This application incorporates by reference the entire content of U.S. Patent Application Pub. No. 2010/0317568, U.S. Patent Application Pub. No. 2011/0092415, U.S. Patent Application Pub. No. 2011/0207699, U.S. Patent Application No. 13/100,827 filed May 4, 2011, and U.S. Provisional Application No. 61/446,800 filed February 25, 2011.

FIELD

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

BACKGROUND

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

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 features compounds of Formulae I, I _A , ¾, Ic, I _D , I _E , I _F or I _G , and pharmaceutically acceptable salts thereof. These compounds and salts can inhibit the replication of HCV and therefore are useful for treating HCV infection.

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

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

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

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

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

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.

DETAILED DESCRIPTION

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

D

Y— A— L-i— X— L ₂ — B— Z

I

wherein:

-Cscycloalkyl or C ₅ -C ₈ cycloalkenyl, and is optionally substituted with one or more R _A or R _F ;

Li and L2 are each independently selected from bond; or Ci-Cealkylene, C ₂ -C ₆ alkenylene or C2-C ₆ alkynylene, each of which is independently optionally substituted at each occurrence with one or more R _L ;

L ₃ is bond or -L _S -K-L _S '-, 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(RB)C(0)-, -N(RB)C(0)0- -OC(0)N(R _B )-, -N(R _B )S(0)-, -N(RB)S(0) ₂ - -S(0)N(R _B )-, -S(0) ₂ N(RB)-, -C(0)N(R _B )C(0)-, -N(R _B )C(0)N(RB')-, -N(R _B )S0 ₂ N(RB')-, or -N(R _B )S(0)N(R _B ')-; A and B are each independently C3-Ci2carbocycle or 3- to 12-membered heterocycle, and are each independently optionally substituted with one or more R _A ;

D is C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more RA; or D is C3-Ci2carbocycle or 3- to 12-membered heterocycle which is substituted with J and optionally substituted with one or more 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 ;

Y is selected from -T'-C(R ₁ R ₂ )N(R ₅ )-T-R _D , -T'-C(R3R4)C(R ₆ R ₇ )-T-RD, -L _K -T-R _d , or Ri and R ₂ are each independently R _c , and R ₅ is R _B ; or Ri is Rc, and R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more R _A ;

R ₃ , R4, R ₆ , and R ₇ are each independently R _c ; or R ₃ and R ₆ are each independently R _c , and R4 and R7, taken together with the atoms to which they are attached, form a 3- to 12- membered carbocycle or heterocycle which is optionally substituted with one or more R _A ;

Z is selected from -T'-C(R ₈ R ₉ )N(R ₁₂ )-T-R _D , -T'-C(R ₁₀ Rn)C(Ri3Ri4)-T-R _D , L _K — T— R _D or

R ₈ and R ₉ are each independently R _c , and Ri ₂ is R _B ; or R ₈ is R _c , and R ₉ and Ri ₂ , taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more R _A ;

Rio, Rn, Ri3, and R _M are each independently Rc; or Ri ₀ and R13 are each independently R _c , and Rn and R14, taken together with the atoms to which they are attached, form a 3- to 12-membered carbocycle or heterocycle which is optionally substituted with one or more RA;

T and T are each independently selected at each occurrence from bond, -L _s - -L _s -M-L _s '-, or -Ls-M-Ls'-M'-Ls"-, wherein M and M' are each independently selected at each occurrence 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(RB)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(RB)-, -C(0)N(RB)C(0)-, -N(R _B )C(0)N(R _B ')-,

-N(R _B )S0 ₂ N(RB')-, -N(R _B )S(0)N(RB')-, C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle, and wherein said C3-Ci ₂ carbocycle and 3- to 12-membered heterocycle are each independently optionally substituted at each occurrence with one or more R _A ;

L _K is independently selected at each occurrence from bond, -L _s -N(R _B )C(0)-L _s '- or -L _s -C(0)N(R _B )-L _s '-; or Ci-Cealkylene, C ₂ -Cealkenylene or C ₂ -Cealkynylene, each of which is independently optionally substituted at each occurrence with one or more R _L ; or C3-Ci2carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more RA;

E is independently selected at each occurrence from C3-Ci2carbocycle or 3- to 12-membered heterocycle, and is independently optionally substituted at each occurrence with one or more R _A ;

R _D is each independently selected at each occurrence from hydrogen or R _A;

R _A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L _S -RE, 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, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -Cehaloalkenyl or C ₂ -Cehaloalkynyl;

R _c is independently selected at each occurrence from hydrogen, halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; 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 Rc is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C6haloalkynyl;

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(Rs)C(0)N(R _s 'Rs"), -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(Rs)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)-R _s ', -S(0)N(R _s R _s '), -P(0)(OR _s ) ₂ , or -C(0)N(R _s )C(0)-Rs'; 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 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, Ci-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(RsRs');

is independently selected at each occurrence from Ci-Ci ₀ alkyl, C ₂ -Ci ₀ alkenyl or C ₂ -Ci ₀ alkynyl, each of which contains 0, 1, 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independently optionally substituted with one or more R _L ; or -(RX-RY)Q-(RX-RY'), wherein Q is 0, 1 , 2, 3 or 4, and each R _x is independently O, S or N(R _B ), wherein each R _Y is independently Ci-Cealkylene, C ₂ -Cealkenylene or C ₂ -C ₆ alkynylene each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, and wherein each R _Y ' is independently Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; 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-Cehaloalkyl, C ₂ -Cehaloalkenyl 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;

L _s ' 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 ; and

R _s ' and R _s " are each independently selected at each occurrence from hydrogen; 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, -0-Ci-C ₆ alkyl, -0-Ci-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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C2-C6haloalkynyl.

A and B preferably are independently selected from C ₅ -C ₆ carbocycle (e.g., phenyl), 5- to 6- membered heterocycle (e.g., pyridinyl or thiazolyl), or 8- to 12-membered bicycles such as where Zi is independently selected at each occurrence from O, S, NH or CH ₂ , Z ₂ is independently selected at each occurrence from N or CH, Z3 is independently selected at each occurrence from N or CH, Z4 is independently selected at each occurrence from O, S, NH or CH ₂ , and Wi, W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are each independently selected at each occurrence from CH or N. A and B are each independently optionally substituted with one or more R _A .

More preferably, A is selected from C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, and is optionally substituted with one or more RA _? B is selected from C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, or and is optionally substituted with one or more R _A ; where Z Z ₂ , Z ₃ , Z ₄ , Wi, W ₂ ,

W ₃ , W ₄ , W ₅ , W ₆ are as defined above. Preferably, Z ₃ is N and Z ₄ is NH. For instance, A can be selected from

and is optionally substituted with one or more R _A ; and B can be selected from phenyl (e.g., ^ \= ^), pyridinyl (e.g., ^ ^), thiazolyl (e.g., and is optionally substituted with one or more R _A . Highly p referably, both A and B are phenyl (e.g., both A and B ar Also highly preferably, A

substituted with one or more R _A

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 Ci-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-tetrahydrobenzo[d]thiazolyl, 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 -L _S -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 , or , wherein 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 RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[ xol-5-yl, and is substituted with one or more R _M . Highly preferably, D

i _{s ? an(} j jg optionally substituted with one or more R _M .

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 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, Ci-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C2-C6alkynyl, 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 Ci-C ₆ 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 -R _E , wherein L _s 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 Rs', -S0 ₂ R _s , -SRs, 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) Ci-C ₆ alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Q-Cealkyl or 3- to 6-membered heterocycle; or R _M is Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C2-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, C2-C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C2-C ₆ haloalkynyl, -C(0)OR _s , or -N(RsRs')- More preferably, R _M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-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 ) ₂ -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 L _s is a bond and R _E is -N(R _S R _S ), -0-R _s , -N(R _s )C(0)OR _s ', -N(R _s )S0 ₂ R _s ', -S0 ₂ R _s , or -SR _S . For example where L _s is a bond, R _E is -N(Ci-C ₆ alkyl) ₂ (e.g., -NMe ₂ ); -N(C C ₆ alkylene-0-Ci-C ₆ alkyl) ₂ (e.g. -N(CH ₂ CH ₂ OMe) ₂ );

-N(Ci-C ₆ alkyl)(Ci-C ₆ alkylene-0-Ci-C ₆ alkyl) (e.g. -N(CH ₃ )(CH ₂ CH ₂ OMe));— 0-Ci-C ₆ alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-hexyl); -0-Ci-C ₆ haloalkyl (e.g., -OCF ₃ , -OCH ₂ CF ₃ ); -0-Ci-C ₆ alkylene-piperidine (e.g., -0-CH ₂ CH ₂ -l-piperidyl);

-N(Ci-C ₆ alkyl)C(0)OCi-C ₆ alkyl (e.g., -N(CH ₃ )C(0)0-CH ₂ CH(CH ₃ ) ₂ ),

-N(Ci-C ₆ alkyl)S0 ₂ Ci-C ₆ alkyl (e.g., -N(CH ₃ )S0 ₂ CH ₃ ); -S0 ₂ Ci-C ₆ alkyl (e.g., -S0 ₂ Me); -S0 ₂ Ci-C ₆ haloalkyl (e.g., -S0 ₂ CF ₃ ); or -S-Ci-C ₆ haloalkyl (e.g., SCF ₃ ). Also preferably R _M is -L _S -R _E where L _s is C C ₆ alkylene (e.g., -CH ₂ - -C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ -) and R _E is -0-R _s , -C(0)OR _s , -N(R _s )C(0)OR _s ', or -P(0)(OR _s ) ₂ . For example R _M is -Ci-C ₆ alkylene-0-R _s (e.g., -C(CH ₃ ) ₂ -CH ₂ -OMe); -Ci-C ₆ alkylene-C(0)OR _s (e.g., -C(CH ₃ ) ₂ -C(0)OMe);

-Ci-C ₆ alkylene-N(R _s )C(0)ORs' (e.g., -C(CH ₃ ) ₂ -CH ₂ -NHC(0)OCH ₃ ); or -Ci-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, Ci-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 '). For example R _M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-methylcycloprop-l -yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, l,l -dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4- methoxycarbonylpiperazin-l-yl, pyrrolidin-l-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 Ci-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, Q-Cealkyl, 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 '), and J can also be optionally substituted with one or more R _A . 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 RA, and J is C ₃ -Cecarbocycle 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or -N(R _S R _S '). 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 spiro bicycle comprising a nitrogen ring atom through which J is covalently attached to D) and is optionally substituted with one or more RA. More preferably, D is phenyl and is substituted with J and optionally substituted with one or more 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 RA, 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, Ci-C C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or

-N(R _S R _S '). Highly 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, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or

-N(R _S R _S '). 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 or 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 -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 '), and J can also be optionally substituted with one or more R _A . Also preferably, D is

, 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or -N(R _S R _S ').

X preferably is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyll and is optionally substituted with one or more RA. X can also be C3-Cscycloalkyl or C ₅ -Cscycloalkenyl which is optionally substituted with one or more RA, wherein two adjacent R _A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle. More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F , wherein two adjacent R _A on X, taken together with the ring atoms to which they are attached, optionally form a 5- to 6-membered carbocycle or heterocycle.

Non-limiting examples of preferred X include the following cyclopropyl rings, each of which is optionally substituted with one or more R _A or R _F : As shown, the relative stereochemistry at the any of the positions of the above cyclopropyl ring may be either cis or trans. The stereochemistries of optional substituents R _A or R _F at any of the positions of the cyclopropyl may vary relative to any substituent at any other position on the cyclopropyl ring. Depending on the particular substituents attached to the cyclopropyl, the stereochemistry at any carbon may be either (R) or (S).

Non-limiting examples of preferred X include the following cyclopentyl or cyclopentenyl rings, each of which is optionally substituted with one or more R _A or R _F :

As shown, the relative stereochemistry at the any of the positions of the above cyclopentyl ring may be either cis or trans. The stereochemistries of optional substituents R _A or R _F at any of the positions of the cyclopentyl or cyclopentenyl may vary relative to any substituent at any other position on the cyclopropyl ring. Depending on the particular substituents attached to the cyclopentyl or cyclopentenyl, the stereochemistry at any carbon may be either (R) or (S). Preferably, R _F is Ci-Cioalkyl, C ₂ -Cioalkenyl or C ₂ -Cioalkynyl, each of which contains 0, 1 , 2, 3, 4 or 5 heteroatoms selected from O, S or N and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Also preferably, R _F is Ci-Ci ₀ alkyl, C ₂ -Ci ₀ alkenyl or C ₂ -Cioalkynyl, each of which contains 0, 1 , 2, 3, 4 or 5 O and is independently optionally substituted with one or more R _L . Also preferably, R _F is -(R _X -RY)Q-(R _X -RY'), wherein Q is 0, 1 , 2, 3 or 4; each R _X is independently O, S or N(R _B ); each R _Y is independently Ci-C ₆ alkylene, C ₂ - Cealkenylene or C ₂ -C ₆ alkynylene each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano; and each R _Y ' is independently Ci-C ₆ alkyl,

C ₂ -C ₆ alkenyl or C ₂ -Cealkynyl each of which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Preferably, each R _X is O. More preferably, X is optionally substituted with one or more RA or R _F , each R _F is independently selected from Ci-Cioalkyl,

C ₂ -Cioalkenyl or C ₂ -Cioalkynyl, each of which contains 0, 1 , 2 or 3 O and is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano. Also preferably, X is optionally substituted with one or more R _A or R _F , each R _F is independently selected from

-(0-Ci-C ₆ alkylene)Q-(0-Ci-C ₆ alkyl), wherein Q preferably is 0, 1 , 2 or 3.

Li and L ₂ are preferably independently bond or Ci-C ₆ alkylene, L ₃ is preferably selected from bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . More preferably, Li, L ₂ and L ₃ are each independently a bond or Ci-Cealkylene (e.g., -CH ₂ - or -CH ₂ CH ₂ -), and are each independently optionally substituted with one or more R _L . Highly preferably, Li, L ₂ and L ₃ are each a bond.

