R _B )S(0)- _> -N(R _B )S(0)2-, - S(0)N(R _B K -S(0) ₂ N(R _B )-, -C(0)N(R _B )C(0)-, -N(R _B )C(0)N(R _B 'K -N(R _B )S0 ₂ N(R _b ')- or - N(R _B )S(0)N(R _B ')-;

D is C3-Ci ₂ carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R _A ; or D is C3-C ₁₂ carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R _A , where J is C3-C12 carbocycle or 3- to 12-membered heterocycle and is optionally substituted with one or more R _A , or J is -SF ₅ ; or D is hydrogen or R _A ;

R _A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-R _E , wherein two adjacent R _A , 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;

R _B and R _B ' are each independently selected at each occurrence from hydrogen; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 R _B or R _B ' 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, Q-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci- C ₆ haloalkyl, C ₂ -C6haloalkenyl or C ₂ -C ₆ haloalkynyl;

R _E is independently selected at each occurrence from -0-R _s , -S-R _s , -C(0)R _s , -OC(0)R _s , - C(0)OR _s , -N(RsRs'), -S(0)R _s , -S0 ₂ R _s , -C(0)N(R _s R _s '), -N(R _s )C(0)R _s \ -N(R _s )C(0)N(R _s 'R _s "), - N(R _S )S0 ₂ Rs\ -S0 ₂ N(R _s R _s '), -N(R _S )S0 ₂ N(R _s ^* R _s "), -N(R _s )S(0)N(R _s ^, R _s "), -OS(0)-R _s , -OS(0) ₂ - Rs, -S(0) ₂ OR _s , -S(0)OR _s , -OC(0)ORs, -N(R _s )C(0)OR _s \ -OC(0)N(R _s R _s '), -Ν^^ΟΗ^', - S(0)N(R _s R _s '), -P(0)(OR _s ) ₂ , or -C(0)N(R _s )C(0)-Rs' ; or C,-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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-C6 carbocycle 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 C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _r C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s , or -N(R _S R _S ');

R _L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-R _s , -S-R _s , -C(0)R _s , -OC(0)R _s , -C(0)OR _s , -N(R _S R _S '), -S(0)R _s , - S0 ₂ R _s , -C(0)N(R _s R _s ') or -N(R _s )C(0)R _s ' ; or C ₃ -C ₆ carbocycle 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 _r C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _r C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl; wherein two adjacent R _L , 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;

Ls and L _s ' are each independently selected at each occurrence from bond; or C C ₆ alkylene,

C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, each of which is independently optionally substituted at each occurrence with one or more R _L ; and

R _s , Rs' and R _s " are each independently selected at each occurrence from hydrogen; Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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-Q-Q alkyl, -0-Ci-C ₆ alkylene-0- C C ₆ alkyl, 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 R _s , Rs' or R _s ' 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 _t -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl.

In another aspect, the present invention relates to a pharmaceutical composition comprising (a) one or more of any of the compounds of Formula (I) or any salts, solvates or prodrugs thereof; and (b) at least one pharmaceutically acceptable carrier or at least one pharmaceutically acceptable excipient. Examples of suitable pharmaceutically acceptable carriers or excipients that can be used in said pharmaceutical compositions include, but are not limited to, sugars (e.g., lactose, glucose or sucrose), starches (e.g., corn starch or potato starch), cellulose or its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose or cellulose acetate), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g., propylene glycol), buffering agents (e.g., magnesium hydroxide or aluminum hydroxide), agar, alginic acid, powdered tragacanth, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solutions, lubricants, coloring agents, releasing agents, coating agents, sweetening, flavoring or perfuming agents, preservatives, or antioxidants.

In addition to containing any one or more compounds of Formula (I) or any salts, solvates or prodrugs thereof, the pharmaceutical compositions of the present invention can also further contain one or more of the following: (a) one or more anti-HCV agents, such as an HCV polymerase inhibitor, HCV protease inhibitor, HCV helicase inhibitor, CD81 inhibitor, cyclophilin inhibitors, IRES inhibitors, or NS5A inhibitors; (b) one or more antiviral agents such as anti-HBV agents, anti-HIV agents, anti-hepatitis agents, anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agents; (c) antibacterial agents; (d) anti-fungal agents; (e) immunomodulators, (f) anti-cancer or chemotherapeutic agents; (g) anti-inflammatory agents; (h) antisense RNA; (i) antibodies; (j) agents for treating cirrhosis or inflammation of the liver; or (k) any combinations of (a)-(k).

The present invention also relates to a method of treating HCV infection. The method involves administering to a patient in need of treatment, a therapeutically effective amount of the above-described pharmaceutical composition of the present invention to treat the HCV infection in said patient.

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.

wherein:

A is a cyclic group independently selected from aryl, heteroaryl, heterocyclic, C ₃ -C ₈ cycloalkyl, and C ₃ -C ₈ cycloalkenyl, wherein A is substituted with -L-E or -L3-D, which are defined hereinabove and below;

W is (a) absent; or (b) an optionally substituted aliphatic group; wherein W, when or if present, is substituted with -L-E or -L ₃ -D, which are defined hereinabove and below;

T is (a) absent; or (b) an optionally substituted linear aliphatic group containing zero to eight carbons; wherein T, when or if present, is substituted with -L-E or -L3-D, which are defined hereinabove and below;

G is (a) absent; or (b) independently selected from optionally substituted aryl and optionally substituted heteroaryl; wherein G, when or if present, is substituted with -L-E or -L3-D, which are defined hereinabove and below;

wherein one or two of W, G, and T can optionally be absent;

R ¹ and R ² at each occurrence are each independently selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C,-C ₄ alkyl,— O— R ¹¹ — NR°R*,— C(0)R",— C0 ₂ R", and— C(0)NR ^a R ^b ; wherein at least one of R ¹ and R ² can be optionally substituted with -L-E or -L3-D as defined below;

R ¹¹ at each occurrence is independently hydrogen or optionally substituted Ci-C ₈ alkyl;

R" and R* at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted CpCg, alkyl, and optionally substituted C ₂ -C ₈ alkenyl; or R" and R* can be taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or optionally substituted heteroaryl group;

u and v at each occurrence are each independently 1 , 2, or 3;

Q and J are each independently selected from:

R ³ and R ⁴ at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted C _r C ₈ , alkyl, optionally substituted C ₂ -C ₈ , alkenyl, and optionally substituted C ₃ -C ₈ , cycloalkyl; preferably hydrogen or optionally substituted C C ₄ alkyl; or alternatively, R ³ and R ⁴ can be taken together with the carbon atom to which they are attached to form optionally substituted C ₃ -C ₈ , cycloalkyl or optionally substituted heterocyclic;

R ⁵ at each occurrence is independently hydrogen, optionally substituted C _r C ₈ , alkyl, or optionally substituted C ₃ -C, cycloalkyl; preferably hydrogen or optionally substituted C1-C4 alkyl;

R ⁶ at each occurrence is independently selected from the group consisting of— C(O)— R ¹² , — C(O)— C(O)— R ¹² ,— S(0) ₂ — R ¹² , and— C(S)— R ¹² , preferably— C(O)— R ¹² , more preferably an optionally substituted amino acid acyl;

R ¹² at each occurrence is independently selected from the group consisting of:— O— R ¹¹ ,— NR ^C R' ^/ , preferably optionally substituted C _r C ₈ alkyl and— O— R ¹¹ ;

R ¹³ at each occurrence is independently selected from the group consisting of hydrogen, C C ₈ , alkyl, C ₂ -C ₈ , alkenyl, C ₂ -C ₈ , alkynyl, C ₃ -C ₈ , cycloalkyl, C ₃ -C ₈ , cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted; preferably optionally substituted C _r C ₈ , alkyl; more preferably C C ₈ , alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(C C ₄ alkyl); or

R ^c and R ^rf at each occurrence are each independently selected from the group consisting of hydrogen,— R ¹³ ,— C(O)— R ¹³ ,— C(O)—OR ¹³ ,— S(0>2— R ¹³ ,— C(0)N (R13) ₂ , and—

S(0) ₂ N(R ¹³ ) ₂ ; m is 0, 1, or 2, preferably 1 ;

n is 1 , 2, 3, or 4, preferably 1 or 2;

X at each occurrence is independently selected from O, S, S(O), S0 ₂ , and C(R ⁷ ) ₂₎ preferably CH ₂ or CHR ⁷ ; provided that when m is 0, X is C(R ⁷ ) ₂ ; or

