WO2012083170A1 - Anti-viral compounds - Google Patents

Anti-viral compounds Download PDF

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Publication number
WO2012083170A1
WO2012083170A1 PCT/US2011/065501 US2011065501W WO2012083170A1 WO 2012083170 A1 WO2012083170 A1 WO 2012083170A1 US 2011065501 W US2011065501 W US 2011065501W WO 2012083170 A1 WO2012083170 A1 WO 2012083170A1
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Prior art keywords
optionally substituted
independently
occurrence
carbocycle
membered
Prior art date
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PCT/US2011/065501
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English (en)
French (fr)
Inventor
Allan C. Krueger
Warren M. Kati
William A. Carroll
John K. Pratt
Douglas K. Hutchinson
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Abbott Laboratories
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Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to MX2013006951A priority Critical patent/MX2013006951A/es
Priority to CN201180066574.3A priority patent/CN103354808B/zh
Priority to JP2013544826A priority patent/JP5906253B2/ja
Priority to EP11806100.1A priority patent/EP2651885A1/en
Priority to CA2819894A priority patent/CA2819894A1/en
Publication of WO2012083170A1 publication Critical patent/WO2012083170A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds effective in inhibiting replication of Hepatitis C virus ("HCV").
  • HCV Hepatitis C virus
  • the present invention also relates to compositions comprising these compounds and methods of using these compounds to treat HCV infection.
  • 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.
  • the present invention features compounds of Formulae I, I A , 3 ⁇ 4, 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.
  • 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.
  • 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.
  • 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.
  • the present invention features processes of making the compounds or salts of the invention.
  • the present invention features compounds having Formula I, and pharmaceutically acceptable salts thereof,
  • 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
  • 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
  • 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)-
  • 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 al
  • 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,
  • 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 ,
  • 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 -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 -Ce
  • 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,
  • 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 .
  • 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.
  • Z 3 is N and Z 4 is NH.
  • A can be selected from
  • both A and B are phenyl (e.g., both A and B ar Also highly preferably, 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 .
  • 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 .
  • 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
  • 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
  • D is , or , wherein is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • 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 .
  • D is , or , wherein is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • R N can also preferably be halo such as F.
  • D is also preferably indanyl, 4,5,6,7- tetrahydro
  • 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, C
  • 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.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • 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
  • 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 .
  • 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 .
  • 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
  • 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
  • -S-Ci-C 6 haloalkyl e.g., SCF 3
  • 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 .
  • 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 .
  • 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
  • -Ci-C 6 alkylene-P(0)(OR s ) 2 e.g., -CH 2 -P(0)(OEt) 2 ).
  • 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 ').
  • 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).
  • cycloalkyl e.g., cyclopropyl, 2,2-dichloro
  • 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 ).
  • 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
  • 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 .
  • 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 .
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phospho
  • 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
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • 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)
  • 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
  • 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.
  • 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 or 6- to 12-membered bicycle and is optionally substituted with one or more RA
  • 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
  • D is , wherein each R N is independently selected from
  • R D and preferably is hydrogen or halogen
  • 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
  • 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
  • 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
  • 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.
  • 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 :
  • 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.
  • the stereochemistry at any carbon may be either (R) or (S).
  • 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.
  • 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 .
  • 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,
  • 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.
  • X is optionally substituted with one or more R A or R F , each R F is independently selected from
  • 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)-
  • L u L 2 and L 3 are each independently optionally substituted with one or more R L .
  • 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 .
  • 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 is C 5 -C 6 carbocycle
  • E preferably is a 7-
  • 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 .
  • Ri is Rc, and R2 and R 5 , taken together with the atoms to which they are attached, form a
  • R 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)).
  • R A such as, but not limited to hydroxy, halo (e.g., fluoro), Ci-C 6 alkyl (e.g., methyl), or C 2 -
  • Y can also be selected from -M-C(R 1 R 2 )N(R 5 )-C(0)-LY'-M'-R D ,
  • 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).
  • 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 .
  • 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 ,
  • 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
  • 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 .
  • Y is selected from
  • 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)).
  • 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 .
  • 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.
  • R L is a Ci-Cealkylene 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, thio
  • L Y is optionally substituted with one or more
  • R L e.g., one or more phenyl or methoxy
  • G preferably is NJ
  • R B " is hydrogen
  • 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, ,
  • 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
  • T-RD may also include certain stereochemical configurations; thus T-R D includes, but is not limited
  • 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 8 R 9 )N(R 12 )-T-R D , -C(0)N(R B )C
  • 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)).
  • 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 RRON)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 hinder)C(R 13 R 14 )-C(O)-L Y '-M'-R D , or -L S -
  • 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 .
  • 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 ,
  • 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
  • Z is selected from
  • L Y is C C 6 alkylene optionally substituted with one or more R L
  • 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.,
  • L Y is each independently L s .
  • 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
  • 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
  • G preferably is ti N ;
  • R B " is hydrogen; -C(R 8 R 9 )N(Ri 2 )- is 1 ⁇ TM v ⁇ ;
  • L s is a bond; and
  • R E is methoxy.
  • preferred Z include:
  • 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, ,
  • 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 "-.
  • 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.,
  • stereochemistry at a carbon within the group T-RD can be either (R) or (S).
  • 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.
  • 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,
  • 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
  • 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.
  • 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.
  • Y-A-Li- is identical to Z-B-L 2 -.
  • Y-A-Li- is different from Z-B-L 2 -.
  • 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.
  • 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 .
  • 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
  • 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 .
  • 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
  • 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
  • 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-
  • RS is Rc, and R9 and R12, taken together with the atoms to which they are
  • 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 "-.
  • at least one of Y and Z is,
  • 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,
  • 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.
  • X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R A or R F .
  • 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 .
  • 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
  • D is or , wherein R M
  • 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
  • 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
  • RS is Rc, and R9 and R12, taken together with the atoms to
  • 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"-.
  • at least one of Y and Z is,
  • 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,
  • 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.
  • 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.
  • C 5 -C 6 carbocycle or 5- to 6-membered heterocycle e.g., phenyl
  • 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.
  • 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 .
  • D is
  • 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 .
  • 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
  • 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
  • RS is Rc, and R9 and R12, taken together with the atoms to
  • 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"-.
  • at least one of Y and Z is,
  • 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,
  • 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.
  • 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 .
  • C 5 -C 6 carbocycle or 5- to 6-membered heterocycle e.g., phenyl
  • 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.
  • 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 .
  • , 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
  • 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
  • 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
  • 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
  • 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-
  • RS is Rc, and R9 and R12, taken together with the atoms to which they are
  • 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
  • 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,
  • A is 5- or 6-membered carbocycle or heterocycle (e.g., phenyl
  • 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.
  • X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R A or R F .
  • 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 .
  • 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 .
  • D is
  • D is
  • 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 .
  • L u L 2 , and L 3 are bond.
  • 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.
  • 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
  • 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
  • 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
  • R 8 is Rc, and R 9 and Ri 2 , taken together with the atoms to
  • 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
  • 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 "-.
  • A is 5- or 6-membered carbocycle or heterocycle
  • B is 5- or 6-membered carbocycle or heterocycle e. . hen l such
  • the present invention also features compounds of Formulae I, I A , 3 ⁇ 4, 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 ,
  • 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.
  • X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more R A or R F .
  • 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 .
  • 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 .
  • D is
  • 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 .
  • 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 ,
  • 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.,
  • 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
  • R A (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 "-,
  • 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.
  • 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.
  • 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 .
  • J is substituted with a C 3 -C 6 carbocycle, 3- to 6-membered heterocycle, 6- to 12-membered bicycle or 7- to
  • 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 .
  • 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
  • 6-membered heterocyclic ring e.g., or 6- to 12-membered
  • 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-
  • 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
  • Rio and R13 are each independently R c , and Rn and R14, taken together with the atoms to which they
  • 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 "-.
  • Y and Z are independently wherein non-limiting examples of R D include (1)
  • the present invention features compounds of Formula IA and pharmaceutically acceptable salts thereof.