Y is preferably selected from -L _S -C(RiR2)N(R ₅ )-T-R _D; -L _S -C(R ₃ R4)C(R ₆ R7)-T-RD,

-G-C(R ₁ R ₂ )N(R ₅ )-T-R _D; -G-C(R ₃ R4)C(R ₆ R ₇ )-T-R _D , -N(RB)C(0)C(R ₁ R ₂ )N(R ₅ )-T-R _D;

-N(R _B )C(0)C(R ₃ R ₄ )C(R ₆ R ₇ )-T-R _D , -C(0)N(R _B )C(R ₁ R ₂ )N(R ₅ )-T-R _D;

-C(0)N(RB)C(R ₃ R4)C(R6R ₇ )-T-RD, -N(R _B )C(0)-L _S -E, or -C(0)N(R _B )-L _S -E. G is C ₅ -C ₆ carbocycle

or 5- to 6-membered heterocycle, such as , and is optionally substituted with one or more RA (e.g., one or more chloro or bromo). E preferably is a 7-

wherein U is independently selected at each occurrence from -(CH ₂ )- or -(NH)-; V and Z ₂ o are each independently selected from Ci-C4alkylene,

C2-C4alkenylene or C2-C4alkynylene, in which at least one carbon atom can be independently optionally replaced with O, S or N), and is optionally substituted with one or more R _A . More preferably, Ri is Rc, and R2 and R ₅ , taken together with the atoms to which they are attached, form a

is optionally substituted with one or more R _A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C ₆ alkyl (e.g., methyl), or C ₂ -C ₆ alkenyl (e.g., allyl)); and R ₃ and R6 are each independently R _c , and R4 and R ₇ , taken together with the atoms to which they are attached, for carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., is optionally substituted with one or more R _A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C ₆ alkyl (e.g., methyl), or C ₂ -C ₆ alkenyl (e.g., allyl)).

Y can also be selected from -M-C(R ₁ R ₂ )N(R ₅ )-C(0)-LY'-M'-R _D ,

-M-C(R ₁ R ₂ )N(R5)-L _Y ' -M'-R _D , -L _S -C(R ₁ R2)N(R ₅ )-C(0)-L _Y '-M'-R _D , -L _S -C(R ₁ R ₂ )N(R ₅ )-L _Y '-M'-R _D , -M-C(R ₃ R4)C(R ₆ R ₇ )-C(0)-LY'-M'-R _D , -M-C(R3R4)C(R6R ₇ )-LY'-M'-R _D ,

-L _S -C(R ₃ R4)C(R ₆ R ₇ )-C(0)-LY'-M'-R _d , or -L _S -C(R ₃ R4)C(R ₆ R ₇ )-LY'-M'-R _d , wherein M preferably is bond, -C(0)N(R _B )- or -N(R _B )C(0)-, M' preferably is bond, -C(0)N(R _B )-, -N(R _B )C(0)- -N(R _B )C(0)0- N(R _B )C(0)N(R _B ')-, -N(R _B )S(0)- or -N(R _B )S(0) ₂ - and L _Y ' preferably is C Cealkylene which is optionally substituted with one or more R _L . L _Y ' is L _s ' . L _Y ', for example, is a

Ci-C ₆ alkylene such as, but not limited to, ^{' "} , , , , or and the optional R _L is a substituent such as, but not limited to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon within the group L _Y ' can be either (R) or (S). More preferably, Ri is Rc, and R2 and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A (e.g., one or more hydroxy); and R ₃ and R ₆ are each independently Rc, and R4 and R ₇ , taken together with the atoms to which they are attached, form a 5- to 6-membered

carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., is optionally substituted with one or more R _A .

Also preferably, Y is selected from -N(RB)CO-C(RIR2)N(R ₅ )-C(0)-LY'-N(RB)C(0)0-R _D , -N(RB)CO-C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y '-N(RB)C(0)-R _D ,

-N(RB)CO-C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y '-N(RB)S(0) ₂ -R _D ,

-N(RB)CO-C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y '-N(RBRB')-RD, -N(RB)CO-C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y '-0-R _D , -N(R _B )CO-C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y '-R _D , -N(RB)CO-C(R!R ₂ )N(R ₅ )-R _D ,

-L _S -C(RIR ₂ )N(R5)-C(0)-L _Y '-N(RB)C(0)0-RD, -L _S -C(RIR ₂ )N(R ₅ )-C(0)-L _Y '-N(RB)C(0)-RD, -L _S -C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y '-N(RB)S(0) ₂ -R _D , -L _S -C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y '-N(R _B RB')-RD, -L _S -C(R ₁ R ₂ )N(R5)-C(0)-L _Y '-0-R _D , -L _S -C(R ₁ R ₂ )N(R5)-C(0)-L _Y '-R _D , -L _S -C(R ₁ R ₂ )N(R ₅ )-RD, -N(RB)CO-C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-N(R _B )C(0)0-R _D ,

-N(RB)CO-C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-N(R _B )C(0)-R _D ,

-N(RB)CO-C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-N(R _B )S(0) ₂ -R _D ,

-N(RB)CO-C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-N(R _B RB')-RD, -N(RB)CO-C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-0-R _D , -N(RB)CO-C(R ₃ R ₄ )C(R ₆ R ₇ )-C(0)-L _Y '-R _D , -N(RB)CO-C(R ₃ R ₄ )C(R ₆ R ₇ )-R _D ,

-L _S -C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-N(RB)C(0)0-R _D , -L _S -C(R ₃ R ₄ )C(R ₆ R ₇ )-C(0)-L _Y '-N(RB)C(0)-R _D , -L _S -C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-N(RB)S(0) ₂ -R _D , -L _S -C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-N(R _B RB')-RD, -L _s -C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-0-R _D , -L _s -C(R ₃ R4)C(R ₆ R ₇ )-C(0)-L _Y '-R _D , or

-L _S -C(R ₃ R4)C(R ₆ R ₇ )-RD, wherein L _Y ' preferably is Ci-C ₆ alkylene which is optionally substituted with one or more R _L . Ri may be Rc, and R ₂ and R ₅ , taken together with the atoms to which they are

attached, may form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A ; and R ₃ and R6 may be each independently Rc, and R4 and R ₇ , taken together with the atoms to which they are attached, may form 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered bicycle (e is optionally substituted with one or more R _A .

Highly preferably, Y is selected from

-N(RB")CO-C(R ₁ R ₂ )N(R ₅ )-C(0)-L _Y -N(RB")C(0)-L _S -R _e or -C(RIR2)N(R ₅ )-C(0)-LY-N(RB")C(0)-L _S -R _e , or Y is -G-C(RIR ₂ )N(R5)-C(0)-LY-N(R _B ")C(0)-L _S -R _E , wherein L _Y is Q-Cealkylene optionally substituted with one or more R _L , and R _B " is each independently R _B . R _B " and Ri are each preferably hydrogen or Q-Cealkyl, and R2 and R ₅ , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or

6- to 12-membered bicycle (e.g., is optionally substituted with one or more R _A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C ₆ alkyl (e.g., methyl), or C ₂ -C ₆ alkenyl (e.g., allyl)). L _Y is each independently L _s . Preferably, L _Y is Ci-C ₆ alkylene substituted with one or more R _L such as a C3-Cecarbocycle 3- to 6-membered heterocycle which is 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, C2-C ₆ alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. Highly preferably, L _Y is a Ci-Cealkylene such

as, but not limited to, , , , ¹ , or (stereochemistry at a carbon within the group L _Y can be either (R) or (S)), L _Y is optionally substituted with one or more

H

R _L (e.g., one or more phenyl or methoxy), G preferably is NJ , R _B " is hydrogen;

-C(RiR ₂ )N(R ₅ )- is ; L _s is a bond; and R _E is methoxy.

wherein T and R _D are as defined herein. T, for example, can be -L _s -M-Ls'-M'-L _s "- w L _s is a bond; M is C( ' is Ci-Cealkylene such as, but not limited to, ,

, or , where L _s ' is optionally substituted with one or more R _L ; RL is a substituent such as, but not limited to phenyl or methoxy; M' is -NHC(O)- or -NMeC(O)-; and L _s " is a bond. Any stereochemistry at a carbon within the group L _s ' can be either (R) or (S). R _D , for example is

or T-RD may also include certain stereochemical configurations; thus T-R _D includes, but is not limited

-limiting examples of preferred Y also include:

Z is preferably selected from -L _S -C(R ₈ R9)N(R ₁₂ )-T-R _D , -L _s -C( ^' Ri ₀ Ri i)C(RuRi ₄ )-T-R _D , -G-C(R ₈ R ₉ )N(R ₁₂ )-T-R _D , -G-C(R ₁₀ Ri i)C(R ₁₃ R ₁₄ )-T-R _D , -N(R _B )C(0)C(R ₈ R ₉ )N(R ₁₂ )-T-R _D , -N(R _B )C(0)C(R ₁ oRn)C(R ₁₃ R ₁₄ )-T-R _D , -C(0)N(R _B )C(R ₈ R ₉ )N(R ₁₂ )-T-R _D , -C(0)N(R _B )C(R ₁ oRn)C(R ₁₃ R ₁₄ )-T-R _D , -N(R _B )C(0)-L _s -E, or -C(0)N(R _B )-L _s -E. G is or , and is optionally substituted with one or more R _A (e.g., one or more chloro or bromo).

E preferably is a 8- to 12-membered bicycle (such as wherein U is independently selected at each occurrence from -(CH ₂ )- or -(NH)-; and V and Z ₂₀ are each independently selected from Ci-C4alkylene, C2-C4alkenylene or C2-C4alkynylene, in which at least one carbon atom is independently optionally replaced with O, S or N), and is optionally substituted with one or more R _A . More preferably, R ₈ is Rc, and R9 and R12, taken together with the atoms to which they are attached,

R _A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C ₆ alkyl (e.g., methyl), or C ₂ -C ₆ alkenyl (e.g., allyl); and Rio and R13 are each independently R _c , and Rn and R14, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocycle/heterocycle or 6- to 12-membered

bicycle (e.g., is optionally substituted with one or more R _A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C ₆ alkyl (e.g., methyl), or C ₂ -C ₆ alkenyl (e.g., allyl)).

Z can also be selected from -M-C(R ₈ R ₉ )N(RI2)-C(0)-LY'-M'-RD, -M-C(R ₈ R ₉ )N(R ₁₂ )-L _Y '-M'-R _D , -L _S -C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-M'-R _D , -L _S -C(R ₈ R ₉ )N(R ₁₂ )-L _Y '-M'-R _D , -M-C(R ₁₀ R„)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-M'-R _D , -M-C(RioRn)C(Ri3Ri4)-L _Y '-M'-R] -L _S -C(R ₁₀ R„)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-M'-R _D , or -L _S -C(RIORII)C(RI ₃ RI4)-LY'-M'-RD, wherein M preferably is bond, -C(0)N(R _B )- or -N(R _B )C(0)-, M' preferably is bond, -C(0)N(R _B )-, -N(R _B )C(0)-, -N(R _B )C(0)0-, N(R _B )C(0)N(R _B ')-, -N(R _B )S(0)- or -N(R _B )S(0) ₂ -, and L _Y ' preferably is Ci-C ₆ alkylene which is optionally substituted with one or more R _L . L _Y ' is each independently L _S '. L _Y ', for example, is a Ci-C ₆ alkylene such as, but

not limited to, ' ^" , , , , or ; and the optional R _L is a substituent such as, but not limited to phenyl, -SMe, or methoxy. Any stereochemistry at a carbon within the group L _Y ' can be either (R) or (S). More preferably, R ₈ is Rc, and R ₉ and R12, taken together with the atoms to which they are attached, form a 5- to 6-membered heterocycle or 6- to 12-

membered bicycle (e.g., which is optionally substituted with one or more R _A (e.g., one or more hydroxy); and Rio and R13 are each independently Rc, and Rn and R _M , taken together with the atoms to which they are attached, form embered

carbocycle/heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A .

Also preferably, Z is selected from -N(R _B )CO-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B )C(0)0-R _D , -N(R _B )CO-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B )C(0)-R _D ,

-N(R _B )CO-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B )S(0) ₂ -R _D ,

-N(R _B )CO-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B R _B ')-R _D , -N(R _B )CO-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _y '-0-R _D ,

-N(R _B )CO-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-R _D , -N(R _B )CO-C(R ₈ R ₉ )N(R ₁₂ )-R _D ,

-L _s -C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B )C(0)0-R _D , -L _s -C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B )C(0)-R _D , -LS_-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B )S(0) ₂ -RD, -L _S -C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-N(R _B R _B ')-RD,

-L _s -C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-0-R _D , -L _s -C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y '-R _D , -L _S -C(R ₈ R ₉ )N(R ₁₂ )-R _D ,

-N(R _B )CO-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B )C(O)O-R _D ,

-N(R _B )CO-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B )C(O)-R _D ,

-N(R _B )CO-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B )S(O) ₂ -R _D ,

-N(R _B )CO-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B R _B ')-RD,

-N(R _B )CO-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-O-R _D , -N(R _B )CO-C(R ₁₀ R _n )C(R ₁₃ R ₁₄ )-C(O)-L _Y '-R _D ,

-N(R _B )CO-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-R _D , -L _s -C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B )C(O)O-R _D ,

-L _s -C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B )C(O)-R _D ,

-L _s -C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B )S(O) ₂ -R _D , -L _S -C(R ₁₀ R„)C(R ₁₃ R ₁₄ )-C(O)-L _Y '-N(R _B R _B ')-RD, -LS-C(RIORII)C(RI ₃ RI4)-C(0)-LY'-0-RD, -LS-C(RIORH)C(RI3RI4)-C(0)-LY'-RD, or

-L _s -C(RioRn)C(Ri ₃ Ri4)-R _D , wherein L _Y ' preferably is Ci-C ₆ alkylene which is optionally substituted with one or more R _L . Rs may be Rc, and Rg and R12, taken together with the atoms to which they are

attached, may form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e optionally substituted with one or more RA; and Rio and R13 may be each independently Rc, and Rn and R14, taken together with the atoms to which they are attached, may

or 6- to 12-membered bicycle or one or more RA.