R ⁷ at each occurrence is independently selected from the group consisting of hydrogen, halogen,— C C ₄ alkyl, cyano,— O— R ^U ,— N ^*, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted— C _r C ₄ alkyl; preferably hydrogen, methyl or halogen; or two vicinal R ⁷ groups can be taken together with the two adjacent atoms to which they are attached to form a fused, optionally substituted C ₃ -C ₈ , cycloalkyl or optionally substituted heterocyclic ring; preferably a fused, optionally substituted cyclopropyl; or alternatively two geminal R ⁷ groups can be taken together with the carbon atom to which they are attached to form a spiro, optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted heterocyclic ring; preferably a spiro, optionally substituted cyclopropyl;

With respect to -L- E as used herein:

E is (i) C3-C14 carbocycle or 3- to 14-membered heterocycle, and is optionally substituted with one or more R _A ; or (ii) E is -LS-RE;

L is -Ls-, -Ls-O-Ls'-, -Ls-C(0)-L _s '-, -Ls-S(0) ₂ -L _s '-, - S(O '- -Ls-OSiC^r-Ls'- , -Ls-S(0) ₂ 0-L _s '-, -Ls-OS(0)-Ls'-, -Ls-S(0)0-L _s '-, -Ls-C(0)0-L _s '-, -Ls-OC(0)-L _s '-, -L _s - OC(0)0-Ls'-, -Ls-C(0)N(R _B )-Ls'-, -L _S -N(R _B )C(0)-L _S '-, -Ls-C(0)N(R _B )0-Ls'-, -Ls- N(R _B )C(0)0-Ls'-, -Ls-OC(0)N(R _B )-Ls'- -Ls-C(0)N(R _B )N(R _B ^' )-L _s '-, -Ls-S-L _s '-, -Ls-C(S)- Ls -, -Ls-C(S)0-Ls'-, -L^OCCS^Ls'-, -L _S -C(S)N(R _B )-Ls'-, -L _S -N(R _B )-Ls'-, -Ls-N(R _B )C(S)- Ls'-, -L _s -N(R _B )S(0)-Ls'-, -Ls-N(R _B )S(0) ₂ -L _s '-, -Ls-S(0) ₂ N(R _B )-Ls'-, -Ls-S(0)N(R _B )-Ls'-, - L _S -C(S)N(R _B )0-L _S '-, -L _S -C(0)N(R _B )C(0)-Ls'-, -Ls-N(R _B )C(0)N(R _B ')-Ls'-, -L _s - N(R _B )S0 ₂ N(R _B ')-L _S '-, -Ls-N(R _B )S(0)N(R _B ')-Ls'-, or -Ls-C(S)N(R _B )N(R _B HV-;

Ls and L _s ' are each independently selected at each occurrence from bond; or d-Ce alkylene,

C ₂ -Ce alkenylene or C ₂ -Ce alkynylene, each of which is independently optionally substituted at each occurrence with one or more R _L ;

R _A is independently selected at each occurrence from halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, p osphonoxy, or phosphono; or -LS-RE;

R _B and R _B are each independently selected at each occurrence from hydrogen; or Ci-C ₆ alkyl,

C ₂ -Cealkenyl or C ₂ -C ₆ alkynyl, 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 ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; or C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; wherein each C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle in R _B or R _B ' 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-C ₆ alkyl, C ₂ -C6alkenyl, C2-C ₆ alkynyl, C _r C ₆ haloalkyl, C2-C6 haloalkenyl or C ₂ -C6 haloalkynyl;

R _E is independently selected at each occurrence from -0-R _S , -S-R _S , -C(0)R _S , -OC(0)R _S , - C(0)OR _S> -N(RsRs'), -S(0)Rs, -S0 ₂ R _S> -C(0)N(RsR _s '), -N(R _S )C(0)R _S ', -N(R _s )C(0)N(R _s 'Rs"), - N(R _s )S0 ₂ Rs', -S0 ₂ N(R _S R _S '), -N(R _s )S0 ₂ N(R _S ^, R _S " ), -N(R _s )S(p)N(Rs'Rs"), -OS(0)-Rs, -OS(0) ₂ - R _S , -S(0) ₂ OR _S , -S(0)OR _S , -OC(0)OR _S , -N(R _S )C(0)OR _S ' , -OC(0)N(R _S R _S '), -N(R _S )S(0)-R _S \ - S(0)N(R _S R _S ') or -C(0)N(R _S )C(0)-Rs'; or C,-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 C ₃ -C ₆ carbocycle 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, Q- C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C,-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl;

R _L is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-R _S , -S-R _S , -C(0)R _S , -OC(0)R _S , -C(0)OR _S , -N(R _S R _S '), -S(0)R _S , - S0 ₂ R _S , -C(0)N(R _S R _S ') or -N(R _s )C(0)R _S ' ; or C ₃ -C ₆ carbocycle 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]-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl;

R _S , R _S ' and R _S " are each independently selected at each occurrence from hydrogen; d-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 R _S , R _S ' 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -Ce haloalkenyl or C ₂ -Ce haloalkynyl;

L3 is bond or -Ls-K-Ls'-, wherein K is selected from bond, -0-, -S-, -N(R _B )-, -C(O)-, - S(0) ₂ -, -S(O)-, -OS(O)-, -OS(0) ₂ - -S(0) ₂ 0-, -S(0)0-, -C(0)0-, -OC(O)-, -OC(0)0-, - C(0)N(R _B )-, -N(R _B )C(0)-, -N(R _B )C(0)0-, -OC(0)N(R _B )-, -N(R _B )S(0)-, -NCRBWO),-, - S(0)N(R _B )-, -S(0) ₂ N(R _B )-, -C(0)N(R _B )C(0)-, -N(R _B )C(0)N(R _B ')-, -N(R _B )S0 ₂ N(RB')- or - N(R _B )S(0)N(R _B ')-; preferably, L ₃ is bond, Ci-C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene; more preferably, L3 is bond; D is C ₃ -C ₎₂ carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R _A ; or D is C3-C ₁₂ carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R _A , where J is C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle and is optionally substituted with one or more R _A , or J is -SF ₅ ; or D is hydrogen or R _A ;

R _A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-R _E , wherein two adjacent R _A , 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;

R _B and R _B ' are each independently selected at each occurrence from hydrogen; or C!-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 R _B or R _B ' 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-Ce alkyl, C ₂ -C6 alkenyl, C ₂ -Ce alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl;

R _E is independently selected at each occurrence from -0-R _s , -S-R _s , -C(0)R _s , -OC(0)Rs, - C(0)OR _s , -N(RsRs'), -S(0)R _s , -S0 ₂ R _s , -C(0)N(R _s R _s '), -N(R _s )C(0)R _s \ -N(R _s )C(0)N(R _s 'R _s "), - N(R _s )S0 ₂ R _s \ -S0 ₂ N(R _s R _s '), -N(R _s )S0 ₂ N(R _s 'R _s " ), -N(R _s )S(0)N(R _s 'R _s "), -OS(0)-Rs, -OS(0) ₂ - R _s , -S(0) ₂ OR _s , -S(0)OR _s , -OC(0)ORs, -N(R _s )C(0)OR _s ', -OC(0)N(R _s R _s '), -N(R _s )S(0)-Rs', - S(0)N(R _s R _s '), -P(0)(OR _s ) ₂ , or -C(0)N(R _s )C(0)-R _s ' ; or C,-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 C ₃ -C ₆ carbocycle 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, d-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s , or -N(R _s R _s ');

RL is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, -0-R _s , -S-R _s , -C(0)R _s> -OC(0)R _s , -C(0)OR _S) -N(R _S R _S '), -S(0)R _s , - S0 ₂ R _S) -C(0)N(R _s Rs') or -N(R _s )C(0)R _s ' ; or C ₃ -C ₆ carbocycle 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl; wherein two adjacent R _L , 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;

Ls and L _s ' are each independently selected at each occurrence from bond; or d-C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, each of which is independently optionally substituted at each occurrence with one or more R _L ; and

R _s , Rs' and R _s " are each independently selected at each occurrence from hydrogen; C _r Qalkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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-C C ₆ alkyl, -0-C C ₆ alkylene-0- Ci-C ₆ alkyl, 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 R _s ' 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 C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _r C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl.