  • 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.
  • 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 .
  • 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 .
  • R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • 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.
  • D is wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • 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
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • 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.
  • 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 .
  • 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 .
  • 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 .
  • D is indanyl, 4,5,6,
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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 substituent
  • 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 .
  • 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 .
  • 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 ).
  • 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 .
  • 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 .
  • 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);
  • 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 ').
  • 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).
  • cycloalkyl e.g., cyclopropyl, 2,2-dichlor
  • 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 ).
  • 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
  • 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 .
  • 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.
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phospho
  • 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
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • 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(
  • 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
  • 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 .
  • D is phenyl and is substituted with J and optionally substituted with one or more RA
  • J is C3-C6carbocycle, 3- to 6-membered heterocycle or 6- to 12-membered bicycle and is optionally substituted with one or more RA
  • 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
  • D is wherein each R N is independently selected from
  • R D and preferably is hydrogen or halogen
  • 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
  • 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
  • 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,
  • 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)-
  • L u L 2 and L 3 are each independently optionally substituted with one or more R L .
  • 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 .
  • 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 ' ,
  • 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-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 ' .
  • -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,
  • 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
  • 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
  • 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.
  • Li and L 2 can be the same or different.
  • 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 .
  • 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 is or , wherein R M and R N are as defined above. Also
  • 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 .
  • 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 ' .
  • R 2 and R 5 taken
  • 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.
  • 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 .
  • 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.
  • 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 .
  • 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
  • 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 .
  • 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
  • the present invention features compounds of Formula I B and pharmaceutically acceptable salts thereof:
  • 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.
  • 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
  • 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
  • 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.
  • Z 3 is N and Z 4 is NH.
  • A can be
  • 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 .
  • 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 .
  • 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.
  • 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
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • 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.
  • 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 .
  • 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 .
  • 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 .
  • R M is substituted with one or more R M .
  • 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
  • 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.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • 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
  • 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.
  • 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 substituent
  • 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 .
  • 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 .
  • 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(Ci-C 6 alkyl)C(0)OCi-C 6 alkyl e.g., -N(CH 3 )C(0)0-CH 2 CH(CH 3 ) 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
  • -S-Ci-C 6 haloalkyl e.g., SCF 3
  • 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 .
  • 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 .
  • 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
  • -Ci-C 6 alkylene-P(0)(OR s ) 2 e.g., -CH 2 -P(0)(OEt) 2 ).
  • 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 ').
  • 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).
  • cycloalkyl e.g., cyclopropyl, 2,2-d
  • 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 ).
  • 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
  • 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 .
  • 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.
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phospho
  • 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
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • 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(
  • 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
  • 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 .
  • 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 or 6- to 12-membered bicycle and is optionally substituted with one or more RA
  • 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
  • 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
  • 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
  • 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)-
  • L u L 2 and L 3 are each independently optionally substituted with one or more R L .
  • 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 .
  • 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 ' ,
  • 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-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' .
  • -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-
  • 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 -
  • 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
  • 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.
  • Li and L 2 can be the same or different.
  • 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 .
  • D is
  • 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 .
  • 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
  • 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 .
  • X is cyclopropyl is and is optionally substituted with one or more R A or R F .
  • A is and optionally substituted
  • R A e.g., halogen
  • B is and is optionally substituted with one or more R A (e.g., halogen)
  • 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 .
  • 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 .
  • 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
  • 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
  • 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.
  • 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 .
  • 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 .
  • 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 .
  • 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
  • R A 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 .
  • 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-
  • the present invention further features compounds of Formula I c and pharmaceutically acceptable salts thereof.
  • 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.
  • 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
  • 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 ;
  • Wi, W 2 , W 3 , W 4 , W 5 and W 6 are each independently selected from CH or N.
  • R A is N
  • A is C
  • 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 .
  • 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.
  • 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.
  • 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
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • 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.
  • 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 .
  • 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 .
  • 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 .
  • R M is substituted with one or more R M .
  • 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
  • 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.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • 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
  • 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.
  • 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 substituent
  • 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 .
  • 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 .
  • 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(Ci-C 6 alkyl)C(0)OCi-C 6 alkyl e.g., -N(CH 3 )C(0)0-CH 2 CH(CH 3 ) 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
  • -S-Ci-C 6 haloalkyl e.g., SCF 3
  • 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 .
  • 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 .
  • 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
  • -Ci-C 6 alkylene-P(0)(OR s ) 2 e.g., -CH 2 -P(0)(OEt) 2 ).
  • 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 ').
  • 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).
  • cycloalkyl e.g., cyclopropyl, 2,2-dichlor
  • 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 ).
  • 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
  • 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 .
  • 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.
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phospho
  • 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
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • 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(
  • 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
  • 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 .
  • 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 or 6- to 12-membered bicycle and is optionally substituted with one or more RA
  • 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
  • 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
  • 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
  • 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)-
  • L u L 2 and L 3 are each independently optionally substituted with one or more R L .
  • 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 .
  • Li, L 2 and L 3 are each a bond.
  • Li and L 2 can be the same or different.
  • 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 ' ,
  • 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-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' .
  • -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,
  • 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
  • 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
  • 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.
  • 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 is optionally substituted with one or more
  • 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 .
  • D is
  • 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 .
  • 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 '.
  • R 2 and R 5 taken
  • 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.
  • 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 .
  • 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.
  • 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 .
  • 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 substituents selected from (1) halogen
  • 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 .
  • 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 '.
  • 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.,
  • 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.,
  • the present invention features compounds of Formula pharmaceutically acceptable salts thereof.
  • 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.
  • 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 .
  • 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 .
  • R M is halogen, nitro, oxo, phosphonoxy, phosphono, thioxo, cyano, or -L S -R E .
  • 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.
  • D is or , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • 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
  • D is , wherein R M is as defined above, and each R N is independently selected from R D and preferably is hydrogen.
  • 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 .
  • 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 .
  • 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 .
  • 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 .
  • R M is substituted with one or more R M .
  • 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
  • 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.
  • R M is Ci-C 6 alkyl which is optionally substituted with one or more substituents selected from halogen, hydroxy, mercapto, amino or carboxy.
  • 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
  • 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.
  • 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 substituent
  • 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 .
  • 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 .
  • 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(Ci-C 6 alkyl)C(0)OCi-C 6 alkyl e.g., -N(CH 3 )C(0)0-CH 2 CH(CH 3 ) 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
  • -S-Ci-C 6 haloalkyl e.g., SCF 3
  • 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 .
  • 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 .
  • 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
  • -Ci-C 6 alkylene-P(0)(OR s ) 2 e.g., -CH 2 -P(0)(OEt) 2 ).
  • 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 ').
  • 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).
  • cycloalkyl e.g., cyclopropyl, 2,2-d
  • 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 ).
  • 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
  • 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 .
  • 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.
  • substituents selected from halogen, hydroxy, mercapto, amino, carboxy, nitro, oxo, phosphonoxy, phospho
  • 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
  • J is C 3 -Cecarbocycle or 3- to 6-membered heterocycle and is optionally substituted with one or more R A
  • 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(
  • 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
  • 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 .
  • 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 or 6- to 12-membered bicycle and is optionally substituted with one or more RA
  • 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
  • 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
  • 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
  • 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)-
  • L u L 2 and L 3 are each independently optionally substituted with one or more R L .
  • 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 .
  • 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-
  • nd G 2 preferably are each independently selected from
  • RA e.g., one or more chloro or bromo
  • 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 ',
  • 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-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 ' .
  • -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'.
  • -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, C 3
  • 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
  • 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
  • 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
  • a and B can be the same or different.
  • Li and L 2 can be the same or different.
  • 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 .
  • 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).
  • substituents selected from halogen, hydroxy,
  • 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 .
  • 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'.
  • R 2 and R 5 taken
  • 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.
  • 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 .
  • 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.
  • 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 .
  • 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,
  • 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 .
  • 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'.
