US2020123132A1PendingUtilityA1
Antiviral compounds
Est. expiryNov 17, 2030(~4.3 yrs left)· nominal 20-yr term from priority
Inventors:Elizabeth M. BaconJeromy J. CottellAshley Anne KatanaDarryl KatoEvan S. KrygowskiJohn O. LinkJames G. TaylorChinh Viet TranTeresa Alejandra Trejo MartinZheng-Yu YangSheila Zipfel
A61K 31/4178A61K 31/5377A61P 31/12A61P 31/14A61P 31/00C07D 405/14A61P 43/00A61K 31/4188C07D 493/04C07D 513/04C07D 403/14C07D 417/14A61K 45/06C07D 491/107C07D 495/04A61P 1/16A61K 31/4184C07D 491/10C07D 471/08C07D 491/113A61P 31/18A61K 2300/00
69
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Claims
Abstract
The invention is related to anti-viral compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
W 1a is selected from A, B, C, D, and E:
and W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, and cyano;
Y 5 is —O—CH 2 —, or —CH 2 —O—; X 5 is —CH 2 —CH 2 — or —CH═CH—;
X 11 is —CH 2 —CH 2 —, —O—CH 2 —, or —CH═CH—;
X 18 is CH═CH—, —CH 2 CH 2 —, or —OCH 2 —;
X 3 is —CH 2 —CH 2 —, or —CH 2 —O—; Y 3 is —CH 2 —CH 2 —, —O—CH 2 —, —CH 2 —O—, or —CH═CH—;
E 1a is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl); or E 1a -V 1a taken together are R 9a ;
E 1b is —N(H)(alkoxycarbonyl), —N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl); or E 1b -V 1b taken together are R 9b ;
V 1a and V 1b are each independently selected from:
when W 1a is selected from A and E, then P 1a and P 1b are each independently selected from:
when W 1a is selected from B, C, and D then one of P 1a and P 1b is
and the other of P 1a and P 1b is selected from:
R 9a and R 9b are each independently:
or a pharmaceutically acceptable salt or prodrug thereof.
2 . The compound of claim 1 wherein W 1a has the formula:
and W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, and cyano.
3 . The compound of claim 1 wherein W 1a has the formula:
and W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, and cyano.
4 . The compound of claim 1 wherein W 1a has the formula:
and W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, and cyano.
5 . The compound of claim 1 wherein W 1a has the formula:
W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, and cyano.
6 . The compound of claim 1 wherein W 1a has the formula:
and W 1a is optionally substituted with one or more groups independently selected from halo, alkyl, haloalkyl, and cyano.
7 . The compound of claim 2 which has formula:
or a pharmaceutically acceptable salt or prodrug thereof.
8 . The compound of claim 2 which has formula:
wherein the imidazole ring shown in formula A2 and A4 is optionally substituted with one or more groups independently selected from halo, haloalkyl, cyano, and alkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
9 . The compound of claim 4 wherein X 18 is CH═CH—.
10 . The compound of claim 4 wherein X 18 is —CH 2 —CH 2 —.
11 . The compound of claim 4 wherein X 18 is —O—CH 2 —.
12 . The compound of claim 6 wherein W 1a is:
wherein any imidazole ring shown in W 1a is optionally substituted with one or more groups independently selected from halo, haloalkyl, cyano, and alkyl.
13 . The compound of any one of claims 1 - 12 wherein at least one of E 1a and E 1b is —N(H)(alkoxycarbonyl).
14 . The compound of any one of claims 1 - 12 wherein at least one of E 1a and E 1b is —N(H)C(═O)OMe.
15 . The compound of any one of claims 1 - 12 wherein both of E 1a and E 1b are —N(H)C(═O)OMe.
16 . The compound of any one of claims 1 - 12 wherein at least one of E 1a and E 1b is —N(H)(cycloalkylcarbonyl) or —N(H)(cycloalkyloxycarbonyl).
17 . The compound of any one of claims 1 - 12 wherein at least one of E 1a and E 1b is cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino.
18 . The compound of any one of claims 1 - 12 wherein E 1a and E 1b are each independently selected from cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino and methoxycarbonylamino.
19 . The compound of any one of claims 1 - 18 wherein at least one of V 1a and V th is selected from:
20 . The compound of any one of claims 1 - 18 wherein at least one of V 1a and V 1b is:
21 . The compound of any one of claims 1 - 18 wherein at least one of V 1a and V 1b is selected from:
22 . The compound of any one of claims 1 - 18 wherein V 1a and V 1b are each independently selected from:
23 . The compound of any one of claims 1 - 12 wherein E 1a -V 1a taken together are R 9a or wherein E 1b -V 1b taken together are R 9b .
24 . The compound of claim 5 wherein E 1a -V 1a taken together are R 9a or wherein E 1b -V 1b taken together are R 9b .
25 . The compound of any one of claims 1 - 24 wherein at least one of P 1a and P 1b is selected from:
26 . The compound of any one of claims 1 - 24 wherein P 1a and P 1b are each independently selected from:
27 . The compound of any one of claims 1 , 2 , 6 , 7 , 8 , and 13 - 24 wherein at least one of P 1a and P 1b is selected from:
28 . The compound of any one of claims 1 - 24 wherein P 1a and P 1b are each independently selected from:
29 . The compound of any one of claims 1 - 24 wherein one of P 1a and P 1b is:
and the other of P 1a and P 1b is:
30 . The compound of any one of claims 1 - 24 wherein one of P 1a and P 1b is:
and the other of P 1a and P 1b is:
31 . The compound of any one of claims 1 , 2 , 6 , 7 , 8 , and 13 - 24 wherein at least one of P 1a and P 1b is:
32 . The compound of any one of claims 1 - 24 wherein at least one of P 1a and P 1b is:
33 . The compound of any one of claims 1 - 24 wherein at least one of P 1a and P 1b is:
34 . The compound of any one of claims 1 - 24 wherein at least one of P 1a and P 1b is:
35 . The compound of any one of claims 1 , 2 , 6 , 7 , 8 , and 13 - 24 wherein at least one of P 1a and P 1b is:
36 . The compound of any one of claims 1 , 2 , 6 , 7 , 8 , and 13 - 24 wherein at least one of P 1a and P 1b is:
37 . The compound of any one of claims 1 - 18 wherein at least one of —V 1a —C(═O)—P 1a —and —P 1b —C(═O)—V 1b — is:
38 . The compound of any one of claims 1 - 18 wherein at least one of —V 1a —C(═O)—P 1a —and —P 1b —C(═O)—V 1b — is:
39 . The compound of any one of claims 1 - 18 wherein both of —V 1a —C(═O)—P 1a and P 1b —C(═O)—V 1b — are independently selected from:
40 . The compound of any one of claims 1 - 18 wherein one of —V 1a C(═O)—P 1a and —P 1b —C(═O)—V 1b — is:
and the other of —V 1a —C(═O)—P 1a —and —P 1b —C(═O)—V 1b — is:
41 . The compound of claim 2 which is a compound of formula:
or a pharmaceutically acceptable salt or prodrug thereof.