Preferably, -L-E comprises C ₅ -C6 carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycle, each of which is optionally substituted with one or more R _A as defined above. Also preferably, the moiety comprises C _r C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each of which is optionally substituted with one or more R _L as defined above. More preferably, the moiety comprises C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, wherein each of said Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl can be further 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 ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle. Highly preferably, the moiety comprises C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Q-Ce alkyl, C -Ce alkenyl, C ₂ -C ₆ alkynyl, C C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl.

In one example, -L-E comprises phenyl optionally substituted with one or more substituents selected from is halogen, hydroxy, mercapto, amino, carboxy, C C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, wherein each of said Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy. In another example, the moiety comprises Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, each of which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano.

In the above Formula I, D in -L3-D preferably is selected from C ₅ -C ₆ carbocycle, 5- to 6- membered heterocycle, or 6- to 12-membered bicycles, and is optionally substituted with one or more R _A . D can also be preferably selected from C C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, and is optionally substituted with one or more substituents selected from R _L . More preferably, D is C ₅ -C ₆ carbocycle (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-tetrahydrobenzofdJthiazoIyl, benzo[d]thiazolyl, indazolyl, benzo[d][ l ,3]dioxol-5-yl), and is substituted with one or more R _M , where R _M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -Ls-R _E . Also preferably, D is phenyl, and is optionally substituted with one or more R _A - More preferably, D is phenyl, and is substituted with one

or more R _M , wherein R _M is as defined above. Highly preferably, D is

wherein R _M is as defined above, and each R _N is independently selected from R _D and preferably is hydrogen. One or more R _N can also preferably be halo such as F.

D is also preferably pyridinyl, pyrimidinyl, or thiazolyl, optionally substituted with one or more R _A . More preferably D is pyridinyl, pyrimidinyl, or thiazolyl, and is substituted with one or

more R _M . Highly preferably, D is , wherein R _M is as defined above, and each R _N is independently selected from R _D and preferably is hydrogen. One or more R _N can 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 R _A . More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, r more R _M . Highly preferably, D

is optionally substituted with one or more R _M .

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C _r C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 C ₃ -C ₆ carbocycle 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 C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C,-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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, R _M is CrQ alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.

Also preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, or cyano; or R _M is -L _S -RE, wherein Ls is a bond or Ci-C ₆ alkylene, and R _E is - N(RsRs'), -O-Rs, -C(0)R _S , -C(0)OR _s , -C(0)N(R _S R _S '), -N(R _S )C(0)R _S '. -N(R _s )C(0)OR _s \ - N(R _s )S0 ₂ R _S \ -S0 ₂ R _S , -SR _S , or -P(0)(OR _s ) ₂ , wherein R _S and R _S ' can be, for example, each independently selected at each occurrence from (1) hydrogen or (2) CpCe alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-CpCealkyl or 3- to 6-membered heterocycle; or R _M is Ci-C ₆ alkyl, C ₂ -Ce alkenyl or C ₂ -C ₆ alkynyl, 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 R _M is C ₃ -C ₆ carbocycle 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C,-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, -C(0)OR _s , or - N(R _s Rs')- More preferably, R _M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or d-C ₆ alkyl (e.g., methyl, isopropyl, tert-butyl), C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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, R _M is CF ₃ , - C(CF ₃ ).-OH, -C(CH ₃ ) ₂ -CN, -C(CH ₃ ) ₂ -CH ₂ OH, or -C(CH ₃ ) ₂ -CH ₂ NH ₂ . Also preferably R _M is -L _s - R _E where Ls is a bond and R _E is -N(R _S R _S ), -0-R _S , -N(R _s )C(0)OR _s \ -N(Rs)S0 ₂ Rs\ -S0 ₂ R _S , or - SR _S . For example where L _s is a bond, R _E is -N(C _r C ₆ alkyl) ₂ (e.g., -NMei); -N(Ci-C ₆ alkylene-0- C,-C ₆ alkyl) ₂ (e.g. -N(CH ₂ CH ₂ OMe) ₂ ); -NiC-Ce alkyOiC Q alkylene-O-C-Ce alkyl) (e.g. - N(CH ₃ )(CH ₂ CH ₂ OMe));-0-C,-C ₆ alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n- hexyl); -0-C,-C ₆ haloalky 1 (e.g., - OCF ₃ , -OCH ₂ CF ₃ ); -0-C,-C ₆ alkylene-piperidine (e.g., -O- CH ₂ CHr-l-piperidyl); -N(C,-C ₆ alkyl)C(0)OC,-C ₆ alkyl (e.g., -N(CH ₃ )C(0)0-CH ₂ CH(CH ₃ ) ₂ ), - N(C,-C ₆ alkyl)S0 ₂ C,-C ₆ alkyl (e.g., -N(CH ₃ )S0 ₂ CH ₃ ); -S0 ₂ C,-C ₆ alkyl (e.g., -S0 ₂ Me); -S0 ₂ C,-C ₆ haloalkyl (e.g., -S0 ₂ CF ₃ ); or -S-C C ₆ haloalkyl (e.g., SCF ₃ ). Also preferably R _M is— Ls— RE where Ls is C,-C ₆ alkylene (e.g., -CHz-, -C(CH ₃ ) ₂ -CH ₂ -) and R _E is -0-R _s , -C(0)OR _s , - N(Rs)C(0)ORs', or -P(0)(OR _s ) ₂ . For example R _M is -C,-C ₆ alkylene-0-R _s (e.g., -C(CH ₃ )r-CHr- OMe); -C,-C ₆ alkylene-C(0)ORs (e.g., -C(CH ₃ ) ₂ -C(0)OMe); -C,-C ₆ alkylene-N(Rs)C(0)OR _s ' (e.g., -C(CH3)2-CH ₂ - HC(0)OCH ₃ ); or -C,-C ₆ alkylene-P(0)(OR _s ) ₂ (e.g., -CH ₂ -P(0)(OEt) ₂ ). Also more preferably R _M is C ₃ -C ₆ carbocycle 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,-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C,-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, -C(0)OR _s , or -N(R _s Rs')- For example R _M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro- 1-methylcycloprop-l-yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, 1 , 1- dioxidothiomoφholin-4-yl, 4-methylpiperazin- 1 -yl, 4-methoxycarbonylpiperazin- 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, R _M is C _r C ₆ alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy (e.g., tert-butyl, CF ₃ ).

More preferably, D is C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle or 6- to 12-membered bicycle and is substituted with J and optionally substituted with one or more R _A , wherein J is C ₃ -C ₆ carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R _A - Preferably, J is substituted with a C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle, wherein said C ₃ -C ₆ carbocycle 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _r C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or - N(R _S R _S '). and J can also be optionally substituted with one or more R _A . Also preferably, D is C ₅ - Cscarbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R _A , and J is C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R _A , and preferably, J is at least substituted with a C ₃ -C ₆ carbocycle 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(O)0R _s or -N(R _s Rs')- Also preferably, D is C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle and is substituted with J and optionally substituted with one or more R _A , and J is 6- to 12-membered bicycle (e.g., a 7- to 12-membered fused, bridged or sipro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more R _A . More preferably, D is phenyl and is substituted with J and optionally substituted with one or more R _A , and J is C ₃ -C ₆ carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R _A , and preferably J is at least substituted with a C ₃ -C ₆ carbocycle 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-Ce alkyl, C2-C ₆ alkenyl, C ₂ -C ₆ alkynyl, C,-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -

N(R _s Rs')- Highly preferably, D is wherein each R _N is independently selected from R _D and preferably is hydrogen or halogen, and J is C3-C ₆ carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more R _A , and preferably J is at least substituted with a C ₃ -C ₆ carbocycle 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-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -

N(R _s Rs')- Also preferably, D is , wherein each R _N is independently selected from R _D and preferably is hydrogen or halogen, and J is C ₃ -C ₆ carbocycle and 3- to 6-membered heterocycle and is substituted with a C ₃ -C ₆ carbocycle 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-C ₆ alkyl, C ₂ -C6 alkenyl, C ₂ -C ₆ alkynyl, C _r C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -

N(R _s Rs'), and J can also be optionally substituted with one or more R _A . Also preferably, D is and J is C3-C ₆ carbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R _A , and preferably J is at least substituted with a C3-C ₆ carbocycle 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, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C _r C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -N(R _S R _S ').

