US2007082900A1PendingUtilityA1
Methods for inhibiting protein kinases
Est. expiryOct 6, 2025(expired)· nominal 20-yr term from priority
A61P 37/06A61P 9/00A61P 43/00A61P 37/02A61P 29/00A61P 31/10A61P 31/12A61P 35/02A61P 31/02A61P 25/00A61P 35/00A61P 25/28A61P 19/02A61K 31/519A61P 19/00A61P 17/14A61K 31/5377A61K 45/06
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Claims
Abstract
The present invention provides methods for inhibiting protein kinases selected from the group consisting of AKT, Checkpoint kinase, Aurora kinase, Pim kinases, and tyrosine kinase using pyrazolo[1,5-a]pyrimidine compounds and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with protein kinases using such compounds.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting activity of one or more kinases in a patient, wherein the kinases are selected from the group consisting of Checkpoint kinases, Pim kinases, and Aurora kinases, the method comprising administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, the compound being selected from the group consisting of the compounds represented by any of the structural formulas I through VI below:
wherein:
R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl,
wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group,
wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is H, halo or alkyl;
R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl;
R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4,
with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not
and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms;
wherein:
R is an aryl, wherein said aryl is either unsubstituted or optionally substituted or fused with one or more heteroaryl;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which groups can be the same or different with each R 9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups,
and heteroaryl substituted with 0-3 aryl or heteroaryl groups which can be the same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —-SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4,
with the following provisos: (i) that when R is an unsubstituted phenyl, then R 2 is not alkyl, —C(O 2 )R 6 , aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R 2 is halogen only;
wherein:
R is heteroaryl, wherein said heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —C(R 4 R 5 ) n OR 5 , C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, aryl, heteroaryl, CF 3 , heterocyclylalkyl, alkynylalkyl, cycloalkyl, —C(O)OR 4 , alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below,
wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —CH 2 OR 5 , —C(O)R 5 , —SO 3 H, —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , —CF 3 , and —OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)OR 4 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R 7 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —CH 2 OR 4 , —C(O)OR 6 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 6 , —(CH 2 ) n OR 4 , —C(O 2 )R 5 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
m is 0 to 4; and
n is 1 to 4;
wherein:
Q is selected from the group consisting of —S(O 2 )NR 6 R 7 —, —C(O)NR 6 R 7 — and —C(O)OR 7 —;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below,
wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, alkyl, alkynyl, —C(O)NR 5 R 6 , —C(O)OR 4 , —NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4;
wherein:
Q is —S(O 2 )— or —C(O)—;
R is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 2 is selected from the group consisting of CN, NR 5 R 6 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; alkynyl, heteroaryl, CF 3 , heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below,
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4; and
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof,
wherein:
R 2 is selected from the group consisting of halo; —CF 3 ; —CN; —SR 6 ; —NO 2 ; —NR 5 R 6a ; —C(O)R 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkyl; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halo; haloalkyl; cycloalkyl; aryl; arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group;
wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic moieties shown immediately above for R 2 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —C(═N—OH), —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 3 is selected from the group consisting of H; —NR 5 R 6a ; —OR 6b ; —SR 6 ; CF 3 ; —C(O)N(R 5 R 6 ); alkyl; alkenyl, alkynyl; cycloalkyl; aryl; arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl;
wherein each of the alkyl, alkynyl; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —C(═N—OH), —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is selected from the group consisting of —CF 3 ; —CN; —NR 5 R 6a ; —(CR 5 R 11 ) p C(O 2 )R 6 ; —(CR 5 R 11 ) p C(O)NR 5 R 10 ; —C(O)—N(R 5 R 10 ); —OR 6b ; —SR 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —C(O)R 6 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aryl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl;
wherein each of the alkyl, cycloalkyl; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl and fused heteroaryl groups of R 4 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(R 5 )(═N—OR 5 ), —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety, and wherein the substituted alkyl group of R 4 is independently substituted with one or more of the above moieties;
R 5 is H, alkyl, aryl or cycloalkyl;
R 6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF 3 , —OCF 3 , —CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —C(═N—OH), and —N(R 5 )C(O)NR 5 R 10 ;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(═N—OH), —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —NR 5 R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, —S(O 2 )R 7 , and
R 9 is selected from the group consisting of halo, —CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —C(═N—OH), —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; and
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —C(═N—OH), —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 11 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5)C(O)NR 5 R 11 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 11 is H, halo or alkyl;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4;
with the provisos that
(1) when R 2 is alkyl, carboxyl, phenyl or cycloalkyl, then R 3 is selected from the group consisting of —NR 5 R 6a ; —C(O)N(R 5 R 6 ); alkynyl; arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl;
wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 is unsubstituted or independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O)NR 5 R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
(2) when R 2 is halo, then R 3 is selected from the group consisting of —OR 6b ; —SR 6 ; —C(O)N(R 5 R 6 ); cycloalkyl; heterocyclyl; heterocyclylalkyl;
wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 10 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; and
(3) when R 2 is NH 2 , R 3 is not methyl.