  • 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.,
  • 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.,
  • the present invention features compounds having Formula I E and pharmaceutically acceptable salts thereof,
  • 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 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 );
  • 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
  • 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, phospho
  • 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
  • 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,
  • 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 ;
  • 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.
  • 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
  • both A and B are phenyl (e.g., both A and B are '); or A is
  • 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 )).
  • halogen e.g., fluoro, chloro
  • L S -R E where L S is bond and R E is -Ci-C 6 alkyl (e.g.,
  • A is and B is as defined hereinabove. In certain other embodiments B is is as defined hereinabove. In certain other embodiments B is is as defined hereinabove.
  • D is C 6 -Ci 0 carbocycle or 3- to 12- membered heterocycle optionally substituted by one or more R M .
  • 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 .
  • aryl e.g., phenyl, naphthyl, indanyl
  • 5- to 10-membered heteroaryl pyridinyl, thiazolyl, 4,5,6,7- tetrahydrobenzo[d]thiazolyl, benzo[d]thiazolyl, indazolyl
  • 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 (
  • D is preferably phenyl or pyridyl and is substituted by one or more R M where one R M is G 2 .
  • 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,
  • 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,
  • G2 is ,
  • a monocyclic 4-8 membered nitrogen-containing heterocycle e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl
  • a monocyclic 4-8 membered nitrogen-containing heterocycle e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl
  • R G 2 and G 3 is optionally substituted with R G 3.
  • ⁇ 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).
  • R M e.g., fluoro, chloro, methyl,
  • L i a -C6 alkylene, -0-, or
  • G 3 is as define d above and is optionally substituted with R G 3.
  • R G 3 can be, for example,
  • 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
  • R M , L 4 , G 3 , and R G 2 are as defined herein.
  • G 2 is ⁇ , N
  • ' ⁇ 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 .
  • a nitrogen-containing heterocycle e.g., 3- azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-2-yl, 6-azas
  • 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).
  • R M e.g., fluoro, chloro, methyl, methoxy
  • 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 .
  • R M can be fluoro, chloro, tert-butyl, -0-CH 2 CH 3 , -0-CF 3 ,
  • R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6 alkyl (e.g., methyl).
  • D is wherein R M is fluoro, chloro, tert-butyl, -0-CH 2 CH 3 ,
  • R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6 alkyl (e.g., methyl).
  • 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).
  • 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).
  • D is wherein R M is -0-CH 2 -(3-ethyloxetan-3-yl),
  • R M selected from the group consisting of halogen (e.g., fluoro, chloro) and Ci-C 6 alkyl (e.g., methyl).
  • 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 pyridin
  • D is wherein Gi is N,
  • 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-
  • G3 is phenyl optionally substituted with one or two RG3; g is 0, 1, or 2; R M is each independently
  • 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.
  • RMI is each independently hydrogen, fluoro, chloro, or methyl; and R G 2 is an optional substituent as described herein.
  • D is wherein L 4 is Ci-C 6 alkylene, -0-, or
  • G 3 is phenyl optionally substituted with one or two RG3; g is 0, 1 , or 2; R M is each
  • D is wherein Gi is
  • D IS wherein g is 0, 1, or 2; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • R M i is each independently hydrogen, fluoro, chloro, or methyl
  • ⁇ - 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).
  • 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.
  • R G 2 at each occurrence is each independently halogen, -C(0)Ci-C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloal
  • R G 2 at each occurrence is each independently methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or
  • R M is each independently fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, or methyl.
  • 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.
  • X is cyclopropyl, cyclopentyl or cyclopentenyl, and Li and L 2 are each methylene (i.e. -CH 2 -), and L 3 is a bond.
  • 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.
  • 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.
  • 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
  • R A is fluoro, methoxy, methyl, ethyl, or cyano.
  • R 5 taken together with the atoms to which they are
  • 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.,
  • a pyrrolidine ring i.e., substituted with 0 or 1 R A wherein R A is fluoro, methoxy, methyl, ethyl, or cyano.
  • R 9 and R 12 taken together with the atoms
  • a chiral carbon in any rings formed by joining R 2 and R 5 or R 9 and R 12 may
  • R 5 or R 9 and Ri 2 preferably possesses the (S) stereochemistry
  • R B 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.
  • R B can be hydrogen (i.e., is -C(0)N(H)-).
  • 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).
  • R A is halogen (e.g., fluoro, chloro), Ci-Cealkyl (e.g., methyl, ethyl), or Ci-Cehaloalkyl (e.g., trifluoromethyl).
  • R A is halogen (e.g., fluoro, chloro), Ci-Cealkyl (e.g., methyl, ethyl), or Ci-Cehaloalkyl (e.g., trifluoromethyl).
  • is imidazolyl i.e.,
  • This aspect of the invention contemplates particular combinations of A with Y and B with Z.
  • A is C 5 -C 6 carbocycle (e.g., phenyl) or 5- to 6-membered heterocycle (e.g., pyridinyl or thiazolyl)
  • preferred Z when B is C 5 -C 6 carbocycle (e.g., phenyl) 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.
  • R A as described herein, or B
  • examples of preferred Z, where T' is a bond include: .
  • 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
  • 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).
  • carbocycle e.g., cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, phenyl
  • heterocycle e.g., tetrahydrofuranyl, tetrahydropyranyl
  • R D is hydrogen or R A wherein R A is as defined herein.
  • 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.
  • 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,
  • 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.
  • RD is preferably LS-RE wherein Ls is a bond and RE is -N(H)C(0)OMe.
  • T-R D includes, but is not limited to:
  • 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:
  • Y-A is :
  • the present invention features compounds of Formula Larmaceutically acceptable salts thereof:
  • X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more RA
  • A is ally substituted with one or more R A ;
  • B is wherein B is optionally substituted with one or more R A ;
  • Y, Z, R A , and D are as described hereinabove (e.g., Y, Z, R A , and D as described for Formula I, I A , IB, IC, ID, or I E , preferably as described for Formula I E ).
  • A is wherein A is
  • B is wherein B is optionally substituted with one or more R A ;
  • D, R A , T and R D are as defined hereinabove (e.g., as described for Formula I, I A , 3 ⁇ 4, Ic, ID or I E , preferably as described for Formula
  • a or B are optionally substituted with one or more substituents selected from: R A wherein R A is each independently halogen (e.g., fluoro, chloro); L S -R E where L s is a single bond, and R E is -Ci-C 6 alkyl (e.g., methyl), -O-Rs (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 a Ci-C 6 alkylene and R E is -O-Rs (e.g., -Ci-C 6 alkyl-0-Ci-C 6 alkyl, -CH 2 OCH 3 ).
  • R A is each independently halogen (e.g., fluoro, chloro)
  • L S -R E where L s is a single bond
  • This embodiment includes compounds where A and B are both substituted by one R A ; compounds where A and B are both substituted by zero R A ; compounds where A is substituted by one R A and B is substituted by zero R A ; and compounds where A is substituted by zero R A and B is
  • T-R D is independently selected at
  • this aspect of the invention features compound of Formula I F and pharmaceutically acceptable salts thereof, wherein:
  • A is wherein A is optionally substituted with one o mo e RA ?
  • B is wherein B is optionally substituted with one or more R A ;
  • Y is D
  • R D are as defined hereinabove.
  • a particular subgroup according to this embodiment includes
  • this aspect of the invention features compounds of Formula I F and pharmaceuticall acceptable salts thereof, wherein: A and B are each Y and Z are each independently
  • Rr or ; and D, T and R D are as defined hereinabove.
  • a particular subgroup according to this embodiment includes compounds where T-R D is each independently selected from ; and D is as defined hereinabove.
  • D is , where R M is fluoro, chloro, tert-butyl,
  • R M is optionally substituted by one or more additional R M , selected from the group consisting of halogen (e.g., fluoro, chloro) or Ci-C 6 alkyl (e.g., methyl).