The present invention also features -L3-D, wherein:

D is C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more R _A ; or D is C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more R _A , where J is C ₃ -Ci ₅ carbocycle 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 R _A , or J is -SF ₅ ; or D is hydrogen or R _A ; R _A and J are as defined herein;

R _E is independently selected at each occurrence from -0-R _s , -S-R _s , -C(0)R _s , -OC(0)R _s , - C(0)OR _s , -N(RsR _s '), -S(0)R _s , -S0 ₂ R _s , -C(0)N(R _s R _s '), -ΝΟΙ^Ο)^. -N(R _s )C(0)N(Rs'Rs"), - N(R _s )S0 ₂ Rs\ -S0 ₂ N(R _s R _s '), -N(R _s )S0 ₂ N(R _s 'R _s "), -N(R _s )S(0)N(R _s 'Rs"), -OS(0)-R _s , -OS(0) ₂ - R _s , -S(0) ₂ OR _s , -S(0)OR _s , -OC(0)OR _s , -N(R _s )C(0)ORs', -OC(0)N(R _s R _s '), -N(R _s )S(0)-Rs', - S(0)N(R _s R _s '), -P(0)(OR _s ) ₂ , =C(R _S R _S '), or -C OWRs^OHV; or C,-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ - C ₆ alkynyl, 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 C ₃ -d ₂ carbocycle or 3- to 12-membered heterocycle (e.g., 7- ot 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, CpCealkyl, C ₂ - Qalkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -C ₆ haloalkenyl, CrQhaloalkynyl, -0-R _s , -S-R _s , - C(0)R _s , -C(0)OR _s , or -N(R _S R _S ').

In one embodiment, D is a Cs-Ce carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is substituted with J and optionally substituted with one or more R _A . J is C ₃ -C ₆ carbocycle, 3- to 6-menibered 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 R _A . Preferably, J is substituted with a C ₃ -C ₆ carbocycle, 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, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci- Qhaloalkyl, Q-Cehaloalkenyl, C ₂ -C ₆ haloaUcynyl, -C(0)OR _s or -N(R _S R _S '), or (2) trimethylsilyl, -O- Rs, -S-Rs, -C(0)R _s ; and J can also be optionally substituted with one or more R _A - Preferably, D is

wherein J is as defined above, and each R _N is independently selected from

R _D and preferably is hydrogen or halo such as F. and are each independently bond or C _r Qalkylene, and L3 is bond, Ci-C ₆ alkylene or -C(O)-, and I_i, \- , and L3 are each independently optionally substituted with one or more R _L . Preferably, Li, L^, and L ₃ are bond. As used herein, R _A preferably is halogen, hydroxy; mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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 C ₃ -C ₆ carbocycle 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, d- Qalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, CrQhaloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl; or -L _A - O-Rs, -L _A -S-Rs, -L _A -C(0)R _s , -L _A -OC(0)R _s , -L _A -C(0)OR _s , -L _A -N(R _S R _S '), -L _A -S(0)R _s ,— L _A — S0 ₂ R _s , -L _A -C(0)N(R _s R _s '), -L _A -N(R _s )C(0)R _s ^, _> -L _A -N(R _s )C(0)N(R _s 'Rs"), -L _A -N(R _s )S0 ₂ R _s \ - L _A -S0 ₂ N(R _s R _s '), -L _A -N(Rs)S0 ₂ N(R _s -Rs' ^, ) ₁ -L _A -N(R _s )S(0)N(R _s 'R _s "), -L _A -OS(0)-Rs,— L _A — OS(0)r-R _s , -L _A -S(0) ₂ OR _s , -L _A -S(0)OR _s , -L _A -OC(0)OR _s , -L _A -N(R _s )C(0)OR _s ',— L _A —

OC(0)N(R _s R _s '), -L _A -N(R _s )S(0)-Rs', -L _A -S(0)N(R _s R _s ') or -L _A -C(0)N(Rs)C(0)-Rs ^, , wherein L _A is bond, C _r C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene.

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo,

phosphonoxy, phosphono, thioxo, cyano; or d-C ₆ alkyl, C ₂ -C6alkenyl or C ₂ -C ₆ alkynyl, 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 C ₃ -C ₆ carbocycle 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, Q- salkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl.

Highly preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or C _r C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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, L _s ' and L _s " preferably are each independently selected at each occurrence from bond; or Ci-C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene.

According to another aspect of the invention, -L3-D are defined as:

L3 is bond or C C ₆ alkylene;

D is C ₆ -Ciocarbocycle or 5- to 12-membered heterocycle, each of which is optionally R _M is independently selected at each occurrence from:

halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, SF ₅ , -N(RsR _s '), -0-R _s , -OC(0)R _s , -OC(0)OR _s , -OC(0)N(R _s R _s '), -C(0)Rs, - C(0)OR _s , -C(0)N(R _s R _s '), -N(R _s )C(0)R _s ', -N(R _s )C(0)OR _s \ -N(R _s )S0 ₂ R _s \ -S(0)R _s , -S0 ₂ R _s , - S(0)N(R _s R _s '), -SRs, -Si(Rs) ₃ , or -P(0)(OR _s ) ₂ ; Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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(R _S R _S '), - O-Rs, -OC(0)R _s , -OC(0)OR _s , -OC(0)N(R _s R _s '), -C(0)R _s , -C(0)OR _s , -C(0)N(RsR _s '), - N(R _s )C(0)R _s \ -N(Rs)C(0)OR _s ', -N(R _s )S0 ₂ R _s ', -S(0)R _s , -S0 ₂ R _s , -S(0)N(R _s R _s '), -SR _S , or - P(0)(OR _s ) ₂ ; or

G ₂ , wherein G ₂ is a C3-C ₎₂ carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more Ro ₂ , and each R _G2 is independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C _r C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ - Qhaloalkenyl, C ₂ -C ₆ haloalkynyl, -0-R _s , -C(0)ORs, -C(0)R _S , -N(R _S R _S '), or -L4-G3;

L4 is a bond, Ci-C ₆ alkylene, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, -0-, -S-, -N(R _B )-, -C(O)-, -S(0)r-, -S(O)-, -C(0)0-, -OC(O)-, -OC(0)0-, -C(0)N(R _B )-, -N(R _B )C(0)-, -N(R _B )C(0)0-, - OC(0)N(R _B )-, -N(R _B )S(0)-, -N(R _B )S(0) ₂ -, -S(0)N(R _B >-, -S(0) ₂ N(R _B )-, -N(R _B )C(0)N(R _B ')-, - N(R _B )S0 ₂ N(R _B , or -N(R _B )S(0)N(R _B ')-;

G ₃ is a C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more Rc ₃ ; and

Rc ₃ is each independently, at each occurrence, halogen, -Ci-C ₆ alkyl, -C(0)C _r C ₆ alkyl, -C _r Q haloalkyl, -O-Ci-Qalkyl, -O-Ci-Cehaloalkyl, C ₃ -C ₆ carbocycle, or 3- to 6-membered heterocycle. substituted with one or more R _M ;

R _s , Rs' and R _s " are each independently selected at each occurrence from hydrogen; C _r C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, 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-C|-C ₆ alkyl, -O-CpCehaloalkyl, 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 R _s , Rs' or R _s " 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, CpCealkyl, C ₂ -C ₆ alkenyl, C2-C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl.

As described hereinabove for this aspect of the invention, D preferably is C ₆ -Ci ₀ carbocycle or

3- to 12-membered heterocycle optionally substituted by one or more R _M . Preferably, D is C ₆ -Ci ₀ aryl (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 R _M . For example, in certain embodiments D is preferably phenyl substituted by one or more R _M , wherein each R _M is independently halogen (e.g., fluoro, chloro, bromo); C C ₆ alkyl (e.g., tert-butyl); C C ₆ alkyl substituted with one or more halogen (e.g., CF ₃ ); -O- R _s such as -0-Ci-C ₆ alkyl (e.g., -0-CH ₂ CH ₃ ); or -0-Ci-C ₆ alkyl substituted at each occurrence with one or more halogen (e.g., -0-CF _3> -0-CH ₂ CHF ₂ ) or -0-C,-C ₆ alkyl (e.g., -O-CH2CH2OCH3); -O- R _s (e.g., -0-Ci-C ₆ alkyl, such as -0-CH ₂ ) substituted with 3- to 12-membered heterocycle (e.g., 3- ethyloxetan-3-yl, 1 ,3-dioxolan-4-yl); -0-R _s where R _s is an optionally substituted 3- to 12-membered carbocycle or heterocycle (e.g., cyclopentyl, cyclohexyl, phenyl, l ,3-dioxan-5-yl); -N(R _s )C(0)R _s ' wherein R _s and R _s ' are each independently C C ₆ alkyl (e.g., -N(t-Bu)C(0)Me); SF ₅ ; -S0 ₂ Rs wherein R _s is C _r C ₆ alkyl (e.g., -S0 ₂ Me); or C ₃ -Ci ₂ carbocycle (e.g., cyclopropyl, cyclohexyl, phenyl).

