WO2006088903A2 - Pyrazole compounds - Google Patents

Pyrazole compounds Download PDF

Info

Publication number
WO2006088903A2
WO2006088903A2 PCT/US2006/005236 US2006005236W WO2006088903A2 WO 2006088903 A2 WO2006088903 A2 WO 2006088903A2 US 2006005236 W US2006005236 W US 2006005236W WO 2006088903 A2 WO2006088903 A2 WO 2006088903A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
cycloalkyl
heteroaryl
aralkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2006/005236
Other languages
French (fr)
Other versions
WO2006088903A3 (en
Inventor
Youhong Hu
Bin Xu
Yun Liao
Kenneth Nawoschik
Yixin Liu
Anthony Sandrasagra
Reza Fathi
Zhen Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vivoquest Inc
Original Assignee
Vivoquest Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vivoquest Inc filed Critical Vivoquest Inc
Priority to EP06720749A priority Critical patent/EP1853257A2/en
Publication of WO2006088903A2 publication Critical patent/WO2006088903A2/en
Publication of WO2006088903A3 publication Critical patent/WO2006088903A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

Definitions

  • HCV Hepatitis C virus
  • the present invention provides pyrazole derivatives of the formula I:
  • ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -OR 11 , -N(R 12 XR 13 ), -N(R ⁇ )C(O)R ⁇ , -N(R U )SO 2 R U , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR
  • Z is selected from O, N-OR 461 ;
  • R 461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, alkyl-O-aryl and -(CH 2 ) ⁇ -R 42
  • R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 are independently selected from H 5 alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and -(CH 2 ) ⁇ -R 42 ;
  • R 45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH 2 ) ⁇ -R 42 ;
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 , -C(O)OR 421 , -C(O)N(R 422 XR 423 ), -OC(O)R 421 , -OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , -SOR 421 , -SO 3 R 421 , -SO 2 N(R 422 XR 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 2 is selected from a group having the formula
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 42 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached form
  • R 5 is selected from H, OR 51 , -SR 51 , alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF 3 , NO 25 SO 2 , -SOR 51 , -SO 3 R 51 , -SO 2 N(R 52 )(R 53 ), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, -C(O)R 51 , -C(O)OR 51 , -C(O)N(R 52 )(R 53 ), -OC(O)R 51 , -OC(O)N(R 52 )(R 53 ), -O(CH 2 ) e C(O)OR 51 , -O(CH 2 ) e C(O)OR 51 , -O(CH 2 ) e C(O)N(R 52 )(R 53 ), -N(R 52 )
  • each R 54 and R 56 is independently selected from -OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, -C(O)R 57 , -C(O)OR 57 , -C(O)N(R 58 XR 59 ), -OC(O)R 57 , -OC(O)N(R 58 )(R 59 ), O(CH 2 ),C(O)OR 57 , -0(CH 2 )AO)N(R 58 XR 59 X -N(R 58 XR 59 ), -N(R 57 )C(O)R 57 , -N(R 57 )SO 2 R 57 , aralkyl, aryl and heteroaryl; each R 57 is independently selected from H, alkyl, cycloalkyl, cycloalkeny
  • X 1 is selected from N and CH; /is 1 to 6; g is O to 4; and h if 0 to 5; or a pharmaceutically acceptable salt or hydrate thereof.
  • the invention provides a compound having the formula V:
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R n )C(O)R ⁇ , -N(R 1 ⁇ SO 2 R 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring atoms my be
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 )(R 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -S
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 , -C(O)OR 421 , -C(O)N(R 422 XR 423 ), -OC(O)R 421 , -OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , -SOR 421 , -SO 3 R 421 , -SO 2 N(R 422 XR 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 2 is selected from a group having the formula
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
  • each R 22 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom
  • each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl
  • each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the
  • the invention also provides a synthetic process for the preparation of compounds of the invention.
  • the process uses mild reaction conditions, which provides a high substituent tolerance.
  • the process is applicable to the preparation of a wide variety of pyrazole derivatives with diverse substitution patterns.
  • the process is appropriate for use with combinatorial synthesis techniques.
  • the process provides a method for producing a library of pyrazole derivatives for biological screening.
  • the invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention in a therapeutically effective amount.
  • halo or halogen as used herein includes fluorine, chlorine, bromine and iodine.
  • alkyl as used herein contemplates both straight and branched chain alkyl radicals containing from one to fifteen carbon atoms.
  • lower alkyl as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.
  • the alkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, - 0-R, -N(R 1 J(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(RO(R"), -OC(O)R, - OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • alkenyl contemplates both straight and branched chain alkene radicals containing from two to 8 carbon atoms. Additionally, the alkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, - C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • alkynyl as used herein contemplates both straight and branched carbon chain containing from two to 8 carbon atoms and having at least one carbon-carbon triple bond.
  • alkynyl includes, for example ethynyl, 1-pro ⁇ ynyl, 2-propynyl, 1-butynyl, 3 -methyl- 1-butynyl, and the like.
  • the alkynyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(RO(R"), - OC(O)R, -OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • cycloalkyl as used herein contemplates cyclic alkyl radicals containing form 3 to 7 carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(RO(R"), - N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), halo, alkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, alkyl, cycloalkenyl, aryl and heteroaryl.
  • cycloalkenyl as used herein contemplates cyclic alkenyl radicals containing form 5 to 7 carbon atoms in which has a double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl, and the like.
  • the cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, - C(O)N(R')(R M ), -OC(O)R 5 -OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), halo, alkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, - C(O)N(R')(
  • aralkyl as used herein contemplates a lower alkyl group which has as a substituent an aromatic group. Additionally, the aralkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO 2 , CO 2 R, C(O)R, - O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(RO(R"), -OC(O)R, - OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • heterocyclic group or "heterocyclic ring” as used herein contemplates aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member.
  • Preferred heterocyclic groups are those containing 5 or 6 ring atoms which includes at least one hetero atom, and includes cyclic amines such as morpholino, piperidino, pyrrolidino, and the like, and cyclic ethers, such as tetrahydrofuran, tetrahydropyran, and the like.
  • Aromatic heterocyclic groups also termed "heteroaryl” groups contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.
  • heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like.
  • the heterocyclic group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO 2 , CO 2 R, C(O)R, -0-R, -N(R 1 XR"), -N(R)C(O)R, -N(R)SO 2 R, -SR, -C(O)N(RO(R"), -OC(O)R, - OC(O)N(RO(R”).
  • aryl contemplates single-ring aromatic groups (for example, phenyl, pyridyl, pyrazole, etc.) and polycyclic ring systems (naphthyl, quinoline, etc.).
  • the polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
  • the aryl group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO 2 , CO 2 R, C(O)R, -0-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, - C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO 2 , -SOR, -SO 3 R, -SO 2 N(R)(RO, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
  • substituents selected from halo, alkyl, CN, NO 2 , CO 2 R, C(O)R, -0-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO 2 R, -SR, - C(O)N(RO(
  • Each R is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl.
  • Each R' and R" are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R" may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom.
  • heteroatom particularly as a ring heteroatom, refers to N, O, and S.
  • AU value ranges for example those given for n and m, are inclusive over the entire range. Thus, a range of O to 4 would include the values 0, 1, 2, 3 and 4.
  • ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R 1 ⁇ C(O)R 11 , -N(R 1 ⁇ SO 2 R 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN 3 CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heter ⁇ aryl; additionally or alternatively two R 1 substituents on
  • R is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR
  • Z is selected from O, N-OR 461 ;
  • R 461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
  • R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
  • R 45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH 2 ) ⁇ -R >42 .
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 , -C(O)OR 421 , -C(O)N(R 422 XR 423 ), -OC(O)R 421 , -OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , -SOR 421 , -SO 3 R 421 , -SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 2 is selected from a group having the formula
  • each R 21 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached form
  • R 5 is selected from H, OR 51 , -SR 51 , alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF 3 , NO 25 SO 2 , -SOR 51 , -SO 3 R 51 , -SO 2 N(R 52 )(R 53 ), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, -C(O)R 51 , -C(O)OR 51 , -C(O)N(R 52 )(R 53 ), -OC(O)R 51 , -OC(O)N(R 52 )(R 53 ), -O(CH 2 ) e C(O)OR 51 , -O(CH 2 ) e C(O)OR 51 , -O(CH 2 ) e C(O)N(R 52 )(R 53 ), -N(R 52 )
  • R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, -O-R 51 is combined with R 41 , R 46 , or R 47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R 5 is selected from a group having the formula:
  • each R 54 and R 56 is independently selected from -OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, -C(O)R 57 , -C(O)OR 57 , -C(O)N(R 58 XR 59 ), -OC(O)R 57 , -OC(O)N(R 58 )(R 59 ), O(CH 2 ) / C(O)OR 57 , -O(CH 2 ) r C(O)N(R 58 )(R 59 ), -N(R 58 )(R 59 ), -N(R 58 )C(O)R 57 , -N(R 57 )SO 2 R 57 , aralkyl, aryl and heteroaryl; each R 57 is independently selected from H, alkyl, cyclol,
  • X 1 is selected from N and CH; /is 1 to 6; g is O to 4; and ⁇ if0 to 5; or a pharmaceutically acceptable salt or hydrate thereof.
  • the dashed line in Ring A represents an optional double bond, as would be understood by the ordinarily skilled worker in the art.
  • the substances according to the invention may also be present as salts.
  • Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in the ail to be generally acceptable for pharmaceutical uses.
  • Pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
  • salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid
  • organic carboxylic or sulfonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid.
  • Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention.
  • ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylarninoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • ammonia or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylarninoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
  • each R 1 group may be selected independently.
  • the R 1 groups may be selected from any of the stated groups so as to be the same or different. This also holds true for any other group or substituent which may be selected independently from among various groups or values.
  • R 5 is selected from OR 51 , -OC(O)R 51 , - OC(O)N(R 52 )(R 53 ), O(CH 2 ) e C(O)OR 51 , -O(CH 2 ) e C(O)N(R 52 )(R 53 ), -N(R 52 )(R 53 ), - N(R 51 )C(O)R 51 , and -N(R 51 )SO 2 R 51 .
  • R 5 is selected to be a group of the formula O-R 6 to give a compound of the formula II
  • ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R 1 ⁇ C(O)R 11 , -N(R 1 ⁇ SO 2 R 1 ⁇ -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 3 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 ) S O 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -S
  • Z is selected from O, N-OR 461 ;
  • R 461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
  • R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and -(CH 2 VR 42 ;
  • R 45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH 2 ) ⁇ -R 42 ;
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 , -C(O)OR 421 , -C(O)N(R 422 XR 423 ), -OC(O)R 421 , -OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , -SOR 421 , -SO 3 R 421 , -SO 2 N(R 422 XR 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is selected from a group having the formula
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached
  • R 6 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 51 , -C(O)N(R 52 )(R 53 ), (CH 2 ) e C(O)OR 51 , and -(CH 2 ) e C(O)N(R 52 )(R 53 ), each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R 5 and R 53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered
  • each R 54 and R 56 is independently selected from -OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, -C(O)R 57 , -C(O)OR 57 , -C(O)N(R 58 XR 59 ), -OC(O)R 57 , -OC(O)N(R 58 )(R 59 ), 0(CH 2 )AO)OR 57 , -O(CH 2 ),C(O)N(R 58 )(R 59 ), -N(R 58 XR 59 ), -N(R 57 )C(O)R 57 , -N(R 57 )SO 2 R 57 , aralkyl, aryl and heteroaryl; each R 57 is independently selected from H, alkyl, cycloalkyl, cycloal
  • X 1 is selected from N and CH; /is 1 to 6; g is O to 4; and A if O to 5; or a pharmaceutically acceptable salt or hydrate thereof.
  • the ring A of the compound according to formula II is selected to be a phenyl or substituted phenyl to give a compound of the formula III:
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R 1 ⁇ C(O)R 1 ⁇ -N(R 11 )SO 2 R 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring atoms my be combined to
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 )(R 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -S
  • Z is selected from O, N-OR 461 ;
  • R 461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
  • R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
  • R 5 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH 2 ) ⁇ -R 42 ;
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 , -C(O)OR 421 , -C(O)N(R 422 XR 423 ), -OC(O)R 421 , -OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , -SOR 421 , -SO 3 R 421 , -SO 2 N(R 422 X
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 422 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached
  • R 6 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 51 , -C(O)N(R 52 )(R 53 ), (CH 2 ) e C(O)OR 51 , and -(CH 2 ) e C(O)N(R 52 )(R 53 ), each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered
  • each R 54 and R 56 is independently selected from -OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, -C(O)R 57 , -C(O)OR 57 , -C(O)N(R 58 XR 59 ), -OC(O)R 57 , -OC(O)N(R 58 )(R 59 ), 0(CH 2 )AO)OR 57 , -O(CH 2 ) 1 C(O)N(R 58 )(R 59 ), -N(R 58 XR 59 ), -N(R 57 )C(O)R 57 , -N(R 57 )SO 2 R 57 , aralkyl, aryl and heteroaryl; each R 57 is independently selected from H, alkyl, cycloalkyl, cyclo
  • X 1 is selected from N and CH; /is 1 to 6; g is O to 4; and HfO to 5; or a pharmaceutically acceptable salt or hydrate thereof.
  • R 4 of a compound according to formula III is selected to be a group of the formula and the ring A is selected to be a phenyl or substituted phenyl to give a compound of the formula IV: wherein: each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 )(R 13 ), -N(R 11 JC(O)R 11 , -N(R n )SO 2 R ⁇ , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 , -C(O)OR 421 , -C(O)N(R 422 XR 423 ), -OC(O)R 421 , -OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , -SOR 421 , -SO 3 R 421 , -SO 2 N(R 422 XR 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is selected from a group having the formula
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 422 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 22 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which
  • R 6 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, - C(O)R 51 , -C(O)N(R 52 )(R 53 ), (CH 2 ) e C(O)OR 5 ⁇ and -(CH 2 ) e C(O)N(R 52 )(R 53 ), each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R 52 and R 53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain
  • each R 54 and R 56 is independently selected from OH, halo, alkyl, cycloalkyl, alkenyl, alkynyl, NO 2 , CN, -C(O)R 57 , -C(O)OR 57 , -C(O)N(R 58 )(R 59 ), -OC(O)R 57 , -OC(O)N(R 58 XR 59 ), 0(CHa) 1 C(O)OR 57 , -O(CH 2 ) ( C(O)N(R 58 )(R 59 ), -N(R 58 )(R 59 ), -N(R 57 )C(O)R 57 , -N(R 57 )SO 2 R 57 , aralkyl, aryl and heteroaryl; each R 57 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl,
  • X 1 is selected from N and CH; /is 1 to 6; g is 0 to 4; and ⁇ if 0 to 5; or a pharmaceutically acceptable salt or hydrate thereof.
  • Table 1 provides representative embodiments for compounds of the formula IV.
  • R 2 of the compound according to the formula IV is selected to be methyl and R 6 is selected to be H to give a compound having the formula V:
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -0-R 11 , -N(R 12 )(R 13 ), -N(R 1 ⁇ C(O)R 11 , -N(R ⁇ )SO 2 R u , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring atoms my be
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR 34
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 , -C(O)OR 421 , -C(O)N(R 422 XR 423 ), -OC(O)R 421 , -OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , -SOR 421 , -SO 3 R 421 , -SO 2 N(R 422 XR 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is selected from a group having the formula
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 422 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH 5 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to
  • R 4 of a compound according to the formula II is selected to be a group of the formula and R 6 is combined with R 41 to give a compound having the formula VI:
  • ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R n )C(O)R n , -N(R n )SO 2 R ⁇ , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR 34
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 422 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to
  • the ring A of the compound according to formula VI is selected to be a phenyl or substituted phenyl to give a compound of the formula VI 0 :
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R 11 JC(O)R 11 , -N(R 1 ⁇ SO 2 R 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring atoms my be combined to form
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR
  • R 43 , and R 44 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH 2 ) ⁇ -R 42 ;
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -SR 421 , -C(O)R 421 ,
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 422 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to
  • Table 2 provides representative embodiments for compounds of the formula VI.
  • R 4 of a compound according to the formula II is selected to be a group of the formula
  • R is combined with R i41 to give a compound having the formula VII: wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R n )C(O)R ⁇ , -N(R n )SO 2 R n , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR
  • each R 21 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached form
  • the ring A of the compound according to formula VII is selected to be a phenyl or substituted phenyl to give a compound of the formula VII ⁇ :