  • D is wherein G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4- (propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4-
  • G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6-dimethylpiperidin-l-yl, 4- (propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l-yl, 3,5-dimethylpiperidin-l-yl, 4-
  • G 2 is piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-1 -yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin- 1 -yl, 4-(trifluoromethyl)piperidin-l-yl, 4-methylpiperidin-l-yl, 4-tert-butylpiperidin-l-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l-yl; and R M i is each independently hydrogen, fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • G 2 is ⁇ ;
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • L 4 is Ci-C 6 alkylene, -0-, or -S(0) 2 -; G 2 is ; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy
  • g is 0, 1 , or
  • 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,
  • compounds D is in L 4 is Ci-C 6 alkylene, -0-, or -S(0) 2 -; G 3 is phenyl optionally substituted with one or two R G 3; g is 0, 1 , or 2; R M is each independently fluoro, chloro, methyl,
  • G 3 is phenyl optionally substituted with one or two R G 3 as defined hereinabove;
  • R M i is each independently hydrogen, fluoro, chloro, or methyl;
  • R G 2 is an optional substituent, as described above, selected from the group consisting of -C(0)C C 6 alkyl, -Ci-C 6 alkyl, -d-Cghaloalkyl, -0-C C 6 alkyl, and -0-Ci-C 6 haloalkyl.
  • D is wherein Gi is N, C-H, or C-R M ; G 2 is , R M , and g are as defined hereinabove.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • g is 0, 1, or 2; and is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-
  • R M is each independently fluoro, chloro, methyl, methoxy,
  • compounds D is each independently hydrogen, fluoro, chloro, or N
  • 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).
  • D is , wherein ⁇ is a monocyclic
  • RG2 at each occurrence is each independently halogen, -C(0)C C 6 alkyl, -C C 6 alkyl, -C C 6 haloalkyl, -0-C C 6 alkyl, or -0-C C 6 haloalkyl; and R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, - ⁇ -Ci-Cealkyl, or -O-Ci-Cehaloalkyl.
  • RG2 at each occurrence is each independently halogen, -C(0)C C 6 alkyl, -C C 6 alkyl, -C C 6 haloalkyl, -0-C C 6 alkyl, or -0-C C 6 haloalkyl
  • R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, - ⁇ -Ci-Cealkyl, or
  • each group of compounds according to the foregoing embodiments is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two RG2, wherein R G2 at each occurrence is each 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-1 -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, or 3,3-dimethylazetidin-l -yl.
  • the present invention features compounds of Formula I G and pharmaceutically acceptable salts thereof,
  • X is cyclopropyl, cyclopentyl or cyclopentenyl, and is optionally substituted with one or more RA A is substituted with one or more R A ;
  • B is or , wherein B is optionally substituted with one or more R A ;
  • Y, Z, R A , and D are as described hereinabove (e.g., as described for Formula I, I A , 3 ⁇ 4, Ic, I D , I E or I F , preferably as described for Formula I E ).
  • this aspect of the invention features compounds of Formula I G and
  • Y and Z are each independently
  • Rr , or Rr T-R D is each independently and D is as defined hereinabove.
  • this aspect of the invention features compounds of Formula I G and
  • L S -R E where L s is a single bond and R E is -Ci-C 6 alkyl (e.g., methyl), -O-Rs (e.g., -O-Ci-Cealkyl, -OCH 3 ), or -Ci-Cealkyl optionally substituted with one or more halogen (e.g., -CF 3 ); or L S -R E where L s is a Ci-C 6 alkylene and R E is -0-R s (e.g., -Ci-C 6 alkyl-0-Ci-C 6 alkyl,
  • T-R D is each independently
  • This subgroup includes compounds where A and B are both substituted by one R A ; compounds where A and B are both substituted by zero R A ; compounds where A is substituted by one R A and B is substituted by zero R A ; and compounds where A is substituted by zero R A and B is substituted by one R A .
  • This subgroup includes compounds where A and B are both substituted by one R A ; compounds where A and B are both substituted by zero R A ; compounds where A is substituted by one R A and B is substituted by zero R A ; and compounds where A is substituted by zero R A and B is substituted by one R A .
  • Groups of compounds according to this aspect of the invention include compounds where 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 .
  • 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]diox
  • R M is halogen (e.g., fluoro, chloro, bromo); Ci-C 6 aikyl (e.g., tert-butyl); Ci-Cealkyl substituted with one or more halogen (e.g., CF 3 ); - ⁇ -Ci-Cealkyl (e.g., -0-CH 2 CH 3 ); -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 (-0-CH 2 CH 2 OCH 3 ); -0-C C 6 alkyl (e.g., -0-CH 2 ) substituted with an optionally substituted 3- to 12-membered heterocycle (e.g., 3-ethyloxetan-3-yl, 1,3-dioxolan- 4-yl
  • R M is halogen (e.g., flu
  • Other subgroups according to this embodiment include compounds wherein D is phenyl substituted by G 2 and optionally substituted by one or more R M , wherein G 2 is a 3- to 12-membered heterocycle (e.g., pyridinyl, piperidinyl, pyrrolidinyl, azetidinyl, oxazolyl) wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, cyano, Ci-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-Ci-C 6 alkyl (e.g., -O-CH3), -C(0)OR s (e.g.
  • D is , where R M is 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 is optionally substituted by one or more additional R M , selected from the group consisting of halogen (e.g., fluoro, chloro) or C C 6 alkyl (e
  • D is wherein G 2 is pyridinyl (e.g., pyridin-2-yl), piperidin-l-yl, 4,4-dimethylpiperidin-l -yl, 4,4-difluoropiperidin-l -yl, 2,6-dimethylpiperidin-l-yl, 4- (propan-2-yl)piperidin-l-yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin-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
  • G 2 is piperidin-l-yl, 4,4-dimethylpiperidin-l-yl, 4,4-difluoropiperidin-l-yl, 2,6- dimethylpiperidin-l -yl, 4-(propan-2-yl)piperidin-l -yl, 4-fluoropiperidin-l -yl, 3,5-dimethylpiperidin- l -yl, 4-(trifluoromethyl)piperidin-l -yl, 4-methylpiperidin-l -yl, 4-tert-butylpiperidin-l-yl, 2- oxopiperidin-l-yl, or 3,3-dimethylazetidin-l -yl; and R M i is each independently hydrogen, fluoro, chloro, or methyl.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • G 2 is ⁇ ;
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • ⁇ is 3-phenylazetidin-l -yl, 3- phenylpyrrolidin- 1 -yl, 4-phenylpiperazin- 1 -yl, 4-phenylpiperidin- 1 -yl, 4-phenyl-3 ,6-dihydropyridin- 1 (2H)-yl, 4,4-diphenylpiperidin- 1 -yl, 4-acetyl-4-phenylpiperidin- 1 -yl, 4-(4-methoxyphenyl)piperidin- 1 -yl, 4-(4-fluorophenyl)piperidin-l-yl, or 3-phenylpiperidin-l-yl; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1 , or 2. In other subgroups, R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • L 4 is Ci-C 6 alkylene, -0-, or -S(0) 2 -; G 2 is ; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • G 2 is ; R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy; and g is 0, 1, or 2.
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or trifluoromethoxy
  • g is 0, 1 , or
  • compounds D is 6 alkylene, -0-, or -S(0) 2 -;
  • G 3 is phenyl optionally substituted with one or two R G 3;
  • g is 0, 1 , or 2;
  • R M is each independently fluoro, chloro, methyl,
  • G 3 is phenyl optionally substituted with one or two R G 3 as defined hereinabove;
  • R M i is each independently hydrogen, fluoro, chloro, or methyl;
  • R G 2 is an optional substituent, as described above, selected from the group consisting of -C(0)Ci-C 6 alkyl, -Ci-C 6 alkyl, -Ci-C 6 haloalkyl, -0-Ci-C 6 alkyl, and -0-Ci-C 6 haloalkyl.
  • D is wherein Gi is N, C-H, or C-R M ; G2 is
  • R M is each independently fluoro, chloro, methyl, methoxy, trifluoromethyl, or
  • g is 0, 1 , or 2; and is 3-azabicyclo[3.2.0]hept-3-yl, 2-azabicyclo[2.2.2]oct-
  • R M is each independently fluoro, chloro, methyl, methoxy,
  • compounds D 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).