In certain embodiments of this aspect of the invention, D is preferably phenyl or pyridyl and is substituted by one or more R _M where one R _M is G ₂ . In certain embodiments where D is phenyl or pyridyl, D is substituted by G ₂ , G ₂ is 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, C _r C ₆ alkyl (e.g., methyl), C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl (e.g., CF ₃ ), C ₂ -C ₆ haloalkenyl, Cz-Qhaloalkynyl, -0-C _r C ₆ alkyl (e.g., -O-CH ₃ ), -C(0)OR _s (e.g., - C(0)OCH ₃ ), -C(0)R _s (e.g., -C(0)CH ₃ ), or -N(R _S R _S '); and D is further optionally substituted by one or more R _M where R _M is halogen (e.g., fluoro, chloro), C C ₆ alkyl (e.g., methyl), C C ₆ haloalkyl (e.g., CF ₃ ), or -0-C,-C ₆ alkyl (e.g., -0-CH ₃ ). In certain other embodiments D is phenyl or pyridyl and G ₂ is, for example, a monocyclic 3-8 membered carbocycle or monocyclic 4-8 membered heterocycle substituted with L4-G3 and optionally substituted with one or more RG ₂ wherein L ₄ , G ₃ and Rc ₂ are as defined herein. L,, for example is a bond, a C _r C ₆ alkylene (e.g., -CH ₂ - -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH2-, etc.), -0-, or -S(0)2-. G ₃ is for example a C ₃ -Ci ₂ carbocycle optionally substituted with one or more Rc ₃ . RG2 and Rc ₃ are each independently at each occurrence halogen, -C(0)Ci-C ₆ alkyl, -Ci-C ₆ alkyl,

-CpCehaloalkyl, -0-C _r C ₆ alkyl, or -0-C _r C ₆ haloalkyl. In certain embodiments G ₂ is

wherein "^ P- 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 L ₄ -G ₃ and optionally substituted with one or more RG ₂ - Thus, in

G ₃

N N

certain embodiments where L4 is a bond G ₂ is ' ^¾ · , where ^ is optionally substituted with

G ₃

Rc ₂ and G ₃ is optionally substituted with Rc ₃ . 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-l(2H)-yl, 4,4-diphenylpiperidin-l-yl, 4-acetyl-4-phenylpiperidin-l-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 R _M (e.g., fluoro, chloro, methyl, methoxy).

In certain other embodiments of this aspect of the invention, L ₄ is a C]-C ₆ alkylene, -0-, or -

S(0) ₂ - and G ₂ is >- , where <- is as defined above and is optionally substituted with R _G2

and G ₃ is as defined above and is optionally substituted with R _G 3. 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.

In certain other embodiments of this aspect of the invention, D is phenyl or pyridyl, D is substituted by G ₂ and G ₂ is a spiro, bridged, or fused bicyclic carbocycle or heterocycle optionally substituted with L4-G3 and one or more RG ₂ , wherein D is optionally substitu with one or more R _M and R _M) and R _G2 are as defined herein. In certain embodiments G ₂ 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, 1 ,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 G ₃ and one or more RG ₂ . Thus, G ₂ is 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, 1 ,3-dihydro-2H- isoindol-2-yl, or l ,4-dioxa-8-azaspiro[4.5]dec-8-yl; L ₄ is a bond and D is optionally substituted with one or more R _M (e.g., fluoro, chloro, methyl, methoxy).

In certain embodiments of this aspect of the invention, D is wherein R _M is as defined above in connection with Formula I _E , and D is optionally substituted by one or more additional R _M . For instance, where D is , R _M can be fluoro, chloro, tert-butyl, -0-CH ₂ CH ₃ , -O-CF3, -O-

CH ₂ CHF ₂ , -0-CH ₂ CH ₂ OCH ₃ , -0-CH ₂ -(3-ethyloxetan-3-yl), -0-CH ₂ -(l ,3-dioxolan-4-yl), -O- cyclopentyl, -O-cyclohexyl, -O-phenyl, -0-<l ,3-dioxan-5-yl), cyclopropyl, cyclohexyl, phenyl, SF ₅ , -S0 ₂ Me, or -N(t-Bu)C(0)Me and D can be optionally substituted by one or more additional R _M selected from the group consisting of halogen (e.g., fluoro, chloro) Ci-C ₆ alkyl (e.g., methyl).

In certain embodiments of this aspect of the invention, D is wherein R _M is fluoro, chloro, tert-butyl, -0-CH ₂ CH ₃ , -O-CF3, -0-CH ₂ CHF ₂ , -O-CH ₂ CH ₂ 0CH ₃ , SF ₅ , -S0 ₂ Me, or -N(t- Bu)C(0)Me and D is optionally substituted by one or more additional R _M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C ₆ alkyl (e.g., methyl).

In certain embodiments of this aspect of the invention, D is wherein R _M is cyclopropyl, cyclohexyl, or phenyl and D is optionally substituted by one or more additional R _M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C ₆ alkyl (e.g., methyl).

In certain embodiments of this aspect of the invention, wherein R _M is -0-CH ₂ - (3-ethyloxetan-3-yl), -0-CH ₂ -(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 R _M selected from the group consisting of halogen (e.g., fluoro, chloro) and C _r C ₆ alkyl (e.g., methyl).

In certain embodiments of this aspect of the invention, D is wherein G ₂ is 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- 1 -yl, 4-(trifluoromethyl)piperidin- 1 -yl, 4-methylpiperidin- 1 -yl, 4-tert-butylpiperidin- 1 -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 R _M selected from the group consisting of halogen (e.g., fluoro, chloro) and C C ₆ alkyl (e.g., methyl).

In another embodiment of this aspect of the invention, D is wherein d is N,

_, N N

C-H, or C-R _M ; G ₂ is ^ , wherein ^ 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-G3 and optionally substituted with one or more RQ2; L ₄ is a bond, C C ₆ alkylene, -0-, or -S(0)2-; G ₃ is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle (e.g., thienyl) wherein each G ₃ is optionally substituted with one or more RG3 _> RG2 and RG3 at each occurrence are each independently halogen, -C(0)Ci-C ₆ alkyl, -C|-C ₆ alkyl, -C C6haloalkyl, - 0-Ci-C ₆ alkyl, or -0-C C6haloalkyl; g is 0, 1 , 2, or 3; and R _M is as defined above in connection with

Formula I _E . In one group of compounds according to this embodiment, D is wherein

G ₃ is phenyl optionally substituted with one or two Rc ₃ ; g is 0, 1 , or 2; R _M is each independently

fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and and RG ₃ are as

defined above. In a further subgroup of compounds of this embodiment, D is

wherein G ₃ is phenyl optionally substituted with one or two RG ₃ ; RMI is each independently hydrogen, fluoro, chloro, or methyl; and R _Q 2 is an optional substituent as described herein. In another group of compounds according to this embodiment, D is wherein L ₄ is C _r C ₆ alkylene, -0-, or -

S(0) ₂ -; G ₃ is phenyl optionally substituted with one or two Rc ₃ ; g is 0, 1 , or 2; R _M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and and Rc3 are as defined above.

In yet another embodiment of this aspect of the invention, D is wherein Gi is

N, C-H, or C-R _M ; G ₂ is 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-G3 and one or more RG ₂ ; L is a bond, CpCe alkylene, -0-, or -S(0) ₂ -; G ₃ is aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl), or heterocycle (e.g. thienyl) wherein each G ₃ is optionally substituted with one or more RQ ₃ ; RG2 and Rc ₃ at each occurrence are each independently halogen, -C(0)C _r C ₆ alkyl, -Ci-C ₆ alkyl, -Ci-Cehaloalkyl, -0-C _r C ₆ alkyl, or -O-Ci-Cehaloalkyl; g is 0, 1, 2, or 3; and R _M is as defined above in connection with

Formula I _E . In one group of compounds according to this embodiment, D is wherein g is 0, 1, or 2; R _M is ndently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; is as defined above. In a further subgroup of compounds D is wherein R _M1 is each independently hydrogen, fluoro, chloro, or 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, 1 ,3-dihydro-2H- isoindol-2-yl, 1 ,4-dioxa-8-azaspiro[4.5]dec-8-yl).