Highly preferably, Z is selected from

-N(RB")CO-C(R ₈ R ₉ )N(R ₁₂ )-C(0)-L _Y -N(RB")C(0)-L _S -R _e or -C(R ₈ R ₉ )N(R ₁₂ )-C(0)-LY-N(RB")C(0)-LS-R _E , or Z is

-G-C(R8R9)N(R ₁₂ )-C(0)-LY-N(RB")C(0)-L _S -R _e , wherein L _Y is C C ₆ alkylene optionally substituted with one or more R _L , and R _B " is each independently R _B . RB" and R§ are each preferably hydrogen or Ci-C6alkyl, and R9 and R12, taken together with the atoms to which they are attached, preferably form

a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g.,

which is optionally substituted with one or more R _A (such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C ₆ alkyl (e.g., methyl), or C ₂ -C ₆ alkenyl (e.g., allyl)). L _Y is each independently L _s . Preferably, L _Y is Ci-C ₆ alkylene substituted with one or more R _L such as a C ₃ -C ₆ carbocycle 3- to 6- membered heterocycle which is 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloal or

C ₂ -C ₆ haloalkynyl. Highly preferably, L _Y is a Q-Cealkylene such as, but not limited to, , or (stereochemistry at a carbon within the group L _Y can be either (R) or (S)); L _Y is optionally substituted with one or more R _L (e.g., one or more phenyl or

methoxy); G preferably is ti N ; R _B " is hydrogen; -C(R ₈ R ₉ )N(Ri ₂ )- is ¹ ·™ v~ ; L _s is a bond; and R _E is methoxy. -limiting examples of preferred Z include:

wherein T and R _D are as defined herein. T, for example, can be -L _s -M-Ls'-M'-L _s "- where L _s is a bond; M is C( ' is Ci-Cealkylene such as, but not limited to, ,

, or , where L _s ' is optionally substituted with one or more R _L ; the optional R _L is a substituent such as, but not limited to phenyl or methoxy; M' is -NHC(O)- or -NMeC(O)-; and L _s " is a bond. Any stereochemistry at a carbon within the group L _s ' can be either (R) or (S). R _D , for

T-R _D may also include certain stereochemical configurations; thus T-RD includes, but is not limited Non-limitin examples of preferred Z also include:

T can be, without limitation, independently selected at each occurrence from -C(0)-L _s '-, -C(0)0-L _S '-, -C(0)-L _S '-N(RB)C(0)-L _S ' '-, -C(0)-L _S '-N(R _B )C(0)0-L _S "-, -N(RB)C(0)-L _S '-N(RB)C(0)-LS"-, -N(R _B )C(0)-L _S '— N(R _B )C(0)0-L _s "-, or -N(R _B )C(0)-L _s '-N(R _B )-L _s "-. Preferably, T is independently selected at each occurrence from -C(0)-L _s '-M'-L _s "- or -N(R _B )C(0)-L _s '-M'-L _s "-. More preferably, T is independently selected at each occurrence from -C(0)-L _S '-N(R _B )C(0)-L _S ' '- or -C(0)-L _S '-N(R _B )C(0)0-L _S ' '-.

T can also be, for example, -L _s -M-L _s '-M'-L _s "- where L _s is a bond; M is C(O); L _s ' is Ci-C ₆ alkylene (e.g., ), where L _s ' is optionally substituted with R _T ; the optional R _T is a substituent selected from -Ci-C ₆ alkyl, -C ₂ -C ₆ alkenyl, -Ci-C ₆ alkyl-OH, -Ci-C ₆ alkyl-0-Ci-C ₆ alkyl, 3- to 6-membered heterocycle (e.g., tetrahydrofuranyl), or C ₃ -C ₆ carbocyclyl (e.g., phenyl, cyclohexyl); M' is -NHC(O)-, -N(Et)C(0)- or -N(Me)C(0)-; and L _s " is a bond. R _D preferably is hydrogen, -Ci-C ₆ alkyl (e.g., methyl), -0-Ci-C ₆ alkyl (e.g., methoxy, tert-butoxy), methoxymethyl, or -N(Ci-C ₆ alkyl) ₂ (e.g., -NMe ₂ ).

T-RD can be either (R) or (S).

T can also be, without limitation, -L _s -M-L _s '- where L _s is a bond; M is C(O); L _s ' is

Ci-C ₆ alkylene (e.g., ) where L _s ' is optionally substituted with R _T ; the optional R _T is a substituent selected from -Ci-C ₆ alkyl, -Ci-C ₆ alkyl-OH, -Ci-C ₆ alkyl-0-Ci-C ₆ alkyl, or a C ₃ -C ₆ carbocyclyl (e.g., phenyl, cyclohexyl). R _D , for example is -OH; -OC(0)Me; -NH(Ci-C ₆ alkyl) (e.g., -NHMe, -NHEt); -N(Ci-C ₆ alkyl) ₂ (e.g., -NMe ₂ , -NEt ₂ ); a 3- to 10-membered heterocyclyl (e.g., pyrrolidinyl, imidazolidinyl, hexahydropyrimidinyl, mo holinyl, piperidinyl) optionally substituted with one or more halogen, oxo; C ₃ -Ci ₀ carbocycle (e.g., cyclopentyl) optionally substituted with -OH; -Ci-C ₆ alkyl (e.g., isopropyl, 3-pentyl) optionally substituted with -OH; or NHR _T where R _T is a 3- to 6-membered heterocyclyl (e.g., thiazolyl, pyrimidinyl). T-R _D includes, but is not limited to:

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

For each compound of Formula I, L _K can also be independently selected at each occurrence from a bond; -L _s '-N(R _B )C(0)-L _s -; -L _s '-C(0)N(R _B )-L _s -; or C C ₆ alkylene, C ₂ -C ₆ alkenylene, C ₂ -C ₆ alkynylene, C ₃ -Ci ₀ carbocycle or 3- to 10-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, R _T> -0-R _s , -S-R _s , -N(R _S R _S '), -OC(0)R _s , -C(0)OR _s , nitro, oxo, phosphonoxy, phosphono, thioxo, formyl or cyano, wherein Ls and Ls' are as defined above.

For Formula I as well as Formulae I _A , Ic, ID, IE, IF or I _G described below, including each and every embodiment described thereunder, R _A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-Cealkyl, C ₂ -Cealkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl 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, Ci-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 R _F ; or -L _A -0-R _s , -L _A -S-R _S , -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 'R _s "), -L _A -N(R _s )S0 ₂ R _s ', -L _A -S0 ₂ N(R _s Rs'), -L _A -N(Rs)S0 ₂ N(R _s 'Rs"), -L _A -N(R _s )S(0)N(R _s 'R _s "), -L _A -OS(0)-R _s , -L _A -OS(0) ₂ -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(R _s )C(0)-R _s ', wherein L _A is bond, Ci-Cealkylene, C ₂ -Cealkenylene or C ₂ -Cealkynylene.

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 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, Ci-Cealkyl, C ₂ -Cealkenyl, C ₂ -C6alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl C ₂ -C6haloalkynyl, C(0)OR _s or R _F . Highly preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 or cyano.

L _s , 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.

A and B can be the same or different. Likewise, Li and L ₂ , or Y and Z, or Y-A- and Z-B-, or -A-Li- and -B-L ₂ -, can be the same or different. In some instances, Y-A-Li- is identical to Z-B-L ₂ -. In some other instances, Y-A-Li- is different from Z-B-L ₂ -.

In one embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as \=/ ^¾ ), and are each independently optionally substituted with one or more R _A . X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more RA or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or is substituted with J and optionally substituted with one or more R _A , wherein 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 . Preferably, J 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 -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 '), J can also be optionally substituted with one or more

R _A . Preferably , wherein R _M and R _N are as defined above. Also

preferably, D is wherein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, Li, L ₂ , and L ₃ are bond. Y is -N(R _B )C(0)C(RiR ₂ )N(R ₅ )-T-R _D , or -N(R _B )C(0)C(R ₃ R4)C(R ₆ R ₇ )-T-RD, and Z is -N(R _B )C(0)C(R ₈ R ₉ )N(R ₁₂ )-T-R _D , or -N(R _B )C(0)C(RioRn)C(Ri ₃ Ri4)-T-RD. Ri is Rc, and R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic

ring (e.g., which is optionally substituted with one or more RA; R3 and R6 are each independently R _C , and R4 and R ₇ , taken together with the atoms to which they are attached, form a 5-

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

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

heterocyclic ring ( ch is optionally substituted with one or more R _A . T is preferably independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _s "- or -C(0)-L _Y '-N(R _B )C(0)0-L _s "-. L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . T can also be, without limitation, selected from -C(0)-L _Y '-L _s "-, -C(0)-L _Y '-0-L _s "-, -C(0)-L _Y '-N(R _B )-L _s "-, or -C(0)- '-N(R _B )S(0) ₂ -L _s "-. In some cases, at least one of Y and Z is,

or both Y and Z are independently, , wherein non-limiting examples of RD include (1) -0-Ci-C ₆ alkyl, -0-C ₂ -C ₆ alkenyl, -0-C ₂ -C ₆ alkynyl, 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, C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; or (2) C3-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, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -Cehaloalkynyl; and non-limiting examples of L _Y ' include Ci-C ₆ alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -0-Ci-C ₆ alkyl, -0-C ₂ -C ₆ alkenyl, -0-C ₂ -C ₆ alkynyl, or 3- to 6- membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C ₆ alkyl, C2-C ₆ alkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C ₆ haloalkynyl.

In another embodiment, A is nd is optionally substituted with one or more R _A ; B is or and is optionally substituted with one or more R _A . Zi is independently selected at each occurrence from O, S, NH or CH ₂ ; and Z ₂ is independently selected at each occurrence from N or CH. X is C ₃ -Cscycloalkyl or C ₅ -Cscycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or 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 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, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C2-C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C2-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 . Preferably, D is or , wherein R _M

and R _N are as defined above. Also preferably, D is wherein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and Li, L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L L ₂ , and L ₃ are bond. Y is -L _s -C(RiR ₂ )N(R ₅ )-T-R _D or -L _S -C(R ₃ R4)C(R ₆ R ₇ )-T-R _D , and Z is -L _S -C(R ₈ R ₉ )N(R ₁₂ )-T-R _D or -L _S -C(R ₁₀ H)C(RI3RI ₄ )-T-RD. Ri is Rc, and R2 and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6- membered heterocyclic ring (e.g., which is optionally substituted with one or more R _A ;

R ₃ and R6 are each independently R _c , and R4 and R ₇ , taken together with the atoms to which they are

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

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

heterocyclic ring (e.g., ch is optionally substituted with one or more R _A . T is preferably independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _s "- or -C(0)-L _Y '-N(R _B )C(0)0-L _s "-. L _Y ' is each independently L _s ' and, preferably, is independently Ci- C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . T can also be, without limitation, selected from -C(0)-L _Y '-L _s "-, -C(0)-L _Y '-0-L _s "-, -C(0)-L _Y '-N(R _B )-Ls"-, or -C(0)-L _Y '-N(R _B )S(0) ₂ -Ls"-. In some cases, at least one of Y and Z is,

or both Y and Z are independently, , wherein non-limiting examples of R -]D include (1) -0-Ci-C ₆ alkyl, -0-C ₂ -C ₆ alkenyl, -0-C ₂ -C ₆ alkynyl, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; or (2) C3-C6carbocycle or 3- to 6-membered heterocycle each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C ₆ alkyl, C ₂ -C6alkenyl, C ₂ -C6alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -Cehaloalkynyl; and non-limiting examples of L _Y ' include Ci-C ₆ alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -0-Ci-C ₆ alkyl, -0-C ₂ -C ₆ alkenyl, -0-C ₂ -C ₆ alkynyl, or 3- to 6- membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Q-Cealkyl, C2-C ₆ alkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C ₆ haloalkynyl.

In still yet another embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as and are each independently optionally substituted with one or more RA. X is C ₃ -Cscycloaikyl or C ₅ -Cscycloalkenyl and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D can be, for example, C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or 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 RA. Preferably, J 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 -C ₆ alkenyl, C2-C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C2-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 . Preferably, D is

s wherein R _M and R _N are as defined above. Also preferably, D is

herein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L L ₂ , and L ₃ are bond. Y is -G-C(RiR ₂ )N(R ₅ )-T-R _D or -G-C(R ₃ R4)C(R ₆ R ₇ )-T-RD, and Z is -G-C(R ₈ R ₉ )N(R ₁₂ )-T-R _D or -G-C(RIORH)C(RI ₃ RI4)-T-RD. G is independently C ₅ -C6carbocycle or 5- to 6-membered heterocycle, such as , and is independently optionally substituted with one or more R _A . Ri is Rc, and R2 and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6- membered heterocyclic ring (e.g., which is optionally substituted with one or more R _A ;

R ₃ and R6 are each independently R _c , and R4 and R ₇ , taken together with the atoms to which they are

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

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

heterocyclic ring (e.g., ch is optionally substituted with one or more R _A . T is preferably independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _s "- or -C(0)-L _Y '-N(R _B )C(0)0-L _s "-. L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . T can also be, without limitation, selected from -C(0)-L _Y '-L _s "-, -C(0)-L _Y '-0-L _s "-, -C(0)-L _Y '-N(R _B )-Ls"-, or -C(0)-L '-N(R _B )S(0) ₂ -Ls"-. In some cases, at least one of Y and Z is,

or both Y and Z are independently,

wherein non-limiting examples of R _D include (1) -O-Ci-Cealkyl, -0-C ₂ -C ₆ alkenyl, -0-C2-C ₆ alkynyl, 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, C ₃ -C ₆ carbocycle or 3- to 6- membered heterocycle; or (2) C3-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, 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; and non-limiting examples of L _Y ' include Ci-Cealkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -0-Ci-C ₆ alkyl, -0-C ₂ -C ₆ alkenyl, -0-C ₂ -C ₆ alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

In yet another embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (e.g., A and B are each independently phenyl, such as and are each independently optionally substituted with one or more R _A . X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D can be, for example, C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or 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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C2-C ₆ haloalkynyl, C(0)OR _S or -N(R _S R _S '), and J can also be

R _N are as defined above. Also preferably, D is or , wherein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, , L ₂ , and L ₃ are bond. Y is -N(R _B )C(0)C(RiR ₂ )N(R ₅ )-T-R _D or -N(RB)C(0)C(R ₃ R4)C(R6R7)-T-RD, and Z is -G-C(R ₈ R ₉ )N(Ri ₂ )-T-R _D or -G-C(RioRn)C(Ri ₃ Ri ₄ )-T-R _D ; or Y is -G-C(RiR ₂ )N(R ₅ )-T-R _D or -G-C(R ₃ R4)C(R ₆ R ₇ )-T-RD, and Z is -N(R _B )C(0)C(R ₈ R9)N(R ₁₂ )-T-R _D or -N(R _B )C(0)C(RioRn)C(Ri ₃ Ri4)-T-R _D . Ri is R _c , and R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic

ring (e.g., which is optionally substituted with one or more R _A ; R ₃ and R ₆ are each independently Rc, and R4 and R7, taken together with the atoms to which they are attached, form a 5-

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

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

heterocyclic ring ( ich is optionally substituted with one or more RA. independently C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle, such as

and is independently optionally substituted with one or more R _A . T is preferably independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _s "- or -C(0)-L _Y '-N(R _B )C(0)0-L _s "-. L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . T can also be, without limitation, selected from -C(0)-L _Y '-L _s "-, -C(0)-L _Y '-0-L _s "-, -C(0)-L _Y '-N(R _B )-L _s "-, or '-N(RB)S(0) ₂ -LS"-. In some cases, as described above,

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

is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as * \=) ). A and B are each independently optionally substituted with one or more R _A . Zi is independently selected at each occurrence from O, S, NH or CH ₂ ; and Z ₂ is independently selected at each occurrence from N or CH. X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or is substituted with J and optionally substituted with one or more R _A , wherein J is C3-C6carbocycle, 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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or '), and J can also be optionally substituted with one or more R _A . Preferably, D is

defined above. Also preferably, D is

above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L _u L ₂ , and L ₃ are bond. When A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as Y is -N(RB)C(0)C(R!R ₂ )N(R ₅ )-T-R _D , -N(R _b )C(0)C(R ₃ R4)C(R ₆ R ₇ )-T-R _D , -G-C(R!R ₂ )N(R ₅ )-T-R _d or -G-C(R ₃ R4)C(R6R ₇ )-T-R _D , and Z is -L _S -C(R ₈ R ₉ )N(R ₁₂ )-T-R _D or -L _S -C(R ₁₀ RH)C(RI3RI4)-T-RD.