42 . The compound of claim 2 which is a compound of formula:
or a pharmaceutically acceptable salt or prodrug thereof.
43 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
E 1a is E 0 , E 1 , or E 2 , or E 1a -V 1a taken together are R 9a ;
E 1b is E 0 , E 1 , or E 2 , or E 1b -V 1b taken together are R 9b ;
V 1a is V 0 or E 1a -V 1a taken together are R 9a ;
V 1b is V 0 or E 1b -V 1b taken together are R 9b ;
P 1a is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 , and P 30 ;
P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 , and P 30 ;
each E 0 is independently —NR Ec R Ed wherein R Ec and R Ed are each independently hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each E 1 is independently selected from hydrogen, hydroxy, alkyl, haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;
each E 2 is independently —NHR Ef wherein R Ef is cycloalkylcarbonyl or cycloalkyloxycarbonyl;
each V 0 is independently alkyl, arylalkyl, alkenyl, CO, (cycloalkyl)alkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, arylalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl-, oxo, and —P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each P 0 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
R P7 and R P8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR Pa R Pb )alkyl; or R P7 and R P8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NR Pz , O, and S; wherein R Pz is selected from hydrogen and alkyl;
R P9 is selected from hydrogen and alkyl;
each P 1 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
at least one R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclyloxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo and heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 3 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo group;
each R P13 is independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 0, 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 5 is independently a ring of the formula:
wherein:
the ring is optionally substituted with one or more groups R P15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pn is 0, 1, or 2;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 6 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo and is optionally substituted with one or more groups R P16 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
pn is 0, 1, or 2;
each R 1 is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6 and R P11 ;
each P 8 is independently a ring of the formula:
wherein:
ps is 2, 3, 4, 5, or 6;
pn is 0, 1 or 2;
each R P13 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each P 10 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
each P P12 is independently:
wherein:
each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq is independently 0, 1, 2, 3, or 4;
pm is independently 0, 1, or 2;
pp is independently 1, 2, or 3;
ps is 1, 2, 3, or 4;
R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 15 is:
which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl;
each P 18 is:
which is optionally substituted, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;
each P 19 is:
each P 30 is independently a ring of the formula:
ps is 2
pn is 0, 1 or 2;
X is selected from O, S, S(O), SO 2 , or CH 2 ; provided that when pn is 0, X is CH 2 ,
each R P13 is independently selected from alkyl-, alkoxyalkyl-, hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-, alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
each R 9a is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfanyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
each R 9b is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X R Y′ )carbonyl, wherein R X and R Y are independently selected from hydrogen and alkyl; and
W 1a is selected from:
wherein each W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
X 1 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Y 1 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
X 2 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
X 3 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Y 3 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
X 4 is a six membered aromatic or heteroaromatic or five membered heteroraromatic ring;
X 5 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Y 5 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
X 6 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Y 6 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
X 7 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Y 7 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Z 7 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
X 8 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Y 8 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Z 8 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —OC(O)—, —(O)CO—, or —CH═CH—;
X 9 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
Y 9 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—; and
Z 9 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —OC(O)—, —(O)CO—, or —CH═CH—;
or a pharmaceutically acceptable salt or prodrug thereof;
provided the compound of formula (I) is not:
44 . The compound of claim 43 wherein E 1a is E 0 .
45 . The compound of claim 43 wherein E 1a is E 1 .
46 . The compound of claim 43 wherein E 1a is selected from:
47 . The compound of claim 43 wherein E 1a is —N(H)alkoxycarbonyl.
48 . The compound of claim 43 wherein E 1a is —N(H)C(═O)OMe.
49 . The compound of any one of claims 43 - 48 wherein E 1b is E 0 .
50 . The compound of any one of claims 43 - 48 wherein E 1b is E 1 .
51 . The compound of any one of claims 43 - 48 wherein E 1b is selected from:
52 . The compound of any one of claims 43 - 48 wherein E 1b is —N(H)alkoxycarbonyl.
53 . The compound of any one of claims 43 - 48 wherein E 1b is —N(H)C(═O)OMe.
54 . The compound of any one of claims 43 - 53 wherein V 1a is V 0 .
55 . The compound of any one of claims 43 - 53 wherein V 1a is selected from:
56 . The compound of any one of claims 43 - 55 wherein V 1b is V 0 .
57 . The compound of any one of claims 43 - 55 wherein V 1b is selected from:
58 . The compound of claim 43 wherein E 1a -V 1a taken together are R 9a .
59 . The compound of claim 58 wherein R 9a is selected from:
60 . The compound of claims 43 , 58 and 59 wherein E 1b -V 1b taken together are R 9b .
61 . The compound of claim 60 wherein R 9b is selected from:
62 . The compound of any one of claims 43 - 61 wherein P 1a is P 0 .
63 . The compound of claim 62 wherein at least one of P 1a is selected from:
64 . The compound of any one of claims 43 - 61 wherein P 1a is P 1 .
65 . The compound of claim 64 wherein P 1a is selected from:
66 . The compound of any one of claims 43 - 61 wherein P 1a is P 3 .
67 . The compound of claim 66 wherein P 1a is selected from:
68 . The compound of any one of claims 43 - 61 wherein P 1a is P 5 .
69 . The compound of claim 68 wherein P 1a is selected from:
70 . The compound of any one of claims 43 - 61 wherein P 1a is P 6 .
71 . The compound of claim 70 wherein P 1a is:
72 . The compound of any one of claims 43 - 61 wherein P 1a is P 7 .
73 . The compound of claim 72 wherein P 1a is:
74 . The compound of any one of claims 43 - 61 wherein P 1a is P 8 .
75 . The compound of claim 74 wherein P 1a is selected from:
76 . The compound of any one of claims 43 - 61 wherein P 1a is P 10 .
77 . The compound of claim 76 wherein P 1a is:
78 . The compound of any one of claims 43 - 61 wherein P 1a is P 12 .
79 . The compound of any one of claims 43 - 61 wherein P 1a is P 15 .
80 . The compound of claim 79 wherein P 1a is selected from:
81 . The compound of any one of claims 43 - 61 wherein P 1a is P 18 .
82 . The compound of claim 81 wherein P 1a is:
83 . The compound of any one of claims 43 - 82 wherein P 1b is P 0 .
84 . The compound of claim 83 wherein at least one of P 1b is selected from:
85 . The compound of any one of claims 43 - 82 wherein P 1b is P 1 .