In still another embodiment of this aspect of the invention, D is , wherein

N

^ is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more R _G 2. wherein R _G2 at each occurrence is each independently halogen, -C(0)C C ₆ alkyl, -C C ₆ alkyl, -CrQhaloalkyl, -0-C,-C ₆ alkyl, or -0-C _r C ₆ haloalkyl; and R _M is each independently halogen, -C C ₆ alkyl, -C C ₆ haloalkyl, -0-C C ₆ alkyl, or

N

-O-Ci-Cehaloalkyl. In one group of compounds according to this embodiment, ^ is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two Ro ₂ , wherein Rc ₂ at each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R _M is

N

each independently fluoro, chloro, or methyl. For example ^ is 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-dimethy Ipiperidin- 1 -yl, 4-(trifluoromethyl)piperidin- 1 -yl, 4-methy lpiperidin- 1 -yl, 4-tert-butylpiperidin-l -yl, 2-oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl.

Non-limited examples of D in -L ₃ -D include:



wherein L ₃ is preferably bond.

The term "alkenyl" as used in connection with the definition of -L-E or -L ₃ -D 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.

The term "alkenylene" as used in connection with the definition of -L-E or -L3-D 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)-CH ₂ -, -C(H)=C(H)-CH ₂ -CH ₂ -, -CH ₂ -C(H)=C(H)-CH ₂ -,

-C(H)=C(H)-CH(CH3)-, and -CH ₂ -C(H)=C(H>-CH(CH ₂ CH ₃ )-.

The term "alkyl" as used in connection with the definition of -L-E or -L3-D 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.

The term "alkylene" as used in connection with the definition of -L-E or -L ₃ -D denotes a divalent saturated hydrocarbyl chain which may be linear or branched. Representative examples of alkylene include, but are not limited to, -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, and - CH ₂ CH(CH ₃ )CH ₂ -.

The term "alkynyl" as used in connection with the definition of -L-E or -L3-D 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.

The term "alkynylene" as used in connection with the definition of -L-E or -L3-D 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-CH ₂ -, -C≡C-CH ₂ -CH ₂ -, -CH ₂ -C≡C-CH ₂ - -C≡C-CH(CH ₃ )-, and

-CH ₂ -C≡C-CH(CH ₂ CH ₃ )-.

The term "carbocycle" or "carbocyclic" or "carbocyclyl" as used in connection with the definition of -L-E or -L3-D 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, cycloburyl, 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.

The term "carbocyclylalkyl" as used in connection with the definition of -L-E or -L3-D refers to a carbocyclyl group appended to the parent molecular moiety through an alkylene group. For instance, C ₃ -C ₆ carbocyclylCi-C6alkyl refers to a C ₃ -C ₆ carbocyclyl group appended to the parent molecular moiety through Ci-Cealkylene.

The term "cycloalkenyl" as used in connection with the definition of -L-E or -L3-D as used in connection with the definition of -L-E or -L^-D 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.

The term "cycloalkyl" as used in connection with the definition of -L-E or -L ₃ -D 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.

The prefix "halo" as used in connection with the definition of -L-E or -L^-D indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, "Ci-Ce halo alky I" means a d-C ₆ alkyl substituent wherein one or more hydrogen atoms are replaced with independently selected halogen radicals. Non-limiting examples of C _r C ₆ haloalkyl include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 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).

The term "heterocycle" or "heterocyclo" or "heterocyclyl" as used in connection with the definition of -L-E or -L^-D 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.

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, and diazepinyl.

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"), 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, 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.

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.

The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix "C _x -C _y ," where x is the minimum and y is the maximum number of carbon atoms in the moiety. Thus, for example, "C C ₆ alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, C ₃ -C ₆ carbocycle means a carbocycle 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, C ₃ -C ₆ carbocyclyl C C ₆ alkyl refers to a C ₃ -C ₆ carbocyclyl appended to the parent molecular moiety through a Q-C6 alkyl group.

Unless otherwise specified, when a moiety links two other elements in a depicted chemical structure, the leftmost-described component of the moiety is bound to the left element in the depicted structure, and the rightmost-described component of the moiety is bound to the right element in the depicted structure. To illustrate, if the chemical structure is -L-LS-RE and Ls is C _\ -C ₆ alkylene, then the chemical structure is -L-Ci-Ce alkylene-R _E .

If a moiety in a depicted structure is a bond, then the element left to the moiety is joined directly to the element right to the linking element via a covalent bond. For example, if a chemical structure is depicted as -L-LS-RE and Ls is selected as bond, then the chemical structure will be -L- R _E . If two or more adjacent moieties in a depicted structure are bonds, then the element left to these moieties is joined directly to the element right to these linking elements via a covalent bond.

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). 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.

In one embodiment, the present invention relates to compounds of Formula (la), or a pharmaceutically acceptable salt thereof:

da)

wherein A, W, G, T, u, v, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as previously defined above. In another embodiment, the present invention relates to compounds of Formula (lb), or a pharmaceutically acceptable salt thereof:

In still another embodiment, the present invention relates to compounds of Formula (Ic), or a pharmaceutically acceptable salt thereof:

(Ic)

In still another embodiment, the present invention relates to compounds of Formula (Id), or a pharmaceutically acceptable salt thereof:

In still another embodiment, the present invention relates to compounds of Formula (Ie), or a pharmaceutically acceptable salt thereof:

wherein A, W, G, T, u, v, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ and R ¹² are as previously defined above and X ¹ independently CH ₂ , CHF, CH(OH), or CF ₂ . In still another embodiment, the present invention relates to compounds of Formula (If), or a pharmaceutically acceptable salt thereof:

(If)

wherein A, W, G, T, u, v, X ¹ , R ¹ , R ² , R ⁷ and R ¹² are as previously defined above.

In still another embodiment, present invention present invention, the absolute stereochemistry of thepyiroUdine and 2-tenz-imicla2»lylme-hylamine moiety is represented by Formulae (Ig-1 , Ig-2 and Ig-3): Ig-1)

Ig-2)

wherein A, W, G, T, R ³ , R ⁵ , and R ¹² are as previously defined above. In still another embodiment, present invention relates to compounds of Formula (Di), or a pharmaceutically acceptable salt thereof: (Ih)

wherein A, W, G, T, X ¹ , and R ¹¹ are as previously defined above. In still another embodiment, the present invention relates to compounds of Formula (Ii), or a pharmaceutically acceptable salt thereof:

wherein A, W, G, T, X ¹ , R", and R* are as previously defined above.

In still another embodiment, the present invention relates to compounds of Formula (Ij), or a pharmaceutically acceptable salt thereof:

Ij)

wherein, A, W, G, T, X ¹ , R ^c and R ^rf are as previously defined above.

In still another embodiment, the present invention relates to compounds of Formula (Ik), or a pharmaceutically acceptable salt thereof:

(Ik)

wherein A, Y, Z, X ¹ , and R ¹³ are as previously defined above.

In still another embodiment, the present invention relates to compounds of Formula (Dc), wherein R is C _r C ₈ alkyl optionally substituted with amino, hydroxy, phenyl, protected amino, or 0(Ci - C ₄ alkyl); or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention relates to compounds of Formula (D), or a pharmaceutically acceptable salt thereof:

(II)

wherein A, W, G, T and X ¹ are as previously defined above and R ¹³ " at each occurrence is independently and optionally substituted C C ₈ alkyl; preferably is C _r C ₈ alkyl optionally substituted with amino, hydroxy, optionally substituted phenyl, protected amino, or 0(Ci - C ₄ alkyl).

In another embodiment, the present invention relates to compounds of Formula (I-IIa), or a pharmaceutically acceptable salt thereof:

(I-IIa)

wherein A, Q, J, u, v, R ¹ , and R ² are as previously defined above and W ¹ is an optionally substituted Ci-C ₄ alkyl and wherein at least A or W ¹ is substituted with -I^E or -L ₃ -D as defined herein. In another embodiment, the compound has the Formula (1-lla), wherein A is a heterocyclic; or a pharmaceutically acceptable salt thereof and and wherein A is substituted with -L— E or -L3-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IIb), or a pharmaceutically acceptable salt thereof:

(I-IIb)

wherein A, Q, J, u, v, R ¹ , and R ² are as previously defined above and W ² is an optionally substituted C ₂ -C4 alkenyl and wherein at least A or W ² is substituted with -L-E or -L ₃ -D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IIc), or a pharmaceutically acceptable salt thereof:

(I-Hc)

wherein A, Q, J, u, v, R ¹ , and R ² are as previously defined above and W ³ is an optionally substituted C ₂ -C ₄ alkenyl and wherein at least A or W ³ is substituted with -L-E or -L3-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IId), or a pharmaceutically acceptable salt thereof:

(I-IId)

wherein A, Q, J, u, v, R ¹ , and R ² are as previously defined above and W ⁴ is selected from O and N(R ^M ); and R ¹¹ is as previously defined above, and wherein at least A or W ⁵ is substituted with -I^E or -L-3-D as defined herein.