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R n )C(O)R n , -N(R 1 ⁇ SO 2 R 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring atoms my be combined
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR
  • R 42 is selected from a group having the formula
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 422 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to
  • Table 3 provides representative embodiments for compounds of the formula VIL.
  • R of a compound according to the formula II is selected to be a group of the formula
  • R 6 is combined with R 41 to give a compound having the formula VIII: wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R 1 ⁇ C(O)R 11 , -N(R n )SO 2 R n , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalky ⁇ , cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR
  • R 461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -SR 421 , -C(O)R 421 ,
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 22 and R 423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached form
  • the ring A of the compound according to formula VIII is selected to be a phenyl or substituted phenyl to give a compound of the formula VIII 0 :
  • each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -N(R 12 XR 13 ), -N(R 1 ⁇ C(O)R 11 , -N(R 1 ⁇ SO 2 R 11 , -SR 11 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 12 XR 13 ), -OC(O)R 11 , -OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , -SOR 11 , -SO 3 R 11 , -SO 2 N(R 12 XR 13 ), -alkyl-O-R 11 , cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring
  • R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
  • R 2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 )(R 33 );
  • R is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -SR 421 , -C(O)R 421 ,
  • R 2 is selected from a group having the formula
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached
  • two compounds of the formula I are linked by a linking group, L, to form a dimeric compound.
  • the two compounds of the formula I which are linked by L to form the dimeric compound may be linked through any position off of the formula I structure.
  • two compounds of the formula I may be linked through a linking group at the position of R 1 , R 2 , R 3 , R 4 , or R 5 .
  • the dimeric compound is linked through R of the compounds of formula I.
  • R 4 of a compound according to formula I is selected to be a group of the formula
  • the resulting "dimeric" compound may be symmetric or unsymmetrical and is represented by the formula X:
  • ring A and ring A' are independently selected from 5- or 6- membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms; each R 1 and R 1 ' are selected independently from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 ,
  • R 2 and R 2 ' are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 and R 3 ' are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 XR 33 );
  • R 3 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which maybe optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , -O-R 34 , -N(R 34 XR 35 ), -N(R 34 )C(O)R 34 , -N(R 34 )SO 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -SOR 34
  • each R 54 and R 56 is independently selected from -OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, -C(O)R 57 , -C(O)OR 57 , -C(O)N(R 58 XR 59 ), -OC(O)R 57 , -OC(O)N(R 58 )(R 59 ), O(CH 2 >C(O)OR 57 , -0(CH 2 )AO)N(R 58 XR 59 ), -N(R 58 XR 59 ), -N(R 58 XR 59 ), -N(R 57 )C(O)R 57 , -N(R 57 )SO 2 R 57 , aralkyl, aryl and heteroaryl; each R 57 is independently selected from H, alkyl,
  • X 1 is selected from N and CH; /is 1 to 6; g is 0 to 4; and Ms 0 to 5;
  • L is a linking group selected from -(CH 2 ) x -, , or a group of the formula
  • A is selected from -N(R)-, -O-, -S-, -C(O)-, -OC(O)-, -N(R)C(O)-,
  • x is 3 to 25; y is 1 to 10; z is 1 to 10; v is 1 to 8; and w is 1 to 8; or a pharmaceutically acceptable salt or hydrate thereof.
  • the dimeric compound is linked through R 5 of the compounds of formula 1.
  • R 5 of a compound according to formula I is selected to be a group of the formula:
  • the resulting dimeric compound may be symmetric or unsymmetrical and is represented by the formula XI: wherein ring A and ringyf are independently selected from 5- or 6- membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms; each R 1 and R 1 ' are selected independently from alkyl, alkenyl, alkynyl, aralkyl, -O-R 11 , -
  • R 2 and R 2 ' are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R 21 , -C(O)OR 21 , -alkyl-O-alkyl, -alkyl-O-aryl;
  • R 21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 3 and R 3 ' are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R 31 , -C(O)OR 31 , -C(O)N(R 32 XR 33 );
  • R 31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
  • R 32 and R 33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 3 , C(O)R 34 , -O-R 34 , -N(R 34 )(R 35 ), -N(R 34 )C(O)R 34 , -N(R 34 ) S O 2 R 34 , -SR 34 , -C(O)N(R 35 XR 36 ), -OC(O)R 34 , -OC(O)N(R 35 )(R 36 ), SO 2 , -
  • Z is selected from O, N-OR 461 ;
  • R 461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
  • R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
  • R ,45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH 2 ) ⁇ -R 42 ;
  • R 42 is selected from -N(R 421 )C(O)R 421 , -N(R 421 )SO 2 R 421 , -OR 421 , -SR 421 , -C(O)R 421 ,
  • each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 42 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 425 and R 426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 425 and R 26 may be taken together with the carbon to which they are attached form a 5- to 7
  • L is a linking group selected from -(CH 2 ) ⁇ -, or a group of the formula
  • A is selected from -N(R)-, -0-, -S-, -C(O)-, -OC(O)-, -N(R)C(O)-,
  • x is 3 to 25; y is 1 to 10; z is 1 to 10; v is 1 to 8; and w is 1 to 8; or a pharmaceutically acceptable salt or hydrate thereof.
  • Step 1 of Scheme 1 preferably involves using a Sonogashira reaction in which a compound of the formula C is prepared by reacting a compound of the formula A with a terminal alkyne represented by the formula B in the presence of base and a transition metal catalyst, wherein R 1 , R 2 , R 3 , R 15 and n are as described above for the compound of the fo ⁇ nula I.
  • a suitable base may be, for example, an organic base such as a primary, secondary or tertiary amine.
  • Non-limiting examples include triethylamine, diisopropylamine, l,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), l,5-diazabicyclo-[4,3,0]-non-5-ene (DBN), or l,4-diazabicyclo-[2.2.2]-octane (DABCO).
  • DBU diisopropylamine
  • DBU l,8-diazabicyclo-[5.4.0]-undec-7-ene
  • DBN l,5-diazabicyclo-[4,3,0]-non-5-ene
  • DABCO l,4-diazabicyclo-[2.2.2]-octane
  • an inorganic base may be used, such as an alkali metal or alkaline earth metal salt, such as a carbonate, bicarbonate or acetate salt.
  • the metal catalyst may be in the form of a salt or a complex with organic ligands.
  • Particularly suitable metal catalysts are, for example, the Group VIII metals, preferably Pd(O) complexes or a Pd(II) salt.
  • the ligands may be selected from, for example, phosphorus-containing ligands, such as triphenylphosphine (PPh 3 ) and l,2-bis(diphenyl-phosphino)ethane (dppe).
  • Preferred palladium catalysts include Pd(PPh3) 2 Cl 2 , Pd(PPh 3 ) 4 and Pd(OAc) 2 .
  • the reaction is performed in the presence of a Cu(I) salt, such as a Cu(I) halide, Cu 2 O, and CuCN, preferably CuI or CuCl.
  • a Cu(I) salt such as a Cu(I) halide, Cu 2 O, and CuCN, preferably CuI or CuCl.
  • Suitable organic solvents include, but are not limited to, dioxane, tetrahydrofuran (THF) dimethylformamide (DMF), acetonitrile, dimethylsulfoxide, and other polar aprotic solvents or mixtures thereof.
  • Step 2 of Scheme 1 involves a reaction in which a compound of the formula E is prepared by reacting a compound of the formula C with a hydrazine represented by the formula D.
  • the hydrazine D is added directly to the pot containing the crude intermediate C.
  • Pd 0 catalysts include Pd(PPh 3 ) 4 , Pd 2 (dba) 3 , 3-Pd 2 (dba) 2 /Pt-Bu 3 , 4- Pd 2 (dba) 3 /dppf, and 5-Pd 2 (dba) 2 /bpy.
  • the base may be selected from appropriate organic and inorganic bases including carbonate salts (for example, potassium carbonate, sodium carbonate, and cesium carbonate) and acetate salts (for example, sodium acetate).
  • carbonate salts for example, potassium carbonate, sodium carbonate, and cesium carbonate
  • acetate salts for example, sodium acetate.
  • aryl pyrazoles may be prepared according to the Scheme III:
  • aryl aldehyde H is treated with p-toluenesulfonyl hydrazide in a polar solvent, followed by treatment with base and N- vinyl imidazole.
  • the resulting pyrazole may be further modified.
  • the pyrazole may be alkylated by treatment with a strong base, such as NaH, followed by reaction with an alkylating agent.
  • Alkylating agents may have the structure alkyl-LG, wherein LG represents a leaving group.
  • the pyrazole ring may be further modified, for example, by treatment with iodosuccinimide followed by reaction with a terminal alkyne and metal catalyst, Boronic acid and metal catalyst, alkene and metal catalyst, alkyl tin and metal catalyst, etc. to give diversified derivatives.
  • Compound V may be cyclized by treatment with a metal catalyst such as Nickel, Palladium, and Rhodium in a polar acidic solvent to give compounds Vila.
  • a metal catalyst such as Nickel, Palladium, and Rhodium in a polar acidic solvent
  • compound Villa can be synthesized by treating a 4-chloro-3- carbonyl-coumarin with a hydrazine using microwave in acetic acid conditions at about 150 °C for about 10 mins.
  • Dimeric compounds according to the present invention may be prepared according to the schemes provided below:
  • RG is a reactive group and RG' is its reactive partner.
  • RG may be a leaving group, such as tosylate
  • RG' may be a nucleophile, such as an amine.
  • RG-RG' pairs include: a) an activated carbonyl-containing group, such as an acyl halide or anhydride, which may be reacted with a nucleophile such as -NH 2 , -OH, etc. b) iodide which maybe reacted with a terminal acetylene using a Sonogashira reaction or with boronic acid using Suzuki coupling, etc.
  • protecting group means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • the compounds and processes disclosed herein are useful in the production of a library of pyrazole derivatives for biological screening.
  • Derivatives of pyrazole posses a range of biological activities.
  • Pryrazole-based compounds have shown efficacy, for example, as antivirals.
  • the compounds of the present invention may be used to prevent or treat infection with HCV.
  • HCV Replicon Assay developed in the laboratories of Bartenschlager (Lohman et al, Science 285, 110-113, 1999) and Rice (Blight et al, Science 290, 1972-1974, 2000).
  • the assay is performed using the Huh-Luc- Neo cell line (Lohman et al, Science 285, 110- 113, 1999).
  • Huh-Luc- Neo cells are a human hepatoma cell line (Huh-7) stably expressing a bi-cistronic subgenomic replicon containing the HCV IRES in which the structural proteins of HCV had been deleted and replaced by a construct containing sequences coding for the firefly luciferase reporter gene, the neomycin selectable marker and the EMCV IRES to direct expression of a truncated HCV genome expressing the structural proteins NS3, NS4A, NS4B, NS 5 A, and NS5B.
  • HCV targets through which inhibitors could act to inhibit replication include the NS3 protease, the helicase/ATPase, NS5A, the NS5B- RNA dependent RNA polymerase, and the HCV IRES.
  • HCV IRES driven luciferase reporter activity and HCV RNA are measured to obtain indirect and direct measures of replication of HCV RNA respectively.
  • Inhibitors of HCV replication and/or proliferation are determined by initially identifying molecules that inhibit expression of the HCV IRES driven luciferase reporter in this HCV Replicon Luciferase Assay. Cell viability assays and control cell based luciferase assays are then run on hits identified in the HCV Replicon Luciferase Assay to eliminate cytoxic compounds and non-specific compounds which act by inhibiting the luciferase enzyme.
  • HCV Replicon Luciferase hits that are specific and non-cytoxic and demonstrating that these compounds inhibit expression of HCV RNA using a quantitative PCR based approach (Taqman) using primers and probes specific for HCV RNA (HCV Replicon RNA Assay).
  • the HCV Replicon Assay may be used to predict compound efficacy in treatment and/or prevention of HCV infection as well as inhibition of HCV replication and/or proliferation.
  • the HCV Replicon encompasses a multiplicity of viral and host targets through which an inhibitor could work to inhibit HCV Replication.
  • Viral targets expressed in the HCV Replicon include the HCV IRES (for translation), NS3 Protease, the HCV Helicase/ATPase, NS5A phosphorylation, and the NS5B polymerase. Without being limited to theory, it is believed that the compounds of the present invention inhibit HCV replication.
  • the present invention provides pharmaceutical compositions comprising an anti-HCV effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier or auxiliary agent.
  • pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion.
  • Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
  • the invention also provides a method of treating HCV infection in a mammal, preferable a human, by administering to the mammal an effective amount of a compound of the present invention, a pharmaceutically acceptable salt or hydrate thereof, or a composition as described above.
  • the compounds of the invention may be administered alone or may be administered in combination with other approved therapeutics, such as: an interferon (pegylated or not), preferably ⁇ -interferon, ribavirin, or interferon and ribavirin, or one or more other anti-HCV agent, such as an HCV protease inhibitor, HCV polymerase inhibitor, HCV IRES inhibitor, HCV Helicase and/or ATPase inhibitor, NS5A phosphorylation inhibitor, HCV NS2 inhibitor, or other HCV life cycle inhibitor.
  • Combination therapies with may include a compound of the invention with multiple different inhibitors of HCV life cycle (immunomodulatory agents, Toll Like Receptor modulators, antisense therapeutics etc.).
  • the agents that comprise a combination therapy may be administered together or separately, e.g., prior to, concurrently with or following the administration of the compound of the invention or pharmaceutically acceptable salt thereof.
  • These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form.
  • these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit.
  • Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may be employed in solid or liquid form including, for example, amorphous powder or crystalline form, in solution or in suspension.
  • parenterally may be administered in numerous different ways, such as orally, parenterally, topically, transdermally or by inhalation. Oral administration or administration by injection is preferred.
  • the choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and well established pharmaceutical practice.
  • the pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the fo ⁇ nulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques.
  • liquid earners examples include syrups, peanut oil, olive oil, water, saline and the like.
  • emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, may be used.
  • Injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • the pha ⁇ naceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents.
  • the pharmaceutical composition of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • Compounds of the invention may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • Carriers for oral use may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.
  • lactose and a liquid carrier such as high molecular weight polyethylene glycols.
  • compositions and dosage forms prepared in accordance with the present invention optionally may contain lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, capsules and the like.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, and capsules may be coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension.
  • Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and mixtures thereof also may be used, hi addition, the active compound may be incorporated into sustained-release preparations and formulations. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • suitable vehicles or carriers for the above noted formulations and compositions can be found in standard pharmaceutical texts, e.g. in "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19.sup.th Ed. Mack Publishing Company, Easton, Pa., (1995).
  • the resulting composition may be administered in vivo to mammals, such as man, to treat or prevent HCV virus infection.
  • mammals such as man
  • Such treatment may also be achieved using a compound of this invention in combination with other anti- viral agents which include, but are not limited to a-interferon and ribavirin.
  • the additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.
  • Reaction solvents were commercially purchased from Aldrich or Acros without further purification and reagents were used as received. Reaction was monitored by thin-layer chromatography (TLC) on 0.25 mm precoated Merck Silica Gel 60 F 254 , visualizing with ultraviolet light. Flash column chromatography was performed on Merck Silica Gel 60 (230-400 mesh) using reagent grade hexanes, dichloromethane, and ACS grade ethyl acetate, and methanol. LC-MS was performed on Water Separation. 1 H and 13 C NMR spectra were recorded on a Varian Unity INPVA 500 MHz spectrometer, CDCl 3 as solvent, TMS as internal reference. 1 H- 1 H coupling are assumed to be first order, and peak multiplicity is reported as a s (single), d (doublet), t (triplet), q (quartet), m (multiplet), or b (broad).
  • Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS + 2mM glutamine; 100 ⁇ l/well).
  • the compounds to be tested are added to the experimental wells (10 ⁇ l/well at 1OX assay concentration) and the cells are then incubated (5% CO 2 , 37 0 C) for 48h.
  • Bright-Glo Luciferase Assay reagent Bright-Glo Luciferase Assay Buffer + Bright-Glo Luciferase Assay Substrate Mixture
  • the well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer.
  • the data is analyzed and IC50s are determined using GraphPad Prism 4 software.
  • Hits validated in the Replicon Luciferase assay have IC50s ⁇ 8.0 ⁇ M and show ⁇ 30% inhibition of Cell Viability at a compound concentration of 100 ⁇ M (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon Luciferase Assay conditions).
  • RNA Isolation and cDNA Synthesis The cells are washed with IX Phosphate Buffered Saline (PBS) once. Cells are then lysed and RNA is isolated in 96 well format using a vacuum manifold and the RNAeasy 96 kit (Qiagen) according to the manufacturer's suggested protocol. cDNA is then synthesized from RNA isolated from each well using the Taqman Reverse Transcription Reagents kit (Applied Biosystems) according to manufacturer's suggested protocol.
  • PBS IX Phosphate Buffered Saline
  • the lyophilized CellTiter-Glo Substrate is equilibrated to room temperature prior to use.
  • 10 ml of CellTiter-Glo Buffer is transferred to 1 vial of CellTiter-Glo Substrate and mixed by gently with a Vortex.
  • 100 ⁇ l of CellTiter-Glo Assay reagent (CellTiter-Glo Buffer + CellTiter-Glo Substrate Mixture) is added to each well.
  • the well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Aryl substituted pyrazole derivatives are provided, as well as processes for their preparation. The invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention, alone or in combination with additional antiviral agents, in a therapeutically effective amount.