2 . A method of treating, or slowing the progression of, a disease by inhibiting one or more kinases in a patient, wherein the kinases are selected from the group consisting of Checkpoint kinases, Pim kinases, and Aurora kinases, said method comprising administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, to a patient in need thereof, the compound being selected from the group consisting of the compounds represented by any of the structural formulas I through VI below:
wherein:
R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl,
wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group,
wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is H, halo or alkyl;
R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl;
R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4,
with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not
and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms;
or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein:
R is an aryl, wherein said aryl is either unsubstituted or optionally substituted or fused with one or more heteroaryl;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which groups can be the same or different with each R 9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups,
and heteroaryl substituted with 0-3 aryl or heteroaryl groups which can be the same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4,
with the following provisos: (i) that when R is an unsubstituted phenyl, then R 2 is not alkyl, —C(O 2 )R 6 , aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R 2 is halogen only;
wherein:
R is heteroaryl, wherein said heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —C(R 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, aryl, heteroaryl, CF 3 , heterocyclylalkyl, alkynylalkyl, cycloalkyl, —C(O)OR 4 , alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below,
wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —CH 2 OR 5 , —C(O)R 5 , —SO 3 H, —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , —CF 3 , and —OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)OR 4 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
wherein each of said alkyl, cycloatkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R 7 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —CH 2 OR 4 , —C(O)OR 6 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 6 , —(CH 2 ) n OR 4 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
m is 0 to 4; and
n is 1 to 4;
wherein:
Q is selected from the group consisting of —S(O 2 )NR 6 R 7 —, —C(O)NR 6 R 7 — and —C(O)OR 7 —;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below,
wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, alkyl, alkynyl, —C(O)NR 5 R 6 , —C(O)OR 4 , —NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4;
wherein:
Q is —S(O 2 )— or —C(O)—;
R is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected 10 from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 5 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 2 is selected from the group consisting of CN, NR 5 R 6 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; alkynyl, heteroaryl, CF 3 , heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below,
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4; and
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof,
wherein:
R 2 is selected from the group consisting of halo; —CF 3 ; —CN; —SR 6 ; —NO 2 ; —NR 5 R 6a ; —C(O)R 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkyl; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halo; haloalkyl; cycloalkyl; aryl; arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group;
wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic moieties shown immediately above for R 2 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —C(═N—OH), —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 3 is selected from the group consisting of H; —NR 5 R 6a ; —OR 6b ; —SR 6 ; CF 3 ; —C(O)N(R 5 R 6 ); alkyl; alkenyl, alkynyl; cycloalkyl; aryl; arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl;
wherein each of the alkyl, alkynyl; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —C(═N—OH), —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is selected from the group consisting of —CF 3 ; —CN; —NR 5 R 6a ; —(CR 5 R 11 ) p C(O 2 )R 6 ; —(CR 5 R 11 ) p C(O)NR 5 R 10 ; —C(O)—N(R 5 R 10 ); —OR 6b ; —SR 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —C(O)R 6 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aryl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl;
wherein each of the alkyl, cycloalkyl; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl and fused heteroaryl groups of R 4 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(R 5 )(═N—OR 5 ), —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety, and wherein the substituted alkyl group of R 4 is independently substituted with one or more of the above moieties;
R 5 is H, alkyl, aryl or cycloalkyl;
R 6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF 3 , —OCF 3 , —CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —C(═N—OH), and —N(R 5 )C(O)NR 5 R 10 ;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(═N—OH), —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —NR 5 R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, —S(O 2 )R 7 , and
