US2013177529A1PendingUtilityA1
Pyrazole Compounds
Est. expiryFeb 15, 2025(expired)· nominal 20-yr term from priority
C07D 231/12C07D 401/10C07D 405/10C07D 405/12C07D 491/052C07D 409/10A61K 31/5377A61K 45/06A61K 31/496C07D 417/12C07D 231/14A61K 31/427A61K 31/415A61K 31/4162C07D 401/06A61K 31/4439A61K 31/454A61K 31/4155
50
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Claims
Abstract
Aryl substituted pyrazole derivatives are provided, as well as processes for their preparation. The invention also provides compositions and methods for the treatment of HCV by administering a compound of the present invention, alone or in combination with additional antiviral agents, in a therapeutically effective amount.
Claims
exact text as granted — not AI-modified1 - 57 . (canceled)
58 . A compound having the formula I:
wherein:
ring A is a 5- or 6-membered aromatic ring which may optionally contain 0 to 3 ring heteroatoms;
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 ,
—OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 4 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
wherein:
Z is O or N—OR 461 ;
R 461 is selected from the group consisting of H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, alkyl-O-aryl and —(CH 2 ) a —R 42 ;
each R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 is independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, or —(CH 2 ) a —R 42 ;
R 45 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —OR 421 ,
—SR 421 , —C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
a is 1 to 6;
R 5 is selected from the group consisting of H, OR 51 , —SR 51 , alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF 3 , NO 2 , SO 2 , —SOR 51 , —SO 3 R 51 , —SO 2 N(R 52 )(R 53 ), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, —C(O)R 51 , —C(O)OR 51 , —C(O)N(R 52 )(R 53 ), —OC(O)R 51 ,
—OC(O)N(R 52 )(R 53 ), —O(CH 2 ) e C(O)OR 51 , —O(CH 2 ) e C(O)N(R 52 )(R 53 ), —N(R 52 )(R 53 ), —N(R 51 )C(O)R 51 , and —N(R 51 )SO 2 R 51 ;
each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 52 and R 53 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
e is 1 to 6;
alternatively, —O—R 51 is combined with R 41 , R 46 , or R 47 to give a 6-membered ring that is fused to ring A and to the pyrazole ring;
or R 5 is
wherein:
each R 54 and R 56 is independently selected from −OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, —C(O)R 57 , —C(O)OR 57 , —C(O)N(R 58 )(R 59 ), —OC(O)R 57 , —OC(O)N(R 58 )(R 59 ), O(CH 2 ) i C(O)OR 57 , —O(CH 2 ) i C(O)N(R 58 )(R 59 ), —N(R 58 )(R 59 ), —N(R 57 )C(O)R 57 , —N(R 57 )SO 2 R 57 , aralkyl, aryl or heteroaryl;
each R 57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 58 and R 59 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
i is 1 to 6;
X 1 is N or CH;
f is 1 to 6;
g is 0 to 4; and
h is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
59 . The compound of claim 58 , having the formula II:
wherein:
ring A is a 5- or 6-membered aromatic ring which may optionally contain 0 to 3 ring heteroatoms;
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OO(O)R 34 ,
—OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 4 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl
wherein:
Z is O or N—OR 461 ;
R 461 is selected from the group consisting of H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, alkyl-O-aryl and —(CH 2 ) a —R 42 ;
each R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 is independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, or —(CH 2 ) a —R 42 ;
R 45 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —OR 421 ,
—SR 421 , —C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
a is 1 to 6;
R 6 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 51 , —C(O)N(R 52 )(R 53 ), (CH 2 ) e C(O)OR 51 , and —(CH 2 ) e C(O)N(R 52 )(R 53 );
each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 52 and R 53 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
e is 1 to 6;
alternatively, R 6 is combined with R 41 , R 46 , or R 47 to give a 6-membered ring that is fused to ring A and to the pyrazole ring;
or R 6 is
wherein:
each R 54 and R 56 is independently selected from −OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, —C(O)R 57 , —C(O)OR 57 , —C(O)N(R 58 )(R 59 ),
—OC(O)R 57 , —OC(O)N(R 58 )(R 59 ), O(CH 2 ) e C(O)OR 57 , —O(CH 2 ) e C(O)N(R 58 )(R 59 ), —N(R 58 )(R 59 ), —N(R 57 )C(O)R 57 , —N(R 57 )SO 2 R 57 , aralkyl, aryl or heteroaryl;
each R 57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 58 and R 59 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
i is 1 to 6;
X 1 is N or CH;
f is 1 to 6;
g is 0 to 4; and
h is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
60 . The compound of claim 59 having the formula III:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5- or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 4 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
wherein:
Z is O or N—OR 461 ;
R 461 is selected from the group consisting of H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, alkyl-O-aryl and —(CH 2 ) a —R 42 ;
each R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 is independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, or —(CH 2 ) a —R 42 ;
R 45 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —OR 421 ,
—SR 421 , —C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
a is 1 to 6;
R 6 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 51 , —C(O)N(R 52 )(R 53 ), (CH 2 ) e C(O)OR 51 , and —(CH 2 ) e C(O)N(R 52 )(R 53 );
each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 52 and R 53 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