Description

PYRAZOLE COMPOUNDS
BACKGROUND OF THE INVENTION
[0001] Strategies in new drug discovery often look to natural products for leads in finding new chemical compounds with therapeutic properties. One of the recurring problems in drug discovery is the availability of organic compounds derived from natural sources. Techniques employing combinatorial chemistry attempt to overcome this problem by allowing the high throughput synthesis and testing of hundreds or thousands of related synthetic compounds, called a chemical library, hi designing the synthesis of a prospective therapeutic compound or a chemical library, one often looks to natural chemical motifs which are known to have broad biological activity.
[0002] Pyrazole has a long history of application in pharmaceutical and agrochemical industry, and posses a widespread occurrence as sub-structures in a large variety of compounds, which exhibit important biological activities and pharmacological properties. Elguero, J. In Comprehensive Heterocyclic Chemistry //;vKatritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Pergamon-Elsevier Science: Oxiford, 1996; Vol. 6, pp. 1- 75; (b) Sutharchanadevi, M.; Murugan, R. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Pergamon-Elsevier Science: Oxiford, 1996; Vol. 6, pp. 221-260.
[0003] Infection with the Hepatitis C virus (HCV) represents a serious worldwide health crisis. In more than 70% of infected individuals, the virus evades clearance by the immune system leading to a persistent HCV infection. The long term effects of persistent HCV infection range from an apparently healthy carrier state to chronic hepatitis, liver fibrosis, cirrhosis, and eventually hepatocellular carcinoma. HCV is a leading cause of chronic liver disease. The best therapy currently available for treatment of HCV infection uses a combination of pegylated α-interferon and ribavirin. However, many of the patients treated with this therapy fail to show a sufficient antiviral response. Additionally, interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life of treated patients. Thus, it is vital that more effective treatments be identified.
SUMMARY OF THE INVENTION
[0004] The present invention provides pyrazole derivatives of the formula I:
Figure imgf000003_0001
wherein: ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -OR11, -N(R12XR13), -N(Rπ)C(O)Rπ, -N(RU)SO2RU, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 2 and R 3 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 is selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000004_0001
wherein Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, alkyl-O-aryl and -(CH2)^-R42 R41, R43, R44, R46, R47, R48 and R49 are independently selected from H5 alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and -(CH2)α-R42 ;
R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)α-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 2 is selected from a group having the formula
Figure imgf000005_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R42 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R5 is selected from H, OR51, -SR51, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF3, NO25SO2, -SOR51, -SO3R51, -SO2N(R52)(R53), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)OR51, -C(O)N(R52)(R53), -OC(O)R51, -OC(O)N(R52)(R53), -O(CH2)eC(O)OR51, -O(CH2)eC(O)N(R52)(R53), -N(R52)(R53), -N(R51)C(O)R51, and -N(R51)SO2R51 each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, -O-R51 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R5 is selected from a group having the formula:
Figure imgf000006_0001
and
Figure imgf000006_0002
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), O(CH2),C(O)OR57, -0(CH2)AO)N(R58XR59X -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and h if 0 to 5; or a pharmaceutically acceptable salt or hydrate thereof.
[0005] In a preferred embodiment, the invention provides a compound having the formula V:
Figure imgf000007_0001
wherein: each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(Rn)C(O)Rπ, -N(R1 ^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34)(R35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)^-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 2 is selected from a group having the formula
Figure imgf000008_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 22 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0006] The invention also provides a synthetic process for the preparation of compounds of the invention. The process uses mild reaction conditions, which provides a high substituent tolerance. Thus, the process is applicable to the preparation of a wide variety of pyrazole derivatives with diverse substitution patterns. Additionally, the process is appropriate for use with combinatorial synthesis techniques. Thus, the process provides a method for producing a library of pyrazole derivatives for biological screening.
[0007] The invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention in a therapeutically effective amount.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The term "halo" or "halogen" as used herein includes fluorine, chlorine, bromine and iodine.
[0009] The term "alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to fifteen carbon atoms. The term "lower alkyl" as used herein contemplates both straight and branched chain alkyl radicals containing from one to six carbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. Additionally, the alkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, - 0-R, -N(R1J(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(RO(R"), -OC(O)R, - OC(O)N(RO(R"), SO2, -SOR, -SO3R, -SO2N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0010] The term "alkenyl" as used herein contemplates both straight and branched chain alkene radicals containing from two to 8 carbon atoms. Additionally, the alkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO2R, -SR, - C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO2, -SOR, -SO3R, -SO2N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0011] The term "alkynyl" as used herein contemplates both straight and branched carbon chain containing from two to 8 carbon atoms and having at least one carbon-carbon triple bond. The term alkynyl includes, for example ethynyl, 1-proρynyl, 2-propynyl, 1-butynyl, 3 -methyl- 1-butynyl, and the like. Additionally, the alkynyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(RO(R"), - OC(O)R, -OC(O)N(RO(R"), SO2, -SOR, -SO3R, -SO2N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0012] The term "cycloalkyl" as used herein contemplates cyclic alkyl radicals containing form 3 to 7 carbon atoms and includes cyclopropyl, cyclopentyl, cyclohexyl, and the like. Additionally, the cycloalkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(RO(R"), - N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO2, -SOR, -SO3R, -SO2N(RO(R"), halo, alkyl, cycloalkenyl, aryl and heteroaryl. [0013] The term "cycloalkenyl" as used herein contemplates cyclic alkenyl radicals containing form 5 to 7 carbon atoms in which has a double bond between two of the ring carbons and includes cyclopentenyl, cyclohexenyl, and the like. Additionally, the cycloalkenyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, -O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO2R, -SR, - C(O)N(R')(RM), -OC(O)R5 -OC(O)N(RO(R"), SO2, -SOR, -SO3R, -SO2N(RO(R"), halo, alkyl, cycloalkenyl, aryl and heteroaryl.
[0014] The term "aralkyl" as used herein contemplates a lower alkyl group which has as a substituent an aromatic group. Additionally, the aralkyl group may be optionally substituted with one or more substituents selected from halo, CN, NO2, CO2R, C(O)R, - O-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(RO(R"), -OC(O)R, - OC(O)N(RO(R"), SO2, -SOR, -SO3R, -SO2N(RO(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0015] The term "heterocyclic group" or "heterocyclic ring" as used herein contemplates aromatic and non-aromatic cyclic radicals having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing 5 or 6 ring atoms which includes at least one hetero atom, and includes cyclic amines such as morpholino, piperidino, pyrrolidino, and the like, and cyclic ethers, such as tetrahydrofuran, tetrahydropyran, and the like. Aromatic heterocyclic groups, also termed "heteroaryl" groups contemplates single-ring hetero-aromatic groups that may include from one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. The term heteroaryl also includes polycyclic hetero-aromatic systems having two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is a heteroaryl, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like. Additionally, the heterocyclic group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO2, CO2R, C(O)R, -0-R, -N(R1XR"), -N(R)C(O)R, -N(R)SO2R, -SR, -C(O)N(RO(R"), -OC(O)R, - OC(O)N(RO(R"). SO2, -SOR, -SO3R, -SO2N(R)(R"), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0016] The terms "aryl", "aromatic group", or "aromatic ring" as used herein contemplates single-ring aromatic groups (for example, phenyl, pyridyl, pyrazole, etc.) and polycyclic ring systems (naphthyl, quinoline, etc.). The polycyclic rings may have two or more rings in which two atoms are common to two adjoining rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g., the other rings can be cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls. Additionally, the aryl group may be optionally substituted with one or more substituents selected from halo, alkyl, CN, NO2, CO2R, C(O)R, -0-R, -N(RO(R"), -N(R)C(O)R, -N(R)SO2R, -SR, - C(O)N(RO(R"), -OC(O)R, -OC(O)N(RO(R"), SO2, -SOR, -SO3R, -SO2N(R)(RO, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0017] Each R is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl. Each R' and R" are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R" may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom.
[0018] The term "heteroatom", particularly as a ring heteroatom, refers to N, O, and S.
[0019] AU value ranges, for example those given for n and m, are inclusive over the entire range. Thus, a range of O to 4 would include the values 0, 1, 2, 3 and 4.
[0020] The present invention provides pyrazole derivatives of the formula I:
Figure imgf000013_0001
wherein: ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(R1 ^C(O)R11, -N(R1 ^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN3 CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heterόaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and maybe further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 is selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000014_0001
wherein Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2)α-R42
R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
-(CH2)α-R42 ;
R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)β-R >42 . R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422)(R423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 2 is selected from a group having the formula
Figure imgf000015_0001
each R 21 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R5 is selected from H, OR51, -SR51, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF3, NO25SO2, -SOR51, -SO3R51, -SO2N(R52)(R53), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)OR51, -C(O)N(R52)(R53), -OC(O)R51, -OC(O)N(R52)(R53), -O(CH2)eC(O)OR51, -O(CH2)eC(O)N(R52)(R53), -N(R52)(R53), -N(R51)C(O)R51, and -N(R51)SO2R51 each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, -O-R51 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R5 is selected from a group having the formula:
Figure imgf000016_0001
and
Figure imgf000016_0002
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), O(CH2)/C(O)OR57, -O(CH2)rC(O)N(R58)(R59), -N(R58)(R59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; 2 is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and Λ if0 to 5; or a pharmaceutically acceptable salt or hydrate thereof.
[0021] The dashed line in Ring A represents an optional double bond, as would be understood by the ordinarily skilled worker in the art. [0022] The substances according to the invention may also be present as salts. In the context of the invention, preference is given to pharmaceutically acceptable salts. Pharmaceutically acceptable salts refers to an acid addition salt or a basic addition salt of a compound of the invention in which the resulting counter ion is understood in the ail to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or to salts with organic carboxylic or sulfonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylarninoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine. (see, Berge et al. J. Pharm. Sci. 1977, 66, 1-19.)
[0023] When one or more chiral centers are present in the compounds of the present invention, the individual isomers and mixtures thereof (e.g., racemates, etc.) are intended to be encompassed by the formulae depicted herein. In certain embodiments, compounds of the invention may exist in several tautomeric forms. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. Compounds of the invention may exist in various hydrated forms.
[0024] It is understood that when n is a value greater than 1, each R1 group may be selected independently. Thus, when more than one R1 group is present, the R1 groups may be selected from any of the stated groups so as to be the same or different. This also holds true for any other group or substituent which may be selected independently from among various groups or values. [0025] In preferred embodiments, R5 is selected from OR51, -OC(O)R51, - OC(O)N(R52)(R53), O(CH2)eC(O)OR51, -O(CH2)eC(O)N(R52)(R53), -N(R52)(R53), - N(R51)C(O)R51, and -N(R51)SO2R51.
[0026] In one embodiment of the invention, R5 is selected to be a group of the formula O-R6 to give a compound of the formula II
Figure imgf000018_0001
wherein: ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(R1 ^C(O)R11, -N(R1^SO2R1 \ -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R3 , C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34) S O2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 is selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000019_0001
wherein
Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2VR' 42 R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and -(CH2VR42 ;
R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)α-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000020_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R6 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)N(R52)(R53), (CH2)eC(O)OR51, and -(CH2)eC(O)N(R52)(R53), each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R5 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, R6 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R6 is selected from a group having the formula:
Figure imgf000021_0001
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), 0(CH2)AO)OR57, -O(CH2),C(O)N(R58)(R59), -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and A if O to 5; or a pharmaceutically acceptable salt or hydrate thereof. [0027] In a preferred embodiment of the invention, the ring A of the compound according to formula II is selected to be a phenyl or substituted phenyl to give a compound of the formula III:
Figure imgf000022_0001
wherein: each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(R1^C(O)R1 \ -N(R11)SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35)(R36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 is selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000023_0001
wherein Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2)α-R42 R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
-(CH2)^-R42 ; R 5 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)α-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000024_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R6 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)N(R52)(R53), (CH2)eC(O)OR51, and -(CH2)eC(O)N(R52)(R53), each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, R6 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R6 is selected from a group having the formula:
Figure imgf000025_0001
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), 0(CH2)AO)OR57, -O(CH2)1C(O)N(R58)(R59), -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and HfO to 5; or a pharmaceutically acceptable salt or hydrate thereof.