86 . The compound of claim 85 wherein P 1b is selected from:
87 . The compound of any one of claims 43 - 82 wherein P 1b is P 3 .
88 . The compound of claim 87 wherein P 1b is selected from:
89 . The compound of any one of claims 43 - 82 wherein P 1b is P 5 .
90 . The compound of claim 89 wherein P 1b is selected from:
91 . The compound of any one of claims 43 - 82 wherein P 1b is P 6 .
92 . The compound of claim 91 wherein P 1b is:
93 . The compound of any one of claims 43 - 82 wherein P 1b is P 7 .
94 . The compound of claim 93 wherein P 1b is:
95 . The compound of any one of claims 43 - 82 wherein P 1b is P 8 .
96 . The compound of claim 95 wherein P 1b is selected from:
97 . The compound of any one of claims 43 - 82 wherein P 1b is P 10 .
98 . The compound of claim 97 wherein P 1b is:
99 . The compound of any one of claims 43 - 82 wherein P 1b is P 12 .
100 . The compound of any one of claims 43 - 82 wherein P 1b is P 15 .
101 . The compound of claim 100 wherein P 1a is selected from:
102 . The compound of any one of claims 43 - 82 wherein P 1b is P 18 .
103 . The compound of claim 102 wherein P 1b is:
104 . The compound of any one of claims 43 - 61 wherein at least one of P 1a and P 1b is:
105 . The compound of any one of claims 43 - 61 wherein at least one of P 1a and P 1b is selected from:
106 . The compound of any one of claims 43 - 61 wherein at least one of P 1a and P 1b is selected from:
107 . The compound of any one of claims 43 - 61 wherein at least one of P 1a and P 1b is selected from:
108 . The compound of any one of claims 43 - 61 wherein at least one of P 1a and P 1b :
109 . The compound of any one of claims 43 - 61 wherein at least one of P 1a and P 1b :
110 . The compound of any one of claims 43 - 61 wherein at least one of P 1a and P 1b :
111 . The compound of any one of claims 43 - 61 wherein P 1a is:
112 . The compound of any one of claims 43 - 61 wherein P 1a is selected from:
113 . The compound of any one of claims 43 - 82 wherein P 1b is selected from
114 . The compound of any one of claims 43 - 82 wherein P 1b is selected from:
115 . The compound of any one of claims 43 - 114 wherein W 1a is 101, 102, 103, or 104.
116 . The compound of any one of claims 43 - 114 wherein W 1a is 105 or 106.
117 . The compound of any one of claims 43 - 114 wherein W 1a is
118 . The compound of claim 117 wherein X 1 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
119 . The compound of claim 117 or 118 wherein Y 1 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
120 . The compound of claim 117 wherein W 1a is:
121 . The compound of any one of claims 43 - 116 wherein W 1a is
122 . The compound of claim 121 wherein X 1 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
123 . The compound of claim 121 wherein W 1a is:
124 . The compound of claim 121 wherein W 1a is:
125 . The compound of any one of claims 43 - 114 wherein W 1a is
126 . The compound of claim 125 wherein X 3 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
127 . The compound of claim 125 or 126 wherein Y 3 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
128 . The compound of claim 125 wherein W 1a is:
129 . The compound of claim 125 wherein W 1a is:
130 . The compound of any one of claims 43 - 114 wherein W 1a is
131 . The compound of any one of claims 43 - 114 wherein W 1a is
132 . The compound of claim 117 wherein W 1a is:
133 . The compound of claim 117 wherein W 1a is:
134 . The compound of claim 115 wherein W 1a is:
135 . The compound of any one of claims 43 - 114 wherein W 1a is
136 . The compound of claim 135 wherein X 5 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
137 . The compound of claim 135 or 136 wherein Y 5 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
138 . The compound of any one of claims 43 - 114 wherein W 1a is
139 . The compound of claim 138 wherein X 6 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
140 . The compound of claim 138 or 139 wherein Y 6 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
141 . The compound of any one of claims 43 - 114 wherein W 1a is
142 . The compound of claim 141 wherein X 7 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
143 . The compound of claim 141 or 142 wherein Y 7 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
144 . The compound of any one of claims 141 - 143 wherein Z 7 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
145 . The compound of any one of claims 43 - 114 wherein W 1a is
146 . The compound of claim 145 wherein X 8 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
147 . The compound of claim 145 or 146 wherein Y 8 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
148 . The compound of any one of claims 145 - 147 wherein Z 8 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
149 . The compound of any one of claims 43 - 114 wherein W 1a is
150 . The compound of claim 149 wherein X 9 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
151 . The compound of claim 149 or 150 wherein Y 9 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
152 . The compound of any one of claims 149 - 151 wherein Z 9 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, or —CH═CH—.
153 . The compound of any one of claims 43 - 152 wherein each W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
154 . The compound of any one of claims 43 - 114 wherein W 1a is 107, 108, or 109.
155 . The compound of claim 128 wherein W 1a is 103a.
156 . The compound of claim 128 wherein W 1a is 103b.
157 . The compound of claim 129 wherein W 1a is 103d.
158 . The compound of claim 129 wherein W 1a is 103e.
159 . The compound of claim 129 wherein W 1a is 103i.
160 . The compound of any one of claims 117 - 159 wherein P 1a is
161 . The compound of any one of claims 117 - 159 wherein P 1b is
162 . The compound of any one of claims 117 - 159 wherein P 1a is
163 . The compound of any one of claims 117 - 160 wherein P 1b is
164 . The compound of any one of claims 43 - 163 wherein each W 1a is substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from
165 . The compound of any one of claims 43 - 163 wherein each W 1a is substituted with one or more fluoro.
166 . A compound which has any one of formulae 1-25, 25b, 25c, and 25d as shown in Table 1 hereinabove, or a pharmaceutically acceptable salt or prodrug thereof.
167 . The compound of any one of claims 43 - 163 which is not a compound of formula:
or a pharmaceutically acceptable salt or prodrug thereof.
168 . The compound of any one of claims 43 - 167 wherein P 30 is:
169 . The compound:
or a pharmaceutically acceptable salt or prodrug thereof.