When B is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl such as \==/ ^? ), Y is -L _S -C(R!R ₂ )N(R5)-T-R _D or -L _S -C(R ₃ R4)C(R ₆ R ₇ )-T-R _D , and Z is -N(R _B )C(0)C(R ₈ R ₉ )N(R ₁₂ )-T-R _D , -N(R _B )C(0)C(R ₁ oRn)C(R ₁₃ R ₁₄ )-T-RD, -G-C(R ₈ R ₉ )N(R ₁₂ )-T-R _D or -G-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-T-RD. Ri is Rc, and R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6-

membered heterocyclic ring (e.g., which is optionally substituted with one or more R _A ;

R ₃ and R6 are each independently R _c , and R4 and R ₇ , taken together with the atoms to which they are

attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., which is optionally substituted with one or more RA. R ₈ is Rc, and R ₉ and Ri ₂ , taken together with the atoms to

which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., which is optionally substituted with one or more RA; and Rio and Ri ₃ are each independently R _c , and Rn and Ri4, taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

heterocyclic ring (e.g., is optionally substituted with one or more RA. G is independently C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle, such as

and is independently optionally substituted with one or more R _A . T is preferably independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-Ls"- or -C(0)-L _Y '-N(R _B )C(0)0-Ls"-. L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . T can also be, without limitation, selected from -C(0)-L _Y '-L _s "-, -C(0)-L _Y '-0-L _s "-, -C(0)-L _Y '-N(R _B )-L _s "-, or -C(0)-L _Y '-N(R _B )S(0) ₂ -L _s "-. In some cases when A is 5- or 6-membered carbocycle or heterocycle

or as described above, and Z is as described above. In some other cases when B is 5- or 6-membered carbocycle or heterocycle e. . hen l such

described above.

The present invention also features compounds of Formulae I, I _A , ¾, Ic and I _D as described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:

D is C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle, and is optionally substituted with one or more RA; or D is C3-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 _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(Rs)C(0)N(R _s 'Rs"), -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(Rs)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)-R _s ', -S(0)N(R _s R _s '), -P(0)(OR _s ) ₂ , =C(R _S R _S '), 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 C3-Ci2carbocycle or 3- to 12- membered heterocycle (e.g., 7- to 12-membered carbocycle or heterocycle), each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, trimethylsilyl, Ci-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, -0-R _s , -S-R _s , -C(0)R _s , -C(0)OR _s , or -N(R _S R _S ').

In one embodiment, A and B are each independently 5- or 6-membered carbocycle or heterocycle (preferably, A and B are each independently phenyl such as and are each independently optionally substituted with one or more R _A (preferably, A and B are each independently substituted with at least one halo such as F). X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is a C ₅ -C6carbocycle 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-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle, or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more 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, Ci-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 '), or (2) trimethylsilyl, -0-R _S , -S-R _S , 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. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L _u L ₂ , and L ₃ are bond. Y is -N(RB)C(0)C(RIR ₂ )N(R ₅ )-T-R _D , -N(R _B )C(0)C(R ₃ R4)C(R ₆ R7)-T-RD, -G-C(RIR ₂ )N(R ₅ )-T-R _d or -G-C(R ₃ R4)C(R6R ₇ )-T-R _D . Z is -N(R _B )C(0)C(R ₈ R ₉ )N(R ₁₂ )-T-R _D ,

-N(R _B )C(0)C(R ₁ oRn)C(R ₁₃ R ₁₄ )-T-RD, -G-C(R ₈ R ₉ )N(R ₁₂ )-T-R _D or -G-C(R ₁₀ Rn)C(R ₁₃ R ₁₄ )-T-RD. Ri is Rc; and R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6- membered heterocyclic ring (e.g.,

which is optionally substituted with one or more R _A ; R3 and R6 are each independently R _C , and R4 and R ₇ , taken together with the atoms to which they are attached, form a 5- to 6-membered carbocyclic or

heterocyclic ring (e.g., - to 12-membered bicycle which is optionally substituted with one or more R _A . R _S is Rc; and R9 and R12, taken together with the atoms to which they are

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

(e.g., which is optionally substituted with one or more R _A ; and Rio and R13 are each independently R _c , and Rn and R14, taken together with the atoms to which they are attached, form a

5- to 6-membered carbocyclic or heterocyclic ring (e.g., or 6- to 12-membered bicycle which is optionally substituted with one or more R . G is independently C ₅ -C ₆ carbocycle or 5- to 6- membered heterocycle, such as and is independently optionally substituted with one or more R _A . T is preferably independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-Ls"- or -C(0)-L _Y '-N(R _B )C(0)0-L _s "-. L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . T can also be, without limitation, selected from -C(0)-L _Y '-L _s "-,

'-0-L _s "-, -C(0)-L _Y '-N(R _B )-L _s "-, or -C(0)-L _Y '-N(R _B )S(0) ₂ -L _s "-. In some cases, Y

escribed above, and Z is or as described above.

In another embodiment, A is nd is optionally substituted with one or more R _A ; B is and is optionally substituted with one or more R _A . Zi is independently selected at each occurrence from O, S, NH or CH ₂ ; and Z ₂ is independently selected at each occurrence from N or CH. Preferably, A and B are each independently substituted with at least one halo such as F. X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is a C ₅ -C ₆ 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-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more 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, Ci-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 '), or (2) trimethylsilyl, -0-R _s , -S-R _s , or -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. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and Li, L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, Li, L ₂ , and L ₃ are bond. Y is -L _S -C(RiR ₂ )N(R ₅ )-T-R _D or -L _S -C(R ₃ R4)C(R ₆ R7)-T-RD. Z is -L _S -C(R ₈ R ₉ )N(R ₁₂ )-T-R _D or -L _s -C(RioRn)C(Ri3Ri4)-T-R _D . Ri is Rc; and R ₂ and R ₅ , taken together with the atoms to which they

are attached, to 6-membered heterocyclic ring (e.g., or 6- to 12-membered

bicycle (e.g., which is optionally substituted with one or more RA; R3 and R6 are each independently R _C , and R4 and R ₇ , taken together with the atoms to which they are attached, form a 5-

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

atoms to which they are attach a 5- to 6-membered heterocyclic ring (e.g., or 6-

to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A ; and

Rio and R13 are each independently R _c , and Rn and R14, taken together with the atoms to which they

are attached, form a 5- to 6-membered carbocyclic or heterocyclic ring (e.g., or 6- to

12-membered bicycle which is optionally substituted with one or more RA. T is preferably independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-Ls"- or -C(0)-L _Y '-N(R _B )C(0)0-L _s "-. L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . T can also be, without limitation, selected from -C(0)-L _Y '-L _s "-, -C(0)-L _Y '-0-L _s "-, '-N(R _B )-L _s "-, or -C(0)-L _Y '-N(R _B )S(0) ₂ -L _s "-. In some cases, Y and Z are independently wherein non-limiting examples of R _D include (1)

-0-Ci-C ₆ alkyl, -0-C ₂ -C ₆ alkenyl, -0-C ₂ -C ₆ alkynyl, 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, C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; or (2) 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, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C ₆ haloalkynyl; and non-limiting examples of L _Y ' include Ci-C ₆ alkylene optionally substituted with halogen, hydroxy, mercapto, amino, carboxy, phosphonoxy, -0-Ci-C ₆ alkyl, -0-C ₂ -C ₆ alkenyl, -0-C ₂ -C ₆ alkynyl, or 3- to 6-membered carbocycle or heterocycle, said 3- to 6-membered carbocycle or heterocycle being optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C ₆ haloalkynyl.

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

IA

wherein:

R _N B is each independently selected from R _B ;

Rc' is each independently selected from R _c ;

R _D ' is each independently selected from R _D ;

R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ;

R ₉ and R ₁₂ , taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ;

A, B, D, X, Li, L ₂ , L ₃ , T, R _A , RB, RC, and R _D are as described above in Formula I.

In this aspect, A and B preferably are independently selected from C ₅ -C ₆ carbocycle or 5- to 6- membered heterocycle, and are each independently optionally substituted with one or more R _A . More preferably, at least one of A and B is phenyl (e.g., and is optionally substituted with one or more R _A . Highly preferably, both A and B are each independently phenyl (e.g., \=/ ^¾ ), and are each independently optionally substituted with one or more RA.

D preferably is selected from C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, or 8- to 12- membered bicycles, and is optionally substituted with one or more RA. D can also be preferably selected from Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, and is optionally substituted with one or more R _L . More preferably, D is C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is substituted with one or more R _M , where R _M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L _S -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 RA. 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 RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l ,3]dioxol-5-yl, and is substituted with one or more R _M . Highly preferably, D

i _{s s an(} j j _s optionally substituted with one or more R _M .

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C ₂ -Cealkenyl, C ₂ -C6alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C6haloalkynyl. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C6alkynyl, 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 Ci-C ₆ alkyl which is independently 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 -R _E , wherein L _s is a bond or Ci-C ₆ alkylene, and R _E is -N(RsRs'), -0-R _s , -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 Rs', -S0 ₂ R _s , -SRs, 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) Ci-Cealkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -O-Q-Cealkyl or 3- to 6-membered heterocycle; or R _M is 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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, -C(0)OR _s , or -N(R _S R _S '). More preferably, R _M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-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 ) ₂ -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 L _s is a bond and R _E is -N(R _S R _S ), -0-R _s , -N(R _s )C(0)OR _s ', -N(R _s )S0 ₂ R _s ', -S0 ₂ R _s , or -SR _S . For example where L _s is a bond, R _E is -N(Ci-C ₆ alkyl) ₂ (e.g., -NMe ₂ ); -N(Ci-C ₆ alkylene-0-Ci-C ₆ alkyl) ₂ (e.g. -N(CH ₂ CH ₂ OMe) ₂ );

-N(Ci-C ₆ alkyl)(Ci-C ₆ alkylene-0-Ci-C ₆ alkyl) (e.g. -N(CH ₃ )(CH ₂ CH ₂ OMe));— 0-Ci-C ₆ alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-hexyl); -0-C C ₆ haloalkyl (e.g., -OCF ₃ , -OCH ₂ CF ₃ ); -0-Ci-C ₆ alkylene-piperidine (e.g., -0-CH ₂ CH ₂ -l-piperidyl);

-N(Ci-C ₆ alkyl)C(0)OCi-C ₆ alkyl (e.g., -N(CH ₃ )C(0)0-CH ₂ CH(CH ₃ ) ₂ ), -N(Ci-C ₆ alkyl)S0 ₂ Ci-C ₆ alkyl (e.g., -N(CH ₃ )S0 ₂ CH ₃ ); -S0 ₂ Ci-C ₆ alkyl (e.g., -S0 ₂ Me); -S0 ₂ Ci-C ₆ haloalkyl (e.g., -S0 ₂ CF ₃ ); or -S-Ci-C ₆ haloalkyl (e.g., SCF ₃ ). Also preferably R _M is -L _S -R _E where L _s is Ci-C ₆ alkylene (e.g., -CH ₂ - -C(CH ₃ ) ₂ - -C(CH ₃ ) ₂ -CH ₂ -) and R _E is -0-R _s , -C(0)OR _s , -N(R _s )C(0)ORs', or -P(0)(OR _s ) ₂ . For example R _M is -Ci-C ₆ alkylene-0-R _s (e.g., -C(CH ₃ ) ₂ -CH ₂ -OMe); -Ci-C ₆ alkylene-C(0)OR _s (e.g., -C(CH ₃ ) ₂ -C(0)OMe);

-Ci-C ₆ alkylene-N(R _s )C(0)OR _s ' (e.g., -C(CH ₃ ) ₂ -CH ₂ -NHC(0)OCH ₃ ); or -Ci-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, Ci-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 '). For example R _M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-methylcycloprop-l -yl, cyclohexyl), phenyl, heterocyclyl (e.g., mo holin-4-yl, l,l -dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4- methoxycarbonylpiperazin-l-yl, pyrrolidin-l-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 Ci-Cealkyl which is independently 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, Ci-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 RA. 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 RA, and J is C ₃ -Cecarbocycle 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -N(R _S R _S '). 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 spiro 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 RA, and J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a 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, Ci-C C ₂ -C ₆ haloalkenyl, C2-C ₆ haloalkynyl, C(0)OR _S or

-N(R _S R _S '). Highly 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, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA, and preferably J is at least substituted with a 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, C2-C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C2-C ₆ haloalkynyl, C(0)OR _S or

-N(R _S R _S '). Also preferably, D is wherein each R _N is independently selected from R _D and preferably is hydrogen or halogen, and J is C3-C6carbocycle or 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-Cealkyl,

C ₂ -C ₆ alkenyl, C2-C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C2-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

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, C2-C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C2-C ₆ haloalkynyl, C(0)OR _s or -N(R _s R _s '). X preferably is C ₃ -Cscycloalkyl or C ₅ -Cscycloalkenyl and is optionally substituted with one or more R _A . More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl and is optionally substituted with one or more RA or R _F . Non-limiting examples of X are described hereinabove.

Li and L ₂ are preferably independently bond or Ci-C ₆ alkylene, L ₃ is preferably selected from bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . More preferably, L L ₂ and L ₃ are each independently bond or Ci-C ₆ alkylene (e.g., -CH ₂ - or -CH ₂ CH ₂ -), and are each independently optionally substituted with one or more R _L . Highly preferably, Li, L ₂ and L ₃ are each a bond.

R ₂ and R ₅ , taken together with the atoms to which they are attached, preferably form a 5- to 6-

membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A .

R ₉ and Ri ₂ , taken together with the atoms to which they are attached, preferably form a 5- to

6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A .