R 9 is selected from the group consisting of halo, —CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —C(═N—OH), —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; and
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 11 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 11 , —C(O)R 5 , —C(═N—OH), —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 11 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5)C(O)NR 5 R 11 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 11 is H, halo or alkyl;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4;
with the provisos that
(1) when R 2 is alkyl, carboxyl, phenyl or cycloalkyl, then R 3 is selected from the group consisting of —NR 5 R 6a ; —C(O)N(R 5 R 6 ); alkynyl; arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl;
wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 is unsubstituted or independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O)NR 5 R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
(2) when R 2 is halo, then R 3 is selected from the group consisting of —OR 6b ; —SR 6 ; —C(O)N(R 5 R 6 ); cycloalkyl; heterocyclyl; heterocyclylalkyl;
wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; and
(3) when R 2 is NH 2 , R 3 is not methyl.
3 . A method of treating, or slowing the progression of, a disease by inhibiting one or more kinases in a patient, wherein the kinases are selected from the group consisting of Checkpoint kinases, Pim kinases, and Aurora kinases, said method comprising comprising administering to a patient in need of such treatment
an amount of a first compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect, wherein the first compound is selected from the group consisting of the compounds represented by any of the structural formulas I through VI below: wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group, wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ; R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; R 4 is H, halo or alkyl; R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ; R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms; or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein: R is an aryl, wherein said aryl is either unsubstituted or optionally substituted or fused with one or more heteroaryl; R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which groups can be the same or different with each R 9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl substituted with 0-3 aryl or heteroaryl groups which can be the same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups; R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , R 6 ; R 4 is H, halo or alkyl; R 5 is H or alkyl; R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ; R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; m is 0 to 4, and n is 1 to 4, with the following provisos: (i) that when R is an unsubstituted phenyl, then R 2 is not alkyl, —C(O 2 )R 6 , aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R 2 is halogen only; wherein: R is heteroaryl, wherein said heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —C(R 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, aryl, heteroaryl, CF 3 , heterocyclylalkyl, alkynylalkyl, cycloalkyl, —C(O)OR 4 , alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below, wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —CH 2 OR 5 , —C(O)R 5 , —SO 3 H, —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , —CF 3 , and —OCF 3 ; R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)OR 4 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; R 4 is H, halo or alkyl; R 5 is H or alkyl; R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R 7 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —CH 2 OR 4 , —C(O)OR 6 , —C(O)R 7 and —S(O 2 )R 7 ; R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 6 , —(CH 2 ) n OR 4 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; m is 0 to 4; and n is 1 to 4; wherein: Q is selected from the group consisting of —S(O 2 )NR 6 R 7 —, —C(O)NR 6 R 7 — and —C(O)OR 7 —; R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below, wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ; R 3 is selected from the group consisting of H, halogen, alkyl, alkynyl, —C(O)NR 5 R 6 , —C(O)OR 4 , —NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylal kyl, heteroaryl, heteroarylal kyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; R 4 is H, halo or alkyl; R 5 is H or alkyl; R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ; R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; m is 0 to 4, and n is 1 to 4; wherein: Q is —S(O 2 )— or —C(O)—; R is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ; R 2 is selected from the group consisting of CN, NR 5 R 6 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; alkynyl, heteroaryl, CF 3 , heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; R 4 is H, halo or alkyl; R 5 is H or alkyl; R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ; R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; m is 0 to 4, and n is 1 to 4; and or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R 2 is selected from the group consisting of halo; —CF 3 ; —CN; —SR 6 ; —NO 2 ; —NR 5 R 6a ; —C(O)R 