170 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
E 1a is E 0 , E 1 , or E 2 , or E 1a -V 1a taken together are R 9a ;
E 1b is E 0 , E 1 , or E 2 , or E 1b -V 1b taken together are R 9b ;
V 1a is V 0 or E 1a -V 1a taken together are R 9a ;
V 1b is V 0 or E 1b -V 1b taken together are R 9b ;
one of P 1a and P 1b is selected from P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ;
each E 0 is independently —NR Ec R Ed wherein R Ec and R Ed are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each E 1 is independently selected from hydrogen, hydroxy, alkyl, haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;
each E 2 is independently —NHR Ef wherein R Ef is cycloalkylcarbonyl or cycloalkyloxycarbonyl;
each V 0 is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl-, oxo, and —P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each P 0 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
R P7 and R P8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR Pa R Pb )alkyl; or R P7 and R P8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NR Pz , O, and S; wherein R Pz is selected from hydrogen and alkyl;
R P9 is selected from hydrogen and alkyl;
each P 1 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
at least one R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo and heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 3 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo group;
each R P13 is independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 0, 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 5 is independently a ring of the formula:
wherein:
the ring is optionally substituted with one or more groups R P15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pn is 0, 1, or 2;
Z is O, S, S(═O) 2 , or NR f ;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 6 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo and is optionally substituted with one or more groups R P11 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
pn is 0, 1, or 2;
each R f is independently —II, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6 and R P11 ;
each P 8 is independently a ring of the formula:
wherein:
ps is 2, 3, 4, 5, or 6;
pn is 0, 1 or 2;
each R P13 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each P 10 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
each P 12 is independently:
wherein:
each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq is independently 0, 1, 2, 3, or 4;
pm is independently 0, 1, or 2;
pp is independently 1, 2, or 3;
ps is 1, 2, 3, or 4;
R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 15 is:
which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl;
each P 18 is:
which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;
each P 19 is:
each P 30 is independently a ring of the formula:
ps is 2
pn is 0, 1 or 2;
X is selected from O, S, S(O), SO 2 , or CH 2 ; provided that when pn is 0, X is CH 2 ,
each R P11 is independently selected from alkyl-, alkoxyalkyl-, hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-, alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groups R P11 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
each R 9a is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; Wand R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
each R 9b is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
W 1a is selected from:
wherein each W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
X 11 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—
Y 11 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—
X 12 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—
X 13 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—; and
X 14 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—; and
each Y 16 is a bicyclic aromatic ring system comprising eight to 12 atoms optionally including one or more heteroatoms selected from O, S, and N, which bicyclic ring system is optionally with one or more groups independently selected from halo, haloalkyl, alkyl and oxo.
or a pharmaceutically acceptable salt or prodrug thereof;
provided the compound of formula (I) is not:
171 . The compound of claim 170 wherein W 1a is formula 116.
172 . The compound of claim 170 wherein W 1a is:
173 . The compound of claim 172 wherein X 12 is:
X 12 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—.
174 . The compound of claim 170 wherein W 1a is:
175 . The compound of claim 170 wherein W 1a is:
176 . The compound of claim 170 wherein W 1a is:
177 . The compound of claim 170 wherein W 1a is:
178 . The compound of claim 170 wherein W 1a is:
179 . The compound of claim 170 wherein W 1a is:
180 . The compound of claim 179 wherein:
X 14 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—
181 . The compound of claim 170 wherein W 1a is:
182 . The compound of claim 181 wherein X 13 is:
X 13 is —CH 2 —CH 2 —, —CH 2 —O—, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—
183 . The compound of claim 170 wherein W 1a is:
wherein W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
X 16 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—; and
Y 16 is a bicyclic aromatic ring system comprising eight to 12 atoms optionally including one or more heteroatoms selected from O, S, and N, which bicyclic ring system is optionally with one or more groups independently selected from halo, haloalkyl, alkyl and oxo.
184 . The compound of any one of claim 183 wherein Y 16 is benzothiophene, quinoline, isoquinoline, and quinazoline.
185 . The compound of claim 183 wherein W 1a is:
186 . The compound of claim 183 wherein W 1a is:
187 . The compound of claim 186 wherein X 16 is:
X 16 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—.
188 . The compound of claim 183 wherein W 1a is:
189 . The compound of claim 183 wherein W 1a is:
190 . The compound of claim 189 wherein X 16 is CH2-CH2, CH2-O, O—CH2-, —S—, —O—, —CO—, —CF2-, or CH═CH.
191 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
E 1a is E 0 , E 1 , or E 2 , or E 1a -V 1a taken together are R 9a ;
E 1b is E 0 , E 1 , or E 2 , or E 1b -V 1b taken together are R 9b ;
V 1a is V 0 or E 1a -V 1a taken together are R 9a ;
V 1b is V 0 or E 1b -V 1b taken together are R 9b ;
one of P 1a and P 1b is selected from P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ;
each E 0 is independently —NR Ec R Ed wherein R Ec and R Ed are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each E 1 is independently selected from hydrogen, hydroxy, alkyl, aryl, and heterocyclyl;
each E 2 is independently —NHR Ef wherein R Ef is cycloalkylcarbonyl or cycloalkyloxycarbonyl;
each V 0 is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl-, oxo, and —P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
W 1a is:
wherein W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
Y 18 is selected from A 0 , A 1 , A 2 , A 3 , A 7 , A 15 , A 16 , and A 20 ;
each A 0 is independently:
wherein:
each R A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl; R a and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each
bb is independently 0, 1, 2, 3, or 4; or
each A 0 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 R A3 groups;
each A 1 is independently:
wherein:
each R A1 is independently selected from cyano, nitro, SOR 4 , SO 2 R 4 , -alkylSO 2 R 4 , haloalkoxy, cyanoalkyl, NR 4 SO 2 R 4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and
each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl;
each cc is independently 1, 2, 3, or 4;
each A 2 is independently:
wherein:
each R A1 is independently selected from cyano, nitro, SOR 4 , SO 2 R 4 , -alkylSO 2 R 4 , haloalkoxy, cyanoalkyl, NR 4 SO 2 R 4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;
each R A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl; R a and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl;
R a and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bb and cc is 1, 2, 3, or 4;
each A 3 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is substituted with one or more R A1 groups, and which ring is optionally substituted with one or more R A3 groups;
each A 7 is independently:
wherein:
each H 7 is independently a five-membered heteroaromatic ring, which H 7 is optionally substituted with one or more groups independently selected from R A1 and R A3 ; and
each X A is independently O, NR, SO, SO 2 , C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each R is independently selected from H or alkyl;
each A 15 is independently:
wherein:
each H 14 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from oxo, R A1 and R A3 ; and
each X A is independently O, NR, SO, SO 2 , C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl;
each A 16 is independently:
wherein:
each H 15 is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R A1 and R A3 ; and
each X A is independently O, NR, SO, SO 2 , C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl;
each A 20 is independently a 5 or 6 membered heteroaryl ring that is optionally substituted with one or more groups independently selected from R A1 and R A3 ;
each P 0 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
R P7 and R P8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR Pa R Pb )alkyl; or R P7 and R P8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NR Pz , O, and S; wherein R Pz is selected from hydrogen and alkyl;
R P9 is selected from hydrogen and alkyl;
each P 1 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
at least one R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR h R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR hh R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo and heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 3 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo group;
each R P13 is independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 0, 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 5 is independently a ring of the formula:
wherein:
the ring is optionally substituted with one or more groups R P15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pn is 0,1, or 2;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 6 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo and is optionally substituted with one or more groups R P16 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
pn is 0,1, or 2;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6 and R P11 ;
each P 8 is independently a ring of the formula:
wherein:
ps is 2, 3, 4, 5, or 6;
pn is 0, 1 or 2;
each R P13 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each P 10 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
each P 12 is independently:
wherein:
each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq is independently 0, 1, 2, 3, or 4;
pm is independently 0, 1, or 2;
pp is independently 1, 2, or 3;
ps is 1, 2, 3, or 4;
R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 15 is:
which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl;
each P 18 is:
which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;
each P 19 is:
each P 20 is:
each P 30 is independently a ring of the formula:
ps is 2
pn is 0, 1 or 2;
X is selected from O, S, S(O), SO 2 , or CH 2 ; provided that when pn is 0, X is CH 2 ,
each R P13 is independently selected from alkyl-, alkoxyalkyl-, hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-, alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
each R 9a is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl; and
each R 9b is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X R Y )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
X 18 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—;
or a pharmaceutically acceptable salt or prodrug thereof.