[0028] In a further embodiment of the invention, R4 of a compound according to formula III is selected to be a group of the formula
Figure imgf000025_0002
and the ring A is selected to be a phenyl or substituted phenyl to give a compound of the formula IV:
Figure imgf000026_0001
wherein: each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R11JC(O)R11, -N(Rn)SO2Rπ, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)α-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000027_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R 22 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R6 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, - C(O)R51, -C(O)N(R52)(R53), (CH2)eC(O)OR5\ and -(CH2)eC(O)N(R52)(R53), each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; or R6 is selected from a group having the formula:
Figure imgf000028_0001
wherein each R54 and R56 is independently selected from OH, halo, alkyl, cycloalkyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58)(R59), -OC(O)R57, -OC(O)N(R58XR59), 0(CHa)1C(O)OR57, -O(CH2)(C(O)N(R58)(R59), -N(R58)(R59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- memb.ered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is 0 to 4; and Λ if 0 to 5; or a pharmaceutically acceptable salt or hydrate thereof.
[0029] Table 1 provides representative embodiments for compounds of the formula IV.
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0002
[0030] In a preferred embodiment of the invention, R2 of the compound according to the formula IV is selected to be methyl and R6 is selected to be H to give a compound having the formula V:
Figure imgf000056_0001
wherein: each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -0-R11, -N(R12)(R13), -N(R1^C(O)R11, -N(Rπ)SO2Ru, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)^-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000058_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH5 alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0031] hi another embodiment of the invention, R4 of a compound according to the formula II is selected to be a group of the formula
Figure imgf000059_0001
and R6 is combined with R41 to give a compound having the formula VI:
Figure imgf000059_0002
wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(Rn)C(O)Rn, -N(Rn)SO2Rπ, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl; R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R 3, and R44 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)α-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 2 is selected from a group having the formula
Figure imgf000060_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0032] hi a preferred embodiment of the invention, the ring A of the compound according to formula VI is selected to be a phenyl or substituted phenyl to give a compound of the formula VI0:
Figure imgf000061_0001
wherein each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(R11JC(O)R11, -N(R1^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each Rn is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom;
R43, and R44 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)^-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000063_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0033] Table 2 provides representative embodiments for compounds of the formula VI.
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
[0034] In another embodiment of the invention, R4 of a compound according to the formula II is selected to be a group of the formula
Figure imgf000068_0002
and R is combined with R i41 to give a compound having the formula VII:
Figure imgf000069_0001
wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(Rn)C(O)Rπ, -N(Rn)SO2Rn, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R48 and R49 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)α-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000070_0001
5 each R 21 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0035] In a preferred embodiment of the invention, the ring A of the compound according to formula VII is selected to be a phenyl or substituted phenyl to give a compound of the formula VIIα:
Figure imgf000071_0001
wherein each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(Rn)C(O)Rn, -N(R1^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R48 and R49 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)«-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3,
NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and lieteroaryl; or R42 is selected from a group having the formula
Figure imgf000073_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0036] Table 3 provides representative embodiments for compounds of the formula VIL.
Figure imgf000074_0002
[0037] In another embodiment of the invention, R of a compound according to the formula II is selected to be a group of the formula
Figure imgf000074_0001
and R6 is combined with R41 to give a compound having the formula VIII:
Figure imgf000075_0001
wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ling heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(R1^C(O)R11, -N(Rn)SO2Rn, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyϊ, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R3 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl and -(CH2)^-R42 R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 2 is selected from a group having the formula
Figure imgf000076_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R 22 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0038] In a preferred embodiment of the invention, the ring A of the compound according to formula VIII is selected to be a phenyl or substituted phenyl to give a compound of the formula VIII0:
Figure imgf000077_0001
(VIIIfl) wherein each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(R1 ^C(O)R11, -N(R1^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each. R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; Z is selected from O, N-OR461; R4δI is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl and -(CH2)α-R42 R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3,
NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 2 is selected from a group having the formula
Figure imgf000079_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
[0039] In another embodiment of the invention, two compounds of the formula I are linked by a linking group, L, to form a dimeric compound. The two compounds of the formula I which are linked by L to form the dimeric compound may be linked through any position off of the formula I structure. Thus, two compounds of the formula I may be linked through a linking group at the position of R1, R2, R3, R4, or R5. [0040] In one embodiment, the dimeric compound is linked through R of the compounds of formula I. In this embodiment, R4 of a compound according to formula I is selected to be a group of the formula
Figure imgf000080_0001
The resulting "dimeric" compound may be symmetric or unsymmetrical and is represented by the formula X:
Figure imgf000080_0002
(X) wherein: ring A and ring A' are independently selected from 5- or 6- membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms; each R1 and R1' are selected independently from alkyl, alkenyl, alkynyl, aralkyl, -O-R11,
N(R12)(R13),
-N(R1 ^C(O)R11, -N(R1^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12XR13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-alkyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 and R2' are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl; R is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 and R3' are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32XR33);
R3 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which maybe optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R5 and R5' are independently selected from H, OR51, -SR51, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF3, NO25SO2, -SOR51, -SO3R51, - SO2N(R52XR53), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)OR51, -C(O)N(R52XR53), -OC(O)R51, -OC(O)N(R52)(R53), -O(CH2)eC(O)OR51, - O(CH2)eC(O)N(R52)(R53), -N(R52XR53), -N(R51)C(O)R51, and -N(R51)SO2R51 each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, -OR51 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R5 is selected from a group having the formula:
Figure imgf000082_0001
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), O(CH2>C(O)OR57, -0(CH2)AO)N(R58XR59), -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is 0 to 4; and Ms 0 to 5;
L is a linking group selected from -(CH2)x-,
Figure imgf000083_0003
, or a group of the formula
-A-B-A- wherein
A is selected from -N(R)-, -O-, -S-, -C(O)-, -OC(O)-, -N(R)C(O)-,
-N(R)C(O)O-, -N(R)SO2-, -(CH2V, and
Figure imgf000083_0005
;
B is selected from -(CH2),-,
Figure imgf000083_0004
, -(CH2V-D-(CH2V wherein D is selected from O, S, -C=C-, -S-S-,
Figure imgf000083_0001
x is 3 to 25; y is 1 to 10; z is 1 to 10; v is 1 to 8; and w is 1 to 8; or a pharmaceutically acceptable salt or hydrate thereof.
[0041] In another embodiment, the dimeric compound is linked through R5 of the compounds of formula 1. In this embodiment, R5 of a compound according to formula I is selected to be a group of the formula:
Figure imgf000083_0002
The resulting dimeric compound may be symmetric or unsymmetrical and is represented by the formula XI:
Figure imgf000084_0001
wherein ring A and ringyf are independently selected from 5- or 6- membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms; each R1 and R1' are selected independently from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -
N(R12)(R13),
-N(Rn)C(O)Rn, -N(Rπ)SO2Rπ, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-alkyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 and R2' are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl; R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 and R3' are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32XR33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R3 , C(O)R34, -O-R34, -N(R34)(R35), -N(R34)C(O)R34, -N(R34) S O2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 and R4' are selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000085_0001
wherein Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2)Ω-R42
R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
42
-(CH2)β-R
R ,45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)^-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-0-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; 2 is selected from a group having the formula
Figure imgf000086_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R42 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R 26 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
L is a linking group selected from -(CH2)^-,
Figure imgf000086_0005
or a group of the formula
-A-B-A- wherein
A is selected from -N(R)-, -0-, -S-, -C(O)-, -OC(O)-, -N(R)C(O)-,
-N(R)C(O)O-, -N(R)SO2-, -(CH2)r, and
Figure imgf000086_0004
B is selected from -(CH2).--,
Figure imgf000086_0003
-(CH2)V-D-(CH2)>V- wherein D is selected from O, S, -C=C-, -S-S-,
Figure imgf000086_0002
x is 3 to 25; y is 1 to 10; z is 1 to 10; v is 1 to 8; and w is 1 to 8; or a pharmaceutically acceptable salt or hydrate thereof.
[0042] In another aspect of the invention, a synthetic process for the preparation of compounds of the formula I-V is provided. The inventive process uses mild reaction conditions, which provides a high substituent tolerance. The product is obtained in high yield and high purity. A process of the present invention is illustrated by Scheme I:
Scheme I step 1
Figure imgf000087_0001
step 2
Figure imgf000087_0002
D
[0043] Step 1 of Scheme 1 preferably involves using a Sonogashira reaction in which a compound of the formula C is prepared by reacting a compound of the formula A with a terminal alkyne represented by the formula B in the presence of base and a transition metal catalyst, wherein R1, R2, R3, R15 and n are as described above for the compound of the foπnula I. A suitable base may be, for example, an organic base such as a primary, secondary or tertiary amine. Non-limiting examples include triethylamine, diisopropylamine, l,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), l,5-diazabicyclo-[4,3,0]-non-5-ene (DBN), or l,4-diazabicyclo-[2.2.2]-octane (DABCO). Alternatively, an inorganic base may be used, such as an alkali metal or alkaline earth metal salt, such as a carbonate, bicarbonate or acetate salt.
[0044] The metal catalyst may be in the form of a salt or a complex with organic ligands. Particularly suitable metal catalysts are, for example, the Group VIII metals, preferably Pd(O) complexes or a Pd(II) salt. The ligands may be selected from, for example, phosphorus-containing ligands, such as triphenylphosphine (PPh3) and l,2-bis(diphenyl-phosphino)ethane (dppe). Preferred palladium catalysts include Pd(PPh3)2Cl2, Pd(PPh3)4 and Pd(OAc)2. The reaction is performed in the presence of a Cu(I) salt, such as a Cu(I) halide, Cu2O, and CuCN, preferably CuI or CuCl. Suitable organic solvents include, but are not limited to, dioxane, tetrahydrofuran (THF) dimethylformamide (DMF), acetonitrile, dimethylsulfoxide, and other polar aprotic solvents or mixtures thereof. For further discussion of the Sonogashira reaction, see Sonogashira, K.; Tohda, Y,; Hagihara, N. Tetrahedron Lett. 1975, 4467-4470; Sonogashira, K. In Comprehensive Organic Synthesis, Trost, B. M.; Fleming, L., Eds., Pergamon Press: New York, 1991, Vol. 3, chapter 2.4; Liao, Y.; Fathi, R.; Reitman, M.; Zhang, Y.; Yang, Z. Tetrahedron Lett. 2001, 42, 1815-1818; Nicolaou, K. C; Smith, A. L. Ace. Chem. Res. 1992, 25, 497-503; Porco, J. A., Jr.; Schoenen, F. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem. Soc. 1990, 112, 7410-7411; Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729-1731, and references therein; Takeuchi, R.; Tanabe, K.; Tanaka, S. J. Org. Chem. 2000, 65, 1558-1561; Arterburn, J. B.; Rao, K. V.; Perry, M. C. Tetrahedron Lett. 2000, 41, 839-842; Gan, Z.; Roy, R. Tetrahedron Lett. 2000, 41, 1155-1159; Godt, A.; Unsal, O.; Roos, M. J. Org. Chem. 2000, 65, 2837-2842; Wu, M. J.; Lin, C. F.; Chen, S. H. Org. Lett. 1999, 1, 767- 768; Yoshimura, F.; Kawata, S.; Hirama, M. Tetrahedron Lett. 1999, 40, 8281-8286; Ma, S.; Shi, Z.; Yu, Z. Tetrahedron Lett. 1999, 40, 2393-2396; Tretyakov, E. V.; Knight, D. W.; Vasilevsky, S. F. J. Chem. Soc, Perkin Trans. 1, 1999, 3713-3720; Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551-8553; and Sonogashira, K. in Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Wiley-VCH: New York, 1998; Chapter 5, each of which is incorporated by reference.
[0045] Step 2 of Scheme 1 involves a reaction in which a compound of the formula E is prepared by reacting a compound of the formula C with a hydrazine represented by the formula D. In a preferred embodiment, the hydrazine D is added directly to the pot containing the crude intermediate C.
[0046] In another aspect of the invention, a synthetic process for the preparation of compounds of the formula VI-VIII is provided. The inventive process uses mild reaction conditions, which provides a high substituent tolerance. The product is obtained in high yield and high purity. A process of the present invention is illustrated by Scheme II:
Scheme II
Figure imgf000089_0001
F G
[0047] A solution of the pyrazole F in a polar aprotic solvent is added to a mixture of an appropriate Pd0 catalyst (0.05 equiv.), Bpy (0.1 equiv.), base (4 equiv) and ArI (2 equiv.) in a polar aprotic solvent and then stirred for overnight at about 50-700C. Appropriate Pd0 catalysts include Pd(PPh3)4, Pd2(dba)3, 3-Pd2(dba)2/Pt-Bu3, 4- Pd2(dba)3/dppf, and 5-Pd2(dba)2/bpy. The base may be selected from appropriate organic and inorganic bases including carbonate salts (for example, potassium carbonate, sodium carbonate, and cesium carbonate) and acetate salts (for example, sodium acetate). For further discussion of conditions and other modifications see: (a) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280. (b) Arcadi, A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Synlett. 2002, 453. (c) Chaplin, J. H.; Flynn, B. L. Chem. Commun. 2001, 1594. (d) Hu, Y.; Nawoschik, K.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z.; J. Org. Chem. 2004, 69, 2235-2239. (e) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670.