e is 1 to 6;
alternatively, R 6 is combined with R 41 , R 46 , or R 47 to give a 6-membered ring that is fused to ring A and to the pyrazole ring;
or R 6 is
wherein:
each R 54 and R 56 is independently selected from −OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, —C(O)R 57 , —C(O)OR 57 , —C(O)N(R 58 )(R 59 ),
—OC(O)R 57 , —OC(O)N(R 58 )(R 59 ), O(CH 2 ) e C(O)OR 57 , —O(CH 2 ) e C(O)N(R 58 )(R 59 ), —N(R 58 )(R 59 ), —N(R 57 )C(O)R 57 , —N(R 57 )SO 2 R 57 , aralkyl, aryl or heteroaryl;
each R 57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 58 and R 59 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 58 and R 59 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
i is 1 to 6;
X 1 is N or CH;
f is 1 to 6;
g is 0 to 4; and
h is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
61 . The compound of claim 60 having the formula IV:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl; additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl,
alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 45 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —OR 421 ,
—SR 421 , —C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
a is 1 to 6;
R 6 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 51 , —C(O)N(R 52 )(R 53 ), (CH 2 ) e C(O)OR 51 , and —(CH 2 ) e C(O)N(R 52 )(R 53 );
each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 52 and R 53 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom;
e is 1 to 6;
or R 6 is
wherein:
each R 54 and R 56 is independently selected from OH, halo, alkyl, cycloalkyl, alkenyl, alkynyl, NO 2 , CN, —C(O)R 57 , —C(O)OR 57 , —C(O)N(R 58 )(R 59 ), —OC(O)R 57 ,
—OC(O)N(R 58 )(R 59 ), O(CH 2 ) i C(O)OR 57 , —O(CH 2 ) i C(O)N(R 58 )(R 59 ), —N(R 58 )(R 59 ), —N(R 57 )C(O)R 57 , —N(R 57 )SO 2 R 57 , aralkyl, aryl or heteroaryl;
each R 57 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 58 and R 59 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
i is 1 to 6;
X 1 is N or CH;
f is 1 to 6;
g is 0 to 4; and
h is 0 to 5;
or a pharmaceutically acceptable salt or hydrate thereof.
62 . The compound of claim 61 having the formula V:
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 45 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —OR 421 ,
—SR 421 , —C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
a is 1 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
63 . The compound of claim 58 having the formula VI:
wherein:
ring A is a 5- or 6-membered aromatic ring which may optionally contain 0 to 3 ring heteroatoms;
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl,
alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 43 and R 44 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl or —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —SR 421 ,
—C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
a is 1 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
64 . The compound of claim 63 having the formula VI a :
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 43 and R 44 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl or —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —SR 421 ,
—C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
a is 1 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
65 . The compound of claim 58 having the formula VII:
wherein:
ring A is a 5- or 6-membered aromatic ring which may optionally contain 0 to 3 ring heteroatoms;
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ), -alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 48 and R 49 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl,
-alkyl-O-alkyl or —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —SR 421 ,
—C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 42 is
or
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
a is 1 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
66 . The compound of claim 65 having the formula VIII a :
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 48 and R 49 are independently selected from H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl or —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —SR 421 ,
—C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
a is 1 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
67 . The compound of claim 58 having the formula VIII:
wherein:
ring A is a 5- or 6-membered aromatic ring which may optionally contain 0 to 3 ring heteroatoms;
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
Z is O or N—OR 461 ;
R 461 is selected from the group consisting of H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —SR 421 ,
—C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
a is 1 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
68 . The compound of claim 67 having the formula VIII a :
wherein:
each R 1 is independently selected from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ),
—N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 , —SO 2 N(R 12 )(R 13 ),
-alkyl-O—R 11 , cycloalkyl, cycloalkenyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 is selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, and -alkyl-O-aryl;
R 21 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , and —C(O)N(R 32 )(R 33 );
R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
Z is O or N—OR 461 ;
R 461 is selected from the group consisting of H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —SR 421 ,
—C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, halo, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom; and
a is 1 to 6;
or a pharmaceutically acceptable salt or hydrate thereof.