-T-RD' can be, without limitation, independently selected at each occurrence from -C(0)-L _Y '-R _D ', -C(0)0-L _Y '-R _D ', -C(0)-L _Y '-N(RB)C(0)-L _S "-R _D ' ,

-C(0)-L _Y ' -N(RB)C(0)0-L _S " -R _D ', -N(RB)C(0)-L _Y '-N(RB)C(0)-L _S "-R _D ', -N(R _B )C(0)-L _Y '-N(R _B )C(0)0-L _s "-R _D ', or -N(R _B )C(0)-L _Y '— N(R _B )-L _S "-R _D ', wherein L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . Preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-M'-L _s "-R _D ' or -N(R _B )C(0)-L _Y '-M'-L _s "-R _D '. More preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _s "-R _D ' or -C(0)-L _Y '-N(R _B )C(0)0-L _s "-R _D ' . Highly preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-R _D ' or -C(0)-L _Y '-N(R _B )C(0)0-R _D ', wherein L _Y ' preferably is each independently Ci-Cealkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L .

R _N B and Rc' are preferably hydrogen, and R _D ' preferably is independently selected at each occurrence from R _E . More preferably, R _D ' is independently selected at each occurrence from 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, C ₃ -C ₆ carbocycle or 3- to 6- membered heterocycle; or C3-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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C2-C ₆ haloalkynyl.

R _A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 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, 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; or -LA-O-RS, -LA-S-R _S , -LA-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 Rs, -LA-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 'R _S "), -L _A -N(R _S )S0 ₂ R _S ' , -LA-S0 ₂ N(R _S R _S '), -LA-N(R _S )S0 ₂ N(R _S 'R _S "), -LA-N(R _S )S(0)N(R _S 'R _S "), -LA-OS(0)-R _S , -LA-OS(0) ₂ -R _S , -LA-S(0) ₂ OR _S , -LA-S(0)OR _S , -LA-OC(0)OR _S , -LA-N(R _S )C(0)OR _S ' , -LA-OC(0)N(R _S R _S '), -LA-N(R _S )S(0)-R _S ', -LA-S(0)N(R _S R _S '), -LA-C(0)N(R _S )C(0)-R _s ', or -L _A -P(0)(OR _S ) ₂ , wherein L _A is bond, Ci-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 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 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, Ci-Cealkyl, C ₂ -Cealkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C ₆ haloalkynyl.

Highly preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 or cyano.

L _s , 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.

A and B can be the same or different. Likewise, Li and L ₂ can be the same or different. In one embodiment of this aspect, A and B are each independently phenyl, and are each independently optionally substituted with one or more R _A ; D is phenyl, and is optionally substituted with one or more R _A , or 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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -N(R _S R _S '), J can also be optionally substituted with one or more

R _A . Preferably, D is or , wherein R _M and R _N are as defined above. Also

preferably, D is wherein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-Cealkylene, and L ₃ is bond, Ci-Cealkylene or -C(O)-, and Li, L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, Li, L ₂ , and L ₃ are bond. -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(0)-LY'-N(RB)C(0)0-LS"-RD', wherein L _Y ' is C C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and L _s " preferably is bond. -T-R _D ' can also be, without limitation, selected from -C(0)-L _Y '-L _S "-R _D ', -C(0)-L _Y '-0-L _S "-R _D ', -C(0)-L _Y ' -N(R _B )-L _S "-R _D ' , or -C(0)-L _Y '-N(R _B )S(0) ₂ - "-R _D ' . Preferably, R ₂ and R ₅ , taken

together with the atoms to which they are attached, form which is optionally substituted with one or more R _A ; Rg and Ri ₂ , taken together with the atoms to which they are attached, form which is optionally substituted with one or more R _A . X is C ₃ -C ₈ cycloalkyl or C ₅ -Cscycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . ther embodiment of this aspect, A and B are each independently phenyl (e.g., and are each independently optionally substituted with one or more R _A (preferably, A and B are each independently substituted with at least one halo such as F). X is C ₃ -Cscycloalkyl or C5-C ₈ Cycloalkenyl and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more RA or R _F . D is 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-membered heterocycle, 6- to 12- membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more 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, Ci-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(RsRs'), or (2) trimethylsilyl, -0-R _s , -S-R _s or -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. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and Li, L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L L ₂ , and L ₃ are bond. -T-RD' is independently selected at each occurrence from -C(0)-LY' -N(R _B )C(0)-LS"-RD' or -C(0)-L _Y '-N(RB)C(0)0-L _S "-R _d ', wherein L _Y ' is C C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and L _s " preferably is bond. -T-R _D ' can also be, without limitation, selected from -C(0)-L _Y '-L _S "-R _D ' , -C(0)-L _Y '-0-L _S "-R _D ', -C(0)-L _Y '-N(R _B )-Ls"-R _D ', or -C(0)-L _Y '-N(R _B )S(0) ₂ -L _S "-R _D ' . R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic

ring (e.g., or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A ; and Rg and Ri ₂ , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g., or 6- to 12-membered bicycle

which is optionally substituted with one or more R _A .

In still another aspect, the present invention features compounds of Formula I _B and pharmaceutically acceptable salts thereof:

wherein:

R _c ' is each independently selected from R _c ;

R _D ' is each independently selected from R _D ;

R2 and R5, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ;

R ₉ and R12, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ;

A, B, D, X, Li, L ₂ , L ₃ , T, R _A , Rc, and R _D are as described above in Formula I.

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

bicycles such as or where Zi is independently selected at each occurrence from O, S, NH or CH ₂ ,

Z ₂ is independently selected at each occurrence from N or CH, Z ₃ is independently selected at each occurrence from N or CH, Z ₄ is independently selected at each occurrence from O, S, NH or CH ₂ , and Wi, W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are each independently selected at each occurrence from CH or N. A and B are each independently optionally substituted with one or more R _A . More preferably, A is selected from is

optionally substituted with one or more R _A ; B is selected from or d is optionally substituted with one or more R _A , where Zi, Z ₂ , Z ₃ , Z ₄ , Wi, W ₂ ,

W ₃ , W ₄ , W ₅ , W ₆ are as defined above. Preferably, Z ₃ is N and Z ₄ is NH. For instance, A can be

e.g., , an is wherein A' and B' are independently selected from

C5-C ₆ carbocycle or 5- to 6-membered heterocycle, and A and B are independently optionally substituted with one or more R _A .

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 Ci-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, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more R _M , where R _M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L _S -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 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 RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R _M . Highly preferably, D

i _{s s an(} j j _s optionally substituted with one or more R _M .

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C ₆ aikyl, 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, Ci-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C2-C6alkynyl, 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 Ci-C ₆ 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 -R _E , wherein L _s 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 Rs', -S0 ₂ R _s , -SRs, 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) Ci-C ₆ alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -Ο-Ci-Cealkyl or 3- to 6-membered heterocycle; or R _M is 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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, -C(0)OR _s , or -N(R _S R _S '). More preferably, R _M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-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 ) ₂ -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 L _s is a bond and R _E is -N(R _S R _S ), -0-R _s , -N(R _s )C(0)OR _s ', -N(R _s )S0 ₂ R _s ', -S0 ₂ R _s , or -SR _S . For example where L _s is a bond, R _E is -N(Ci-C ₆ alkyl) ₂ (e.g., -NMe ₂ ); -N(C C ₆ alkylene-0-Ci-C ₆ alkyl) ₂ (e.g. -N(CH ₂ CH ₂ OMe) ₂ ); -N(Ci-C ₆ alkyl)(Ci-C ₆ alkylene-0-Ci-C ₆ alkyl) (e.g. -N(CH ₃ )(CH ₂ CH ₂ OMe));— 0-Ci-C ₆ alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-hexyl); -0-C C ₆ haloalkyl (e.g., -OCF ₃ , -OCH ₂ CF ₃ ); -0-Ci-C ₆ alkylene-piperidine (e.g., -0-CH ₂ CH ₂ -l-piperidyl);

-N(Ci-C ₆ alkyl)C(0)OCi-C ₆ alkyl (e.g., -N(CH ₃ )C(0)0-CH ₂ CH(CH ₃ ) ₂ ),

-N(Ci-C ₆ alkyl)S0 ₂ Ci-C ₆ alkyl (e.g., -N(CH ₃ )S0 ₂ CH ₃ ); -S0 ₂ Ci-C ₆ alkyl (e.g., -S0 ₂ Me); -S0 ₂ Ci-C ₆ haloalkyl (e.g., -S0 ₂ CF ₃ ); or -S-Ci-C ₆ haloalkyl (e.g., SCF ₃ ). Also preferably R _M is -L _S -R _E where L _s is C C ₆ alkylene (e.g., -CH ₂ - -C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ -) and R _E is -0-R _s , -C(0)OR _s , -N(R _s )C(0)OR _s ', or -P(0)(OR _s ) ₂ . For example R _M is -Ci-C ₆ alkylene-0-R _s (e.g., -C(CH ₃ ) ₂ -CH ₂ -OMe); -Ci-C ₆ alkylene-C(0)OR _s (e.g., -C(CH ₃ ) ₂ -C(0)OMe);

-Ci-C ₆ alkylene-N(R _s )C(0)ORs' (e.g., -C(CH ₃ ) ₂ -CH ₂ -NHC(0)OCH ₃ ); or -Ci-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, Ci-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 '). For example R _M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-methylcycloprop-l -yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, l,l -dioxidothiomo holin-4-yl, 4-methylpiperazin-l-yl, 4- methoxycarbonylpiperazin-l-yl, pyrrolidin-l-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 Ci-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 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 . 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, Ci-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 RA. 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 RA, and J is C ₃ -Cecarbocycle 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -N(R _S R _S '). 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 spiro 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 RA, 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or

-N(R _S R _S '). Highly 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, 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or

-N(R _S R _S '). 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 or 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 -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 S'), and J can also be optionally substituted with one or more R _A . Also preferably, D is

, 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-Cealkyl, C ₂ -Cealkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or -N(R _S R _S ').

X preferably is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl and is optionally substituted with one or more R _A or R _F . Non-limiting examples of X are described hereinabove.

Li and L ₂ are preferably independently bond or Ci-C ₆ alkylene, L ₃ is preferably selected from bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . More preferably, L L ₂ and L ₃ are each independently bond or Ci-C ₆ alkylene (e.g., -CH ₂ - or -CH ₂ CH ₂ -), and are each independently optionally substituted with one or more R _L . Highly preferably, Li, L ₂ and L ₃ are each a bond. R2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-

membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA. R9 and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A .

-T-RD' can be, without limitation, independently selected at each occurrence from -C(0)-L _Y ' -R _D ', -C(0)0-L _Y '-R _D ' , -C(0)-L _Y '-N(RB)C(0)-L _S "-R _D ' ,

-C(0)-L _Y ' -N(RB)C(0)0-L _S " -R _D ', -N(RB)C(0)-L _Y '-N(RB)C(0)-L _S "-R _D ', -N(RB)C(0)-LY' -N(RB)C(0)0-L _S "-RD', or -N(R _B )C(0)-L _Y '— N(R _B )-L _S "-R _D ', wherein L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . Preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-M'-L _S "-RD' or -N(R _B )C(0)-L _Y '-M'-L _S "-RD'. More preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(0)-LY'-N(RB)C(0)0-LS"-RD' . Highly preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-R _D ' or -C(0)-L _Y '-N(R _B )C(0)0-R _D ', wherein L _Y ' preferably is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L .

R _C ' is preferably hydrogen, and R _D ' preferably is independently selected at each occurrence from R _E . More preferably, R _D ' is independently selected at each occurrence from Ci-Cealkyl, C2-C ₆ alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; 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, Ci-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C ₆ haloalkynyl.

R _A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C2-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, 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; or -L _A -0-R _s , -L _A -S-R _S , -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 'R _s "), -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"), -L _A -N(R _s )S(0)N(R _s 'R _s "), -L _A -OS(0)-R _s , -L _A -OS(0) ₂ -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 '), -L _A -C(0)N(R _s )C(0)-R _s ', or -L _A -P(0)(OR _s ) ₂ wherein L _A is bond, Ci-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 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 or cyano; or C3-C6carbocycle or 3- to 6-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C ₂ -Cealkenyl, C ₂ -C6alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C6haloalkynyl.

Highly preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 or cyano.

L _s , 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.

A and B can be the same or different. Likewise, Li and L ₂ can be the same or different.

In one embodiment of this aspect,

optionally substituted with one or more R _A ; B is optionally substituted with one or more R _A ; and D is C ₅ -C6carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or 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 which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Q-Cealkyl, 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 '), and J can also be optionally substituted with one or more R _A . Preferably, D is

s wherein R _M and R _N are as defined above. Also preferably, D is

_s wherein and R _N are as defined above. Zi is independently selected at each occurrence from O, S, NH or CH ₂ ; and Z ₂ is independently selected at each occurrence from N or CH. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, Li, L ₂ , and L ₃ are bond. -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(0)-L _Y '-N(R _B )C(0)0-L _S "-R _D ' , wherein L _Y ' is Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and Ls" preferably is bond. -T-RD' can also be, without limitation, selected from -C(0)-L _Y ' -L _S " -R _D ', -C(0)-L _Y '-0-L _S "-R _D ' , -C(0)-L _Y '-N(R _B )-L _S "-R _D ', or

-C(0)-L _Y ' -N(R _B )S(0) ₂ -L _S "-R _D ' . X is C ₃ -C ₈ cycloaikyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F .

More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F .

In another embodiment of this aspect, A is and optionally substituted

with one or more R _A (e.g., halogen); B is and is optionally substituted with one or more R _A (e.g., halogen); and D is C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or 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 which is independently optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C ₂ -Cealkenyl, C ₂ -Cealkynyl, Ci-Cehaloalkyl, C2-C6haloalkenyl, C2-C6haloalkynyl, C(0)ORs or -N(R _s Rs') _> ^an d J can also be

R _N are as defined above. Also preferably, D is or , wherein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L L ₂ , and L ₃ are bond. -T-R _D ' is independently selected at each occurrence from -C(0)-L '-N(R )C(0)-L "-R _d ' or -C(0)-L _Y '-N(R _B )C(0)0-L _S "-R _D ' , wherein L _Y ' is Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and Ls" preferably is bond. -T-R ' can also be, without limitation, selected from -C(0)-L _Y ' -L _S " -R _D ', -C(0)-L _Y '-0-L _S "-R _D ' , -C(0)-L _Y '-N(R _B )-L _S "-R _D ', or

-C(0)-L _Y ' -N(R _B )S(0) ₂ -L _S "-R R2 and R ₅ , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R R9 and Ri ₂ , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or

6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R preferably, R ₂ and R ₅ , taken together with the atoms to which they are

attached, form which is optionally substitut one or more R R9 and Ri ₂ , taken

together with the atoms to which they are attached, form which is optionally substituted with one or more R _A . X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F .