[0048] In alternative embodiments, aryl pyrazoles may be prepared according to the Scheme III:
Scheme III
Figure imgf000090_0001
Figure imgf000090_0002
in which an aryl aldehyde H is treated with p-toluenesulfonyl hydrazide in a polar solvent, followed by treatment with base and N- vinyl imidazole. The resulting pyrazole may be further modified. For example the pyrazole may be alkylated by treatment with a strong base, such as NaH, followed by reaction with an alkylating agent. Alkylating agents may have the structure alkyl-LG, wherein LG represents a leaving group. The pyrazole ring may be further modified, for example, by treatment with iodosuccinimide followed by reaction with a terminal alkyne and metal catalyst, Boronic acid and metal catalyst, alkene and metal catalyst, alkyl tin and metal catalyst, etc. to give diversified derivatives.
[0049] Compounds of the formula VIIa may be prepared, for example, according to Scheme IV: Scheme IV
Figure imgf000091_0001
Compound V may be cyclized by treatment with a metal catalyst such as Nickel, Palladium, and Rhodium in a polar acidic solvent to give compounds Vila.
[0050] Compounds of the formula VIIIa may be prepared, for example, according to Scheme V:
Scheme V
Figure imgf000091_0002
According to Scheme V, compound Villa can be synthesized by treating a 4-chloro-3- carbonyl-coumarin with a hydrazine using microwave in acetic acid conditions at about 150 °C for about 10 mins.
[0051] Dimeric compounds according to the present invention may be prepared according to the schemes provided below:
Figure imgf000091_0003
Figure imgf000092_0001
in which RG is a reactive group and RG' is its reactive partner. For example, RG may be a leaving group, such as tosylate, and RG' may be a nucleophile, such as an amine. Further examples of RG-RG' pairs include: a) an activated carbonyl-containing group, such as an acyl halide or anhydride, which may be reacted with a nucleophile such as -NH2, -OH, etc. b) iodide which maybe reacted with a terminal acetylene using a Sonogashira reaction or with boronic acid using Suzuki coupling, etc.
Other reactive groups/reactive partners will be apparent to the ordinarily skilled worker.
[0052] It may be advantageous to employ a temporary protecting group in achieving the final product. The phrase "protecting group" as used herein means temporary modifications of a potentially reactive functional group which protect it from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
[0053] Further guidance for the synthesis of pyrazoles may be found in, for example, J. Elguero, Comprehensive Heterocyclic Chemistry II, Pergamon Press, Oxford, 1996, v. 3 , p.1. Starting materials useful for preparing compounds of the invention and intermediates thereof may be commercially available or can be prepared by well-known synthetic methods. Other methods for synthesis of the compounds described herein and/or starting materials are either described in the art or will be readily apparent to the skilled artisan, (see, e.g., Harrison et al., "Compendium of Synthetic Organic Methods", VoIs. 1-8 (John Wiley and Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry," Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., "Reagents for Organic Synthesis," Volumes 1-21, Wiley Interscience; Trost et al., "Comprehensive Organic Synthesis," Pergamon Press, 1991; "Theilheimer's Synthetic Methods of Organic Chemistry," Volumes 1-45, Karger, 1991; March, "Advanced Organic Chemistry," Wiley Interscience, 1991; Larock "Comprehensive Organic Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis," 3d Edition, John Wiley & Sons, 1995). Alternatives to the reagents and conditions may be found in the references provided above and in other compendiums well known to the skilled artisan. Accordingly, the synthetic methods and strategies presented herein are illustrative rather than comprehensive.
[0054] The compounds and processes disclosed herein are useful in the production of a library of pyrazole derivatives for biological screening. Derivatives of pyrazole posses a range of biological activities. Pryrazole-based compounds have shown efficacy, for example, as antivirals. Particularly, the compounds of the present invention may be used to prevent or treat infection with HCV.
[0055] The identification of inhibitors of HCV replication and/or proliferation has been facilitated by the development of a cell based system to study HCV replication and assay for HCV inhibitors. Inhibition of HCV replication may be performed using the HCV Replicon Assay developed in the laboratories of Bartenschlager (Lohman et al, Science 285, 110-113, 1999) and Rice (Blight et al, Science 290, 1972-1974, 2000). The assay is performed using the Huh-Luc- Neo cell line (Lohman et al, Science 285, 110- 113, 1999). Huh-Luc- Neo cells are a human hepatoma cell line (Huh-7) stably expressing a bi-cistronic subgenomic replicon containing the HCV IRES in which the structural proteins of HCV had been deleted and replaced by a construct containing sequences coding for the firefly luciferase reporter gene, the neomycin selectable marker and the EMCV IRES to direct expression of a truncated HCV genome expressing the structural proteins NS3, NS4A, NS4B, NS 5 A, and NS5B. HCV targets through which inhibitors could act to inhibit replication include the NS3 protease, the helicase/ATPase, NS5A, the NS5B- RNA dependent RNA polymerase, and the HCV IRES.
[0056] Expression of HCV IRES driven luciferase reporter activity and HCV RNA is measured to obtain indirect and direct measures of replication of HCV RNA respectively. Inhibitors of HCV replication and/or proliferation are determined by initially identifying molecules that inhibit expression of the HCV IRES driven luciferase reporter in this HCV Replicon Luciferase Assay. Cell viability assays and control cell based luciferase assays are then run on hits identified in the HCV Replicon Luciferase Assay to eliminate cytoxic compounds and non-specific compounds which act by inhibiting the luciferase enzyme. Validated inhibitors of HCV replication and/or proliferation are identified by evaluating HCV Replicon Luciferase hits that are specific and non-cytoxic and demonstrating that these compounds inhibit expression of HCV RNA using a quantitative PCR based approach (Taqman) using primers and probes specific for HCV RNA (HCV Replicon RNA Assay).
[0057] The HCV Replicon Assay may be used to predict compound efficacy in treatment and/or prevention of HCV infection as well as inhibition of HCV replication and/or proliferation. The HCV Replicon encompasses a multiplicity of viral and host targets through which an inhibitor could work to inhibit HCV Replication. Viral targets expressed in the HCV Replicon include the HCV IRES (for translation), NS3 Protease, the HCV Helicase/ATPase, NS5A phosphorylation, and the NS5B polymerase. Without being limited to theory, it is believed that the compounds of the present invention inhibit HCV replication. The compounds of the invention may inhibit replication as by acting on the IRES, NS3 protease, NS5B polymerase, Helicase/ATPase, or NS5A phosphorylation. [0058] Thus, in another embodiment, the present invention provides pharmaceutical compositions comprising an anti-HCV effective amount of a compound of formula I, or a pharmaceutically acceptable salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier or auxiliary agent. As used herein, the terms "pharmaceutically acceptable salts" and "hydrates" refer to those salts and hydrated forms of the compound that would favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which those skilled in the art may take into account in the selection include the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.
[0059] The invention also provides a method of treating HCV infection in a mammal, preferable a human, by administering to the mammal an effective amount of a compound of the present invention, a pharmaceutically acceptable salt or hydrate thereof, or a composition as described above. The compounds of the invention may be administered alone or may be administered in combination with other approved therapeutics, such as: an interferon (pegylated or not), preferably α-interferon, ribavirin, or interferon and ribavirin, or one or more other anti-HCV agent, such as an HCV protease inhibitor, HCV polymerase inhibitor, HCV IRES inhibitor, HCV Helicase and/or ATPase inhibitor, NS5A phosphorylation inhibitor, HCV NS2 inhibitor, or other HCV life cycle inhibitor. Combination therapies with may include a compound of the invention with multiple different inhibitors of HCV life cycle (immunomodulatory agents, Toll Like Receptor modulators, antisense therapeutics etc.). The agents that comprise a combination therapy may be administered together or separately, e.g., prior to, concurrently with or following the administration of the compound of the invention or pharmaceutically acceptable salt thereof. These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form. Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit. Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of wherein a compound of formula (I), or a pharmaceutically acceptable salt thereof. [0060] The compounds of the present invention may be employed in solid or liquid form including, for example, amorphous powder or crystalline form, in solution or in suspension. They may be administered in numerous different ways, such as orally, parenterally, topically, transdermally or by inhalation. Oral administration or administration by injection is preferred. The choice of carrier and the content of active compound in the carrier are generally determined in accordance with the solubility and chemical properties of the desired product, the particular mode of administration and well established pharmaceutical practice. The pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the foπnulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques.
[0061] Examples of liquid earners include syrups, peanut oil, olive oil, water, saline and the like. For parenteral administration, emulsions, suspensions or solutions of the compounds according to the invention in vegetable oil, for example sesame oil, groundnut oil or olive oil, or aqueous-organic solutions such as water and propylene glycol, injectable organic esters such as ethyl oleate, as well as sterile aqueous solutions of the pharmaceutically acceptable salts, may be used. Injectable forms must be fluid to the extent they can be easily syringed, and proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prolonged absorption of the injectable compositions can be brought about by use of agents delaying absorption, for example, aluminum monostearate and gelatin. The phaπnaceutical composition may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents. [0062] The pharmaceutical composition of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. Compounds of the invention may be enclosed in hard or soft shell gelatin capsules, or compressed into tablets. Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like. Carriers for oral use (solid or liquid) may include time delay materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax. To prepare a capsule, it may be advantageous to use lactose and a liquid carrier, such as high molecular weight polyethylene glycols.
[0063] Compositions and dosage forms prepared in accordance with the present invention optionally may contain lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silica gels combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for preparing tablets, capsules and the like. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, and capsules may be coated with shellac, sugar or both. When aqueous suspensions are used they may contain emulsifying agents or agents which facilitate suspension. Diluents such as sucrose, ethanol, polyols such as polyethylene glycol, propylene glycol and glycerol, and mixtures thereof also may be used, hi addition, the active compound may be incorporated into sustained-release preparations and formulations. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Other suitable vehicles or carriers for the above noted formulations and compositions can be found in standard pharmaceutical texts, e.g. in "Remington's Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19.sup.th Ed. Mack Publishing Company, Easton, Pa., (1995).
[0064] When these compounds or their pharmaceutically acceptable salts are formulated together with a pharmaceutically acceptable carrier, the resulting composition may be administered in vivo to mammals, such as man, to treat or prevent HCV virus infection. Such treatment may also be achieved using a compound of this invention in combination with other anti- viral agents which include, but are not limited to a-interferon and ribavirin. The additional agents may be combined with compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form.
EXAMPLES
General Methods
[0065] Reaction solvents were commercially purchased from Aldrich or Acros without further purification and reagents were used as received. Reaction was monitored by thin-layer chromatography (TLC) on 0.25 mm precoated Merck Silica Gel 60 F254, visualizing with ultraviolet light. Flash column chromatography was performed on Merck Silica Gel 60 (230-400 mesh) using reagent grade hexanes, dichloromethane, and ACS grade ethyl acetate, and methanol. LC-MS was performed on Water Separation. 1H and 13C NMR spectra were recorded on a Varian Unity INPVA 500 MHz spectrometer, CDCl3 as solvent, TMS as internal reference. 1H-1H coupling are assumed to be first order, and peak multiplicity is reported as a s (single), d (doublet), t (triplet), q (quartet), m (multiplet), or b (broad).
Example 1
General Procedure for Synthesis ofPyrazole 8, 9D-20D
Figure imgf000098_0001
[0066] A mixture of iodochromone A (0.5 mmol), acetylene B (0.6 mmol), copper (I) iodide (0.01 mmol), and dichloribis(triphenylphosphine)palladium (0.005 mmol) in CH3CN (6 ml) was added with DIEPA (2 mmol) and then stirred for 5 h at room temperature. The reaction mixture was treated with hydrazine C (I mmol) and stirred at RT overnight. After evaporation, the crude product was directly purified by a flash column chromatography to give the pure product.
Figure imgf000099_0001
Compound 8
[0067] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 8 in 92 % yield. 1H NMR: δ 10.70 (s, IH), 8.58 (dd, J= 8.0, 1.5 Hz, IH), 7.65 (s, IH), 7.55 (dd, J= 7.5, 1.5 Hz, 2H), 7.36 (m, 3H), 7.26 (m, IH), 7.05 (dd, J= 8.5, 1.5 Hz, IH), 6.97 (td, J= 7.5, 1.5 Hz), 3.97 (s, 3H); 13C NMR: δ 155.9, 150.4, 134.5, 131.2, 129.7, 128.4, 128.2, 127.1, 123.4, 119.1, 116.9, 116.7, 100.8, 92.6, 81.4, 39.3. LC-MS: m/z, 275 (M+l).
Figure imgf000099_0002
Compound 9D
[0068] Purification by a flash chromatography (Hexanes/EtOAc = 2/1 ) gave 9D in 72 % yield. 1H NMR: δ 10.71 (s, IH), 8.58 (dd, J= 8.0, 1.5 Hz, IH), 7.58 (s, IH), 7.42 (d, J= 7.5 Hz, 2H), 7.25 (m, IH), 7.17 (d, J= 7.5 Hz, 2H), 7.04 (dd, J= 8.0, 1.0 Hz, IH), 6.94 (td, J= 7.0, 1.0 Hz), 3.97 (s, 3H), 2.37 (s, 3H); 13C NMR: δ 155.9, 150.3, 138.4, 134.4, 131.1, 129.6, 129.2, 127.1, 120.3, 119.1, 116.9, 116.7, 100.9, 92.7, 80.7, 39.2, 21.5. LC-MS: m/z, 289 (M+l).
Figure imgf000099_0003
Compound 1OD
[0069] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 1OD in 78 % yield. 1HNMR: δ 10.72 (s, IH), 8.57 (dd, J= 7.5, 1.0 Hz, IH), 7.58 (s, IH), 7.46 (d, J= 9.0 Hz, 2H), 7.23 (td, J= 8.5, 1.5 Hz, IH), 7.03 (d, J= 8.5 Hz, IH), 6.94 (t, J= 7.5 Hz, IH), 6.89 (d, J= 9.0 Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H); 13C NMR: δ 159.6, 155.9, 150.2, 134.3, 132.7, 129.6, 127.1, 119.0, 116.9, 116.8, 115.5, 114.1, 101.1, 92.5, 79.9, 55.3, 39.2.
Figure imgf000100_0001
Compound HD
[0070] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave HD in 63 % yield. 1HNMR: δ 10.64 (s, IH), 8.50 (dd, J= 7.5, 1.5 Hz, IH), 7.64 (s, IH), 7.45 (d, J= 9.0 Hz5 2H), 7.34 (d, J= 9.0 Hz, 2H), 7.26 (td, J= 8.5, 1.5 Hz, IH), 7.04 (d, J= 7.5 Hz, IH), 6.96 (t, J= 7.5 Hz, IH), 3.96 (s, 3H); 13C NMR: δ 156.0, 150.6, 134.5, 134.2, 132.4, 129.8, 128.8, 127.0, 121.9, 119.1, 117.0, 116.6, 100.5, 91.5, 82.4, 39.3; LC- MS: m/z, 309 (M+l).
Figure imgf000100_0002
Compound 12D