192 . The compound of claim 191 wherein W 1a is:
193 . The compound of claim 192 wherein X 18 is:
X 16 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—.
194 . The compound of claim 191 wherein W 1a is:
195 . The compound of claim 194 wherein X 18 is X 16 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—.
196 . The compound of claim 191 wherein W 1a is:
197 . The compound of claim 196 wherein X 18 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—.
198 . The compound of claim 191 wherein W 1a is:
199 . The compound of claim 198 wherein X 18 is X 16 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —O—, —CO—, —CF 2 —, or —CH═CH—.
200 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
E 1a is E 0 , E 1 , or E 2 , or E 1a -V 1a taken together are R 9a ;
E 1b is E 0 , E 1 , or E 2 , or E 1b -V 1b taken together are R 9b ;
V 1a is V 0 or E 1a -V 1a taken together are R 9a ;
V 1b is V 0 or E 1b -V 1b taken together are R 9b ;
each E 0 is independently —NR Ec R Ed wherein R Ec and R Ed are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each E 1 is independently selected from hydrogen, hydroxy, alkyl, aryl, and heterocyclyl;
each E 2 is independently —NHR Ef wherein R Ef is cycloalkylcarbonyl or cycloalkyloxycarbonyl;
each V 0 is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl-, oxo, and —P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
P 1a and P 1b are each independently selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ;
each P 0 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
R P7 and R P8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR Pa R Pb )alkyl; or R P7 and R P8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NR Pz , O, and S; wherein R Pz is selected from hydrogen and alkyl;
R P9 is selected from hydrogen and alkyl;
each P 1 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
at least one R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo and heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 3 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo group;
each R P13 is independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 0, 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 5 is independently a ring of the formula:
wherein:
the ring is optionally substituted with one or more groups R P15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pn is 0, 1, or 2;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 6 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo and is optionally substituted with one or more groups R P16 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
pn is 0, 1, or 2;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6 and R P11 ;
each P 8 is independently a ring of the formula:
wherein:
ps is 2, 3, 4, 5, or 6;
pn is 0, 1 or 2;
each R P13 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each P 10 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
each P 12 is independently:
wherein:
each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq is independently 0, 1, 2, 3, or 4;
pm is independently 0, 1, or 2;
pp is independently 1, 2, or 3;
ps is 1, 2, 3, or 4;
R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 15 is:
which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl;
each P 18 is:
which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;
each P 19 is:
each P 30 is independently a ring of the formula:
ps is 2
pn is 0, 1 or 2;
X is selected from O, S, S(O), SO 2 , or CH 2 ; provided that when pn is 0, X is CH 2 .
each R P13 is independently selected from alkyl-, alkoxyalkyl-, hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-, alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
each R 9a is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
each R 9b is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
W 1a is selected from:
wherein each W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
X 20 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 , —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—
Y 21 is a bicyclic aromatic ring system comprising eight to 12 atoms optionally including one or more heteroatoms selected from O, S, and N, which bicyclic ring system is optionally with one or more groups independently selected from halo, haloalkyl, alkyl and oxo;
Y 22 is selected from A 0 , A 1 , A 2 , A 3 , A 7 , A 15 , A 16 , and A 20 ;
each A 0 is independently:
wherein:
each R A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl; R 1 and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each bb is independently 0, 1, 2, 3, or 4; or
each A 0 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 R A3 groups;
each A 1 is independently:
wherein:
each R A1 is independently selected from cyano, nitro, SOR 4 , SO 2 R 4 , -alkylSO 2 R 4 , haloalkoxy, cyanoalkyl, NR 4 SO 2 R 4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo; and
each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl;
each cc is independently 1, 2, 3, or 4;
each A 2 is independently:
wherein:
each R A1 is independently selected from cyano, nitro, SOR 4 , SO 2 R 4 , -alkylSO 2 R 4 , haloalkoxy, cyanoalkyl, NR 4 SO 2 R 4 , cycloalkyl, (halo)cycloalkyl, heterocycle, (cycloalkyl)alkyl, (heterocycle)alkyl, wherein each alkyl, heterocycle and cycloalkyl is optionally substituted with one or more halo;
each R A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl; R a and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
each R 4 is independently selected from H, alkyl, haloalkyl, aryl, and arylalkyl;
R a and R b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
each bb is 0, 1, 2, 3, or 4; each cc is 1, 2, 3, or 4; and the sum of bb and cc is 1, 2, 3, or 4;
each A 3 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is substituted with one or more R A1 groups, and which ring is optionally substituted with one or more R A3 groups;
each A 7 is independently:
wherein:
each H 7 is independently a five-membered heteroaromatic ring, which H 7 is optionally substituted with one or more groups independently selected from R A1 and R A3 ; and
each X A is independently 0, NR, SO, SO 2 , C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent; and each R is independently selected from H or alkyl;
each A 15 is independently:
wherein:
each H 14 is independently a fused unsaturated, partially unsaturated or saturated tricyclic carbocycle which is optionally substituted with one or more groups independently selected from oxo, R A1 and R A3 ; and
each X A is independently O, NR, SO, SO 2 , C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl;
each A 16 is independently:
wherein:
each H 15 is independently a fused unsaturated, partially unsaturated or saturated tricyclic heterocycle that comprises at least one heteroatom in the ring system, which ring system is optionally substituted with one or more groups independently selected from R A1 and R A3 ; and
each X A is independently O, NR, SO, SO 2 , C(═O), NRC(═O), C(═O)NR, CR═CR, NRC(═O)NR, allenyl, alkynyl, or absent and each R is independently selected from H or alkyl;
each A 20 is independently a 5 or 6 membered heteroaryl ring that is optionally substituted with one or more groups independently selected from R A1 and R A3 ;
each L 9 is independently a fused-tetracyclic saturated, partially unsaturated, or aromatic heterocyclic ring system that is optionally substituted with one or more groups independently selected from oxo, halo, —R L9 , —OR L9 , —SR L9 , —CF 3 , —CCl 3 , —OCF 3 , —CN, —NO 2 , —N(R L9 )C(═O)R L9 , —C(═O)R L9 , —OC(═O)R L9 , —C(O)OR L9 , —C(═O)NR L9 , —S(═O)R L9 , —S(═O) 2 OR L9 , —S(═O) 2 R L9 , —OS(═O) 2 OR L9 , —S(═O) 2 NR L9 , alkoxyalkyl, arylalkoxycarbonyl, halo, haloalkyl, hydroxyalkyl, —NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl;
each R L9 is independently —H, alkyl, aryl, arylalkyl, or heterocycle; and
R a and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
201 . The compound of claim 200 wherein W 1a is:
202 . The compound of claim 200 wherein W 1a is:
203 . The compound of claim 200 wherein W 1a is:
204 . The compound of claim 200 wherein W 1a is:
205 . The compound of claim 200 wherein W 1a is:
206 . The compound of claim 200 wherein W 1a is:
207 . The compound of claim 200 wherein W 1a is:
208 . The compound of claim 200 wherein W 1a is:
209 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
E 1a is E 0 , E 1 , or E 2 , or E 1a -V 1a taken together are R 9a ;
E 1b is E 0 , E 1 , or E 2 , or E 1b -V 1b taken together are R 9b ;
V 1a is V 0 or E 1a -V 1a taken together are R 9a ;
V 1b is V 0 or E 1b -V 1b taken together are R 9b ;
each E 0 is independently —NR Ec R Ed wherein R Ec and R Ed are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each E 1 is independently selected from hydrogen, hydroxy, alkyl, haloalkyl, —NHhaloalkyl, aryl, and heterocyclyl;
each E 2 is independently —NHR Ef wherein R Ef is cycloalkylcarbonyl or cycloalkyloxycarbonyl;
each V 0 is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl-, oxo, and —P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
P 1a and P 1b are each independently selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 , and P 30 ;
each P 0 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P16 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R 1s a and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
R P7 and R P8 are each independently selected from hydrogen, alkenyl, alkoxyalkyl, alkyl, haloalkyl, and (NR Pa R Pb )alkyl; or R P7 and R P8 , together with the carbon atom to which they are attached, form a five or six membered saturated ring optionally containing one or two heteroatoms selected from NR Pz , O, and S; wherein R Pz is selected from hydrogen and alkyl;
R P9 is selected from hydrogen and alkyl;
each P 1 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
at least one R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyloxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclyloxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo and heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 3 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo group;
each R P13 is independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 0, 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 5 is independently a ring of the formula:
wherein:
the ring is optionally substituted with one or more groups RP 15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pn is 0,1, or 2;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 6 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo and is optionally substituted with one or more groups R P16 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
pn is 0,1, or 2;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6 and R P11 ;
each P 8 is independently a ring of the formula:
wherein:
ps is 2, 3, 4, 5, or 6;
pn is 0, 1 or 2;
each R P13 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each P 10 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
each P 12 is independently:
wherein:
each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq is independently 0, 1, 2, 3, or 4;
pm is independently 0, 1, or 2;
pp is independently 1, 2, or 3;
ps is 1, 2, 3, or 4;
R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 15 is:
which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl;
each P 18 is:
which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;
each P 19 is:
each R 9a is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
each R 9b is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
W 1a is selected from:
wherein each W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and wherein each W 1a is substituted with one or more (e.g. 1, 2, 3, or 4):
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
X 11 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—
Y 11 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—
X 12 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—
X 13 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—; and
X 14 is —CH 2 —, —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, —CH 2 —O—CH 2 —, —S—, —S(O) 2 —, —C(O)—, —CF 2 —, —O—, —S—CH 2 —, —CH 2 —S—, —O—C(O)—, —C(O)—O—, —CH═N—; —N═CH—; or —CH═CH—;
or a pharmaceutically acceptable salt or prodrug thereof.
210 . The compound of claim 209 wherein W 1a is:
211 . The compound of claim 209 wherein W 1a is:
212 . The compound of claim 209 wherein W 1a is:
213 . The compound of claim 209 wherein W 1a is:
214 . The compound of claim 213 wherein X 11 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, or —CH═CH—.
215 . The compound of claim 213 or 214 wherein Y 11 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, or —CH═CH—.
216 . The compound of claim 209 wherein W 1a is:
217 . The compound of claim 216 wherein X 11 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, or —CH═CH—.
218 . The compound of claim 216 or 217 wherein Y 11 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, or —CH═CH—.
219 . The compound of claim 209 wherein W 1a is:
220 . The compound of claim 219 wherein X 11 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, or —CH═CH—.
221 . The compound of claim 220 wherein Y 11 is —CH 2 —CH 2 —, —CH 2 —O—, —O—CH 2 —, or —CH═CH—.