In still another embodiment of this aspect, A is and optionally substituted with one or more R _A (preferably, A is substituted with at least one halogen such as F); B is and is optionally substituted with one or more R _A (preferably, B is substituted with at least one halogen such as F). X is C ₃ -Cscycloalkyl or C ₅ -Cscycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is 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-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more 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, Ci-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 '), or (2) trimethylsilyl, -0-R _s , -S-R _s or -C(0)R _s ; and J can also be optionally substituted with one or more

R _A . Preferably, D is or , 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. Li and L ₂ are each independently bond or Ci-Cealkylene, and L ₃ is bond, Ci-Cealkylene or -C(O)-, and Li, L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, Li, L ₂ , and L ₃ are bond. -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(0)-LY'-N(RB)C(0)0-LS"-RD', wherein L _Y ' is C C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and L _s " preferably is bond. -T-R _D ' can also be, without limitation, selected from -C(0)-L _Y '-L _S "-R _D ', -C(0)-L _Y '-0-L _S "-R _D ', -C(0)-L _Y ' -N(R _B )-L _S "-R _D ', or -C(0)-L _Y '-N(R _B )S(0) ₂ -L _S "-R _D ' . R ₂ and R ₅ , taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12- membered bicycle (e.g., which is optionally substituted with one or more

RA- R9 and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-

membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA. More preferably, R2 and R ₅ , taken together with the

atoms to which they are attached, form which is optionally substituted with one or more

RA; R9 and R12, taken together with the atoms to which they are attache which is optionally substituted with one or more R _A .

In yet another aspect, the present invention further features compounds of Formula I _c and pharmaceutically acceptable salts thereof.

Ic

wherein:

R _C ' is each independently selected from R _C ;

R _D ' is each independently selected from R _D ;

R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ;

R ₉ and R12, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ; A, B, D, X, Li, L ₂ , L ₃ , T, R _A , RB, RC, and R _D are as described above in Formula I.

In this aspect, A preferably is C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle, and is optionally substituted with one or more R _A ; and B preferably is 8- to 12-membered bicycle (such as or and is optionally substituted with one or more

R _A . Zi is O, S, NH or CH ₂ ; Z ₂ is N or CH; Z ₃ is N or CH; Z ₄ is O, S, NH or CH ₂ ; and Wi, W ₂ , W ₃ , W ₄ , W ₅ and W ₆ are each independently selected from CH or N.

More preferably, A is phenyl (e.g., \=/ ), and is optionally substituted with one or

more R _A ; and and is optionally substituted with one or more R _A , where Zi, Z ₂ , Z ₃ , Z ₄ , Wi, W ₂ , W ₃ , W , W ₅ , W ₆ are as defined above. Preferably, Z ₃ is N

and is optionally substituted with one or more R _A .

Also preferably, A is C

membered heterocycle; and B is

from C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle. A and B are independently optionally substituted with one or more R _A .

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 Ci-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, 5- to 6-membered heterocycle, or 6- to 12-membered bicycles, and is substituted with one or more R _M , where R _M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L _S -RE. 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 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 RA. More preferably D is indanyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R _M . Highly preferably, D

i _{s s an(} j j _s optionally substituted with one or more R _M .

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C ₆ aikyl, 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, Ci-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C2-C6alkynyl, 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 Ci-C ₆ 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 -R _E , wherein L _s 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 Rs', -S0 ₂ R _s , -SRs, 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) Ci-C ₆ alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -Ο-Ci-Cealkyl or 3- to 6-membered heterocycle; or R _M is 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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, -C(0)OR _s , or -N(R _S R _S '). More preferably, R _M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-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 ) ₂ -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 L _s is a bond and R _E is -N(R _S R _S ), -0-R _s , -N(R _s )C(0)OR _s ', -N(R _s )S0 ₂ R _s ', -S0 ₂ R _s , or -SR _S . For example where L _s is a bond, R _E is -N(Ci-C ₆ alkyl) ₂ (e.g., -NMe ₂ ); -N(C C ₆ alkylene-0-Ci-C ₆ alkyl) ₂ (e.g. -N(CH ₂ CH ₂ OMe) ₂ ); -N(Ci-C ₆ alkyl)(Ci-C ₆ alkylene-0-Ci-C ₆ alkyl) (e.g. -N(CH ₃ )(CH ₂ CH ₂ OMe));— 0-Ci-C ₆ alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-hexyl); -0-C C ₆ haloalkyl (e.g., -OCF ₃ , -OCH ₂ CF ₃ ); -0-Ci-C ₆ alkylene-piperidine (e.g., -0-CH ₂ CH ₂ -l-piperidyl);

-N(Ci-C ₆ alkyl)C(0)OCi-C ₆ alkyl (e.g., -N(CH ₃ )C(0)0-CH ₂ CH(CH ₃ ) ₂ ),

-N(Ci-C ₆ alkyl)S0 ₂ Ci-C ₆ alkyl (e.g., -N(CH ₃ )S0 ₂ CH ₃ ); -S0 ₂ Ci-C ₆ alkyl (e.g., -S0 ₂ Me); -S0 ₂ Ci-C ₆ haloalkyl (e.g., -S0 ₂ CF ₃ ); or -S-Ci-C ₆ haloalkyl (e.g., SCF ₃ ). Also preferably R _M is -L _S -R _E where L _s is C C ₆ alkylene (e.g., -CH ₂ - -C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ -) and R _E is -0-R _s , -C(0)OR _s , — N(Rs)C(0)OR _s \ or -P(0)(OR _s ) ₂ . For example R _M is -C C ₆ alkylene-0-R _s (e.g., -C(CH ₃ ) ₂ -CH ₂ -OMe); -Ci-C ₆ alkylene-C(0)OR _s (e.g., -C(CH ₃ ) ₂ -C(0)OMe);

-Ci-C ₆ alkylene-N(R _s )C(0)ORs' (e.g., -C(CH ₃ ) ₂ -CH ₂ -NHC(0)OCH ₃ ); or -Ci-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, Ci-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 '). For example R _M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-methylcycloprop-l -yl, cyclohexyl), phenyl, heterocyclyl (e.g., mo holin-4-yl, l,l -dioxidothiomorpholin-4-yl, 4-methylpiperazin-l-yl, 4- methoxycarbonylpiperazin-l-yl, pyrrolidin-l-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 Ci-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 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 . 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, Ci-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 RA. 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 RA, and J is C ₃ -Cecarbocycle 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -N(R _S R _S '). 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 spiro 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 RA, 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or

-N(R _S R _S '). Highly 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, 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or

-N(R _S R _S '). 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 or 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 -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 S'), and J can also be optionally substituted with one or more R _A . Also preferably, D is

, 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-Cealkyl, C ₂ -Cealkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or -N(R _S R _S ').

X preferably is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl and is optionally substituted with one or more R _A or R _F . Non-limiting examples of X are described hereinabove.

Li and L ₂ are preferably independently bond or Ci-C ₆ alkylene, L ₃ is preferably selected from bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . More preferably, Li, L ₂ and L ₃ are each independently a bond or Ci-Cealkylene (e.g., -CH ₂ - or -CH ₂ CH ₂ -), and are each independently optionally substituted with one or more R _L . Highly preferably, Li, L ₂ and L ₃ are each a bond. Li and L ₂ can be the same or different. R2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-

membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA. R9 and R12, taken together with the atoms to which they are attached, preferably form a 5- to 6-membered heterocycle or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more R _A .

-T-RD' can be, without limitation, independently selected at each occurrence from -C(0)-L _Y '-R _D ', -C(0)0-L _Y '-R _D ', -C(0)-L _Y '-N(RB)C(0)-L _S "-R _D ' ,

-C(0)-L _Y ' -N(RB)C(0)0-L _S " -R _D ', -N(RB)C(0)-L _Y '-N(RB)C(0)-L _S "-R _D ', -N(RB)C(0)-LY' -N(RB)C(0)0-L _S "-RD', or -N(R _B )C(0)-L _Y '— N(R _B )-L _S "-R _D ', wherein L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . Preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-M'-L _S "-RD' or -N(R _B )C(0)-L _Y '-M'-L _S "-RD'. More preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _s "-R _D ' or -C(0)-LY'-N(RB)C(0)0-LS"-RD' . Highly preferably, -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-R _D ' or -C(0)-L _Y '-N(R _B )C(0)0-R _D ', wherein L _Y ' preferably is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L .

RNB and Rc' are preferably hydrogen, and R _D ' preferably is independently selected at each occurrence from R _E . More preferably, R _D ' is independently selected at each occurrence from 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, C ₃ -C ₆ carbocycle or 3- to 6- membered heterocycle; 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, 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.

R _A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 or cyano; or C3-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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl; or -L _A -0-R _s , -L _A -S-R _S , -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 'R _s "), -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"), -L _A -N(R _s )S(0)N(R _s 'R _s "), -L _A -OS(0)-R _s , -L _A -OS(0) ₂ -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 '), -L _A -C(0)N(R _s )C(0)-R _s ', or -L _A -P(0)(OR _s ) ₂ , wherein L _A is bond, Ci-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 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 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, Ci-Cealkyl, C ₂ -Cealkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C ₆ haloalkynyl.

Highly preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 or cyano.

L _s , L _s ' and L _s " preferably are each independently selected at each occurrence from bond; or Ci-C ₆ alkylene, C ₂ -Cealkenylene or C ₂ -C ₆ alkynylene.

In one embodiment of this aspect, A is phenyl, and is optionally substituted with one or more

R _A ; and B , and is optionally substituted with one or more R _A , wherein Z is O, S, NH or CH ₂ ; and Z ₂ is N or CH. D is C ₅ -C ₆ carbocycle or 5- to 6- membered heterocycle (e.g., phenyl), and is optionally substituted with one or more R _A , or 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 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, Ci-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 Rs') _> and J can also be optionally substituted with one or more R _A . Preferably, D is

s wherein R _M and R _N are as defined above. Also preferably, D is

herein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L L ₂ , and L ₃ are bond. -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(O)— L _Y '-N(R _B )C(0)0-L _S "-R _D ', wherein L _Y ' is C C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and L _s " preferably is bond. -T-R _D ' can also be, without limitation, selected from -C(0)-L _y '-0-L _S "-R _D ', -C(0)-L _Y '-N(R _B )-L _S "-R _D ', or -C(0)-L _Y '-N(R _B )S(0) ₂ "-R _D '. Preferably, R ₂ and R ₅ , taken

together with the atoms to which they are attached, form which is optionally substituted with one or more R _A ; R9 and Ri ₂ , taken together with the atoms to which they are attached, form which is optionally substituted with one or more R _A . X is C ₃ -C ₈ cycloalkyl or C ₅ - Cscycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F .

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

B is , and is optionally substituted with one or more R _A (preferably, B is substituted with at least one halogen such as F). X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is 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-membered heterocycle, 6- to 12-membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more 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, Ci-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 '), or (2) trimethylsilyl, -0-R _S , -S-R or -C 0 R and J can also be optionally substituted with one or more

R _A . Preferably, D is in J is as defined above, and each R _N is independently selected from R _D and preferably is hydrogen or halo such as F. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, Li, L ₂ , and L ₃ are bond. -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-LS"-RD' or -C(0)-L _Y '-N(R _B )C(0)0-L _S "-R _D ', wherein L _Y ' is C C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and L _s " preferably is bond. -T-R _D ' can also be, without limitation, selected from -C(0)-L _Y '-L _S "-R _D ', -C(0)-L _Y '-0-L _S "-R _D ', -C(0)-L _Y '-N(R _B )-L _S "-R _D ', or -C(0)-L _Y '-N(R _B )S(0) ₂ -L _S "-R _D '. Preferably, R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g., which is optionally substituted with r more R _A ; R9 and Ri ₂ , taken together with the atoms to which they are attached, form a 5- to 6-

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

which is optionally substituted with one or more R _A .

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

wherein:

Gi and G ₂ are each independently selected from C ₅ -C ₆ carbocycle or 5- to 6-membered heterocycle, and are each independently optionally substituted with one or more R _A ; R _c ' is each independently selected from R _c ;

R _D ' is each independently selected from R _D ;

R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ;

Rg and R12, taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A ;

A, B, D, X, Li, L ₂ , L ₃ , T, R _A , Rc, and R _D are as described above in Formula I.

In this aspect, A and B preferably are independently selected from C ₅ -C ₆ carbocycle or 5- to 6- membered heterocycle, and are each independently optionally substituted with one or more R _A . More preferably, at least one of A and B is phenyl (e.g., and is optionally substituted with one or more R _A . Highly preferably, both A and B are each independently phenyl (e.g., and are each independently optionally substituted with one or more R _A .

D preferably is selected from C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, or 8- to 12- membered bicycles, and is optionally substituted with one or more R _A . D can also be preferably selected from Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl, and is optionally substituted with one or more R _L . More preferably, D is C ₅ -C ₆ carbocycle, 5- to 6-membered heterocycle, or 6- to 12- membered bicycles, and is substituted with one or more R _M , where R _M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L _S -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 or , 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, indazolyl, or benzo[d][l,3]dioxol-5-yl, and is substituted with one or more R _M . Highly preferably, D

i _{s s an(} j j _s optionally substituted with one or more R _M .

Preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C ₆ aikyl, 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, Ci-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl. More preferably, R _M is halogen, hydroxy, mercapto, amino, carboxy; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C2-C6alkynyl, 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 Ci-C ₆ 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 -R _E , wherein L _s 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 Rs', -S0 ₂ R _s , -SRs, 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) Ci-C ₆ alkyl optionally substituted at each occurrence with one or more halogen, hydroxy, -Ο-Ci-Cealkyl or 3- to 6-membered heterocycle; or R _M is 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 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, -C(0)OR _s , or -N(R _S R _S '). More preferably, R _M is halogen (e.g., fluoro, chloro, bromo, iodo), hydroxy, mercapto, amino, carboxy, or Ci-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 ) ₂ -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 L _s is a bond and R _E is -N(R _S R _S ), -0-R _s , -N(R _s )C(0)OR _s ', -N(R _s )S0 ₂ R _s ', -S0 ₂ R _s , or -SR _S . For example where L _s is a bond, R _E is -N(Ci-C ₆ alkyl) ₂ (e.g., -NMe ₂ ); -N(C C ₆ alkylene-0-Ci-C ₆ alkyl) ₂ (e.g. -N(CH ₂ CH ₂ OMe) ₂ ); -N(Ci-C ₆ alkyl)(Ci-C ₆ alkylene-0-Ci-C ₆ alkyl) (e.g. -N(CH ₃ )(CH ₂ CH ₂ OMe));— 0-Ci-C ₆ alkyl (e.g., -O-Me, -O-Et, -O-isopropyl, -O-tert-butyl, -O-n-hexyl); -0-C C ₆ haloalkyl (e.g., -OCF ₃ , -OCH ₂ CF ₃ ); -0-Ci-C ₆ alkylene-piperidine (e.g., -0-CH ₂ CH ₂ -l-piperidyl);

-N(Ci-C ₆ alkyl)C(0)OCi-C ₆ alkyl (e.g., -N(CH ₃ )C(0)0-CH ₂ CH(CH ₃ ) ₂ ),

-N(Ci-C ₆ alkyl)S0 ₂ Ci-C ₆ alkyl (e.g., -N(CH ₃ )S0 ₂ CH ₃ ); -S0 ₂ Ci-C ₆ alkyl (e.g., -S0 ₂ Me); -S0 ₂ Ci-C ₆ haloalkyl (e.g., -S0 ₂ CF ₃ ); or -S-Ci-C ₆ haloalkyl (e.g., SCF ₃ ). Also preferably R _M is -L _S -R _E where L _s is C C ₆ alkylene (e.g., -CH ₂ - -C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ -CH ₂ -) and R _E is -0-R _s , -C(0)OR _s , -N(R _s )C(0)OR _s ', or -P(0)(OR _s ) ₂ . For example R _M is -Ci-C ₆ alkylene-0-R _s (e.g., -C(CH ₃ ) ₂ -CH ₂ -OMe); -Ci-C ₆ alkylene-C(0)OR _s (e.g., -C(CH ₃ ) ₂ -C(0)OMe);

-Ci-C ₆ alkylene-N(R _s )C(0)ORs' (e.g., -C(CH ₃ ) ₂ -CH ₂ -NHC(0)OCH ₃ ); or -Ci-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, Ci-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 '). For example R _M is cycloalkyl (e.g., cyclopropyl, 2,2-dichloro-l-methylcycloprop-l -yl, cyclohexyl), phenyl, heterocyclyl (e.g., morpholin-4-yl, l,l -dioxidothiomo holin-4-yl, 4-methylpiperazin-l-yl, 4- methoxycarbonylpiperazin-l-yl, pyrrolidin-l-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 Ci-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 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 . 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, Ci-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 RA. 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 RA, and J is C ₃ -Cecarbocycle 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or -N(R _S R _S '). 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 spiro 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 RA, 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _s or

-N(R _S R _S '). Highly 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, 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or

-N(R _S R _S '). 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 or 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 -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 S'), and J can also be optionally substituted with one or more R _A . Also preferably, D is

, 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-Cealkyl, C ₂ -Cealkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl, C ₂ -C ₆ haloalkynyl, C(0)OR _S or -N(R _S R _S ').

X preferably is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl and is optionally substituted with one or more R _A . More preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl and is optionally substituted with one or more R _A or R _F . Non-limiting examples of X are described hereinabove.

Li and L ₂ are preferably independently bond or Ci-C ₆ alkylene, L ₃ is preferably selected from bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . More preferably, L L ₂ and L ₃ are each independently bond or Ci-C ₆ alkylene (e.g., -CH ₂ - or -CH ₂ CH ₂ -), and are each independently optionally substituted with one or more R _L . Highly preferably, L L ₂ and L ₃ are bond. R2 and R5, taken together with the atoms to which they are attached, preferably form a 5- to 6-

membered heterocycle or 6- to 12-membered bicycle (e.g., which optionally substituted with one or more R _A .

R ₉ and R12, taken together with the atoms to which they are attached, preferably form a 5-

6-membered heterocycle or 6- to 12-membered bicycle (e

optionally substituted with one or more R _A . nd G ₂ preferably are each independently selected from

or , and are each independently optionally substituted with one or more

H

RA (e.g., one or more chloro or bromo). More preferably, Gi is N- (including any tautomer thereof), and G ₂ is (including any tautomer thereof), and each Gi and G ₂ is independently optionally substituted with one or more RA (e.g., one or more chloro or bromo).

-T-RD' can be, without limitation, independently selected at each occurrence from -C(0)-L _Y '-, -C(0)0-L _Y '-R _D ' , -C(0)-L _Y '-N(RB)C(0)-L _S "-R _D ', -C(0)-L _Y '-N(R _B )C(0)0-L _S "-R _D ',

-N(R _B )C(0)-L _Y '-N(R _B )C(0)-L _S "-R _] -N(R _B )C(0)-L _Y '— N(R _B )C(0)0-L _S "-R] or

-N(R _B )C(0)-L _Y '— (R _B )-L _S "-R _D ', wherein L _Y ' is each independently L _s ' and, preferably, is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L . Preferably, -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-M'-Ls"-R _D ' or -N(R _B )C(0)-L _Y '-M'-L _S "-R _D ' . More preferably, -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(0)-L _Y ' -N(RB)C(0)0-L _S "-RD'. Highly preferably, -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-R _D ' or -C(0)-L _Y '-N(R _B )C(0)0-R _D ', wherein L _Y ' preferably is each independently Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L .

R _C ' is preferably hydrogen, and R _D ' preferably is independently selected at each occurrence from R _E . More preferably, R _D ' is independently selected at each occurrence from Ci-Cealkyl, C2-C6alkenyl or C2-C6alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, C ₃ -C ₆ carbocycle or 3- to 6-membered heterocycle; 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, Ci-C6alkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

R _A preferably is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; or Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl or C2-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 -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, Ci-C ₆ alkyl, C2-C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -C ₆ haloalkynyl; or -L _A -0-R _s , -L _A -S-R _S , -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 'R _s "), -L _A -N(R _s )S0 ₂ R _s ', -L _A -S0 ₂ N(R _s R _s '), -L _A -N(R _s )S0 ₂ N(Rs'R _s "), -L _A -N(R _s )S(0)N(R _s 'R _s "), -L _A -OS(0)-R _s , -L _A -OS(0) ₂ -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)-R _s ', -L _A -S(0)N(R _s R _s ') -L _A -C(0)N(R _s )C(0)-R _s ', or -L _A -P(0)(OR _s )2, wherein L _A is bond, Ci-C ₆ alkylene, C ₂ -C ₆ alkenylene or C2-C ₆ alkynylene.

More preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 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, Ci-Cealkyl, C2-Cealkenyl, C2-C6alkynyl, Ci-Cehaloalkyl, C2-Cehaloalkenyl or C2-C6haloalkynyl.

Highly preferably, R _A is halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano; 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 or cyano.

L _s , 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 C2-C ₆ alkynylene. A and B can be the same or different. Likewise, Li and L ₂ can be the same or different.

In one embodiment of this aspect, A and B are each independently phenyl, and are each independently optionally substituted with one or more R _A ; D is phenyl, and is independently optionally substituted with one or more R _A , or 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 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, Ci-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 ; and Gi is N , G ₂ is , and each Gi and G ₂ is independently optionally substituted with one or more R _A (e.g., one or more chloro or bromo).

wherein

preferably, D is ein J and R _N are as defined above. Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, Li, L ₂ , and L ₃ are bond. -T-RD' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(0)-LY'-N(RB)C(0)0-LS"-RD', wherein L _Y ' is C C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and L _s " preferably is bond. -T-R _D ' can also be, without limitation, selected from -C(0)-L _Y '-L _S "-R _D ', -C(0)-L _Y '-0-L _S "-R _D ', -C(0)-L _Y ' -N(R _B )-LS"-RD', or -C(0)-L _Y '-N(R _B )S(0) ₂ "-RD'. Preferably, R ₂ and R ₅ , taken

together with the atoms to which they are attached, form which is optionally substituted with one or more R _A ; R ₉ and Ri ₂ , taken together with the atoms to which they are attached, form which is optionally substituted with one or more R _A . X is C ₃ -C ₈ cycloalkyl or C ₅ - Cscycloalkenyl and is optionally substituted with one or more RA. Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F .

ther embodiment of this aspect, A and B are each independently phenyl (e.g., and are each independently optionally substituted with one or more R _A (preferably, A and B are each independently substituted with at least one halogen such as F). X is C ₃ -Cscycloalkyl or C ₅ -Cscycloalkenyl and is optionally substituted with one or more R _A . Specific examples of X are described hereinabove. Preferably, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A or R _F . More preferably, X is cyclopropyl is and is optionally substituted with one or more R _A or R _F . D is 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-membered heterocycle, 6- to 12- membered bicycle, 10- to 15-membered tricycle or 13- to 15-membered carbocycle/heterocycle, and J is optionally substituted with one or more 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, Ci-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 '), or (2) trimethylsilyl, -0-R _s , -S-R _s or -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 inde endentl selected from R _D and preferably is hydrogen or halo such as F.

Gi is , and each Gi and G ₂ is independently optionally substituted with one or more R _A (e.g., one or more chloro or bromo). Li and L ₂ are each independently bond or Ci-C ₆ alkylene, and L ₃ is bond, Ci-C ₆ alkylene or -C(O)-, and L _u L ₂ , and L ₃ are each independently optionally substituted with one or more R _L . Preferably, L L ₂ , and L ₃ are bond. -T-R _D ' is independently selected at each occurrence from -C(0)-L _Y '-N(R _B )C(0)-L _S "-R _D ' or -C(0)-LY' -N(R _B )C(0)0-LS"-RD', wherein L _Y ' is Ci-C ₆ alkylene (e.g., -CH ₂ -) and optionally substituted with one or more substituents selected from R _L , and L _s " preferably is bond. -T-R _D ' can also be, without limitation, selected from -C(0)-L _Y '-L _S "-R _D ', -C(0)-L _Y '-0-L _S "-R _D ', -C(0)-LY' -N(R _B )-LS"-RD', or -C(0)-L _Y '-N(RB)S(0) ₂ -L _S "-RD'. Preferably, R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 5- to 6-membered heterocyclic ring (e.g.,

or 6- to 12-membered bicycle (e.g., which is optionally substituted with one or more RA; R9 and R12, taken together with the atoms to which they are attached, form a 5- to 6-

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

which is optionally substituted with one or more R _A .

In another aspect, the present invention features compounds having Formula I _E and pharmaceutically acceptable salts thereof,

D I

L ₃

I

Y— A— L— X— L ₂ — B— Z

wherein:

X is C ₃ -C ₈ cycloalkyl or C ₅ -C ₈ cycloalkenyl, and is optionally substituted with one or more R _A ; Li and L ₂ are each independently selected from bond or Ci-Cealkylene which is independently optionally substituted at each occurrence with one or more halo, hydroxy, -O-Ci-Cealkyl, or -0-Ci-C ₆ haloalkyl;

L ₃ is bond or Ci-C ₆ alkylene;

A and B are each independently phenyl, pyridinyl, thiazolyl, Zi is independently selected at each occurrence from O, S, NH or CH ₂ , Z ₃ is independently selected at each occurrence from N or CH, and Wi, W ₂ , and W ₃ are each independently selected at each occurrence from CH or N; A and B are each independently optionally substituted with one or more R _A .

D is C6-Ciocarbocycle or 5- to 12-membered heterocycle, each of which is optionally substituted with one or more R _M ;

Y is -T'-C(R ₁ R ₂ )N(R ₅ )-T-R _D ;

Z is -T'-C(R ₈ R ₉ )N(R ₁₂ )-T-R _D ;

Ri is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl or -0-Ci-C ₆ haloalkyl;

R ₂ and R ₅ are each independently hydrogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl or -0-Ci-C ₆ haloalkyl; or R ₂ and R ₅ , taken together with the atoms to which they are attached, form a 3- to 12- membered heterocycle which is optionally substituted with one or more R _A (e.g., 1, 2, 3, or 4 R _A );

R ₈ is hydrogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, or 3- to 6-membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl or -0-Ci-C ₆ haloalkyl;

R ₉ and R ₁₂ are each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, or 3- to 6- membered carbocycle or heterocycle, wherein each said 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl or -O-Ci-Cehaloalkyl; or R ₉ and R ₁₂ , taken together with the atoms to which they are attached, form a 3- to 12-membered heterocycle which is optionally substituted with one or more R _A (e.g., 1, 2, 3, or 4 R _A );

T is independently selected at each occurrence from bond or -C(0)-L _s '-;

T' is independently selected at each occurrence from bond, -C(0)N(R _B )-, -N(R _B )C(0)-, or 3- to 12-membered heterocycle, wherein said 3- to 12-membered heterocycle is independently optionally substituted at each occurrence with one or more R _A ;

R _D is each independently selected at each occurrence from hydrogen or R _A ;

R _A is independently selected at each occurrence from halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L _S -R _E ;

R _B and R _B ' are each independently selected at each occurrence from hydrogen; or Ci-C ₆ alkyl which is independently optionally substituted at each occurrence with one or more substituents selected from halogen or 3- to 6-membered carbocycle or heterocycle; or 3- to 6-membered carbocycle or heterocycle; wherein each 3- to 6-membered carbocycle or heterocycle in R _B or R _B ' is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, Ci-C ₆ alkyl, Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl, or -0-C C ₆ haloalkyl;

R _E is independently selected at each occurrence from -0-R _s , -S-Rs, -C(0)Rs, -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(Rs)C(0)N(R _s 'Rs"), -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(Rs)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)-R _s ', -S(0)N(R _s R _s '), -C(0)N(R _s )C(0)-R _s ', or =C(R _S 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 -Ci ₂ carbocycle or 3- to 12- membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C ₆ haloalkynyl; 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)Rs, -S0 ₂ Rs, -C(0)N(R _s Rs'), or -N(R _s )C(0)R _s '; or C ₃ -Ci ₂ carbocycle or 3- to 12- membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-Cehaloalkyl, C ₂ -Cehaloalkenyl or C ₂ -C ₆ haloalkynyl; is independently selected at each occurrence from bond; or Ci-C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -C ₆ alkynylene, each independently optionally substituted with halogen;

is independently selected at each occurrence from bond; or Ci-C ₆ alkylene, C ₂ -C ₆ alkenylene or C ₂ -Cealkynylene, each of which is independently optionally substituted at each occurrence with one or more R _L ;

Rs' and Rs" are each independently selected at each occurrence from hydrogen; Ci- Cealkyl, 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, -0-Ci-C ₆ alkyl, -0-Ci-C ₆ haloalkyl, 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 , 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, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl or C ₂ -Cehaloalkynyl;

s independently selected at each occurrence from: halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, SF ₅ , -N(R _S R _S '), -0-R _s , -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(R _s R _s '), -N(R _s )C(0)R _s ', -N(R _s )C(0)OR _s ', -N(R _s )S0 ₂ Rs', -S(0)R _s , -S0 ₂ R _s , -S(0)N(R _s R _s '), -SR _S , -Si(R _s ) 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 '), -0-R _s , -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(R _s R _s '), -N(R _s )C(0)R _s ', -N(R _s )C(0)OR _s ', -N(R _s )S0 ₂ Rs', -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 C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more R _G2 , and each R _G2 is independently selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phosphono, thioxo, formyl, cyano, Ci-Cealkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, Ci-C ₆ haloalkyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ haloalkynyl,

-0-R _s , -C(0)OR _s , -C(0)R _s , -N(R _S R _S '), or -L ₄ -G ₃ ;

L ₄ 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) ₂ - -S(O)-, -C(0)0- -OC(O)-, -OC(0)0- -C(0)N(R _B )-, -N(RB)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(RB)C(0)N(RB')- -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 R _G3 ; and

R _G3 is each independently, at each occurrence, halogen, -Ci-C ₆ alkyl, -C(0)Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl, -0-Ci-C ₆ haloalkyl, C ₃ -C ₆ carbocycle, or 3- to 6- membered heterocycle.