[0071] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 12D in 54 % yield. 1H NMR: δ 10.64 (s, IH), 8.40 (dd, J= 8.0, 1.0 Hz, IH), 7.54 (s, IH), 7.24 (t, J= 8.0 Hz, IH), 7.02 (d, J= 8.5 Hz, IH), 6.93 (t, J= 7.5 Hz, IH), 3.92 (s, 3H), 2.67 (t, J= 6.5 Hz, 2H), 2.57 (t, J= 7.5 Hz, 2H), 1.99 (m, 2H); 13C NMR: δ 155.8, 150.2, 134.6, 129.7, 126.7, 119.1, 118.9, 117.0, 116.7, 100.6, 90.3, 74.3, 39.2, 24.6, 18.8, 16.3; LC- MS: m/z, 264 (M+-I).
Figure imgf000101_0001
Compound 13D
[0072] Purification by a flash chromatography (Hexanes/EtOAc = 1/1) gave 13D in 74 % yield. 1H NMR: δ 10.64 (s, IH), 8.44 (dd, J= 8.0, 1.5 Hz, IH), 7.58 (s, IH), 7.23 (t, J= 8.5 Hz, IH), 7.02 (d, J= 8.5 Hz, IH), 6.92 (t, J= 7.5 Hz, IH), 4.38 (s, 2H), 3.92 (s, 3H), 3.47 (s, 3H); 13C NMR: δ 155.9, 150.5, 135.1, 129.7, 127.0, 119.0, 117.0, 116.5, 100.1, 88.6, 78.4, 60.6, 57.7, 39.2; LC-MS: m/z, 242 (M+).
Figure imgf000101_0002
Compound 14D
[0073] Purification by a flash chromatography (Hexanes/EtOAc = 3/1) gave 14D in 67 % yield. 1HNMR: δ 10.63 (s, IH), 8.29 (d, J= 8.0 Hz, IH), 7.50 (s, IH), 7.48 (m, 2H), 7.33 (t, J= 8.0 Hz, 2H), 7.20 (m, 2H), 7.00 (d, J= 8.0 Hz, IH), 6.77 (t, J= 7.5 Hz, IH), 3.91 (s, 2H), 3.88 (s, 3H); 13C NMR: δ 155.8, 150.5, 135.3, 134.8, 130.0, 129.6, 129.0, 127.0, 126.9, 119.1, 116.8, 116.5, 100.3, 88.6, 75.4, 39.2, 23.9.
Figure imgf000101_0003
Compound 15D
[0074] Purification by a flash chromatography (Hexanes/EtOAc = 1/1) gave 15D in 84 % yield. 1H NMR: δ 10.65 (s, IH), 8.48 (d, J= 8.0 Hz, IH), 7.50 (s, IH), 7.23 (t, J = 8.0 Hz, IH), 7.00 (d, J= 8.0 Hz, IH), 6.88 (t, J= 7.5 Hz, IH), 3.86 (s, 3H), 2.35 (bs, IH), 2.05 (m, 2H), 1.77-1.57 (bm, 8H); 13C NMR: δ 155.8, 150.3, 134.7, 129.6, 127.0, 118.8, 116.9, 116.6, 100.3, 96.3, 76.2, 69.4, 39.9, 39.1, 25.2, 23.3; LC-MS: m/z, 297 (M+l).
Figure imgf000102_0001
Compound 16D
[0075] Purification by a flash chromatography (Hexanes/EtOAc = 1/1) gave 16D in 82 % yield. 1HNMR: δ 10.61 (s, IH), 8.58 (dd, J= 8.5, 1.5 Hz, IH), 7.78 (s, IH), 7.43 (d, J= 8.0 Hz, 2H), 7.28 (td, J= 8.5, 1.5 Hz, IH), 7.18 (d, J= 8.0 Hz, IH), 7.04 (d, J= 8.5 Hz, IH), 6.96 (t, J= 8.0 Hz, IH), 4.30 (t, J= 5.0 Hz, 2H), 4.06 (t, J= 5.0 Hz, 2H), 2.39 (s, 3H); 13C NMR: δ 155.8,150.8, 138.5, 134.9, 131.2, 129.8, 129.2, 127.3, 120.2, 119.2, 116.9, 116.7, 101.1, 92.9, 80.5, 61.2, 54.6, 21.5; LC-MS: m/z, 319 (M+l).
Figure imgf000102_0002
Compound 17D
[0076] Purification by a flash chromatography (Hexanes/EtOAc = 3/1) gave 17D in 43 % yield. 1H NMR: δ 10.71 (s, IH), 8.58 (dd, J= 8.0, 1.5 Hz, IH), 7.63 (s, IH), 7.38 (bm, 5H), 7.27 (m, 3H), 7.16 (d, J= 7.5 Hz, 2H), 7.03 (d, J= 8.0 Hz, IH), 6.94 (t, J= 7.0 Hz, IH), 5.31 (s, 2H), 2.37 (s, 3H); 13C NMR: δ 156.0, 150.4, 138.4, 134.9, 133.7, 131.1, 129.7, 129.2, 129.1, 128.7, 128.0, 127.2, 120.2, 119.1, 116.9, 116.7, 101.3, 92.9, 80.6, 56.4, 21.5.
Figure imgf000103_0001
Compound 18D
[0077] Purification by a flash chromatography (Hexanes/EtOAc = 3/1) gave 18D in 57 % yield. 1E NMR: δ 10.49 (s, IH), 8.43 (d, J= 2.0 Hz, IH), 7.59 (s, IH), 7.43 (d, J = 8.0 Hz, 2H), 7.17 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 8.0, 2.0 Hz, IH), 6.93 (d, J= 7.5 Hz, IH), 3.92 (s, 3H), 2.37 (s, 3H)5 2.34 (s, 3H); 13C NMR: δ 153.7, 150.4, 138.3, 134.2, 130.9, 130.3, 129.2, 127.9, 127.5, 120.4, 116.6, 116.3, 100.9, 92.8, 81.0, 39.2, 21.5, 20.8.
Figure imgf000103_0002
Compound 19D
[0078] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 19D in 67 % yield. 1H NMR: δ 10.69 (s, IH), 8.70 (d, J= 2.5 Hz, IH), 7.62 (s, IH), 7.49 (d, J = 8.0 Hz, 2H), 7.19 (m, 3H), 6.97 (d, J= 8.0 Hz, IH), 3.93 (s, 3H), 2.37 (s, 3H); 13C NMR: δ 154.6, 149.0, 138.5, 134.1, 131.0, 129.3, 129.2, 126.6, 123.8, 120.0, 118.2, 117.8, 101.4, 93.7, 80.2, 39.3, 21.5.
Figure imgf000103_0003
Compound 2OD
[0079] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 2OD in 90 % yield. 1H NMR: δ 11.63 (s, IH), 9.70 (s, IH), 8.15 (dd, J= 9.0, 2.5 Hz, IH), 7.66 (s, IH), 7.58 (d, J= 7.5 Hz, 2H), 7.21 (d, J= 8.0 Hz, 2H), 7.06 (d, J= 9.0 Hz, IH), 3.97 (s, 3H), 2.38 (s, 3H); 13C NMR: δ 161.7, 148.1, 141.8, 138.8, 134.5, 131.4, 129.3, 125.3, 123.3, 119.7, 117.5, 116.7, 102.0, 94.8, 79.2, 39.4, 21.5. Example 2
General Procedure for Synthesis ofPyrazolo[3,4]benzopyran 1E~12E
Figure imgf000104_0001
[0080] To a mixture of Pd2(dba)3 (O.Olmmol), Bpy (0.02 mmol), K2CO3 (0.8 mmol) and ArI (0.4 mmol) in DMF (3 mL) was added with the DMF (1 mL) solution of Pyrazole D (0.2 mmol) and then stirred for overnight at 60 0C. The reaction mixture was added with aq. NH4Cl (10 ml) and then extracted with EtOAc (3 x 20 mL). The organic phase was washed by H2O, brine and then dried over Na2SO4. After evaporation, the crude product was directly purified by a flash column chromatography to give the pure product.
Figure imgf000104_0002
Compound IE
[0081] Purification by a flash chromatography (Hexanes/EtOAc = 1/1) gave IE in 74 % yield. 1H NMR: δ 8.04 (d, J= 8.5 Hz, 2H), 7.78 (dd, J= 8.0, 1.5 Hz, IH), 7.45 (d, J= 8.5 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H) 7.25 (td, J= 9.0, 1.5 Hz, IH), 7.12 (d, J= 7.5 Hz, 2H), 7.06 (m, 2H), 5.93 (s, IH), 3.73 (s, 3H), 2.68 (s, 3H), 2.35 (s, 3H); 13C NMR: δ 197.9, 152.5, 146.6, 143.5, 141.1, 136.1, 135.9, 135.8, 131.8, 129.5, 129.4, 129.3, 128.6, 128.0, 122.6, 121.8, 116.3, 116.0, 114.2, 111.7, 39.4, 26.7, 21.2; LC-MS: m/z, 407 (M+l).
Figure imgf000105_0001
Compound 2E
[0082] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 2E in 78 % yield. 1H NMR: δ 7.77 (d, J= 7.5 Hz, IH), 7.42 (d, J= 6.0 Hz, 2H), 7.20 (bm, 5H) 7.10 (d, J= 8.0 Hz, 2H), 7.04 (d, J= 8.0 Hz, IH), 7.01 (t, J= 7.0 Hz, IH), 5.75 (s, IH), 3.67 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H); 13C NMR: δ 152.6, 143.3, 140.8, 138.0, 136.4, 135.3, 131.1, 130.2, 129.3, 129.2, 128.4, 128.3, 122.3, 121.6, 116.2, 114.8, 112.2, 39.1, 21.4, 21.14; LC-MS: m/z, 379 (M+l).
Figure imgf000105_0002
Compound 3E
[0083] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 3E in 74 % yield. 1H NMR: δ 7.78 (d, J= 7.5 Hz, IH), 7.44 (d, J= 8.0 Hz, 2H), 7.38 (t, J= 7.5 Hz, IH), 7.24 (m, IH) 7.12 (d, J= 7.5 Hz, 2H), 7.05 (d, J= 7.5 Hz, IH), 7.03 (t, J= 7.5 Hz, IH), 6.96 (dd, J= 7.0, 1.0 Hz, IH), 6.92 (d, J= 7.5 Hz, IH), 6.84 (s, IH), 5.76 (s, IH), 3.79 (s, 3H), 3.72 (s, 3H), 2.34 (s, 3H); 13C NMR: δ 160.6, 152.6, 143.3, 142.4, 140.9, 136.0, 135.5, 130.4, 129.4, 129.1, 128.5, 128.4, 123.7, 122.4, 121.7, 116.2, 116.1, 116.1, 114.7, 113.6, 112.1, 55.3, 39.2, 21.1; LC-MS: m/z, 395 (M+l).
Figure imgf000106_0001
Compound 4E
[0084] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 4E in 72 % yield. 1B. NMR: δ 7.79 (d, J= 8.0 Hz, IH), 7.72 (d, J= 7.5 Hz, 2H), 7.47 (d, J=
7.5 Hz, 2H), 7.34 (d, J= 8.0 Hz, 2H), 7.25 (d, J= 6.0 Hz, IH), 7.13 (d, J= 7.5 Hz, 2H),
7.06 (t, J= 8.0 Hz, 2H), 5.79 (s, IH), 3.73 (s, 3H), 2.35 (s, 3H); 13C NMR: δ 152.4, 145.2, 143.5, 141.3, 135.8, 132.0, 129.5, 129.2, 128.6, 127.9, 126.4, 126.3, 122.6, 121.8, 116.2, 115.9, 113.8, 111.6, 39.3, 21.2; LC-MS: m/z, 433 (M+l).
Figure imgf000106_0002
Compound 5E
[0085] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 5E in 80 % yield. 1HNMR: δ 7.78 (d, J= 8.0 Hz, IH), 7.38 (m, 4H), 7.32 (s, IH), 7.23 (m, 2H), 7.13 (d, J= 8.0 Hz, 2H), 7.04 (t, J= 8.0 Hz, 2H), 5.82 (s, IH), 3.72 (s, 3H), 2.34 (s, 3H); 13C NMR: δ 152.4, 143.4, 143.0, 141.3, 135.8, 135.7, 135.1, 131.5, 130.7, 129.7, 129.4, 129.2, 128.6, 128.1, 127.7, 122.5, 121.7, 116.2, 116.0, 113.7, 111.7, 39.3, 21.2; LC-MS: m/z, 399 (M+l).
Figure imgf000106_0003
Compound 6E [0086] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 6E in 62 % yield. 1H NMR: δ 7.79 (d, J= 7.5 Hz, IH), 7.35 (d, J= 7.0 Hz, 2H), 7.24 (t, J= 8.5 Hz, 2H), 7.13 (m, 3H), 7.04 (m, 3H), 5.92 (s, IH), 3.77 (s, 3H), 2.34 (s, 3H); 13C NMR: δ 152.4, 152.0 (d, J= 12.8 Hz), 150.9 (d, J= 12.8 Hz), 149.9 (d, J= 12.8 Hz), 148.9 (d, J= 12.3 Hz), 143.4, 141.4, 138.0 (t, J= 5.0 Hz), 135.8, 135.7, 129.5, 129.0, 128.6, 127.7, 127.7 (t, J= 3.0 Hz), 122.6, 121.7, 120.3 (d, J= 15.5 Hz), 118.2 (d, J= 16.5 Hz), 116.2, 115.9, 113.0, 111.6, 39.3, 21.1; LC-MS: m/z, 401 (M+l).
Figure imgf000107_0001
Compound 7E
[0087] Purification by a flash chromatography (Hexanes/EtOAc = 3/1) gave 7E in 78 % yield. 1H NMR: δ 8.06 (d, J= 8.0 Hz, 2H), 7.79 (d, J= 6.5 Hz, IH), 7.45 (d, J= 8.0 Hz, 2H), 7.38 (d, J= 7.0 Hz, 2H), 7.25 (t, J= 8.5 Hz, IH), 7.06 (t, J= 8.0 Hz, 2H), 6.86 (d, J= 7.0 Hz, 2H), 5.92 (s, IH), 3.82 (s, 3H), 3.72 (s, 3H), 2.68 (s, 3H); 13C NMR: δ 197.9, 157.8, 152.5, 146.7, 143.4, 140.6, 136.1, 131.8, 131.4, 130.6, 129.5, 129.4, 127.9, 122.6, 121.8, 116.2, 116.0, 113.9, 113.3, 111.7, 55.2, 39.4, 26.7; LC-MS: m/z, 423 (M+l).
Figure imgf000107_0002
Compound 8E
[0088] Purification by a flash chromatography (Hexanes/EtOAc = 3/1) gave 8E in 50 % yield. 1H NMR: δ 8.06 (d, J= 7.5 Hz, 2H), 7.81 (d, J= 7.5 Hz, IH), 7.44 (d, J= 7.0 Hz, 2H), 7.37 (d, J= 7.0 Hz, 2H), 7.28 (m, 2H), 7.09 (t, J= 7.5 Hz, IH), 7.05 (d, J= 8.0 Hz, IH), 5.95 (s, IH), 3.74 (s, 3H), 2.68 (s, 3H); 13C NMR: δ 197.7, 152.2, 146.0, 143.5, 142.0, 137.3, 136.3, 131.8, 131.6, 130.7, 129.6, 129.5, 128.2, 128.0, 122.8, 121.9, 116.2, 115.9, 112.9, 111.3, 39.4, 26.7; LC-MS: m/z, 427 (M+l).
Figure imgf000108_0001
Compound 9E
[0089] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 9E in 68 % yield. 1H NMR: δ 8.02 (d, J= 8.0 Hz, 2H), 7.75 (d, J= 7.5 Hz, IH), 7.36 (d, J= 7.5 Hz, 2H), 7.26 (t, J= 7.5 Hz, IH), 7.17 (d, J= 7.5 Hz, IH), 7.04 (t, J= 8.0 Hz, IH), 6.07 (s, IH), 3.70 (s, 3H), 2.80 (t, J= 7.5 Hz, 2H), 2.65 (s, 3H), 2.42 (t, J= 7.5 Hz, 2H), 1.77 (m, 2H); 13C NMR: δ 197.7, 152.6, 145.8, 143.1, 141.6, 136.2, 130.2, 129.6, 129.4, 127.5, 122.5, 121.8, 119.9, 116.1, 115.8, 111.8, 110.6, 39.3, 30.3, 26.7, 23.8, 16.6; LC- MS: m/z, 384 (M+l).
Figure imgf000108_0002
Compound 1OE
[0090] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave 1OE in 52 % yield. 1R NMR: δ 8.04 (d, J= 8.0 Hz, 2H), 7.60 (s, IH), 7.44 (d, J= 7.5 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 7.11 (d, J= 8.0 Hz, 2H), 7.05 (d, J= 8.5 Hz, IH), 6.94 (d, J= 8.0 Hz, IH), 5.91 (s, IH), 3.71 (s, 3H), 2.67 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H); 13C NMR: δ 197.9, 150.5, 146.8, 143.6, 141.3, 136.0, 136.0, 135.7, 132.0, 131.8, 130.2, 129.4, 129.3, 128.6, 128.5, 128.0, 121.9, 115.9, 115.5, 113.9, 111.7, 39.3, 26.7, 21.2, 20.7; LC- MS: m/z, 421 (M+l).
Figure imgf000109_0001
Compound HE
[0091] Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave HE in 91 % yield. 1H NMR: δ 8.05 (d, J= 7.0 Hz, 2H), 7.76 (s, IH), 7.44 (d, J= 7.5 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.5 Hz, IH), 7.12 (d, J= 8.0 Hz, 2H), 6.96 (d, J= 7.5 Hz, IH), 5.92 (s, IH), 3.73 (s, 3H), 2.68 (s, 3H), 2.35 (s, 3H); 13C NMR: δ 197.8, 150.9, 146.3, 142.4, 140.6, 136.2, 136.1, 135.6, 131.6, 129.4, 129.3, 129.2, 128.6, 128.1, 127.7, 121.5, 117.5, 117.4, 114.8, 111.8, 39.4, 26.7, 21.2; LC-MS: m/z, 441 (M+l).
Figure imgf000109_0002
Compound 12E
[0092] Purification by a flash chromatography (Hexanes/EtOAc = 1/1) gave 12E in 81 % yield. 1H NMR: δ 8.66 (s, IH), 8.12 (d, J= 8.0 Hz, IH), 8.07 (d, J= 7.5 Hz, 2H), 7.45 (d, J= 6.5 Hz, 2H), 7.29 (d, J= 8.0 Hz, 2H), 7.15 (d, J= 7.0 Hz, 2H), 7.07 (d, J= 8.5 Hz, IH), 5.98 (s, IH), 3.76 (s, 3H), 2.69 (s, 3H), 2.37 (s, 3H); 13C NMR: δ 197.7, 156.7, 145.6, 142.9, 141.4, 140.0, 136.7, 136.4, 135.1, 131.4, 129.5, 129.4, 128.8, 128.2, 124.9, 117.9, 116.8, 116.8, 111.6, 39.6, 26.7, 21.2; LC-MS: m/z, 452 (M+l). Example 3
Figure imgf000110_0001
5O 0C
Procedure for Synthesis of 2.
[0093] The aldehyde 1 (1.5 mmol) was added to a solution of p-Toluenesulfonyl hydrazide (1.5 mmol) in acetonitrile (250 mL). After the mixture was stirred for 3 h at room temperature, a solution of 5 N NaOH (1.5 mmol) was added and the mixture was stirred for a further 20 min. The N-vinylimidazole (7.5 mmol) was added, and the mixture was stirred at 50 0C for 2 days. The volatiles were evaporated under reduced pressure, and the residue was dissolved in a 1:1 mixture OfH2O-EtOAc (70 mL). The organic layer was separated and dried over Na2SO4. After filtration and removal of the solvent under reduced pressure, the crude material was purified by flash chromatography on silica gel to give pure product 2 in 40% yield.
1H NMR: δ 7.71 (d, J= 8 Hz, IH), 7.69 (d, J= 8 Hz, IH), 7.59 (d, J= 2.5 Hz, IH), 7.58 (t, J= 7.5 Hz, IH), 7.47 (t, J= 7.5 Hz, IH), 6.47 (d, J= 2.5 Hz, IH). LC-MS: (4.01 min, m/z, ES+): calcd: 189.05; Found: 190.08.
Procedure for Synthesis of 3 and 4.
[0094] To the suspension of NaH (1.15 mmol) in dry THF (2 mL), 2 (0.53 mmol) in THF (3 mL) was added dropwise. After added up, the given mixture was stirred for 20 min at room temperature and then iodomethane (2.57 mmol) was added slowly. Stirred overnight, the reaction was quenched with H2O and extracted with EtOAc. After removal of the solvent, the residue was purified by flash chromatography to afford 3 (49% yield) and 4 (22% yield). 3 i:. 11HNMR: δ 7.73 (d, J= 8 Hz, IH), 7.69 (d, J= 8 Hz, IH), 7.57 (t, J= 7.0 Hz, IH), 7.43 (t, J= 7.0 Hz, IH), 7.39 (d, J= 2.5 Hz, IH), 6.38 (d, J= 2.5 Hz, IH), 3.94 (s, 3H). LC-MS: (4.44 min, m/z, ES+): calcd: 203.07; Found: 204.06.
4 i .: i 1H NMR: δ 8.08 (d, J= 8.5 Hz, IH), 7.71 (t, J= 7.5 Hz, IH), 6.64 (t, J= 8.5 Hz, IH), 7.54 (d, J = 1.5 Hz, IH), 7.45 (d, J= 7.0 Hz, IH), 6.25 (d, J= 2.0 Hz, IH), 3.70 (s, 3H). LC-MS: (4.40 min, m/z, ES+): calcd: 203.07; Found: 204.06.
Example 4
Figure imgf000111_0001
General Procedure for Synthesis of 5.
[0095] The mixture of 3 (2.94 mmol) and N-Iodosuccinimide (4.41 mmol) in DMF (5.0 niL) was stirred for 3 days at room temperature. The DMF was removed in vacuo, the residue was dissolved in EtOAc and washed with TSIa2SO3, brine and dried over MgSO4. After removal of the solvent, the residue was purified by flash chromatography on silica gel (eluent: EtO Ac/Petroleum = 1:3) to give 5 in 84% yield.
1H NMR: δ 7.99 (d, J= 8.0 Hz, IH), 7.65 (t, J= 8.0 Hz, IH), 7.55 (d, J= 8.0 Hz, IH), 7.55 (t, J= 8.0 Hz, IH), 7.49 (s, IH), 3.94 (s, 3H). LC-MS: (4.63 min, m/z, ES+): calcd: 328.97; Found: 329.93.
General Procedure for Synthesis of 6.
[0096] To a degassed solution of 5 (0.15 mmol), CuI (0.003 mmol) and Et3N (0.6 mmol) in dry benzene (1 mL), Pd(PPh3)4 (0.015 mmol) and 3, 3 -Dimethyl- 1-butyne (0.6 mmol) was added sequentially at room temperature and the reaction mixture was stirred overnight. The reaction mixture was filtered over Celite and washed with EtOAc. After removal of the solvent, the residue was purified by flash chromatography on silica gel (eluent: EtOAc/ petroleum ether = 1:3) to give 6 in 88% yield.
1H NMR: δ 7.91 (d, J= 8.0 Hz, IH), 7.76 (d, J= 8.0 Hz, IH), 7.61 (t, J= 8.0 Hz, IH), 7.49 (t, J= 8.0 Hz, IH), 7.45 (s, IH), 3.81 (s, 3H), 1.22 (s, 9H). LC-MS: (5.45 min, m/z, ES+): calcd: 283.13; Found: 284.07.
Example 5
Figure imgf000112_0001
Procedure for Synthesis of 7.
[0097] 7 was synthesized in 80% yield by similar procedure as of 5.
1H NMR: δ 8.18 (d, J= 8.0 Hz, IH), 7.76 (t, J= 8.0 Hz, IH), 7.69 (t, J= 8.0 Hz, IH), 7.52 (s, IH), 7.38 (d, J= 8.0 Hz, IH), 3.72 (s, 3H). LC-MS: (4.62 min, m/z, ES+): calcd: 328.97; Found: 329.93.
Procedure for Synthesis of SA.
[0098] 8A was synthesized in 86% yield by similar procedure as of 6.
1H NMR: δ 8.11 (d, J= 8.5 Hz, IH), 7.11 (t, J= 7.5 Hz, IH), 7.63 (t, J= 8.0 Hz, IH), 7.51 (s, IH), 7.44 (d, J= 8.0 Hz, IH) 3.69 (s, 3H), 1.07 (s, 9H). LC-MS: (5.45 min, m/z, ES+): calcd: 283.13; Found: 284.07.
Ill Example 6
Figure imgf000113_0001
General Procedure for Synthesis of8B.
[0099] A solution of 8A (0.16 mmol), zinc dust (0.8 mmol) and CaSO4 (0.8 mmol) in 4:1 ethanol/EkO (2mL) was refluxed for 3 h. The reaction mixture was filtered over Celite and washed with 4:1 ethanol/H2O. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (eluent: EtOAc: Petroleum ether = 1 :3) to afford pure product 8B in 92% yield.
1H NMR: δ 7.59 (s, IH), 7.23 (t, J= 6.5 Hz, IH), 7.11 (d, J= 7.0 Hz, IH), 6.82 (t, J= 6.5 Hz, IH), 6.79 (d, J- 8.5 Hz, IH), 3.80 (br, 2H), 3.72 (s, 3H), 1.18 (s, 9H). 13C NMR: δ ' 145.418, 142.861, 141.149, 131.373, 130.602, 118.385, 116.133, 114.578, 103.843, 101.117, 70.265, 37.714, 31.199, 28.229. LC-MS: (5.12 min, m/z, ES+): calcd: 253.16; Found: 254.14.
Example 7
Figure imgf000113_0002
Procedure for Synthesis of 9.