  • D is is a monocyclic
  • R G 2 at each occurrence is each independently halogen, -C(0)C C 6 alkyl, -C C 6 alkyl, -C C 6 haloalkyl, -0-C C 6 alkyl, or -0-C C 6 haloalkyl; and R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, - ⁇ -Ci-Cealkyl, or -O-Ci-Cehaloalkyl.
  • R G 2 at each occurrence is each independently halogen, -C(0)C C 6 alkyl, -C C 6 alkyl, -C C 6 haloalkyl, -0-C C 6 alkyl, or -0-C C 6 haloalkyl
  • R M is each independently halogen, -Ci-Cealkyl, -Ci-Cehaloalkyl, - ⁇ -Ci-Cealkyl, or
  • each group of compounds according to the foregoing embodiments is azetidinyl, pyrrolidinyl, or piperidinyl substituted with one or two RG2, wherein R G2 at each occurrence is each methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or trifluoromethyl; and R M is each independently
  • G2 fluoro, chloro, or methyl For example is 4,4-dimethylpiperidin-l -yl, 4,4- difluoropiperidin-1 -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, or 3,3-dimethylazetidin-l -yl.
  • the present invention also features compounds of Formulae I E , IF and IG as described herein (including each embodiment described hereunder) and pharmaceutically acceptable salts thereof, wherein:
  • 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 ,
  • the compounds of the present invention can be used in the form of salts.
  • a salt of a compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability under certain conditions or desired solubility in water or oil.
  • a salt of a compound may be useful for the isolation or purification of the compound.
  • the salt preferably is pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include, but are not limited to, acid addition salts, base addition salts, and alkali metal salts.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids.
  • suitable inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid.
  • suitable organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylammosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, buty
  • Pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts and organic salts.
  • suitable metallic salts include alkali metal (group la) salts, alkaline earth metal (group Ila) salts, and other pharmaceutically acceptable metal salts.
  • Such salts may be made, without limitation, from aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc.
  • suitable organic salts can be made from tertiary amines and quaternary amine, such as tromethamine, diethylamine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups can be quaternized with agents such as alkyl halides (e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • alkyl halides e.g., methyl, ethyl, propyl, butyl, decyl, lauryl, myristyl, and stearyl chlorides/bromides/iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates
  • the compounds or salts of the present invention may exist in the form of solvates, such as with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to form, respectively, methanolate, ethanolate or acetonitrilate).
  • solvates such as with water (i.e., hydrates), or with organic solvents (e.g., with methanol, ethanol or acetonitrile to form, respectively, methanolate, ethanolate or acetonitrilate).
  • the compounds or salts of the present invention may also be used in the form of prodrugs.
  • Some prodrugs are aliphatic or aromatic esters derived from acidic groups on the compounds of the invention. Others are aliphatic or aromatic esters of hydroxyl or amino groups on the compounds of the invention. Phosphate prodrugs of hydroxyl groups are preferred prodrugs.
  • the compounds of the invention may comprise asymmetrically substituted carbon atoms known as chiral centers. These compounds may exist, without limitation, as single stereoisomers (e.g., single enantiomers or single diastereomer), mixtures of stereoisomers (e.g. a mixture of enantiomers or diastereomers), or racemic mixtures.
  • Individual stereoisomers of the compounds of this invention can be prepared using a variety of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers followed by chromatographically separation of the diastereomers and regeneration of the individual enantiomers, and enzymatic resolution.
  • Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or substantial optically pure materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at the chiral centers.
  • Mixtures of stereoisomers of compounds, including racemic mixtures, resulting from a synthetic reaction may be separated, for example, by chromatographic techniques as appreciated by those of ordinary skill in the art. Chromatographic resolution of enantiomers can be accomplished by using chiral chromatography resins, many of which are commercially available.
  • racemate is placed in solution and loaded onto the column containing a chiral stationary phase. Enantiomers can then be separated by HPLC.
  • Resolution of enantiomers can also be accomplished by converting enantiomers in a mixture to diastereomers by reaction with chiral auxiliaries.
  • the resulting diastereomers can be separated by column chromatography or crystallization/re-crystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary.
  • suitable chiral auxiliaries include chirally pure amino acids, organic carboxylic acids or organosulfonic acids.
  • Enzymes such as esterases, phosphatases or lipases, can be useful for the resolution of derivatives of enantiomers in an enantiomeric mixture.
  • an ester derivative of a carboxyl group in the compounds to be separated can be treated with an enzyme which selectively hydrolyzes only one of the enantiomers in the mixture.
  • the resulting enantiomerically pure acid can then be separated from the unhydrolyzed ester.
  • salts of enantiomers in a mixture can be prepared using any suitable method known in the art, including treatment of the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization/re-crystallization of the enantiomerically pure salts.
  • a suitable optically pure base such as alkaloids or phenethylamine
  • Methods suitable for the resolution/separation of a mixture of stereoisomers, including racemic mixtures can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et al, 1981, John Wiley and Sons, New York, NY).
  • a compound of this invention may possess one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as the cis (Z) and trans (E) isomers, and mixtures thereof are intended to be encompassed within the scope of a recited compound unless otherwise specified. In addition, where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms.
  • Certain compounds of the invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotations about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the invention encompasses each conformational isomer of these compounds and mixtures thereof.
  • Certain compounds of the invention may also exist in zwitterionic form and the invention encompasses each zwitterionic form of these compounds and mixtures thereof.
  • the compounds of the present invention are generally described herein using standard nomenclature. For a recited compound having asymmetric center(s), it should be understood that all of the stereoisomers of the compound and mixtures thereof are encompassed in the present invention unless otherwise specified. Non-limiting examples of stereoisomers include enantiomers, diastereomers, and cis-transisomers. Where a recited compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms. Certain compounds are described herein using general formulas that include variables (e.g., A, B, D, X, Li, L 2 , L 3 , Y, Z, T, R A or R B ).
  • variables e.g., A, B, D, X, Li, L 2 , L 3 , Y, Z, T, R A or R B ).
  • each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. If moieties are described as being "independently" selected from a group, each moiety is selected independently from the other. Each moiety therefore can be identical to or different from the other moiety or moieties.
  • C x -C y The number of carbon atoms in a hydrocarbyl moiety can be indicated by the prefix "C x -C y ,” where x is the minimum and y is the maximum number of carbon atoms in the moiety.
  • Ci-Cealkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • C3-Cecycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
  • a prefix attached to a multiple-component substituent only applies to the first component that immediately follows the prefix.
  • the term "carbocyclylalkyl” contains two components: carbocyclyl and alkyl.
  • C 3 -C 6 carbocyclylCi-C 6 alkyl refers to a C 3 -C 6 carbocyclyl appended to the parent molecular moiety through a Ci-Cealkyl group.
  • a linking element links two other elements in a depicted chemical structure
  • the leftmost-described component of the linking element is bound to the left element in the depicted structure
  • the rightmost-described component of the linking element is bound to the right element in the depicted structure.
  • the chemical structure is -Ls-M-Ls'- and M is -N(R B )S(0)-
  • the chemical structure is -L s -N(R B )S(0)-L s '-.
  • a linking element in a depicted structure is a bond
  • the element left to the linking element is joined directly to the element right to the linking element via a covalent bond.
  • a chemical structure is depicted as -L s -M-L s '- and M is selected as bond
  • the chemical structure will be -L s -L s '-.
  • two or more adjacent linking elements in a depicted structure are bonds, then the element left to these linking elements is joined directly to the element right to these linking elements via a covalent bond.
  • the dash(s) indicates the portion of the moiety that has the free valence(s).
  • a moiety is described as being “optionally substituted", the moiety may be either substituted or unsubstituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either unsubstituted, or substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heterocycle optionally substituted with up to three non-hydrogen radicals, then any heterocycle with less than three substitutable positions will be optionally substituted by up to only as many non- hydrogen radicals as the heterocycle has substitutable positions.