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkyl; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halo; haloalkyl; cycloalkyl; aryl; arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic moieties shown immediately above for R 2 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —C(═N—OH), —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; R 3 is selected from the group consisting of H; —NR 5 R 6a ; —OR 6b ; —SR 6 ; CF 3 ; —C(O)N(R 5 R 6 ); alkyl; alkenyl, alkynyl; cycloalkyl; aryl; arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkyl, alkynyl; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —C(═N—OH), —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; R 4 is selected from the group consisting of —CF 3 ; —CN; —NR 5 R 6a ; —(CR 5 R 11 ) p C(O 2 )R 6 ; —(CR 5 R 11 ) p C(O)NR 5 R 10 ; —C(O)—N(R 5 R 10 ); —OR 6b ; —SR 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —C(O)R 6 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aryl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl; wherein each of the alkyl, cycloalkyl; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl and fused heteroaryl groups of R 4 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(R 5 )(═N—OR 5 ), —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety, and wherein the substituted alkyl group of R 4 is independently substituted with one or more of the above moieties; R 5 is H, alkyl, aryl or cycloalkyl; R 6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S( 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF 3 , —OCF 3 , —CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —C(═N—OH), and —N(R 5 )C(O)NR 5 R 10 ; R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(═N—OH), —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —OR 6 , —NR 5 R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, —S(O 2 )R 7 , and R 9 is selected from the group consisting of halo, —CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —C(═N—OH), —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; and R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 11 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 11 , —C(O)R 5 , —C(═N—OH), —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 11 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 11 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 11 is H, halo or alkyl; m is 0 to 4; n is 1 to 4; and p is 1 to 4; with the provisos that (1) when R 2 is alkyl, carboxyl, phenyl or cycloalkyl, then R 3 is selected from the group consisting of —NR 5 R 6a ; —C(O)N(R 5 R 6 ); alkynyl; arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 is unsubstituted or independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O)NR 5 R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; (2) when R 2 is halo, then R 3 is selected from the group consisting of —OR 6b ; —SR 6 ; —C(O)N(R 5 R 6 ); cycloalkyl; heterocyclyl; heterocyclylalkyl; wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; and (3) when R 2 is NH 2 , R 3 is not methyl.
4 . A method of treating, or slowing the progression of, a disease by inhibiting one or more kinases in a patient, said kinases being selected from the group consisting of Checkpoint kinases, Pim kinases, and Aurora kinases, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination (i) at least one pharmaceutically acceptable carrier and (ii) at least one compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein said compound is selected from the group consisting of the compounds represented by any of the structural formulas I through VI below:
wherein:
R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl,
wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group,
wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is H, halo or alkyl;
R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl;
R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4,
with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not
and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms;
or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein:
R is an aryl, wherein said aryl is either unsubstituted or optionally substituted or fused with one or more heteroaryl;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which groups can be the same or different with each R 9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups,
and heteroaryl substituted with 0-3 aryl or heteroaryl groups which can be the same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4,
with the following provisos: (i) that when R is an unsubstituted phenyl, then R 2 is not alkyl, —C(O 2 )R 6 , aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R 2 is halogen only;
wherein:
R is heteroaryl, wherein said heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —C(R 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, aryl, heteroaryl, CF 3 , heterocyclylalkyl, alkynylalkyl, cycloalkyl, —C(O)OR 4 , alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below,
wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —CH 2 OR 5 , —C(O)R 5 , —SO 3 H, —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , —CF 3 , and —OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)OR 4 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R 7 . can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —CH 2 OR 4 , —C(O)OR 6 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 6 , —(CH 2 ) n OR 4 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