In still another embodiment, the first aspect of the present invention relates to compounds of Formula (Ι-Πε), or a pharmaceutically acceptable salt thereof:

(I-IIe)

wherein A, Q, J, u, v, R ¹ and R ² are as previously defined above and W ⁵ is selected from C(O), S(O) C(0)0, C(0)N(R"), OC(0)0, OC(0)N(R"), S(0) ₂ N(R ^U ), N(R")C(0)N(R ^U ),

N(R ¹¹ )C(0)C(0)N(R ¹¹ ), NiR'^SCO^NCR ^{1 1} ), C(0)N(R ^H )S(0) ₂ and C(0)N(R")S (0) ₂ N(R"); and R ¹ is as previously defined above and wherein at least A or W ⁵ is substituted with -L-E or -L3-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IIf), or a pharmaceutically acceptable salt thereof:

(I-Hf)

wherein A, Q, J, u, v, R ¹ and R ² are as previously defined above and W ⁶ is an optionally substituted C ₃ -C ₈ cycloalkyl or optionally substituted C ₃ -C ₈ cycloalkenyl, wherein at least A or W ⁶ is substituted with -L-E or -L3-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IIg), or a pharmaceutically acceptable salt thereof:

(I-IIg)

wherein A, Q, J, u, v, R ¹ and R ² are as previously defined above and W ⁷ is an optionally substituted heterocyclic and wherein at least A or W ⁷ is substituted with -L-E or -L3-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IIIa), or a pharmaceutically acceptable salt thereof:

(I-ma)

wherein A, Q, J, u, v, R ¹ and R ² are as previously defined above and G' is an optionally substituted aryl.

In still another embodiment, the the present invention relates to compounds of Formula (I- nib), or a pharmaceutically acceptable salt thereof:

(I-mb)

wherein A, Q, J, u, v, R ¹ and R ² are as previously defined above and G ² is an optionally substituted aryl and wherein at least A or G ² is substituted with -L-E or -Lj-D as defined herein.

In still another embodiment, the the present invention relates to compounds of Formula (I- nic), or a pharmaceutically acceptable salt thereof:

(I-IIIc)

wherein Q, J, u, v, R ¹ and R ² are as previously defined above; G is present and as previously defined above; and A ¹ is an optionally substituted aryl and wherein at least G or A ¹ is substituted with -L-E or -L3-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IIId), larmaceutically acceptable salt thereof:

(I-ind)

wherein Q, J, u, v, R ¹ and R ² are as previously defined above; G is present and as previously defined above; and A ² is an optionally substituted heteroaryl and wherein at least G or A ² is substituted with -L-E or -L ₃ -D as defined herein. In still another embodiment, the present invention relates to compounds of Formula (I-IIIe), or a pharmaceutically acceptable salt thereof:

(I-me)

wherein Q, J, u, v, R ¹ and R ² are as previously defined above; G is present and as previously defined above; and A ³ is an optionally substituted heterocyclic and wherein at least G or A ³ is substituted with -L-E or -L ₃ -D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-EIIf) or a pharmaceutically acceptable salt thereof:

(i-mf) wherein Q, J, u, v, R ¹ and R ² are as previously defined above; G is present and as previously defined above; and A ⁴ is an optionally substituted C ₃ -C ₈ cycloalkyj and wherein at least G or A ⁴ is substituted with -L-E or -L3-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-HIg), or a pharmaceutically acceptable salt thereof: (I-IIIg)

wherein Q, J, u, v, R ¹ and R ² are as previously defined above; G is present and as previously defined above; and A ⁵ is an optionally substituted C ₃ -C ₈ cycloalkyl and and wherein at least G or A ⁵ is substituted with -h-E or -Lj-D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I-IVa), or a pharmaceutically acceptable salt thereof: -IVa)

wherein A, Q, J, u, v, R ¹ and R ² are as previously defined above and W ⁸ and T ¹ are each independently linear aliphatic group containing zero to six carbons, optionally contain one or more groups selected from O, N(R ^M ), C(0), S(0) ₂ , C(0)0, and C(0)N(R ^H ); and R ¹¹ is as previously defined above, and wherein at least one of A, W ⁸ or T ¹ is substituted with -I^E or -L ₃ -D as defined herein.

In still another embodiment, the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof; wherein

at each occurrence is independently illustrated by one of the following groups:

Except for the above definitions provided for -L-E or -L3-D, the remaining substitutents in the compounds having the above Formula I as well as other formulae described above are to be interpreted according to the meaning provided for the substitutents in US Patent Publication 2010/0221215, the contents of which are herein incorporated by reference.

Methods for making compounds of Formula I as well as other formulae described above are described in US Patent Publication 2010/0221215 (see the description of compounds having the formula I) and US Application No. 12/959,941 filed on December 3, 2010, the contents of which are herein each incorporated by reference.

In one embodiment, the present invention features the below compounds.

In another embodiment, the compounds of the invention can be prepared according to the following scheme:

wherein R _z can be, for example, R ¹² ; and wherein W can be, for example, hydrogen 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.

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, cyclohexylaminosulfonate, 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.

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 Ha) 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 quatemized 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.

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). 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% 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.

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.

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.

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.

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).

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.

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.

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

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., R _A or R _B ). 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.

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. 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.

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 or carboxy 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.

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.

The present invention also features pharmaceutical compositions comprising the compounds of the invention. A pharmaceutical composition of the present invention can comprise one or more compounds of the invention.

In addition, the present invention features pharmaceutical compositions comprising pharmaceutically acceptable salts, solvates, or prodrugs of the compounds of the invention. Without limitation, pharmaceutically acceptable salts can be zwitterions or derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable salt retains the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation, or allergic response, has a reasonable benefit/risk ratio, is effective for the intended use, and is not biologically or otherwise undesirable.

The present invention further features pharmaceutical compositions (a) one or more compounds of the present invention (namely, one or more of compounds having Formula (I) or salts, solvates or prodrugs thereof; and (b) another therapeutic agent. By way of illustration not limitation, these other therapeutic agents can be selected from antiviral agents (e.g., anti-HIV agents, anti-HBV agents, or other anti-HCV agents such as HCV protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, IRES inhibitors or NS5A inhibitors), anti-bacterial agents, anti-fungal agents, immunomodulators, anti-cancer or chemotherapeutic agents, anti-inflammation agents, antisense RNA, siRNA, antibodies, or agents for treating cirrhosis or inflammation of the liver. Specific examples of these other therapeutic agents include, but are not limited to, ribavirin, cc-interferon, β- interferon, pegylated interferon-α, pegylated interferon-lambda, ribavirin, viramidine, R-5158, nitazoxanide, amantadine, Debio-025, NIM-81 1, R7128, R1626, R4048, T-l 106, PSI-7851 , PF- 00868554, ANA-598, IDX184, IDX102, IDX375, GS-9190, VCH-759, VCH-916, MK-3281 , BCX- 4678, MK-3281 , VBY708, ANA598, GL59728, GL60667, BMS-790052, BMS-791325, BMS- 650032, GS-9132, ACH-1095, AP-H005, A-831 , A-689, AZD2836, telaprevir, boceprevir, ITMN- 191 , BI-201335, VBY-376, VX-500 (Vertex), PHX-B, ACH-1625, IDX136, IDX316, VX-813 (Vertex), SCH 900518 (Schering-Plough), TMC-435 (Tibotec), ITMN-191 (Intermune, Roche), MK- 7009 (Merck), IDX-PI (Novartis), BI-201335 (Boehringer Ingelheim) , R7128 (Roche), PSI-7851 (Pharmasset), MK-3281 (Merck), PF-868554 (Pfizer), IDX-184 (Novartis), IDX-375 (Pharmasset), BILB-1941 (Boehringer Ingelheim), GS-9190 (Gilead), BMS-790052 (BMS), ABT-450

(Abbott/Enanta), ABT-072 (Abbott), ABT-333 (Abbott), Albuferon (Novartis), ritonavir, another cytochrome P450 monooxygenase inhibitor, or any combination thereof.