  • alkenyl means a straight or branched hydrocarbyl chain containing one or more double bonds. Each carbon-carbon double bond may have either cis or trans geometry within the alkenyl moiety, relative to groups substituted on the double bond carbons.
  • Non-limiting examples of alkenyl groups include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl.
  • alkenylene refers to a divalent unsaturated hydrocarbyl chain which may be linear or branched and which has at least one carbon-carbon double bond.
  • alkyl means a straight or branched saturated hydrocarbyl chain.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, iso-amyl, and hexyl.
  • alkylene denotes a divalent saturated hydrocarbyl chain which may be linear or branched.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkynyl means a straight or branched hydrocarbyl chain containing one or more triple bonds.
  • Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
  • alkynylene refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon triple bonds.
  • Representative alkynylene groups include, by way of example, — C ⁇ C— , — C ⁇ C— CH 2 — , — C ⁇ C— CH 2 — CH 2 — , -CH 2 -C ⁇ C-CH 2 - -C ⁇ C-CH(CH 3 )-, and -CH 2 -C ⁇ C-CH(CH 2 CH 3 )-.
  • Carbocycle or “carbocyclic” or “carbocyclyl” refers to a saturated (e.g., “cycloalkyl"), partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl") or completely unsaturated (e.g., "aryl”) ring system containing zero heteroatom ring atom.
  • Ring atoms or “ring members” are the atoms bound together to form the ring or rings.
  • a carbocyclyl may be, without limitation, a single ring, two fused rings, or bridged or spiro rings.
  • a substituted carbocyclyl may have either cis or trans geometry.
  • carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, decalinyl, and norpinanyl.
  • a carbocycle group can be attached to the parent molecular moiety through any substitutable carbon ring atom.
  • a carbocycle group is a divalent moiety linking two other elements in a depicted chemical structure (such as A in Formula I)
  • the carbocycle group can be attached to the two other elements through any two substitutable ring atoms.
  • a carbocycle group is a trivalent moiety linking three other elements in a depicted chemical structure (such as X in Formula I)
  • the carbocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.
  • Carbocyclylalkyl refers to a carbocyclyl group appended to the parent molecular moiety through an alkylene group.
  • C3-C6carbocyclylCi-C6alkyl refers to a C 3 -C 6 carbocyclyl group appended to the parent molecular moiety through Ci-C 6 alkylene.
  • cycloalkenyl refers to a non-aromatic, partially unsaturated carbocyclyl moiety having zero heteroatom ring member.
  • Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octahydronaphthalenyl.
  • cycloalkyl refers to a saturated carbocyclyl group containing zero heteroatom ring member.
  • Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl.
  • Ci-Cehaloalkyl means a Ci-C6alkyl substituent wherein one or more hydrogen atoms are replaced with independently selected halogen radicals.
  • Non-limiting examples of Ci-Cehaloalkyl include chloromethyl, 1-bromoethyl, fluorom ethyl, difluoromethyl, trifluorom ethyl, and 1,1 ,1-trifluoroethyl. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated).
  • heterocycle or “heterocyclo” or “heterocyclyl” refers to a saturated (e.g., “heterocycloalkyl"), partially unsaturated (e.g., “heterocycloalkenyl” or “heterocycloalkynyl”) or completely unsaturated (e.g., “heteroaryl”) ring system where at least one of the ring atoms is a heteroatom (i.e., nitrogen, oxygen or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur.
  • a heterocycle may be, without limitation, a single ring, two fused rings, or bridged or spiro rings.
  • a heterocycle group can be linked to the parent molecular moiety via any substitutable carbon or nitrogen atom(s) in the group.
  • a heterocycle group is a divalent moiety that links two other elements in a depicted chemical structure (such as A in Formula I)
  • the heterocycle group can be attached to the two other elements through any two substitutable ring atoms.
  • a heterocycle group is a trivalent moiety that links three other elements in a depicted chemical structure (such as X in Formula I)
  • the heterocycle group can be attached to the three other elements through any three substitutable ring atoms, respectively.
  • a heterocyclyl may be, without limitation, a monocycle which contains a single ring.
  • monocycles include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl
  • a heterocyclyl may also be, without limitation, a bicycle containing two fused rings, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl, and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl (including pyrido[3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, and pyrido[4,3-b]-pyridinyl), pyridopyrimidine, and pteridinyl.
  • naphthyridinyl including [1,8]
  • fused-ring heterocycles include benzo-fused heterocyclyls, such as indolyl, isoindolyl, indoleninyl (also known as “pseudoindolyl”), isoindazolyl (also known as “benzpyrazolyl” or indazolyl), benzazinyl (including quinolinyl (also known as “1- benzazinyl”) and isoquinolinyl (also known as “2 -benzazinyl”)), benzimidazolyl, phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as “1,2-benzodiazinyl”) and quinazolinyl (also known as "1,3 -benzodiazinyl”)), benzopyranyl (including “chromenyl” and “isochromenyl”), benzothiopyranyl (also known as "thiochromenyl”)
  • a heterocyclyl may also be, without limitation, a spiro ring system, such as, for example, 1 ,4- dioxa-8-azaspiro[4.5]decanyl.
  • a heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases, the sulfur atom(s) is oxidized to SO or SO 2 .
  • the nitrogen heteroatom(s) in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to N-oxide. In addition, the nitrogen heteroatom(s) may or may not be N-protected.
  • pharmaceutically acceptable is used adjectivally to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.
  • terapéuticaally effective amount refers to the total amount of each active substance that is sufficient to show a meaningful patient benefit, e.g. a reduction in viral load.
  • prodrug refers to derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo.
  • a prodrug of a compound may be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy or carboxy group).
  • Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in mammals (see, Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985).
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine.
  • Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amine functional groups within the compounds of the invention.
  • solvate refers to the physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association often includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, and methanolates.
  • N-protecting group or “N-protected” refers to those groups capable of protecting an amino group against undesirable reactions. Commonly used N-protecting groups are described in Greene and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (3 rd ed., John Wiley & Sons, NY (1999).
  • N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-); sulfinyl groups such as p-methylphenylsulfinyl (p- methylphenyl-S(O)-)
  • N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • the compounds of the present invention can be prepared as shown in Scheme I.
  • the diamine (1-1) may be reacted with a suitably protected proline acid [i-butoxycarbonyl (Boc) is shown, although benzyloxycarbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc), or 9-fluorenylmethoxycarbonyl (Fmoc) may be substituted] in the presence of a peptide coupling reagent, such as A ⁇ 3-dimethylaminopropyl)-A ⁇ -ethylcarbodiimide hydrochloride/1 - hydroxybenzotriazole [EDAC/HOBT], (benzotriazol- 1 -yl-oxy)tripyrrolidinophosphonium hexafluorophosphate [PyBOP®], 0-(7-azabenzotriazol-l -yl)-A ⁇ ,A ⁇ ,A ⁇ ',A'-tetra
  • the alkene (1-2) may be reacted with 1 to 5 equivalents or more of compounds of formula (1-4) in the presence of a suitable acid such as toluene sulfonic acid or other reagents such as boron trifluoride etherate in organic solvents such as dichloromethane or toluene to give cyclopropane compounds of formula (1-5) [Sugawara, M.; et al. J. Am. Chem. Soc. 1997, 1 19, 11986]. Removal of the i-butoxycarbonyl (Boc) protecting groups to give (1-6) may be accomplished by treatment with an acid, such as trifluoroacetic acid, HC1, or formic acid.
  • Compounds of the present invention (1-7) wherein T and R D are as described above, may be prepared by coupling of (1-6) with an acid of choice using the standard peptide coupling reagents and conditions described above.
  • Dibromostilbene (II- 1) can be reacted with bis(pinacolato)diboron with potassium acetate in solvents such as, but not limited to, toluene at temperatures from about 80 °C to about 120 °C to give alkene ( ⁇ -2).