As described hereinabove for compounds of Formula I _E A and B are each phenyl, pyridinyl,

thiazolyl, or where Zi is independently selected at each occurrence from O, S,

NH or CH ₂ , Z ₃ is independently selected at each occurrence from N or CH, and Wi, W ₂ , and W ₃ are each independently selected at each occurrence from CH or N; A and B are each independently optionally substituted with one or more R _A . Pre thiazolyl (e

optionally substituted with one or more R _A .

Prefera thiazolyl (e.g.,

is optionally substituted with one or more R _A .

Highly preferably, both A and B are phenyl (e.g., both A and B are '); or A is

substituted with one or more R _A .

In certain embodiments of this aspect of the invention, A and B are substituted by one or more R _A , wherein each R _A is independently selected from halogen (e.g., fluoro, chloro), L _S -R _E (where L _S is bond and R _E is -Ci-C ₆ alkyl (e.g., methyl), -0-R _S (e.g., -0-Ci-C ₆ alkyl, -OCH ₃ ), or -Ci-C ₆ alkyl optionally substituted with one or more halogen (e.g., -CF ₃ )), or L _S -R _E (where L _S is Ci-C ₆ alkylene and R _E is -0-R _S (e.g., -Ci-C ₆ alk -0-Ci-C ₆ alkyl, -CH ₂ OCH ₃ )). For example, in certain

embodiments A is and B is as defined hereinabove. In certain other embodiments B is is as defined hereinabove. In

As described hereinabove for compounds of Formula I _E D 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); Ci-C ₆ alkyl (e.g., tert-butyl); Ci-C ₆ alkyl substituted with one or more halogen (e.g., CF ₃ ); -0-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., -0-CH ₂ CH ₂ OCH ₃ ); -0-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, l ,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 R _s wherein R _s is Ci-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, Ci-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, C ₂ -C ₆ haloalkynyl, -0-C C ₆ alkyl (e.g., -0-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), Ci-C ₆ alkyl (e.g., methyl), Ci-C ₆ haloalkyl (e.g., CF ₃ ), or -0-Ci-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 L ₄ -G ₃ and optionally substituted with one or more RG2 wherein L , G3 and RG2 are as defined herein. L ₄ , for example is a bond, a Ci-C ₆ alkylene (e.g., -CH ₂ - -CH ₂ CH ₂ -, -CH2CH2CH2-, etc.), -0-, or -S(0) ₂ -. G ₃ is for example a C ₃ -Ci ₂ carbocycle optionally substituted with one or more RG3- RG2 and R _G 3 are each independently at each occurrence halogen, -C(0)Ci-C ₆ alkyl, -Ci-C ₆ alkyl,

-Ci-Cehaloalkyl, -O-Ci-Cealkyl, or -O-Ci-Cehaloalkyl. In certain embodiments G2 is ,

wherein is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl) attached to the parent molecular moiety through a nitrogen atom and substituted with one or two L4-G3 and optionally substituted with one or more RG2- Thus, in

certain embodiments where L ₄ is a bond G ₂ is is optionally substituted with

R _G 2 and G ₃ is optionally substituted with R _G 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- 1 (2H)-yl, 4,4-diphenylpiperidin- 1 -yl, 4-acetyl-4-phenylpiperidin- 1 -yl, 4-(4- methoxyphenyl)piperidin-l -yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl, and wherein D can be further optionally substituted with one or more R _M (e.g., fluoro, chloro, methyl, methoxy).

In certain other embodiments of this as ect of the invention L i a -C6 alkylene, -0-, or

-S(0) ₂ - and G ₂ is substituted with R _G

and G ₃ is as define d 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 L ₄ -G ₃ and one or more RG2, wherein D is optionally substituted with one or more R _M

N

and R _M , L ₄ , G ₃ , and R _G 2 are as defined herein. In certain embodiments G ₂ is ^ , N

wherein '^ is a spiro, bridged, or fused bicyclic nitrogen-containing heterocycle (e.g., 3- azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azaspiro[2.5]oct-6-yl, octahydro-2H- isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l ,3-dihydro-2H-isoindol-2-yl, l ,4-dioxa-8-azaspiro[4.5]dec- 8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with G ₃ and one or more R _G2 . 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, l ,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 , -0-CF ₃ ,

-0-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) and Ci-C ₆ alkyl (e.g., methyl).

In certain embodiments, D is wherein R _M is fluoro, chloro, tert-butyl, -0-CH ₂ CH ₃ ,

-O-CF ₃ , -0-CH ₂ CHF ₂ , -0-CH ₂ CH ₂ OCH 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, 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, D is 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 Ci-C ₆ alkyl (e.g., methyl).

In certain embodiments, D is wherein G ₂ is pyridinyl (e.g., pyridin-2-yl), piperidin-1- yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l -yl, 2,6-dimethylpiperidin-l-yl, 4-(propan-2- yl)piperidin-l -yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin-l -yl, 4-(trifluoromethyl)piperidin-l - yl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l -yl, 2-oxopiperidin-l -yl, 3,3-dimethylazetidin-l -yl, or oxazolyl (e.g., l ,3-oxazol-2-yl) and D is optionally substituted by one or more additional R _M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C ₆ alkyl (e.g., methyl).

In another embodiment of this as ect of the invention, D is wherein Gi is N,

C-H, or C-R _M ; G ₂ 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 L ₄ -G ₃ and optionally substituted with one or more R _G2 ; L ₄ is a bond, Ci-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 RQ ₃ ; RG ₂ and RQ3 at each occurrence are each independently halogen, -C(0)Ci-Cealkyl, -Ci-Cealkyl, -Ci-Cehaloalkyl, -O-Ci-Cealkyl, 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

G3 is phenyl optionally substituted with one or two RG3; g is 0, 1, or 2; R _M is each independently

fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and and RG3 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 R _G 3; RMI is each independently hydrogen, fluoro, chloro, or methyl; and R _G 2 is an optional substituent as described herein. In another group of

compounds according to this embodiment, D is wherein L ₄ is Ci-C ₆ alkylene, -0-, or

-S(0) ₂ -; G ₃ is phenyl optionally substituted with one or two RG3; g is 0, 1 , or 2; R _M is each

independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and and R _G 3 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 wherein is a spiro, bridged, or fused bicyclic nitrogen- containing heterocycle (e.g., 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6- azaspiro[2.5]oct-6-yl, octahydro-2H-isoindol-2-yl, 3-azaspiro[5.5]undec-3-yl, l ,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl) attached to the parent molecular moiety through a nitrogen atom and optionally substituted with L ₄ -G ₃ and one or more R _G 2; L4 is a bond, Ci-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 G3 is optionally substituted with one or more RG3; RG2 and RG3 at each occurrence are each independently halogen, -C(0)Ci-C ₆ alkyl, -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl, or -0-Ci-C ₆ haloalkyl; 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 each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or

trifluoromethoxy; and as defined above. In a further subgroup of compounds D is

wherein R _M i 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, l ,3-dihydro-2H- isoindol-2-yl, l,4-dioxa-8-azaspiro[4.5]dec-8-yl). till another embodiment of this aspect of the invention, D is wherein is a monocyclic 4-8 membered nitrogen-containing heterocycle (e.g., azetidinyl, pyrrolidinyl, piperidinyl) substituted with one or more RG2, wherein R _G 2 at each occurrence is each independently halogen, -C(0)Ci-C ₆ alkyl, -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl, or -0-Ci-C ₆ haloalkyl; and R _M is each independently halogen, -Ci-C ₆ alkyl, -Ci-C ₆ haloalkyl, -0-Ci-C ₆ alkyl, or -0-Ci-C ₆ haloalkyl. In one group of compounds according to this embodiment, is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two RG2, wherein R _G 2 at each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or

trifluoromethyl; and R _M is 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- 1 -yl, 4-fluoropiperidin- 1 -yl, 3 ,5 -dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin- 1 - yl, 4-methylpiperidin-l -yl, 4-tert-butylpiperidin-l-yl, 2-oxopiperidin-l-yl, or 3,3-dimethylazetidin-l- yl-

In certain preferred embodiments of this aspect of the invention, X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R _A ; and Li, L ₂ , and L ₃ are each a bond. In another embodiment, X is cyclopropyl, cyclopentyl or cyclopentenyl, and Li and L ₂ are each methylene (i.e. -CH ₂ -), and L ₃ is a bond.

In compounds of Formula I _E , Y is-T'-C(RiR2)N(R ₅ )-T-R _D and Z is -T'-C(RSR9) (RI2)-T-RD; wherein T' , Ri, R ₂ , R5, Rs, R9, R12, T, and R _D are as defined herein.

Preferably Ri, R ₂ , R5, Rs, R9, and R12 are each independently hydrogen; Ci-C ₆ alkyl; or 3- to 6- membered carbocycle or heterocycle, wherein each 3- to 6-membered carbocycle or heterocycle is independently optionally substituted at each occurrence with one or more substituents selected from halogen or Ci-Cealkyl; wherein R ₂ and R ₅ , taken together with the atoms to which they are attached, optionally form a 3- to 12-membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R _A , and R ₉ and R12 taken together with the atoms to which they are attached, optionally form a 3- to 12- membered heterocycle which is substituted with 0, 1, 2, 3, or 4 R _A wherein R _A is as defined herein. In certain embodiments of this aspect of the invention, Ri is hydrogen and R2 and R5, taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (e.g.,

R _A is halogen (e.g., fluoro, chloro); cyano; L _S -R _E where L _s is a single bond and R _E is Ci-C ₆ alkyl (e.g., methyl, ethyl), -0-Ci-C ₆ alkyl (e.g., methoxy), or -0-Ci-C ₆ haloalkyl (e.g., trifluoromethoxy); or

K CH

L _S -R _E where L _s is a double bond and R _E is =C(R _s Rs') (e.g., H H ³ ). In a preferred embodim R ₅ , taken together with the atoms to which they are attached form a pyrrolidine

ring (i.e., substituted with 0 or 1 R _A wherein R _A is fluoro, methoxy, methyl, ethyl, or cyano. In another preferred embodi and R ₅ , taken together with the atoms to which they are

attached form a pyrrolidine ring (i.e.,

In certain other embodiments of this aspect of the invention, R ₈ is hydrogen and R9 and R12, taken together with the atoms to which they are attached form a 3- to 12-membered heterocycle (e.g.,

R _A wherein R _A is halogen (e.g., fluoro, chloro); cyano; L _S -R _E where L _S is a single bond and R _E is Ci-C ₆ alkyl (e.g., methyl, ethyl), -0-Ci-C ₆ alkyl (e.g., methoxy), or -0-Ci-C ₆ halo (e.g., trifluoromethoxy); or L _S -RE where L _S is a double bond and R _E is =C(R _S R _S ') (e.g., ^M , In a preferred embodime and R ₁₂ , taken together with the atoms to which they are attached form

a pyrrolidine ring (i.e., substituted with 0 or 1 R _A wherein R _A is fluoro, methoxy, methyl, ethyl, or cyano. In another preferred embodiment R ₉ and R ₁₂ , taken together with the atoms

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

As used herein, a chiral carbon in any rings formed by joining R ₂ and R ₅ or R ₉ and R ₁₂ may

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

and R ₅ or R ₉ and Ri ₂ preferably possesses the (S) stereochemistry

In this aspect of the invention, is independently selected at each occurrence from a bond, -C(0)N(R _B )-, -N(R _B )C(0)-, or 3- to 12-membered heterocycle, and wherein said 3- to 12-membered heterocycle is each independently optionally substituted at each occurrence with one or more RA, and R _A and R _B are as described herein. In particular, where T is -C(0)N(R _B )-, R _B can be hydrogen (i.e., is -C(0)N(H)-). In certain embodiments, T' is imidazolyl (i.e., , N— ) optionally substituted at each occurrence with one or more R _A wherein R _A is halogen (e.g., fluoro, chloro), Ci-Cealkyl (e.g., methyl, ethyl), or Ci-Cehaloalkyl (e.g., trifluoromethyl). In certain embodiments, is imidazolyl (i.e.,

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

In certain embodiments of this aspect of the inventio optionally substituted with one or more RA as described herein, or Y-A is and non-limiting examples of preferred Y, where T' is a bond, include: , wherein T and R _D are as defined herein. In certain embodiments of this aspect of the inventi optionally substituted with one or more R _A as described herein, or B

examples of preferred Z, where T' is a bond, include: .

wherein T and R _D are as defined herein.

T at each occurrence is independently a bond or -C(0)-L _s '-, wherein L _s ' is as defined

includes, but is not limited to, , or , where L _s ' is optionally substituted with one or more R _L ; and R _L is a substituent such as, but not limited to carbocycle (e.g., cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl), methoxy, or heterocycle (e.g., tetrahydrofuranyl, tetrahydropyranyl).

R _D is hydrogen or R _A wherein R _A is as defined herein. Thus R _D includes, but is not limited to, R _A wherein R _A is L _S -R _E , and L _S and R _E are as defined herein. Thus R _D includes, but is not limited to, LS-RE wherein L _S is a bond and R _E is-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', — N(R _s )S0 ₂ N(R _s 'Rs"), -N(R _s )S(0)N(R _s 'R _s "), -N(R _s )C(0)OR _s ', or -N(R _s )S(0)-R _s '; or C ₃ -Ci ₂ carbocycle or 3- to 12-membered heterocycle, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, hydroxy, cyano, Ci-C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or Ci-C ₆ haloalkyl.

In one embodiment of this aspect of the invention, R _D is L _S -R _E wherein L _S is a bond and R _E is -N(R _s )C(0)OR _s ' or 3- to 12-membered heterocycle (e.g., pyrrolidine, piperidine, azepanyl) wherein Rs and Rs' are as defined herein. For example RD is preferably LS-RE wherein Ls is a bond and RE is -N(H)C(0)OMe.

Thus according to the foregoing description T-R _D includes, but is not limited to:

etc.

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