m is 0 to 4; and
n is 1 to 4;
wherein:
Q is selected from the group consisting of —S(O 2 )NR 6 R 7 —, —C(O)NR 6 R 7 — and —C(O)OR 7 —;
R 2 is selected from the group consisting of R 9 , alkyl, alkynyl, alkynylalkyl, cycloalkyl, —CF 3 , —C(O 2 )R 6 , aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown later below,
wherein the aryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, alkyl, alkynyl, —C(O)NR 5 R 6 , —C(O)OR 4 , —NR 5 R 6 , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4;
wherein:
Q is —S(O 2 )— or —C(O)—;
R is aryl or heteroaryl, wherein said aryl or heteroaryl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, CN, —OR 5 , SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 2 is selected from the group consisting of CN, NR 5 R 6 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ; alkynyl, heteroaryl, CF 3 , heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below,
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)NR 5 R 6 , alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
R 4 is H, halo or alkyl;
R 5 is H or alkyl;
R 6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4, and
n is 1 to 4; and
or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof,
wherein:
R 2 is selected from the group consisting of halo; —CF 3 ; —CN; —SR 6 ; —NO 2 ; —NR 5 R 6a ; —C(O)R 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkyl; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halo; haloalkyl; cycloalkyl; aryl; arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl;
alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group;
wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic moieties shown immediately above for R 2 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p R 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —C(═N—OH), —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 3 is selected from the group consisting of H; —NR 5 R 6a ; —OR 6b ; —SR 6 ; CF 3 ; —C(O)N(R 5 R 6 ); alkyl; alkenyl, alkynyl; cycloalkyl; aryl; arylalkyl; heterocyclyl;
heterocyclylalkyl; heteroaryl; heteroarylalkyl;
wherein each of the alkyl, alkynyl; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —C(═N—OH), —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is selected from the group consisting of —CF 3 ; —CN; —NR 5 R 6a ; —(CR 5 R 11 ) p C(O 2 )R 6 ; —(CR 5 R 11 ) p C(O)NR 5 R 10 ; —C(O)—N(R 5 R 10 ); —OR 6b ; —SR 6 ; —S(O 2 )R 7 ; —S(O 2 )NR 5 R 10 ; —C(O)R 6 ; —N(R 5 )S(O 2 )R 7 ; —N(R 5 )C(O)R 7 ; —N(R 5 )C(O)NR 5 R 10 ; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aryl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl;
wherein each of the alkyl, cycloalkyl; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl and fused heteroaryl groups of R 4 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, heteroaryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(R 5 )(═N—OR 5 ), —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety, and wherein the substituted alkyl group of R 4 is independently substituted with one or more of the above moieties;
R 5 is H, alkyl, aryl or cycloalkyl;
R 6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(═N—OH), —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF 3 , —OCF 3 , —CN, —OR 5 , —NR 5 R 10 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —C(═N—OH), and —N(R 5 )C(O)NR 5 R 10 ;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(═N—OH), —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —NR 5 R 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, —S(O 2 )R 7 , and
R 9 is selected from the group consisting of halo, —CN, —NR 5 R 10 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —C(═N—OH), —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; and
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 11 , —C(R 5 R 11 ) p —R 9 , —N(R 5 )Boc, —(CR 5 R 11 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 11 , —C(O)R 5 , —C(═N—OH), —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 11 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5)C(O)NR 5 R 11 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 11 is H, halo or alkyl;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4;
with the provisos that
(1) when R 2 is alkyl, carboxyl, phenyl or cycloalkyl, then R 3 is selected from the group consisting of —NR 5 R 6a ; —C(O)N(R 5 R 6 ); alkynyl; arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl;
wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 is unsubstituted or independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of —CN, —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O)NR 5 R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 ;
(2) when R 2 is halo, then R 3 is selected from the group consisting of —OR 6b ; —SR 6 ; —C(O)N(R 5 R 6 ); cycloalkyl; heterocyclyl; heterocyclylalkyl;
wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, and the heterocyclic moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, —CF 3 , —CN, —OCF 3 , —(CR 11 R 11 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 5 R 11 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; and
(3) when R 2 is NH 2 , R 3 is not methyl.