69 . A compound having the formula X:
wherein:
ring A and ring A′ are independently selected from 5- or 6-membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms;
each R 1 and R 1 ′ is selected independently from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 ,
—SO 2 N(R 12 )(R 13 ), -alkyl-O-alkyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 and R 2 ′ are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, or -alkyl-O-aryl;
each R 21 is independently selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 and R 3 ′ are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , or —C(O)N(R 32 )(R 33 );
each R 31 is selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 5 and R 5 ′ are independently selected from H, OR 51 , —SR 51 , alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, CN, CF 3 , NO 2 , SO 2 , —SOR 51 , —SO 3 R 51 , —SO 2 N(R 52 )(R 53 ), -alkyl-O-alkyl, halo, aralkyl, aryl, heteroaryl, —C(O)R 51 , —C(O)OR 51 , —C(O)N(R 52 )(R 53 ), —OC(O)R 51 ,
—OC(O)N(R 52 )(R 53 ), —O(CH 2 ) e C(O)OR 51 , —O(CH 2 ) e C(O)N(R 52 )(R 53 ), —N(R 52 )(R 53 ), —N(R 51 )C(O)R 51 , or —N(R 51 )SO 2 R 51 ;
each R 51 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 52 and R 53 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
e is 1 to 6;
alternatively, —O—R 51 is combined with R 41 , R 46 , or R 47 to give a 6-membered ring that is fused to ring A and to the pyrazole ring;
or R 5 is
wherein:
each R 54 and R 56 is independently selected from −OR 57 , halo, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, NO 2 , CN, —C(O)R 57 , —C(O)OR 57 , —C(O)N(R 58 )(R 59 ), —OC(O)R 57 , —OC(O)N(R 58 )(R 59 ), O(CH 2 ) i C(O)OR 57 , —O(CH 2 ) i C(O)N(R 58 )(R 59 ), —N(R 58 )(R 59 ), —N(R 57 )C(O)R 57 , —N(R 57 )SO 2 R 57 , aralkyl, aryl or heteroaryl;
each R 57 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 58 and R 59 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 52 and R 53 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
i is 1 to 6;
X 1 is N or CH;
f is 1 to 6;
g is 0 to 4; and
h is 0 to 5;
L is a linking group selected from the group consisting of —(CH 2 ) x —,
and a group of the formula -A-B-A-;
wherein:
A is selected from the group consisting of —N(R)—, —O—, —S—, —C(O)—, —OC(O)—, —N(R)C(O)—, —N(R)C(O)O—, —N(R)SO 2 —, —(CH 2 ) y —, and —C≡C—;
B is selected from the group consisting of —(CH 2 ) z —,
and —(CH 2 ) v -D-(CH 2 ) w — wherein D is selected from the group consisting of O, S, —C═C—, —S—S—, —C≡C—, —C≡C—C≡C—,
x is 3 to 25;
y is 1 to 10;
z is 1 to 10;
v is 1 to 8; and
w is 1 to 8;
or a pharmaceutically acceptable salt or hydrate thereof.
70 . A compound having the formula XI:
wherein:
ring A and ring A′ are independently selected from 5- or 6-membered aromatic rings which may optionally contain 0 to 3 ring heteroatoms;
each R 1 and R 1 ′ is selected independently from alkyl, alkenyl, alkynyl, aralkyl, —O—R 11 , —N(R 12 )(R 13 ), —N(R 11 )C(O)R 11 , —N(R 11 )SO 2 R 11 , —SR 11 , —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ), —OC(O)R 11 , —OC(O)N(R 12 )(R 13 ), CN, CF 3 , NO 2 , SO 2 , —SOR 11 , —SO 3 R 11 ,
—SO 2 N(R 12 )(R 13 ), -alkyl-O-alkyl, halo, aryl or heteroaryl;
additionally or alternatively two R 1 substituents on adjacent ring atoms may be combined to form a fused 5 or 6-membered ring, wherein the fused 5- or 6-membered ring may contain from 0 to 3 ring heteroatoms and may be further substituted with one or more substituents selected from R 1 ;
each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 12 and R 13 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
n is 0 to 4;
R 2 and R 2 ′ are selected independently from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl, heteroaryl, —C(O)R 21 , —C(O)OR 21 , -alkyl-O-alkyl, or -alkyl-O-aryl;
each R 21 is independently selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
R 3 and R 3 ′ are independently selected from H, alkyl, cycloalkyl, cyloalkenyl, alkenyl, alkynyl,
-alkyl-O-alkyl, alkyl-O-aryl, aralkyl, aryl, heteroaryl, —C(O)R 31 , —C(O)OR 31 , or —C(O)N(R 32 )(R 33 );
each R 31 is independently selected from the group consisting of H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and heteroaryl;