[00100] A solution of 6 (0.06 mmol) in EtOH (1 mL) was added to a solution of zinc dust (3.07 mmol) and acetic acid (1.5 mL). The reaction mixture was stirred overnight under reflux. The reaction mixture was filtered over Celite and washed with EtOAc. The filtrate was adjusted to pH 7 with 5% NaHCO3, washed with H2O, dried over Na2SO4 and taken to dryness under reduced pressure. The crude was purified flash chromatography (eluent: EtO Ac/Petroleum = 1 :3) to give 9 in 32% yield.
1H NMR: δ 8.44 (d, J= 8.0 Hz, IH), 8.08 (d, J= 7.5 Hz, IH), 8.02 (s, IH), 7.65 (t, J= 8.0 Hz, IH), 7.55 (t, J= 8.0 Hz, IH), 4.28 (s, 3H), 3.0 (s, 2H), 1.08 (s, 9H). LC-MS: (3.56 min, m/z, ES+): calcd: 253.16; Found: 254.20.
Figure imgf000114_0001
Procedure for Synthesis of 10.
[00101] Compound 10 was synthesized in 89% yield by similar procedure as of 8B.
1H NMR: δ 8.22 (d, J= 9.0 Hz, IH), 7.48 (s, IH), 7.13 (t, J= 8.5 Hz, IH), 6.75 (d, J= 7.5 Hz, IH), 6.74 (t, J= 8.0 Hz, IH), 5.27 (br, IH), 3.89 (s, 3H), 1.31 (s, 9H). 13C NMR: δ 151.464, 145.140, 133.680, 129.608, 128.879, 116.891, 116.622, 116.327, 102.262, 100.998, 71.635, 39.346, 31.121, 28.462. LC-MS: (4.42 min, m/z, ES+): calcd: 253.16; Found: 254.20. Example 11
Figure imgf000115_0001
General Procedure for Synthesis of 12.
[00102] The mixture of 11 and R1R2NH (5 equiv.) was heated to 80 0C in Pyridine overnight. After removal of the solvent, the residue was purified by flash chromatography on silica gel (eluent: EtO Ac/Petroleum ether = 1:3) to give 12 as yellow solid.
Figure imgf000115_0002
99% yield. 1H NMR: δ 9.40 (s, IH), 8.59 (br, IH), 8.10 (d, J= 8.5 Hz, IH), 7.58 (s, IH), 6.62 (d, J= 8.5 Hz, IH), 6.05-5.90 (m, IH), 5.40-5.20 (m, 2H), 3.90 (s, 3H), 1.36 (s, 9H). LC-MS: (4.01 min, m/z, ES+): calcd: 338.17; Found: 339.20.
Example 12
Figure imgf000115_0003
12
Procedure for Synthesis of 13 and 14. [00103] A mixture of 12 (0.08 mmol), 10% Pd/C and additives (CF3SO3H or BF3- Et2O, 0.08 mmol)) in absolute ethanol (1 mL) was heated to 95 0C for 1.5 h. The reaction mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by plate chromatography (eluent: EtO Ac/Petroleum ether = 1 : 1) to give 13 (31% yield) and 14 (46% yield).
13: 1H NMR: δ 9.36 (d, J= 2.5 Hz, IH), 8.44 (dd, J= 9.0, 2.5 Hz, IH), 8.16 (d, J= 9.0 Hz, IH), 8.12 (s, IH), 4.32 (s, 3H), 3.02 (s, 2H), 1.18 (s, 9H). 13C NMR: δ 161.488, 148.072, 145.227, 130.675, 127.666, 127.502, 122.625, 119.168, 118.906, 118.734, 51.028, 40.920, 33.322, 30.626. LC-MS: (3.80 min, m/z, ES+): calcd: 298.14; Found: 299.19.
14: 1H NMR: δ 11.01 (s, IH), 9.19 (d, J= 2.5 Hz, IH), 8.17 (dd, J= 9.0, 2.5 Hz, IH), 7.99 (s, IH), 7.08 (d, J= 9.0 Hz, IH), 4.04 (s, 3H), 2.70 (s, 2H), 1.09 (s, 9H). 13C NMR: δ 161.836, 148.921, 140.550, 136.261, 127.402, 126.121, 123.207, 118.137, 117.177, 54.454, 39.803, 32.097, 30.403. LC-MS: (3.81 min, m/z, ES+): calcd: 317.14; Found: 318.15.
Example 13
Figure imgf000116_0001
Procedure for Synthesis of 15.
[00104] To a degassed solution of 12 (19.5 mmol) and N, N'-dimethylbarbituric acid (NDMBA, 39.0 mmol) in dry CH2Cl2 (200 mL), Pd(PPh3)4 (3.9 mmol) was added quickly and the reaction mixture was heated to 35 0C and stirred overnight. After cooling, the CH2Cl2WaS removed under vacuum and the residue was dissolved in EtOAc. The formed solution was washed with saturated Na2CO3, H2O and brine and dried over Na2SO4. After removal of the solvent, the residue was purified by flash chromatography (eluent: EtOAc/ petroleum ether = 1:3) to give 15 in 62% yield.
15: 1R NMR: δ 9.41 (d, J= 2.5 Hz, IH), 8.02 (dd, J= 9.0, 2.5 Hz, IH), 7.55 (s, IH), 6.68 (d, J= 9.0 Hz, IH), 6.35 (br, 2H), 3.92 (s, 3H), 1.36 (s, 9H). LC-MS: (5.58 min, m/z, ES+): calcd: 298.14; Found: 299.19.
Procedure for Synthesis of 16.
[00105] 16 was synthesized in 78% yield by similar procedure as of 8B.
1H NMR: δ 7.62 (d, J= 2.0 Hz, IH), 7.43 (s, IH), 6.65 (d, J= 8.0 Hz, IH), 6.59 (dd, J= 8.0, 2.0 Hz, IH), 3.81 (s, 3H), 1.56 (br, 4H), 1.32 (s, 9H). LC-MS: (3.35 min, m/z, ES+): calcd: 268.17; Found: 269.20.
Example 14
Figure imgf000117_0001
General Procedure for Synthesis of 17.
[00106] To the solution of 15 (0.1 mmol) and pyridine (0.3 mmol) in CH2Cl2 (1.0 mL), sulfonyl chloride (0.3 mmol) was added slowly at room temperature. The reaction mixture was stirred overnight. After quenching with H2O, the reaction was extracted with EtOAc and dried over Na2SO4. After removal of the solvent, the residue was purified by plate chromatography (eluent: EtO Ac/Petroleum ether = 1 :2) to give pure compound 17.
Figure imgf000118_0001
73% yield. 1H NMR: δ 11.54 (s, IH), 9.42 (d, J= 2.0 Hz, IH), 8.06 (dd, J= 8.0, 2.0 Hz, IH), 7.71 (AABB, J= 8.5, 7.0 Hz, 4H), 7.57 (s, IH), 7.22 (d, J= 8.0 Hz, IH), 4.0 (s, 3H), 2.37 (s, 3H), 1.34 (s, 9H). 13C NMR: δ 147.391, 144.473, 142.903, 141.177, 136.376, 134.908, 129.997, 127.444, 124.151, 124.060, 120.508, 118.494, 103.840, 103.690, 69.584, 39.816, 31.067, 28.579, 23.902, 21.796. LC-MS: (6.50 min, m/z, BS+): calcd: 452.15; Found: 453.11.
Example 15
Figure imgf000118_0002
General Procedure for Synthesis of 18 and 19.
[00107] To the suspension of 15 (0.1 mmol) and K2CO3 (0.5 mmol) in acetone (1.0 niL), benzyl bromide (0.3 mmol) was added at room temperature. The reaction mixture was sealed and raised to 65 0C and stirred overnight. After cooled, the reaction mixture was filtered over Celite and washed with EtOAc. After removal of the solvent, the residue was purified by plate chromatography on silica gel (eluent: EtOAc/Petrpleum ether = 1:3) to give pure compound 18 and 19 (in some cases, only compound 18 was isolated).
Figure imgf000119_0001
87% yield. 1HNMR: δ 9.45 (d, J= 2.0 Hz, IH), 8.90 (t, J= 4.5 Hz, IH), 8.07 (dd, J= 9.5, 2.5 Hz, IH), 7.56 (s, IH), 6.99 (s, 2H), 6.94 (s, IH), 6.62 (d, J= 9.5 Hz, IH), 4.50 (d, J = 5.0 Hz, 2H), 3.88 (s, 3H), 2.32 (s, 6H), 1.37 (s, 9H). 13C NMR: δ 151.253, 149.261, 138.623, 138.071, 136.796, 134.385, 129.291, 125.763, 125.477, 124.889, 115.003, 109.970, 103.121, 102.835, 70.417, 47.593, 39.432, 31.205, 28.612, 21.581. LC-MS: (6.75 min, m/z, ES+): calcd: 416.22; Found: 417.19.
Figure imgf000119_0002
7% yield. 1HNMR: δ 8.41 (d, J= 2.5 Hz, IH), 8.17 (dd, J= 8.5, 2.5 Hz, IH), 7.41 (s, IH), 6.89 (d, J= 8.5 Hz, IH), 6.86 (s, 2H), 6.77 (s, 4H), 4.15 (s, 4H), 3.83 (s, 3H), 2.26 (s, 12H), 1.19 (s, 9H). LC-MS: (6.87 min, m/z, ES+): calcd: 534.30; Found: 535.27.
Figure imgf000120_0001
15 20
General Procedure for Synthesis of 20.
[00108] To the solution of 15 (0.1 mmol) and DMAP (0.1 mmol) in CH2Cl2 (1.0 mL), benzoyl chloride (0.3 mmol) was added slowly at 0 0C. The reaction mixture was raised to room temperature and stirred overnight. After removal of the solvent, the residue was purified by plate chromatography (eluent: EtOAc/Petrpleum ether = 1 :3) to give pure compound 20.
Figure imgf000120_0002
95% yield. 1H NMR: δ 12.25 (s, IH), 9.38 (d, J= 3.0 Hz, IH), 8.98 (d, J= 9.5 Hz, IH), 8.45-8.3 (m, IH), 8.24 (dd, J= 9.5, 3.0 Hz, IH), 7.9-7.75 (m, IH), 7.60 (s, IH), 7.34 (t, J = 9.5 Hz, IH), 3.92 (s, 3H), 1.34 (s, 9H). 13C NMR: δ 162.947, 161.162, 160.907, 147.737, 143.262, 141.331, 134.931, 130.954 (m), 129.722 (m), 128.034 (q), 124.293, 124.142, 121.591, 121.464, 117.626, 117.426, 103.898, 103.625, 69.525, 39.347, 31.065, 28.551. LC-MS: (6.85 min, m/z, ES+): calcd: 488.15; Found: 489.06. Example 17
Preparation ofPyrazole Dimers
Figure imgf000121_0001
[00109] A mixture of iodochromone A (0.5 mmol), acetylene B (0.2 mmol), Cupper (I) iodide (0.01 mmol), and dichloribis(triphenylphosphine)palladium (0.005 mmol) in CH3CN (6 ml) was added with DIEPA (2 mmol) and then stirred for 5 h at room temperature. The reaction mixture was treated with methyl hydrazine (1 mmol) and stirred at RT overnight. After evaporation, the crude product was directly purified by a flash column chromatography to give the pure product.
Figure imgf000121_0002
VQ25048
Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave VQ25048. 1H NMR: δ 10.73 (s, 2H), 8.54 (d, J= 7.5 Hz, 2H), 7.46 (s, 2H), 7.21 (m, 2H), 7.02 (d, J= 8.0 Hz, 2H), 6.92 (m, 2H), 3.87 (s, 6H), 2.56(m, 4H), 1.86 (m, 4H); LC-MS: m/z, 451 (M+l).
Figure imgf000122_0001
Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave VQ25049. 1H NMR: δ 11.64 (s, 2H), 9.56 (d, J= 2.5 Hz, 2H), 8.03 (dd, J= 3.0, 9.0 Hz, 2H), 7.58 (s, 2H), 7.00 (d, J= 9.0 Hz, 2H), 3.94 (s, 6H), 2.64(m, 4H), 1.95 (m, 4H); LC-MS: m/z, 541 (M+l) .
Figure imgf000122_0002
VQ25050
Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave VQ25050. 1H NMR: δ 10.52 (s, 2H), 8.32 (s, 2H), 7.45 (s, 2H), 7.02 (d, J= 8.0 Hz, 2H), 6.91 (d, J= 8.5 Hz, 2H), 3.89 (s, 6H), 2.56(m, 4H), 2.97 (s, 6H), 1.89 (m, 4H); LC-MS: m/z, 479 (M+l).
Figure imgf000122_0003
Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave VQ25052. 1H NMR: δ 10.72 (s, 2H), 8.56 (d, J= 2.5 Hz, 2H), 7.48 (s, 2H), 7.16 (dd, J= 2.5, 8.5 Hz, 2H), 6.93 (d, J= 8.5 Hz, 2H), 3.90 (s, 6H), 2.58(m, 4H), 1.92 (m, 4H); LC-MS: m/z, 519(M+) .
Figure imgf000123_0001
Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave VQ25053. 1H NMR: δ 10.75 (s, 2H), 8.69 (d, J= 2.5 Hz, 2H), 7.48 (s, 2H), 7.29 (dd, J= 2.0, 7.5 Hz, 2H), 6.88 (d, J= 7.5 Hz, 2H), 3.90 (s, 6H), 2.59(m, 4H), 1.94 (m, 4H); LC-MS: m/z, 609 (M+l).
Figure imgf000123_0002
VQ25055
Purification by a flash chromatography (Hexanes/EtOAc = 2/1) gave VQ25055. 1H NMR: δ 10.60 (s, 2H), 8.53 (s, 2H), 7.47 (s, 2H), 6.87 (s, 2H), 3.89 (s, 6H), 2.58 (m, 4H), 2.34 (s, 6H), 1.93 (m, 4H); LC-MS: m/z, 547 (M+) . Example 18
General Procedure for Synthesis ofDimers
Figure imgf000124_0001
[00110] A mixture of A (0.11 mmol), B (0.055 mmol) and pyridine (1.0 mL) in a sealed tube was heated to 100 0C and stirred overnight. After removal of the solvent, the residue was purified by column chromatography (eluent: MeOH:CH2Cl2 = 1:100) to give the pure product.
Figure imgf000124_0002
1H NMR: δ 9.42 (d, J = 3 Hz, 2H), 8.73 (br, 2H), 8.14 (dd, J = 9.5, 3.0 Hz, 2H), 7.43 (s, 2H), 6.75 (d, J = 9 Hz, 2H), 3.75-3.68 (m, 4H), 3.54 (s, 6H), 1.38 (s, 18H). LC-MS: (6.98 min, m/z, ES+): calcd: 622.30; Found: 623.26.
Figure imgf000124_0003
1U NMR: δ 9.41 (d, J = 3 Hz, 2H), 8.73 (t, J = 5.5 Hz, 2H), 8.11 (dd, J = 9.5, 3.0 Hz, 2H), 7.49 (s, 2H), 6.68 (d, J = 9 Hz, 2H), 3.70 (s, 6H), 3.60-3.48 (m, 4H), 2.20-2.10 (m, 2H), 1.38 (s, 18H). LC-MS: (7.08 min, m/z, ES+): calcd: 636.32; Found: 637.29.
Figure imgf000125_0001
1H NMR: δ 9.41 (d, J = 3 Hz, 2H), 8.49 (t, J = 5.5 Hz, 2H), 8.12 (dd, J = 9.5, 3.0 Hz, 2H), 7.51 (s, 2H), 6.65 (d, J = 9 Hz, 2H), 3.80 (s, 6H), 3.45-3.35 (m, 4H), 1.98-1.90 (m, 4H), 1.36 (s, 18H). LC-MS: (7.18 min, m/z, ES+): calcd: 650.33; Found: 651.28.
Figure imgf000125_0002
1H NMR: δ 9.40 (d, J = 3 Hz, 2H), 8.44 (t, J = 5.5 Hz, 2H), 8.12 (dd, J = 9.5, 3.0 Hz, 2H), 7.50 (s, 2H), 6.64 (d, J = 9 Hz, 2H), 3.78 (s, 6H), 3.40-3.30 (m, 4H), 1.90-1.75 (m, 4H), 1.72-1.68 (m, 2H), 1.38 (s, 18H). LC-MS: (7.34 min, m/z, ES+): calcd: 664.35; Found: 665.33.
Figure imgf000125_0003
1H NMR: δ 9.43 (d, J = 3 Hz, 2H), 8.80 (t, J = 5.5 Hz, 2H), 8.08 (dd, J = 9.5, 3.0 Hz, 2H), 7.46 (s, 2H), 6.68 (d, J = 9 Hz, 2H), 3.60 (s, 6H), 3.35 (d, J = 5.5 Hz, 4H), 1.38 (s, 18H), 1.24 (s, 6H). LC-MS: (7.37 min, m/z, ES+): calcd: 636.35; Found: 665.41.
Figure imgf000125_0004
1H NMR: δ 9.38 (d, J = 3 Hz, 2H), 8.63 (br, 2H), 8.10 (dd, J = 9.5, 3.0 Hz, 2H), 7.54 (s, 2H), 6.72 (d, J = 9 Hz, 2H), 4.35-4.25 (m, 2H), 3.82 (s, 6H), 3.65-3.48 (m, 4H), 1.35 (s, 18H). LC-MS: (6.547 min, m/z, ES+): calcd: 652.31; Found: 653.36.
Figure imgf000126_0001
1H NMR: δ 9.42 (d, J = 3 Hz, 2H), 8.73 (br, 2H), 8.14 (dd, J = 9.5, 3.0 Hz, 2H), 7.43 (s, 2H), 6.75 (d, J = 9 Hz, 2H), 3.90 (s, 6H), 3.10 (s, 8H), 1.28 (s, 18H). LC-MS: (6.57 min, m/z, ES+): calcd: 648.32; Found: 649.32.
Figure imgf000126_0002
1E NMR: δ 9.41 (d, J = 3 Hz, 2H), 8.56 (t, J = 5.5 Hz, 2H), 8.11 (dd, J = 9.5, 3.0 Hz, 2H), 7.56 (s, 2H), 6.74 (d, J = 9 Hz, 2H), 3.88 (s, 6H), 3.20 (t, J = 9 Hz, 4H), 2.04-1.96 (m, 4H), 1.78-1.65 (m, 2H), 1.35 (s, 18H), 1.24-1.1 (m, 4H). LC-MS: (7.64 min, m/z, ES+): calcd: 704.38; Found: 705.40.
Figure imgf000126_0003
1B NMR: δ 9.42 (d, J = 3 Hz, 2H), 8.62 (t, J = 5.5 Hz, 2H), 8.12 (dd, J = 9.5, 3.0 Hz, 2H), 7.48 (s, 2H), 6.65 (d, J = 9 Hz, 2H), 3.72 (s, 6H), 3.30-3.20 (m, 4H), 3.20-3.10 (m, 2H), 2.14-2.05 (m, 2H), 1.95-1.85 (m, 4H), 1.85-1.70 (m, 2H), 1.38 (s, 18H). LC-MS: (7.64 min, m/z, ES+): calcd: 704.38; Found: 705.39. Example 18
HCV Replicon Luciferase Assay
[00111] Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS + 2mM glutamine; 100 μl/well). The compounds to be tested are added to the experimental wells (10 μl/well at 1OX assay concentration) and the cells are then incubated (5% CO2, 370C) for 48h.
[00112] Day 2, Reagent Preparation and Luciferase Assay: The Bright-Glo Luciferase Assay Buffer (Promega) is thawed and equilibrated to room temperature prior to use. The lyophilized Bright-Glo Luciferase Assay Substrate is equilibrated to room temperature prior to use. 10 ml of Bright-Glo Luciferase Assay Buffer is transferred to 1 vial of Bright-Glo Luciferase Assay Substrate bottle and mixed by gently with a Vortex. 100 ul of Bright-Glo Luciferase Assay reagent (Bright-Glo Luciferase Assay Buffer + Bright-Glo Luciferase Assay Substrate Mixture) is added to each well. The well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer. The data is analyzed and IC50s are determined using GraphPad Prism 4 software. Hits validated in the Replicon Luciferase assay have IC50s < 8.0 μM and show < 30% inhibition of Cell Viability at a compound concentration of 100 μM (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon Luciferase Assay conditions).
Example 19
HCV Replicon RNA Assay
[00113] Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS + 2mM glutamine; 100 μl/well). The compounds to be tested are added to the experimental wells (10 μl/well at 1OX assay concentration) and the cells are then incubated (5% CO2, 37°C). [00114] Day 1, Media Change and Compound Treatment: 24 hours after the initial compound treatment the cell culture media is aspirated from the wells and fresh Growth Medium is added (DMEM phenol red free + PS + 2mM glutamine; 100 μl/well). The compounds to be tested are then added to the appropriate experimental wells (10 μl/well at 1OX assay concentration) and the cells are then incubated (5% CO2, 37°C) for an additional 24 hrs.
[00115] Day 2, RNA Isolation and cDNA Synthesis: The cells are washed with IX Phosphate Buffered Saline (PBS) once. Cells are then lysed and RNA is isolated in 96 well format using a vacuum manifold and the RNAeasy 96 kit (Qiagen) according to the manufacturer's suggested protocol. cDNA is then synthesized from RNA isolated from each well using the Taqman Reverse Transcription Reagents kit (Applied Biosystems) according to manufacturer's suggested protocol.
[00116] Day 3, Quantitative PCR Based Measurement of HCV RNA (Taqman Assay): Quantitative PCR analysis to measure HCV RNA expression from cDNA synthesized on Day 2 is performed using the ABI 9700 HT Sequence Detection System (Applied Biosystems) as previously described (Lohman et al, Science 285, 110-113, 1999). The data is analyzed and IC50s are determined using GraphPad Prism 4 software. Hits validated in the Replicon RNA Assay have IC50s < 8.0 μM and show < 30% inhibition of Cell Viability at a compound concentration of 50 μM (Cell Titer Glow Assay, cell viability assay conditions identical to HCV Replicon RNA Assay conditions).
Example 20
CellTiter-Glo Cell Viability Assay (Promega)
[00117] Day 0, Cell Seeding and Compound Treatment: Huh-Luc-Neo Cells are seeded at 25,000/well in an opaque-walled 96 plate with Growth Medium (DMEM phenol red free + PS + 2mM glutamine; lOOul/well). The compounds to be tested for inhibition of cell viability are added to the experimental wells (10 μl/well at 1OX assay concentration) and the cells are then incubated (5% CO2, 370C) for 48h. [00118] Day 2, Reagent Preparation and Assay: The CellTiter-Glo Buffer is thawed and equilibrated to room temperature prior to use. The lyophilized CellTiter-Glo Substrate is equilibrated to room temperature prior to use. 10 ml of CellTiter-Glo Buffer is transferred to 1 vial of CellTiter-Glo Substrate and mixed by gently with a Vortex. 100 μl of CellTiter-Glo Assay reagent (CellTiter-Glo Buffer + CellTiter-Glo Substrate Mixture) is added to each well. The well contents are mixed for 5 min. on an orbital shaker at room temperature to induce cell lysis and the luminescence is then measured using a luminometer.
Table 5
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001