5 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is selected from the group consisting of:
6 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is selected from the group consisting of:
7 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is selected from the group consisting of:
8 . The method according to any of claims 1 to 4 , wherein the compound of Formula VI is selected from the group consisting of:
9 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
10 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
11 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
12 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
13 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
14 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
15 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
16 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
17 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
18 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
19 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
20 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
21 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
22 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
23 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
24 . The method according to any of claims 1 to 4 , wherein the compound of Formula I is:
25 . The method according to any of claims 1 to 4 , wherein the compound of Formula VI is:
26 . The method according to any of claims 1 to 4 , wherein the compound of Formula VI is:
27 . The method according to any of claims 1 to 4 , wherein the compound of Formula II is:
28 . The method according to any of claims 1 to 4 , wherein the compound of Formula II is:
29 . The method according to any of claims 1 to 4 , wherein the compound of Formula II is:
30 . The method according to any of claims 1 to 4 , wherein the compound of Formula II is:
31 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
32 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
33 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
34 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
35 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
36 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
37 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
38 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
39 . The method according to any of claims 1 to 4 , wherein the compound of Formula III is:
40 . The method according to claim 3 , wherein the one or more anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.
41 . The method according to any of claims 1 to 4 , wherein the Checkpoint kinase is CHK1.
42 . The method according to any of claims 1 to 4 , wherein the Checkpoint kinase is CHK2.
43 . A method of inhibiting activity of a Checkpoint kinase, the method comprising administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound to a patient in need thereof, the compound being represented by the structural formula I:
wherein:
R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl,
wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group,
wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is H, halo or alkyl;
R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl;
R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4,
with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not
and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.
44 . A method of treating, or slowing the progression of, a disease by inhibiting a Checkpoint kinase, said method comprising administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, the compound being represented by the structural formula I:
wherein:
R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl,
wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group,
wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is H, halo or alkyl;
R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl;
R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4,
with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not
and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.
45 . A method of treating a disease by inhibiting a Checkpoint kinase, comprising administering to a patient in need of such treatment
an amount of a first compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect, wherein the first compound is a compound of formula I: wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group, wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ; R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; R 4 is H, halo or alkyl; R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ; R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.
46 . A method of treating, or slowing the progression of, a disease by inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination (i) at least one pharmaceutically acceptable carrier and (ii) at least one compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein the compound is a compound of formula I:
wherein:
R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl,
wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group,
wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ;
R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl,
wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety;
R 4 is H, halo or alkyl;
R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl;
R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ;
R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ;
R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 6 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ;
m is 0 to 4;
n is 1 to 4; and
p is 1 to 4,
with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not
and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.
47 . The method according to any of claims 2 , 3 , 4 , 44 , 45 or 46 , wherein the disease is a proliferative disease, autoimmune disease, viral disease, fungal disease, neurological/neurodegenerative disorder, arthritis, inflammation, anti-proliferative disease, neuronal, alopecia or cardiovascular disease.
48 . The method according to claim 47 , wherein the disease is a proliferative disease.
49 . The method according to claim 48 , wherein the proliferative disease is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, Burkett's lymphoma; acute and chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
50 . The method according to claim 48 , further comprising treatment with radiation therapy.
51 . The method according to claim 45 , wherein said one or more anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.
52 . A method of treating a cancer comprising administering a therapeutically effective amount of at least one compound of any of formulas I-VI in claim 1 .