each R 32 and R 33 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 32 and R 33 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and which may be optionally substituted with one or more CN, NO 2 , CO 2 R 34 , C(O)R 34 , —O—R 34 , —N(R 34 )(R 35 ), —N(R 34 )C(O)R 34 , —N(R 34 )SO 2 R 34 , —SR 34 , —C(O)N(R 35 )(R 36 ), —OC(O)R 34 , —OC(O)N(R 35 )(R 36 ), SO 2 , —SOR 34 , —SO 3 R 34 , —SO 2 N(R 35 )(R 36 ), halo, cycloalkyl, cycloalkenyl, aryl or heteroaryl;
each R 34 is independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 35 and R 36 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 35 and R 36 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
R 4 and R 4 ′ are selected from H, alkyl, -alkyl-O-alkyl, cycloalkyl, aralkyl, aryl, heteroaryl,
wherein:
Z is O or N—OR 461 ;
R 461 is selected from the group consisting of H, alkyl, alkenyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, alkyl-O-aryl and —(CH 2 ) a —R 42 ;
each R 41 , R 43 , R 44 , R 46 , R 47 , R 48 and R 49 is independently selected from H, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, cycloalkenyl, -alkyl-O-alkyl, -alkyl-O-aryl, or —(CH 2 ) a —R 42 ;
R 45 is selected from the group consisting of H, alkyl, -alkyl-O-alkyl, -alkyl-O-aryl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and —(CH 2 ) a —R 42 ;
R 42 is selected from the group consisting of —N(R 421 )C(O)R 421 , —N(R 421 )SO 2 R 421 , —OR 421 ,
—SR 421 , —C(O)R 421 , —C(O)OR 421 , —C(O)N(R 422 )(R 423 ), —OC(O)R 421 , —OC(O)N(R 422 )(R 423 ), CN, CF 3 , NO 2 , SO 2 , —SOR 421 , —SO 3 R 421 , —SO 2 N(R 422 )(R 423 ), -alkyl-O-alkyl, -alkyl-O-aryl, halo, cycloalkyl, cycloalkenyl, aryl and heteroaryl; or R 42 is
each R 421 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 422 and R 423 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 422 and R 423 may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
each R 424 is independently selected from H, OH, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl;
each R 425 and R 426 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl or heteroaryl; or R 425 and R 426 may be taken together with the carbon to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom;
a is 1 to 6;
L is a linking group selected from the group consisting of —(CH 2 ) x —,
and a group of the formula -A-B-A-;
wherein:
A is selected from the group consisting of —N(R)—, —O—, —S—, —C(O)—, —OC(O)—, —N(R)C(O)—, —N(R)C(O)O—, —N(R)SO 2 —, —(CH 2 ) y —, and —C≡C—;
B is selected from the group consisting of —(CH 2 ) z —,
and —(CH 2 ) v -D-(CH 2 ) w —, wherein D is selected from the group consisting of O, S, —C═C—, —S—S—, —C≡C—, —C≡C—C≡C—,
x is 3 to 25;
y is 1 to 10;
z is 1 to 10;
v is 1 to 8; and
w is 1 to 8;
or a pharmaceutically acceptable salt or hydrate thereof.
71 . The compound of claim 58 , which is selected from the group consisting of:
72 . A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to claim 58 .
73 . A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to claim 69 .
74 . A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a compound of according to claim 70 .
75 . A method of treating HCV infection in a human comprising administering a therapeutically effective amount of a combination of the compound according to claim 58 , or a therapeutically acceptable salt or hydrate thereof, and at least one additional agent selected from an interferon, ribavirin, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV IRES inhibitor, an HCV Helicase, an HCV ATPase inhibitor, an NS5A phosphorylation inhibitor, and an HCV NS2 inhibitor.
76 . A pharmaceutical composition for the treatment of HCV infection comprising a therapeutically effective amount of a compound of according to claim 58 in a pharmaceutically acceptable carrier.
77 . The pharmaceutical composition of claim 76 , further comprising a second antiviral agent, wherein the second anti-viral agent is selected from the group consisting of an interferon, ribavirin, an HCV protease inhibitor, an HCV polymerase inhibitor, an HCV IRES inhibitor, an HCV Helicase, an HCV ATPase inhibitor, an NS5A phosphorylation inhibitor, and an HCV NS2 inhibitor.Cited by (0)
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