  • the alkene ( ⁇ -2) may be reacted with 1 to 5 equivalents or more of compounds of formula (1-4) in the presence of a suitable acid such as toluene sulfonic acid or other reagents such as boron trifluoride etherate in organic solvents such as dichloromethane or toluene to give cyclopropane compounds of formula (II-3).
  • the cyclopropane compounds ( ⁇ -3) can be reacted with bromoimidazoles ( ⁇ -4), wherein Pi is a nitrogen-protecting group, using Suzuki reaction conditions to give the phenylimidazole ( ⁇ -5).
  • Suzuki reaction conditions A variety of reaction conditions are well known to those of skill in the art to be effective in mediating the Suzuki reaction.
  • the reaction of ( ⁇ -3) with (II-4) to produce ( ⁇ -5) can be performed with [l,l '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) [Pd(dppf)Cl 2 ] catalyst and potassium carbonate in a mixture of toluene and water and with heating to about 100 °C.
  • Alcohols (III-l) can be oxidized to aldehydes ( ⁇ -2) using well-known methods such as, for example, reacting the alcohols (III-l) with Dess-Martin periodinane in the presence of sodium bicarbonate in a solvent such as, but not limited to, dichloromethane.
  • Compounds ( ⁇ -2) can be reacted with glyoxal and ammonium hydroxide in methanol/water to give (III-3).
  • Compounds ( ⁇ -3) in turn can be brominated using ⁇ -bromosuccinimide in solvents such as, but not limited to, dichloromethane at temperatures from 0 °C to room temperature to give ( ⁇ -4).
  • Compounds ( ⁇ -4) can be mono-debrominated by reaction with sodium sulfite (Na 2 S0 3 ) in a mixture of dioxane and water with heating to reflux to give intermediates ( ⁇ -4). Although no particular stereochemistry is designated for intermediate ( ⁇ -4), the foregoing chemical methods can be used to prepare ( ⁇ -4) as a racemate or a single enantiomer (R or S stereochemistry). The choice of (R) or (S) stereochemistry in the starting alcohol (III-l) will lead to compounds of the invention having a single absolute stereochemistry at the corresponding carbon of the final compound.
  • Benzimidazole derivatives of general structural formula (VI-2) can be prepared by synthetic sequences summarized in Schemes IV- VI.
  • the requisite stilbene derivative (IV-6) can be prepared starting by treatment of bromide (IV- 1) with di-teri-butyl dicarbonate in the presence of a suitable base such as, but not limited to, aqueous sodium bicarbonate solution, to afford bis-i-butoxycarbonyl protected (IV-2).
  • Bromide (IV-2) is reacted with an acetylene derivative such as trimethylsilylacetylene under Sonogashira conditions using a suitable palladium catalyst such as bis(triphenylphosphine)palladium (II) chloride in the presence of a copper salt, such as, but not limited to, copper (I) iodide, and a suitable amine base, such as triethylamine or diisopropyl amine.
  • a suitable palladium catalyst such as bis(triphenylphosphine)palladium (II) chloride
  • a copper salt such as, but not limited to, copper (I) iodide
  • a suitable amine base such as triethylamine or diisopropyl amine.
  • Acetylene (IV-3) so obtained is then deprotected by treatment with a suitable alcoholic base, such as potassium carbonate or potassium hydroxide, or by treatment with fluoride ion, in the form of tetrabutylammonium fluoride to afford acetylene derivative (IV-4).
  • a suitable alcoholic base such as potassium carbonate or potassium hydroxide
  • fluoride ion in the form of tetrabutylammonium fluoride
  • acetylene derivative (IV-4) acetylene derivative
  • Boronate (IV-5) is prepared by hydroboration of (IV-4) with diisopmocampheylborane followed by reaction of the resulting trialkylborane with an aldehyde, such as acetaldehyde, and aqueous hydrolysis of the dialkyl borate to afford boronic acid (IV-5).
  • Stilbene (IV-6) can then be obtained from the Suzuki-Miyaura coupling of boronic acid (IV-5) with bromide (IV-2), catalyzed by either a palladium (II) salt or a palladium (0) source, such as tris(dibenzylideneacetone)dipalladium (0) or the like in conjunction with a phosphine ligand, preferably with a Cytec® phenyl phosphaadamantyl ligand (PA-Ph) (Adjabeng, J., et al. Org. Lett. 2003, 5, 953; Adjabeng, J., et al. J. Org. Chem.
  • a palladium (II) salt or a palladium (0) source such as tris(dibenzylideneacetone)dipalladium (0) or the like in conjunction with a phosphine ligand, preferably with a Cytec® phenyl pho
  • aqueous base such as tribasic potassium phosphate, potassium carbonate, or the like
  • a suitable solvent such as tetrahydrofuran, dimethoxyethane, or the like.
  • Tetraamine (V-2) can be coupled with two equivalents of a suitably protected proline acid (i-butoxycarbonyl (Boc) is shown, other protecting groups such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl would also be useful) using preferably coupling agent 0-(7-azabenzotriazol-l-yl)-A ⁇ ,A ⁇ ,A ⁇ ',A ⁇ '-tetramethyluronium hexafluorophosphate (HATU) in the presence of an amine base such as diisopropylethylamine or Af-methylmorpholine, or other coupling agents known to those skilled in the art, to afford the two regioisomeric anilides (V-3) and (V-4).
  • i-butoxycarbonyl (Boc) i-butoxycarbonyl (Boc)
  • other protecting groups such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl would also be useful
  • the regioisomeric anilides are not separated, but directly cyclized to (V-6) by treatment with 5-10 equivalents of glacial acetic acid in toluene or tetrahydrofuran (or mixtures thereof) at a temperature in the range of 50-85 °C.
  • Benzimidazole (V-6) can be transformed to representative compounds of this invention by the sequence of transformations shown in Scheme VI. As shown, treatment of (V-6) with a suitable acid removes the two t-butoxycarbonyl (Boc) protecting groups to afford diamine (VI-1). Diamine (VI- 1) can then be coupled with two equivalents of an appropriately functionalized amino acid derivative, by use of amino acid coupling methods known to those skilled in the art to afford final benzimidazole derivative (VI-2), wherei I and n, R D and T are as defined above.
  • Compounds (VII-2) can be converted to compounds (VII-3) by reaction with a triflating source such as triflic anhydride.
  • a triflating source such as triflic anhydride.
  • Compounds (VII-3) may be converted to further compounds of the invention using well- known organic transformations of aromatic triflates such as Suzuki, Sonogashira, or Buchwald reactions.
  • (VII-3) may be converted to compounds (VII-4), wherein R 00 is group such as alkenyl, aryl, heteroaryl, or cycloalkenyl, by reaction with a suitable boronic acid or ester Ri 0 oB(OR') 2 , wherein R' is hydrogen, alkyl, or together with the oxygen atoms and adjacent boron atom to which they are attached form a dioxaborolane or a dioxaborinane, such as, but not limited to, 1-cyclohexen-yl-boronic acid pinacol ester or other boronic acids/esters, in the presence of a source of palladium and phosphine ligand (e.g., PdCl 2 [dppfj 2 ) and base (e.g., triethylamine, sodium carbonate, potassium carbonate, potassium phosphate, sodium bicarbonate), in solvents such as, but not limited to, DME and water at
  • the compounds (VII-4) derived from Suzuki reaction with an alkeneboronic acid/ester or cycloalkenylboronic acid/ester and having an alkene in the R100 group may be further elaborated to compounds of the invention by reaction of the alkene present in R100 (e.g. reduction by catalytic hydrogenation).
  • reaction conditions are well known to those of skill in the art to be effective in mediating the Suzuki reaction.
  • Other substrates utilized in the Suzuki reaction such as aromatic, heteroaromatic, or heterocyclic boronates or boronic acids may provide compounds (VII-4) having heteroaryl, heterocyclic, or aryl groups at Rioo.
  • Suitably substituted amines may combine with a triflate (VII-3) in a Buchwald-type reaction to provide compounds (VII-5), wherein R101 and R102 are each alkyl or taken together with the nitrogen atom to which they are attached form a heterocycloalkyl.