Claims

CLAIMSWhat is claimed is:
1. A compound having the formula I:
Figure imgf000139_0001
wherein: ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(Rn)C(O)Ru, -N(R11JSO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl; R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 is selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000140_0001
wherein Z is selected from O, N-OR461 ;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2)α-R42
R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and -(CH2)^-R42 ; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)^-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3,
NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000141_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R5 is selected from H, OR51, -SR51, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF3, NO2,SO2, -SOR51, -SO3R51, -SO2N(R52)(R53), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)OR51, -C(O)N(R52)(R53), -OC(O)R51, -OC(O)N(R52)(R53), -O(CH2)eC(O)OR51, -O(CH2)eC(O)N(R52)(R53), -N(R52)(R53), -N(R51)C(O)R51, and -N(R51)SO2R51 each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, -O-R51 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R5 is selected from a group having the formula:
Figure imgf000142_0001
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), 0(CH2)AO)OR57, -O(CH2),C(O)N(R58)(R59), -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and Hf O to 5; or a pharmaceutically acceptable salt or hydrate thereof.
2. The compound of claim 1, having the formula II:
Figure imgf000143_0001
wherein: ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R1^C(O)R11, -N(R11JSO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 is selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000144_0001
wherein Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2)α-R42 R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
-(CH2)a-R42 ; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)^-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422)(R423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000145_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R423 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R6 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)N(R52)(R53), (CH2)eC(O)OR51, and -(CH2)eC(O)N(R52)(R53), each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, R6 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R6 is selected from a group having the formula:
Figure imgf000146_0001
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), O(CH2),C(O)OR57, -O(CH2),C(O)N(R58)(R59), -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and /z ifO to 5; or a pharmaceutically acceptable salt or hydrate thereof.
3. The compound of claim 2 having the formula III:
Figure imgf000147_0001
wherein: each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R1^C(O)R1 ', -N(Ru)SO2Rπ, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-0-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 is selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000148_0001
wherein Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2)Ω-R42 R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
-(CH2)α-R42 ; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)a-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3,
NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000149_0001
each R j421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R 2β are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
R6 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)N(R52)(R53), (CH2)eC(O)OR51, and -(CH2)eC(O)N(R52)(R53), each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, R6 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R6 is selected from a group having the formula:
Figure imgf000150_0001
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), O(CH2),C(O)OR57, -O(CH2),C(O)N(R58)(R59), -N(R58)(R59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and /z ifO to 5; or a pharmaceutically acceptable salt or hydrate thereof.
4. The compound of claim 3 having the formula TV:
Figure imgf000150_0002
wherein: each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -0-R11, -N(R12)(R13), -N(Rn)C(O)Rn, -N(R1^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-Rπ, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to foπn a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R35 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)^-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000152_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 maybe taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6; R6 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, - C(O)R51, -C(O)N(R52XR53), (CH2)^C(O)OR51, and -(CH2)eC(O)N(R52)(R53), each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; or R6 is selected from a group having the formula:
Figure imgf000153_0001
wherein each R54 and R56 is independently selected from OH, halo, alkyl, cycloalkyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58)(R59), -OC(O)R57, -OC(O)N(R58XR59), 0(CH2)AO)OR57, -0(CH2)AO)N(R58XR59), -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R58 and R59 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is O to 4; and HfO to 5; or a pharmaceutically acceptable salt or hydrate thereof.
5. The compound of claim 4 having the formula V:
Figure imgf000154_0001
wherein: each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(Rn)C(O)Ru, -N(Ru)SO2Rπ, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R3+)(R35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)α-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000155_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached foπn a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
6. The compound of claim 1 having the formula VI:
Figure imgf000156_0001
wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(Rπ)C(O)Rπ, -N(R1 ^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O- alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O~alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R43, and R44 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)α-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422)(R423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000158_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
7. The compound of claim 6 having the formula VIα:
Figure imgf000158_0002
wherein each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12)(R13), -N(R1 ^C(O)R11, -N(RU)SO2RU, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12)(R13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4; R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R3 , C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R43, and R44 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)α-R42 ; R42 is selected from -N(R421JC(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000160_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
8. The compound of claim 1 having the formula VII:
Figure imgf000161_0001
wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain
0 to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(Rπ)C(O)Rπ, -N(Rπ)SO2Rn, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R48 and R49 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)α-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422)(R423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000162_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R maybe taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
9. The compound of claim 8 having the formula VIIα:
Figure imgf000163_0001
wherein each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(R11JC(O)R1 \ -N(R11JSO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is 0 to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R48 and R49 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and -(CH2)Ω-R42 ; R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-0-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000165_0001
each R 2 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R 2 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R 26 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached foπn a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
10. The compound of claim 1 having the formula VIII:
Figure imgf000165_0002
wherein ring A is selected from a 5- or 6- membered aromatic rings which may optionally contain O to 3 ring heteroatoms; each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -0-R11, -N(R12)(R13), -N(R11JC(O)R11, -N(R11JSO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34) S O2R34, -SR34, -C(O)N(R35)(R36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R )(R ), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl and -(CH2)α-R42 R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000167_0001
each R 21 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R 26 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
11. The compound of claim 10 having the formula VIIIα:
Figure imgf000168_0001
(VIIIΩ) wherein each R1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -N(R12XR13), -N(Rπ)C(O)Rπ, -N(R1 ^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12XR13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-R11, cycloalkyl, cycloalkenyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 is selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl;
R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl; R3 is selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32)(R33); R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35)(R36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl and -(CH2)α-R42 R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -SR421, -C(O)R421,
-C(O)OR421, -C(O)N(R422XR423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000169_0001
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 may be taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; and a is 1 to 6; or a pharmaceutically acceptable salt or hydrate thereof.
12. A compound having the formula X:
Figure imgf000170_0001
(X) wherein: ring A and ring A' are independently selected from 5- or 6- membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms; each R1 and R1' are selected independently from alkyl, alkenyl, alkynyl, aralkyl, -O-R11,
N(R12)(R13),
-N(Ru)C(O)Rπ, -N(Ru)SO2Rn, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12XR13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-alkyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, 77 is 0 to 4;
R2 and R2' are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl; R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 and R3' are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32XR33);
R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34XR35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R3 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R5 and R5' are independently selected from H, OR51, -SR51, alkyl, cycloalkyl, cycloalkeαyl, alkenyl, alkynyl, CN, CF3, NO25SO2, -SOR51, -SO3R51, - SO2N(R52)(R53), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, -C(O)R51, -C(O)OR51, -C(O)N(R52XR53), -OC(O)R51, -OC(O)N(R52)(R53), -O(CH2)eC(O)OR51, - O(CH2)eC(O)N(R52)(R53), -N(R52)(R53), -N(R51)C(O)R51, and -N(R51)SO2R51 each R51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
R52 and R53 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; e is 1 to 6; alternatively, -O-R51 is combined with R41, R46, or R47 to give a 6- membered ring that is fused to ring A and to the pyrazole ring; or R5 is selected from a group having the formula:
Figure imgf000172_0001
and
Figure imgf000172_0002
wherein each R54 and R56 is independently selected from -OR57, halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO2, CN, -C(O)R57, -C(O)OR57, -C(O)N(R58XR59), -OC(O)R57, -OC(O)N(R58)(R59), O(CH2),C(O)OR57, -O(CH2),C(O)N(R58)(R59), -N(R58XR59), -N(R57)C(O)R57, -N(R57)SO2R57, aralkyl, aryl and heteroaryl; each R57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; R58 and R59 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R52 and R53 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; i is 1 to 6;
X1 is selected from N and CH; /is 1 to 6; g is 0 to 4; and h is 0 to 5;
L is a linking group selected from -(CH2V,
Figure imgf000173_0004
, or a group of the formula
-A-B-A- wherein
A is selected from -N(R)-, -O-, -S-, -C(O)-, -OC(O)-, -N(R)C(O)-,
-N(R)C(O)O-, -N(R)SO2-, -(CH2)r, and
Figure imgf000173_0005
ϊ
B is selected from -(CH2).-,
Figure imgf000173_0003
, -(CH2)v-£)-(CH2)M,- wherein D is selected from O, S, -C=C-, -S-S-,
Figure imgf000173_0002
x is 3 to 25; y is 1 to 10; z is 1 to 10; v is 1 to 8; and w is 1 to 8; or a pharmaceutically acceptable salt or hydrate thereof.
13. A compound having the formula XI:
Figure imgf000173_0001
wherein ring A and ring A' are independently selected from 5- or 6- membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms; each R1 and R1' are selected independently from alkyl, alkenyl, alkynyl, aralkyl, -O-R11, -
N(R12XR13),
-N(Rπ)C(O)Rπ, -N(R1^SO2R11, -SR11, -C(O)R11, -C(O)OR11, -C(O)N(R12)(R13), -OC(O)R11, -OC(O)N(R12)(R13), CN, CF3, NO2, SO2, -SOR11, -SO3R11, -SO2N(R12XR13), -alkyl-O-alkyl, halo, aryl and heteroaryl; additionally or alternatively two R1 substituents on adjacent ring atoms my be combined to form a fused 5 or 6- membered ring, wherein the fused 5- or 6- membered ring may contain from O to 3 ring heteroatoms and may be further substituted with on or more substituents selected from R1; each R11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl;
J each R12 and R13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom, n is O to 4;
R2 and R2' are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, -C(O)R21, -C(O)OR21, -alkyl-O-alkyl, -alkyl-O-aryl; R21 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R3 and R3' are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl, -alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, -C(O)R31, -C(O)OR31, -C(O)N(R32XR33);
R31 is selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R32 and R33 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R32 and R33 may be taken together with the nitrogen to which they are attached foπn a 5- to 7- membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO2, CO2R34, C(O)R34, -O-R34, -N(R34)(R35), -N(R34)C(O)R34, -N(R34)SO2R34, -SR34, -C(O)N(R35XR36), -OC(O)R34, -OC(O)N(R35)(R36), SO2, -SOR34, -SO3R34, -SO2N(R35XR36), halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; each R34 is independently selected from H, alkyl, cycloalkyl, cycloalkeneyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R35 and R36 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R35 and R36 maybe taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; R4 and R4' are selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
Figure imgf000175_0001
wherein Z is selected from O, N-OR461;
R461 is selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl, alkyl-O-aryl and -(CH2)α-R42
R41, R43, R44, R46, R47, R48 and R49 are independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, and
-(CH2VR42 ;
R45 is selected from H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and -(CH2)^-R42 ;
R42 is selected from -N(R421)C(O)R421, -N(R421)SO2R421, -OR421, -SR421, -C(O)R421, -C(O)OR421, -C(O)N(R422)(R423), -OC(O)R421, -OC(O)N(R422)(R423), CN, CF3, NO2, SO2, -SOR421, -SO3R421, -SO2N(R422XR423), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R42 is selected from a group having the formula
Figure imgf000175_0002
each R421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R422 and R423 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R422 and R423 may be taken together with the nitrogen to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; each R424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; each R425 and R426 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heteroaryl; or R425 and R426 maybe taken together with the carbon to which they are attached form a 5- to 7- membered ring which may optionally contain a further heteroatom; a is 1 to 6;
L is a linking group selected from -(CH2)*-,
Figure imgf000176_0003
or a group of the foπnula
-A-B-A- wherein
A is selected from -N(R)-, -O-, -S-, -C(O)-, -OC(O)-, -N(R)C(O)-,
-N(R)C(O)O-, -N(R)SO2-, -(CH2)r, and
Figure imgf000176_0004
;
B is selected from -(CH2V,
Figure imgf000176_0002
, -(CH2VZ)-(CH2)V1,- wherein D is selected from O, S, -C=C-, -S-S-,
Figure imgf000176_0001
x is 3 to 25; y is 1 to 10; 2 is 1 to 10; v is 1 to 8; and w is 1 to 8; or a pharmaceutically acceptable salt or hydrate thereof.
14. The compound of claim 1 having the formula
Figure imgf000177_0001
15. The compound of claim 1 having the formula
Figure imgf000177_0002
16. The compound of claim 1 having the formula
Figure imgf000177_0003
17. The compound of claim 1 having the formula
Figure imgf000177_0004
18. The compound of claim 1 having the formula
Figure imgf000178_0001
19. The compound of claim 1 having the formula
Figure imgf000178_0002
20. The compound of claim 1 having the formula
Figure imgf000178_0003
21. The compound of claim 1 having the formula
Figure imgf000178_0004
22. The compound of claim 1 having the formula
Figure imgf000179_0001
23. The compound of claim 1 having the formula
Figure imgf000179_0002
24. The compound of claim 1 having the formula
Figure imgf000179_0003
25. The compound of claim 1 having the formula
Figure imgf000179_0004
26. The compound of claim 1 having the formula
Figure imgf000180_0001
27. The compound of claim 1 having the formula
Figure imgf000180_0002
28. The compound of claim 1 having the formula
Figure imgf000180_0003
29. The compound of claim 1 having the formula
Figure imgf000180_0004
30. The compound of claim 1 having the formula
Figure imgf000181_0001
31. The compound of claim 1 having the formula
Figure imgf000181_0002
32. The compound of claim 1 having the formula
Figure imgf000181_0003
33. The compound of claim 1 having the formula
Figure imgf000181_0004
34. The compound of claim 1 having the formula
Figure imgf000182_0001
35. The compound of claim 1 having the formula
Figure imgf000182_0002
36. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 1.
37. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 2.
38. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 3.
39. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 4.
40. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 5.
41. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 6.
42. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 7.
43. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 8.
44. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 9.
45. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 10.
46. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 11.
47. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 12.
48. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to Claim 13.
49. A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a combination of the compound according to claim 1, or a therapeutically acceptable salt or hydrate thereof, and at least one additional agent selected from an interferon, ribavirin, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV IRES inhibitor, an HCV Helicase, an HCV ATPase inhibitor, an NS5A phosphorylation inhibitor, and an HCV NS2 inhibitor.
50. The method of claim 49, wherein the at least one additional agent is an interferon.
51. The method of claim 50, wherein the at least one additional agent is α-interferon.
52. The method of claim 49, wherein the at least one additional agent is an interferon and ribavirin.
53. A pharmaceutical composition for the treatment of HCV infection comprising a therapeutically effective amount of a compound of according to Claim 1 in a pharmaceutically acceptable carrier.
54. The pharmaceutical composition of claim 53, further comprising a second antiviral agent.
55. The pharmaceutical composition of claim 54, wherein the second anti- viral agent is selected from the group consisting of an interferon, ribavirin, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV IRES inhibitor, an HCV Helicase, an HCV ATPase inhibitor, an NS5A phosphorylation inhibitor, and an HCV NS2 inhibitor.
56. The pharmaceutical composition of claim 55, wherein the second agent is an interferon.
57. The pharmaceutical composition of claim 56, wherein the second agent is α- interferon.
PCT/US2006/005236 2005-02-15 2006-02-14 Pyrazole compounds Ceased WO2006088903A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06720749A EP1853257A2 (en) 2005-02-15 2006-02-14 Pyrazole compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/058,852 2005-02-15
US11/058,852 US8329703B2 (en) 2005-02-15 2005-02-15 Pyrazole compounds

Publications (2)

Publication Number Publication Date
WO2006088903A2 true WO2006088903A2 (en) 2006-08-24
WO2006088903A3 WO2006088903A3 (en) 2007-05-10

Family

ID=36816435

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/005236 Ceased WO2006088903A2 (en) 2005-02-15 2006-02-14 Pyrazole compounds

Country Status (3)

Country Link
US (2) US8329703B2 (en)
EP (1) EP1853257A2 (en)
WO (1) WO2006088903A2 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796253B2 (en) 2007-05-18 2014-08-05 Bayer Intellectual Property Gmbh Heteroaryl substituted pyrazole derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
CN105061441A (en) * 2015-07-10 2015-11-18 南京大学 Coumarin pyrazole compounds containing nitrogen heterocycles such as piperazine and the like, preparation of coumarin pyrazole compounds and application of coumarin pyrazole compounds in tumor cell inhibition
CN105061440A (en) * 2015-07-10 2015-11-18 南京大学 Coumarin pyrazole compounds containing acetylamino nitrogen heterocycles, preparation of coumarin pyrazole compounds and application of coumarin pyrazole compounds in tumor cell inhibition
KR20180015262A (en) 2015-06-23 2018-02-12 깃세이 야쿠힌 고교 가부시키가이샤 A pyrazole derivative, or a pharmacologically acceptable salt thereof

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008048589A2 (en) * 2006-10-13 2008-04-24 Xtl Biopharmaceuticals Ltd Compounds and methods for treatment of hcv
EP2142215B1 (en) 2007-05-04 2012-03-07 Vertex Pharmceuticals Incorporated Combination therapy for the treatment of hcv infection
US7776877B2 (en) 2007-06-22 2010-08-17 Chemocentryx, Inc. N-(2-(hetaryl)aryl) arylsulfonamides and N-(2-(hetaryl) hetaryl arylsulfonamides
CN105102448B (en) 2013-02-28 2018-03-06 百时美施贵宝公司 Phenylpyrazole derivatives as ROCK1 and ROCK2 inhibitor
AR094929A1 (en) 2013-02-28 2015-09-09 Bristol Myers Squibb Co DERIVATIVES OF PHENYLPIRAZOL AS POWERFUL INHIBITORS OF ROCK1 AND ROCK2
WO2019168874A1 (en) 2018-02-27 2019-09-06 The Research Foundation For The State University Of New York Difluoromethoxylation and trifluoromethoxylation compositions and methods for synthesizing same
CN110818630B (en) * 2019-08-12 2022-06-10 西南大学 Synthesis method of conjugated (E) -3-cycloalkenyl acrylate derivative

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3832570A1 (en) 1988-09-24 1990-03-29 Hoechst Ag 7-SUBSTITUTED DERIVATIVES OF 3,5-DIHYDROXYHEPT-6-ACID, METHODS FOR THE PRODUCTION THEREOF, THEIR USE AS MEDICINAL PRODUCTS AND INTERMEDIATE PRODUCTS
HU9301218D0 (en) 1992-05-13 1993-08-30 Sandoz Ag Method for producing new pyrazole derivatives
AU7319100A (en) 1999-09-24 2001-04-24 Agro-Kanesho Co. Ltd. Insecticidal and acaricidal agents
DE10064823A1 (en) 2000-12-22 2002-06-27 Knoll Ag New (hetero)aryl-substituted aliphatic carboxylic acid derivatives, useful as integrin receptor ligands for treating, e.g. atherosclerosis, restenosis, rheumatoid arthritis, cancer, osteoporosis or hypertension
US20020183366A1 (en) 2001-03-23 2002-12-05 Garvey David S. Cyclooxygenase-2 inhibitors, compositions and methods of use
JP2004107264A (en) 2002-09-19 2004-04-08 Nippon Nohyaku Co Ltd Method for producing arylethynylpyrazoles
CH697574B1 (en) 2003-01-07 2008-12-15 Lanxess Deutschland Gmbh Pyrazolylarylalkine.
CH697663B1 (en) 2003-01-07 2009-01-15 Lanxess Deutschland Gmbh Pyrazolylalkine.
JP4485152B2 (en) 2003-06-05 2010-06-16 株式会社エス・ディー・エス バイオテック Herbicidal composition
EP1522541A1 (en) 2003-10-07 2005-04-13 Lipideon Biotechnology AG Novel hypocholesterolemic compounds
WO2006028524A2 (en) 2004-04-29 2006-03-16 Pharmix Corporation Compositions and treatments for inhibiting kinase and/or hmg-coa reductase
NZ551253A (en) 2004-06-01 2010-07-30 Hoffmann La Roche Pyridin-4-yl-ethynyl-imidazoles and pyrazoles as MGLU5 receptor antagonists
WO2008048589A2 (en) * 2006-10-13 2008-04-24 Xtl Biopharmaceuticals Ltd Compounds and methods for treatment of hcv

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8796253B2 (en) 2007-05-18 2014-08-05 Bayer Intellectual Property Gmbh Heteroaryl substituted pyrazole derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis
KR20180015262A (en) 2015-06-23 2018-02-12 깃세이 야쿠힌 고교 가부시키가이샤 A pyrazole derivative, or a pharmacologically acceptable salt thereof
US10287251B2 (en) 2015-06-23 2019-05-14 Kissei Pharmaceutical Co., Ltd. Pyrazole derivative or pharmaceutically acceptable salt thereof
EP3686188A1 (en) 2015-06-23 2020-07-29 Kissei Pharmaceutical Co., Ltd. Pyrazole derivative, or pharmaceutically acceptable salt thereof
CN105061441A (en) * 2015-07-10 2015-11-18 南京大学 Coumarin pyrazole compounds containing nitrogen heterocycles such as piperazine and the like, preparation of coumarin pyrazole compounds and application of coumarin pyrazole compounds in tumor cell inhibition
CN105061440A (en) * 2015-07-10 2015-11-18 南京大学 Coumarin pyrazole compounds containing acetylamino nitrogen heterocycles, preparation of coumarin pyrazole compounds and application of coumarin pyrazole compounds in tumor cell inhibition

Also Published As

Publication number Publication date
EP1853257A2 (en) 2007-11-14
US20130177529A1 (en) 2013-07-11
US8329703B2 (en) 2012-12-11
WO2006088903A3 (en) 2007-05-10
US20060183751A1 (en) 2006-08-17

Similar Documents

Publication Publication Date Title
US7994360B2 (en) Benzofuran compounds
CN104797561B (en) Fused bicyclic sulfamoyl derivatives and their use as medicines for the treatment of hepatitis B
US20130177529A1 (en) Pyrazole Compounds
JP7016809B2 (en) Tetracyclic pyridone compound as an antiviral agent
US7923004B2 (en) 4-ethynyl pyrazole derivative compounds and methods for treatment of HCV
CN107148417A (en) Benzo-aza * sulfonamide compounds
US20060223783A1 (en) 3,4-Disubstituted coumarin and quinolone compounds
EP3870295B1 (en) Novel tricyclic compounds for the treatment and prophylaxis of hepatitis b virus disease
EP2028938A1 (en) 3,4-disubstituted coumarin and quinolone compounds
CN102971305B (en) Heterocyclic antiviral compounds
US8143276B2 (en) 4-thio substituted quinoline and naphthyridine compounds
WO2008024423A2 (en) 4-thio substituted quinoline and naphthyridine compounds
CN101668528A (en) Compounds and methods for treatment of hcv
CN105175326A (en) 5-methyl-2(1H)pyridone derivatives, preparation method and application
HK1210156B (en) Fused bicyclic sulfamoyl derivatives and the use thereof as medicaments for the treatment of hepatitis b
HK40053680A (en) Novel tricyclic compounds for the treatment and prophylaxis of hepatitis b virus disease
WO2019120256A1 (en) Five-membered heteroaryl ring derivative, pharmaceutical composition containing same, and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2006720749

Country of ref document: EP