In one embodiment, a pharmaceutical composition of the present invention comprises (a) one or more compounds of the present invention (namely, one or more of compounds having Formula (I)), or salts, solvates or prodrugs thereof; and (b) one or more other antiviral agents.

In another embodiment, a pharmaceutical composition of the present invention comprises (a) one or more compounds of the present invention (namely, one or more of compounds having Formula (I)), or salts, solvates or prodrugs thereof; and (b) and one or more other anti-HCV agents, such as an agent selected from HCV polymerase inhibitors (including nucleoside or non-nucleoside type of polymerase inhibitors), HCV protease inhibitors, HCV helicase inhibitors, CD81 inhibitors, cyclophilin inhibitors, IRES inhibitors, or NS5A inhibitors.

In yet another embodiment, a pharmaceutical composition of the present invention comprises (a) one or more compounds of the present invention (namely, one or more of compounds having

Formula (I)), or salts, solvates or prodrugs thereof; and (b) one or more other antiviral agents, such as anti-HBV, anti-HIV agents, or anti-hepatitis A, anti-hepatitis D, anti-hepatitis E or anti-hepatitis G agents. Non-limiting examples of anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-1 14, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S- 1360, enfuvirtide, T-l 249, or other HIV protease, reverse transcriptase, integrase or fusion inhibitors. Any other desirable antiviral agents can also be included in a pharmaceutical composition of the present invention, as appreciated by those skilled in the art.

A pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable carriers/excipients include sugars (e.g., lactose, glucose or sucrose), starches (e.g., corn starch or potato starch), cellulose or its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose or cellulose acetate), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g., propylene glycol), buffering agents (e.g., magnesium hydroxide or aluminum hydroxide), agar, alginic acid, powdered tragacanth, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, or phosphate buffer solutions.

Lubricants, coloring agents, releasing agents, coating agents, sweetening, flavoring or perfuming agents, preservatives, or antioxidants can also be included in a pharmaceutical composition of the present invention.

The pharmaceutical compositions of the present invention can be formulated based on their routes of administration using methods well known in the art. For example, a sterile injectable preparation can be prepared as a sterile injectable aqueous or oleagenous suspension using suitable dispersing or wetting agents and suspending agents. Suppositories for rectal administration can be prepared by mixing drugs with a suitable nonirritating excipient such as cocoa butter or polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drugs. Solid dosage forms for oral administration can be capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose lactose or starch. Solid dosage forms may also comprise other substances in addition to inert diluents, such as lubricating agents. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents commonly used in the art. Liquid dosage forms may also comprise wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes, as described in U.S. Patent No. 6,703,403. Formulation of drugs that are applicable to the present invention is generally discussed in, for example, Hoover, John E., REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, PA: 1975), and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker, New York, N.Y., 1980).

Any compound described herein (i.e, any compounds having a formula (I) - Formula (XXII)), or a pharmaceutically acceptable salt thereof, can be used to prepared pharmaceutical compositions of the present invention.

The present invention further features methods of using the compounds of the present (namely, one or more of compounds having Formula (Γ)), or salts, solvates or prodrugs thereof to inhibit HCV replication. The methods comprise contacting cells infected with HCV virus with an effective amount of a compound of the present invention (namely, one or more of compounds having Formula (I) or salts, solvates or prodrugs thereof thereby inhibiting the replication of HCV virus in the cells. As used herein, "inhibiting" means significantly reducing, or abolishing, the activity being inhibited (e.g., viral replication). In many cases, representative compounds of the present invention can reduce the replication of HCV virus (e.g., in an HCV replicon assay as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

The compounds of the present invention may inhibit one or more HCV subtypes. Examples of HCV subtypes that are amenable to the present invention include, but are not be limited to, HCV genotypes 1 , 2, 3, 4, 5 and 6, including HCV genotypes la, lb, 2a, 2b, 2c or 3a. In one embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of HCV genotype 1 a. In another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of HCV genotype lb. In still another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of both HCV genotypes la and lb.

The present invention also features methods of using the compounds of the present invention (or salts, solvates or prodrugs thereof) to treat HCV infection. The methods typically comprise administering a therapeutic effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), or a pharmaceutical composition comprising the same, to an HCV patient, thereby reducing the HCV viral level in the blood or liver of the patient. As used herein, the term "treating" refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition, or one or more symptoms of such disorder or condition to which such term applies. The term "treatment" refers to the act of treating. In one embodiment, the methods comprise

administering a therapeutic effective amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof), or a pharmaceutical composition comprising the same, to an HCV patient, thereby reducing the HCV viral level in the blood or liver of the patient.

A compound of the present invention (or a salt, solvate or prodrug thereof) can be administered as the sole active pharmaceutical agent, or in combination with another desired drug, such as other anti-HCV agents, anti-HIV agents, anti-HBV agents, anti-hepatitis A agents, anti- hepatitis D agents, anti-hepatitis E agents, anti-hepatitis G agents, or other antiviral drugs. Any compound described herein, or a pharmaceutically acceptable salt thereof, can be employed in the methods of the present invention.

A compound of the present invention (namely, one or more of compounds having Formula (I) or salts, solvates or prodrugs thereof can be administered to a patient in a single dose or divided doses. A typical daily dosage can range, without limitation, from 0.1 to 200 mg/kg body weight, such as from 0.25 to 100 mg/kg body weight. Single dose compositions can contain these amounts or submultiples thereof to make up the daily dose. Preferably, each dosage contains a sufficient amount of a compound of the present invention that is effective in reducing the HCV viral load in the blood or liver of the patient. The amount of the active ingredient, or the active ingredients that are combined, to produce a single dosage form may vary depending upon the host treated and the particular mode of administration. It will be understood that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.

The present invention further features methods of using the pharmaceutical compositions of the present invention to treat HCV infection. The methods typically comprise administering a pharmaceutical composition of the present invention to an HCV patient, thereby reducing the HCV viral level in the blood or liver of the patient. Any pharmaceutical composition described herein can be used in the methods of the present invention.

In addition, the present invention features use of the compounds or salts of the present invention for the manufacture of medicaments for the treatment of HCV infection. Any compound described herein, or a pharmaceutically acceptable salt thereof, can be used to make medicaments of the present invention.

The compounds of the present invention can also be isotopically substituted. Preferred isotopic substitution include substitutions with stable or nonradioactive isotopes such as deuterium, ^l3 C, ¹⁵ N or ^l8 0. Incorporation of a heavy atom, such as substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. In one example, at least 10 mol % of hydrogen in a compound of the present invention is substituted with deuterium. In another example, at least 25 mole % of hydrogen in a compound of the present invention is substituted with deuterium. In a further example, at least 50, 60, 70, 80 or 90 mole % of hydrogen in a compound of the present invention is substituted with deuterium. The natural abundance of deuterium is about 0.015%. Deuterium substitution or enrichment can be achieved, without limitation, by either exchanging protons with deuterium or by synthesizing the molecule with enriched or substituted starting materials. Other methods known in the art can also be used for isotopic substitutions.

The compounds of the present invention can also be isotopically substituted. Preferred isotopic substitution include substitutions with stable or nonradioactive isotopes such as deuterium, ¹³ C, ¹³ N or ^l8 0. Incorporation of a heavy atom, such as substitution of deuterium for hydrogen, can give rise to an isotope effect that could alter the pharmacokinetics of the drug. In one example, at least 10 mol % of hydrogen in a compound of the present invention is substituted with deuterium. In another example, at least 25 mole % of hydrogen in a compound of the present invention is substituted with deuterium. In a further example, at least 50, 60, 70, 80 or 90 mole % of hydrogen in a compound of the present invention is substituted with deuterium. The natural abundance of deuterium is about 0.015%. Deuterium substitution or enrichment can be achieved, without limitation, by either exchanging protons with deuterium or by synthesizing the molecule with enriched or substituted starting materials. Other methods known in the art can also be used for isotopic substitutions.

The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference.

The foregoing description of the present invention provides illustration and description, but is not intended to be exhaustive or to limit the invention to the precise one disclosed. Modifications and variations are possible in light of the above teachings or may be acquired from practice of the invention. Thus, it is noted that the scope of the invention is defined by the claims and their equivalents.