  • Suitable conditions for effecting this transformation may be found in the following references: Wolfe and Buchwald, J. Org. Chem. 1997, 1264-1267; Louie et al, J. Org. Chem. 1997, 1268-1273; Peng, T.; Yang, D. Organic Lett. 2010, 12, 496-499; Hartwig, J. F. in Handbook of Organopalladium
  • substituted alkynes may couple in a Sonogashira reaction with (VII-3) to provide compounds (VII-6), wherein R103 is aryl or heteroaryl.
  • compounds (VIII-3) can be converted to compounds (VIII -4) by reaction with PBr 3 .
  • Compounds (VIII-4) may be converted to compounds (VIII-5) by reaction with 4-(teri-butoxycarbonylamino)phenylboronic acid or teri-butyl 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenylcarbamate using Suzuki reaction conditions (see for example: J. Chem. Soc. Chem. Commun. (1994) 2305-2306; Org. Lett. (1999) 1839-1842).
  • Compounds (VIII-5) may be converted to compounds (VIII-6) by catalytic hydrogenation using Pt0 2 or Pd/C as described for enone reduction in Aust. J. Chem. (1997) 149-152; J. Med. Chem. (1976) 414-419 (see bottom of table III on page 417); and Org. Lett. (2009) 5450-5453 and supporting information.
  • Compounds (VIII-6) may be converted to compounds (VIII-7) by treatment with base (e.g., NaH, LiHMDS, KHMDS) followed by reaction with (Tf) 2 NPh as shown in the following references: Ang. Chem. Int. Ed. Eng. (2005) 403-406 and supporting information; J. Med. Chem.
  • compounds (VIII-5) may be converted directly to compounds (VIII-7) by reduction with L-selectride or sodium selectride followed by trapping of the in-situ formed enolate with (Tf) 2 NPh or Comins' reagent as described in the following references: see J. Org. Chem. (2007) 4616 and supporting information on page S33; also WO2007144174 on page 25; see also http://en.wikipedia.org/wiki/L-selectride.
  • Compounds (VIII-7) may be converted to compounds (VIII-8) by a Suzuki reaction with an appropriate boronic acid or ester as described above or as generally known in the art.
  • Compounds (VIII-8) may be converted to compounds (VIII-9) by Boc removal using standard conditions such as TFA/CH 2 CI 2 or HC1 in dioxane.
  • Compounds (VIII-9) may be converted to compounds (VIII- 10) by reaction with (.S)-l-(teri-butoxycarbonyl)pyrrolidine-2-carboxylic acid using standard amide bond forming techniques such as the use of a peptide coupling reagent (e.g., EDAC/HOBT, PyBOP®, HATU, T3P, or DEPBT), in a solvent such as THF, DMF, dichloromethane, or DMSO, with or without the addition of an amine base such as A-methylmorpholine, Hunig's base, pyridine, 2,6- lutidine, or triethylamine.
  • a peptide coupling reagent e.g., EDAC/HOBT, PyBOP®, HATU, T3P,
  • Compounds (VIII- 10) may be converted to compounds (VIII- 11) using the Boc removal conditions referred to above.
  • Compounds (VIII- 11) may be converted to compounds (VIII-12) by reaction with an appropriate carboxylic acid such, but not limited to, 2- (methoxycarbonylamino)-3-methylbutanoic acid, 2-(methoxycarbonylamino)-3,3-dimethylbutanoic acid, 2-cyclohexyl-2-(methoxycarbonylamino)acetic acid, 2-(methoxycarbonylamino)-2-(tetrahydro- 2//-pyran-4-yl)acetic acid, etc., using the standard amide bond forming conditions referred to above.
  • Compounds (VIII-12) may be converted to compounds (VIII- 13) by catalytic hydrogenation using catalysts such as Pt0 2 or Pd/C under 1-4 atmospheres of hydrogen in typical organic solvents (e.g., ethyl acetate, methanol, etc).
  • catalysts such as Pt0 2 or Pd/C under 1-4 atmospheres of hydrogen in typical organic solvents (e.g., ethyl acetate, methanol, etc).
  • Scheme VIII By analogy with the methods outlined in Scheme VIII, further compounds of the invention may be prepared according to the methods outlined in Scheme IX.
  • Compounds (VIII-4) may be reacted with compound (IX- 1) under standard Suzuki conditions to give compounds (IX-2).
  • Compounds (IX-2) may be converted to compounds (IX-3) using conditions and steps analogous to those in Scheme VIII used to convert (VIII-5) to (VIII-8).
  • the benzimidazole of (IX-1) and (IX-2) may be protected as a SEM derivative.
  • Schemes VIII-X may also be modified to produce compounds of the invention bearing different groups flanking the central core by appropriate choice of a distinct boronic acid or ester for each Suzuki reaction.
  • compounds may be prepared having a benzimidazole moiety on one side and a
  • Compounds (XI-1), where X13 is alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, etc., can be coupled with an acid (e.g., (5)-l-(te ⁇ butoxycarbonyl)pyrrolidine-2-carboxylic acid) using peptide coupling procedures described above to give an amide that can be heated in acetic acid to about 100 °C to give (XI-2).
  • Compounds (XI-2) can be reacted with SEM-C1 and
  • Compound (VIII-2) may react with a variety of boronic acids or esters as mentioned above.
  • Certain boronic acids suitable for reaction with (VIII-2) may be prepared as outlined in Scheme XII, where q is 0, 1, or 2; R A is halo, alkyl, cycloalkyl, alkoxy, haloalkyl, haloalkoxy, etc.; and n is 0, 1, 2, 3, or 4.
  • Bromoanilines may be reacted with a dihaloalkane (e.g., 1,5-dibromopentane) generally in solvents such as benzene, toluene, DMF, etc.
  • a dihaloalkane e.g., 1,5-dibromopentane
  • compounds of formula (XIII-4) can be treated with hydroxylamine hydrochloride in the presence of potassium hydroxide in a heated mixture of ethanol and water to remove the 2,4- dimethylpyrrole. Then treatment with acid under conditions known to one skilled in the art removes the teri-butoxycarbonyl protecting group to deliver compounds of formula (VIII-9).
  • Compounds of formula (VIII-9) can be coupled with compounds of formula (XIII-5) under standard amide bond coupling procedures to give compounds of formula (VIII-12).
  • Compounds of formula (VIII-12) can be further transformed as described in Scheme VIII.
  • a moiety described herein e.g., -NH 2 or -OH
  • the moiety may be protected with a suitable protecting group that is stable to the reaction conditions used in the methods.
  • the protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound.
  • Suitable protecting groups and methods for protecting or deprotecting moieties are well know in the art, examples of which can be found in Greene and Wuts, supra.
  • Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art based on the present invention.
  • Example compounds below were named using either ChemDraw version 9.0 or ACD/Name release 12.00 12 (ACD vl2). Final compounds for Examples 1-8 were named using ChemDraw unless otherwise indicated as being named using ACD vl2. Intermediates were named using ChemDraw, unless otherwise indicated as being named using ACD vl2.
  • Example compounds below were named using ACD Name version 12 (ACD Name vl2).
  • Certain compounds in the Examples below can be purified using normal phase silica gel chromatography including traditional flash chromatography or an automated purification system (e.g., Isco CombiFlash®, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 ⁇ silica gel, Isco gold columns). Compounds can also be purified by preparative thin-layer chromatography.
  • normal phase silica gel chromatography including traditional flash chromatography or an automated purification system (e.g., Isco CombiFlash®, Analogix Intelliflash) using pre-packed silica gel columns (55 or 35 ⁇ silica gel, Isco gold columns).
  • Compounds can also be purified by preparative thin-layer chromatography.
  • Typical solvents for silica gel chromatography include: Ethyl acetate in hexanes, diethyl ether in hexanes, tetrahydrofuran in hexanes, ethyl acetate in methylene chloride, methanol in methylene chloride, methanol in methylene chloride with ammonium hydroxide, acetone in hexanes, and methylene chloride in hexanes.

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