222 . The compound of claim 209 wherein W 1a is:
223 . The compound of claim 209 wherein W 1a is:
224 . The compound of any one of claims 209 - 223 wherein R is H, methyl, cyclopropyl, phenyl, or
225 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
E 1a is E 0 , E 1 , or E 2 , or E 1a -V 1a taken together are R 9a ;
E 1b is E 0 , E 1 , or E 2 , or E 1b -V 1b taken together are R 9b ;
V 1a is V 0 or E 1a -V 1a taken together are R 9a ;
V 1b is V 0 or E 1b -V 1b taken together are R 9b ;
one of P 1a and P 1b is selected from P 0a and the other of P 1a and P 1b is selected from P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 , and P 30 ;
each E 0 is independently —NR Ec R Ed wherein R Ec and R Ed are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each E 1 is independently selected from hydrogen, hydroxy, alkyl, aryl, and heterocyclyl;
each E 2 is independently —NHR Ef wherein R Ef is cycloalkylcarbonyl or cycloalkyloxycarbonyl;
each V 0 is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , —(NR X R Y )alkyl, oxo, and —P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
W 1a is:
wherein W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
each A 0 is independently:
wherein:
each R A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl; R a and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each
bb is independently 0, 1, 2, 3, or 4; or
each A 0 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 R A3 groups;
each P 0a is independently:
wherein:
each R P5 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
ps is independently 0, 1, 2, 3, or 4;
pn is independently 0, 1, or 2;
po is independently 1, 2, or 3;
each P 1 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
at least one R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h a)lkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 3 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo group;
each R P13 is independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 0, 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 5 is independently a ring of the formula:
wherein:
the ring is optionally substituted with one or more groups RP 15 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; and where two groups R P15 that are attached to the same carbon when taken together with the carbon to which they are attached can form a 3-6 membered carbocyclic or heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pn is 0, 1, or 2;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 6 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo and is optionally substituted with one or more groups R P16 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
pn is 0, 1, or 2;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6 and R P11 ;
each P 8 is independently a ring of the formula:
wherein:
ps is 2, 3, 4, 5, or 6;
pn is 0, 1 or 2;
each R P11 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups; where in at least one case two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each P 10 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn or pm is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
each R P5 and R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq and ps are independently 0, 1, 2, 3, or 4;
pm and pn are independently 0, 1, or 2;
po and pp are independently 1, 2, or 3;
each P 12 is independently:
wherein:
each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq is independently 0, 1, 2, 3, or 4;
pm is independently 0, 1, or 2;
pp is independently 1, 2, or 3;
ps is 1, 2, 3, or 4;
R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 15 is:
which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl;
each P 18 is:
which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;
each P 19 is:
each P 30 is independently a ring of the formula:
ps is 2
pn is 0, 1 or 2;
X is selected from O, S, S(O), SO 2 , or CH 2 ; provided that when pn is 0, X is CH 2 .
each R P13 is independently selected from alkyl-, alkoxyalkyl-, hydroxyalkyl-, alkyl-S-alkyl-, sulfanylalkyl-, aminoalkyl-, alkylaminoalkyl-, dialkylaminoalkyl-, alkyl-SO2-alkyl where two groups R P13 that are attached to the same carbon are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
each R 9a is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
each R 9b is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R′ and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
or a pharmaceutically acceptable salt or prodrug thereof.
226 . A compound of formula (I):
E 1a -V 1a —C(═O)—P 1a —W 1a —P 1b —C(═O)—V 1b -E 1b (I)
wherein:
E 1a is E 0 , E 1 , or E 2 , or E 1a -V 1a taken together are R 9a ;
E 1b is E 0 , E 1 , or E 2 , or E 1b -V 1b taken together are R 9b ;
V 1a is V 0 or E 1a -V 1a taken together are R 9a ;
V 1b is V 0 or E 1b -V 1b taken together are R 9b ;
one of P 1a and P 1b is selected from P 0b and the other of P 1a and P 1b is selected from P 21 , P 3 , P 6 , P 7 , P 28 , P 12 , P 15 and P 38 ;
each E 0 is independently —NR Ec R Ed wherein R Ec and R Ed are each independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
each E 1 is independently selected from hydrogen, hydroxy, alkyl, aryl, and heterocyclyl;
each E 2 is independently —NHR Ef wherein R Ef is cycloalkylcarbonyl or cycloalkyloxycarbonyl;
each V 0 is independently alkyl, arylalkyl, alkenyl, CO, cycloalkylalkyl, cycloalkyl, alkoxyalkyl, alkoxyalkylcarbonylalkyl, alkoxycarbonylalkyl, alkylsulfanylalkyl, aryalkoxyalkylcarbonylalkyl, carboxyalkyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, hydroxyalkyl, NRRCOalkyl, wherein each R is independently selected from hydrogen and alkyl; and where in arylalkyl the alkyl can be substituted with up to three aryl groups, and the alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkyocarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy; and the aryl part can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , —(NR X R Y )alkyl, oxo, and —P(O)OR 2 , wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; and the heterocyclyl can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, —NR X R Y , (NR X R Y )alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl; the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro;
W 1a is:
wherein W 1a is optionally substituted with one or more (e.g. 1, 2, 3, or 4) groups independently selected from halo, alkyl, haloalkyl, cyano, and
wherein each R is independently H, alkyl, haloalkyl, cycloalkyl, aryl, or heteroaryl;
each A 0 is independently:
wherein:
each R A3 is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxyalkyl, —NR a R b , (NR a R b )alkyl, and (NR a R b )carbonyl; R a and R b are each independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl; and each
bb is independently 0, 1, 2, 3, or 4; or
each A 0 is independently a six-membered heteroaromatic ring containing one, two, or three nitrogen atoms, which ring is optionally substituted with 1, 2, 3, or 4 R A3 groups;
each P 0b is independently:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb
each R P5 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
ps is independently 0, 1, 2, 3, or 4;
pn is independently 0, 1, or 2;
each P 21 is independently:
wherein:
X is selected from O, S, S(O), SO 2 , CH 2 , CHR P10 , and C(R P10 ) 2 ; provided that when pn is 0, X is selected from CH 2 , CHR P10 , and C(R P10 ) 2 ;
each R P10 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
at least one R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyalkyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, —NR hh R h , (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl;
ps is 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 3 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo group;
each R P13 is independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
ps is 0, 1, 2, 3, or 4;
pn is 0, 1, or 2;
each P 6 is independently a ring of the formula:
wherein:
the ring is substituted with one or more oxo and is optionally substituted with one or more groups R P16 that are independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently 1-1, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
Z is O, S, S(═O), S(═O) 2 , or NR f ;
pn is 0, 1, or 2;
each R f is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, —S(═O) 2 NR h R h , —S(═O) 2 R h , C(═O)R h , C(═O)OR h , —C(═O)NR h R h ; each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; or when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 7 is a bridged 5-15 membered bicyclic heterocyclic ring that is attached to the remainder of the compound of formula I through one N-link and through one C-link; wherein the ring is optionally substituted with one or more groups independently selected from R P6 and R P11 ;