53 . The method of claim 52 , wherein said cancer is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;
leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma and Burkett's lymphoma; acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; head and neck, mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
54 . A method of treating a cancer, comprising administering to a mammal in need of such treatment
an amount of a first compound, which is a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect, wherein said compound of formula I is: wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), —(CHR 5 ) n -aryl, —(CHR 5 ) n -heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 2 is selected from the group consisting of H, R 9 , alkyl, alkenyl, alkynyl, CF 3 , heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R 9 groups which can be the same or different and are independently selected from the list of R 9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, heteroaryl fused with an aryl or heteroaryl group, wherein one or more of the aryl and/or one or more of the heteroaryl in the above-noted definitions for R 2 can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, —CN, —OR 5 , —SR 5 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , CF 3 , alkyl, aryl and OCF 3 ; R 3 is selected from the group consisting of H, halogen, —NR 5 R 6 , —OR 6 , —SR 6 , —C(O)N(R 5 R 6 ), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 3 and the heterocyclyl moieties whose structures are shown immediately above for R 3 can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) p OR 5 , —OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) p NR 5 R 6 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 , —N(R 5 )C(R 4 R 5 ) n N(R 5 R 6 ) and —N(R 5 )C(O)NR 5 R 6 , with the proviso that no carbon adjacent to a nitrogen atom on a heterocyclyl ring carries a —OR 5 moiety; R 4 is H, halo or alkyl; R 5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R 6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; R 10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 4 R 5 , —C(R 4 R 5 ) p —R 9 , —N(R 5 )Boc, —(CR 4 R 5 ) p OR 5 , —C(O 2 )R 5 , —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 4 R 5 ;
or optionally (i) R 5 and R 10 in the moiety —NR 5 R 10 , or (ii) R 5 and R 6 in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R 9 groups;
R 7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10 and —N(R 5 )C(O)NR 5 R 10 ; R 8 is selected from the group consisting of R 6 , —OR 6 , —C(O)NR 5 R 10 , —S(O 2 )NR 5 R 10 , —C(O)R 7 , —C(═N—CN)—NH 2 , —C(═NH)—NHR 5 , heterocyclyl, and —S(O 2 )R 7 ; R 9 is selected from the group consisting of halogen, —CN, —NR 5 R 10 , —SCN, —NO 2 , —C(O)R 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S (O 2 )R 7 , —N(R 5 )C(O)R 7 and —N(R 5 )C(O)NR 5 R 10 ; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R 2 is phenyl, R 3 is not alkyl, alkynyl or halogen, and that when R 2 is aryl, R is not and with the further proviso that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms.
55 . The method of claim 5 , further comprising treatment with radiation therapy.
56 . The method of claim 54 , wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leu prolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.
57 . A method of inhibiting activity of a Checkpoint kinase, the method comprising administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound to a patient in need thereof, the compound being selected from the group consisting of:
58 . A method of treating, or slowing the progression of, a disease by inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination (i) at least one pharmaceutically acceptable carrier and (ii) at least one compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein the compound is selected from the group consisting of:
59 . A method of treating a proliferative disease, comprising administering to a mammal in need of such treatment
an amount of a first compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect, wherein said first compound is selected from the group consisting of:
60 . The method of claim 59 , further comprising treatment with radiation therapy.
61 . The method of claim 59 , wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine, cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL-101,731.
62 . A method of treating, or slowing the progression of, a proliferative disease in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising in combination (i) at least one pharmaceutically acceptable carrier and (ii) at least one compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein said compound is selected from the group consisting of:
63 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
64 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
65 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
66 A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
67 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
68 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
69 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
70 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
71 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
72 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
73 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
74 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
75 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
76 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
77 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
78 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
79 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
80 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
81 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
82 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
83 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
84 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
85 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
86 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
87 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
88 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
89 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
90 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
91 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
92 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
93 . A method of inhibiting a Checkpoint kinase, comprising administering a therapeutically effective amount of a compound of formula:
94 . A compound exhibiting CHK-1 inhibition which is at least five-fold said compound's CDK2 inhibition.
95 . A compound exhibiting CHK-1 inhibition which is at least ten-fold said compound's CDK2 inhibition.
96 . A compound exhibiting CHK-1 inhibition which is at least fifty-fold said compound's CDK2 inhibition.
97 . A pyrazolopyrimidine compound exhibiting CHK-1 inhibition which is at least five-fold said compound's CDK2 inhibition.
98 . A pyrazolopyrimidine compound exhibiting CHK-1 inhibition which is at least ten-fold said compound's CDK2 inhibition.
99 . A pyrazolopyrimidine compound exhibiting CHK-1 inhibition which is at least fifty-fold said compound's CDK2 inhibition.Join the waitlist — get patent alerts
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