each P 28 is independently a ring of the formula:
wherein:
each R P13 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , where in two R P13 groups are taken together with the carbon to which they are attached and form a 4-6 membered heterocyclic ring;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
each P 12 is independently:
wherein:
each R P6 is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and —NR Pa R Pb , wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;
R Pa and R Pb are each independently H, alkyl, aryl, or arylalkyl; or R Pa and R Pb taken together with the atom to which they are attached form a heterocycle;
pq is independently 0, 1, 2, 3, or 4;
pm is independently 0, 1, or 2;
pp is independently 1, 2, or 3;
ps is 1, 2, 3, or 4;
R P11 is independently selected from cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl, —NR hh R h , (NR hh R h )alkyl, (NR hh R h )carbonyl, wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring; wherein each R hh is independently aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl, (NR h R h )sulfonyl, heteroarylsulfonyl, —S(═O) 2 R h , —C(═O)R h , —C(═O)NR h R h ; and the remaining R P11 are independently selected from R P5 , cyano, alkylsulfonyl, arylsulfonyl, (NR h R h )sulfonyl, heterocyclylsulfonyl, heteroarylsulfonyl, haloalkoxy, alkoxyalkyloxy, haloalkoxyalkyloxy, cycloalkyoxyalkyloxy, aryloxyalkyloxy, heteroaryloxyakyloxy, heterocyclooxyalkyloxy, (NR h R h )alkyloxy, cyanoalkoxy, cyanocycloalkyloxy, cycloalkyloxy, oxo, heterocyclyl; wherein each R h is independently —H, alkyl, alkoxyamino, aryl, arylalkyl, heterocycle, heterocyclyoxy, alkenyl, alkenyloxy, alkynyl, alkoxyalkyl, haloalkyl, cyanoalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, sulfonylalkyl; and when two R h groups are present then they may come together with the atoms to which they are bound to form a 4-15 membered heterocyclic ring;
each P 15 is:
which is substituted with one or two groups independently selected from alkoxyalkyl, haloalkoxyalkyl, alkylsulfanyl, alkylsulfanylalkyl, cyanoalkyl, and cycloalkylalkyl;
each P 38 is:
which is optionally substituted with one or two groups independently selected from halo, alkyl, alkoxyalkyl, haloalkyl, cycloalkyl, and cycloalkylalkyl;
each R 9a is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
each R 9b is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, —NR c R d , (NR c R d )alkenyl, (NR c R d )alkyl, and (NR c R d )carbonyl; R c and R d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkyl sulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, aryl sulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR e R f )alkyl, (NR e R f )alkylcarbonyl, (NR e R f )carbonyl, (NR e R f )sulfonyl, —C(NCN)OR′, and —C(NCN)NR X R Y , wherein R′ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one —NR e R f group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro; R e and R f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, —(NR X R Y )alkyl, and —(NR X R Y )carbonyl; R X and R Y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR X′ R Y′ )carbonyl, wherein R X′ and R Y′ are independently selected from hydrogen and alkyl;
or a pharmaceutically acceptable salt or prodrug thereof;
provided the compound of formula (I) is not:
227 . The compound of any one of claims 203 - 226 wherein E 1a is E 0 .
228 . The compound of any one of claims 203 - 226 wherein E 1a is E 1 .
229 . The compound of any one of claims 203 - 226 wherein E 1a is selected from:
230 . The compound of any one of claims 203 - 226 wherein E 1a is —N(H)alkoxycarbonyl.
231 . The compound of any one of claims 203 - 226 wherein E 1a is —N(H)C(═O)OMe.
232 . The compound of any one of claims 203 - 231 wherein E 1b is E 0 .
233 . The compound of any one of claims 203 - 231 wherein E 1b is E 1 .
234 . The compound of any one of claims 203 - 231 wherein E 1b is selected from:
235 . The compound of any one of claims 203 - 231 wherein E 1b is —N(H)alkoxycarbonyl.
236 . The compound of any one of claims 203 - 231 wherein E 1b is —N(H)C(═O)OMe.
237 . The compound of any one of claims 203 - 236 wherein V 1a is V 0 .
238 . The compound of any one of claims 203 - 237 wherein V 1b is selected from:
239 . The compound of any one of claims 203 - 236 wherein E 1a -V 1a taken together are R 9a .
240 . The compound of claim 239 wherein R 9a is selected from:
241 . The compound of any one of claims 203 - 226 wherein E 1b -V 1b taken together are R 9a .
242 . The compound of claim 241 wherein R 9a is selected from:
243 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
244 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
245 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
246 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 15 , P 18 , P 19 and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
247 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 15 , P 18 , P 19 and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
248 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 15 , P 18 , and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
249 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 15 , and P 18 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
250 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 7 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
251 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 18 , and P 19 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
252 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , and P 30 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
253 . The compound of any one of claims 203 - 242 wherein one of P 1a and P 1b is selected from P 3 , P 6 , P 7 , P 10 , and P 18 ; and the other of P 1a and P 1b is selected from P 0 , P 1 , P 3 , P 5 , P 6 , P 7 , P 8 , P 10 , P 12 , P 15 , P 18 , P 19 and P 30 .
254 . The compound of any one of claims 203 - 242 wherein P 1a is P 0 .
255 . The compound of any one of claims 203 - 242 wherein P 1a is selected from:
256 . The compound of any one of claims 203 - 242 wherein P 1a is P 1 .
257 . The compound any one of claims 203 - 242 wherein P 1a is selected from:
258 . The compound any one of claims 203 - 242 wherein P 1a is P 3 .
259 . The compound of any one of claims 203 - 242 wherein P 1a is selected from:
260 . The compound of any one of claims 203 - 242 wherein P 1a is P 5 .
261 . The compound of claim 260 wherein P 1a is selected from:
262 . The compound of any one of claims 203 - 242 wherein P 1a is P 6 .
263 . The compound of claim 262 wherein P 1a is:
264 . The compound of any one of claims 203 - 242 wherein P 1a is P 7 .
265 . The compound of claim 264 wherein P 1a is:
266 . The compound of any one of claims 203 - 242 wherein P 1a is P 8 .
267 . The compound of claim 266 wherein P 1a is selected from:
268 . The compound of any one of claims 203 - 242 wherein P 1a is P 10 .
269 . The compound of claim 268 wherein P 1a is:
270 . The compound of any one of claims 203 - 242 wherein P 1a is P 12 .
271 . The compound of any one of claims 203 - 242 wherein P 1a is P 15 .
272 . The compound of claim 271 wherein P 1a is selected from:
273 . The compound of any one of claims 203 - 242 wherein P 1a is P 18 .
274 . The compound of claim 273 wherein P 1a is:
275 . The compound of any one of claims 203 - 242 wherein P 1b is P 0 .
276 . The compound of claim 275 wherein at least one of P 1b is selected from:
277 . The compound of any one of claims 203 - 274 wherein P 1b is P 1 .
278 . The compound of claim 277 wherein P 1b is selected from:
279 . The compound of any one of claims 203 - 274 wherein P 1b is P 3 .
280 . The compound of claim 279 wherein P 1b is selected from:
281 . The compound of any one of claims 203 - 274 wherein P 1b is P 5 .
282 . The compound of claim 281 wherein P 1b is selected from:
283 . The compound of any one of claims 203 - 274 wherein P 1b is P 6 .
284 . The compound of claim 283 wherein P 1b is:
285 . The compound of any one of claims 203 - 274 wherein P 1b is P 7 .
286 . The compound of claim 285 wherein P 1b is:
287 . The compound of any one of claims 203 - 274 wherein P 1b is P 8 .
288 . The compound of claim 287 wherein P 1b is selected from:
289 . The compound of any one of claims 203 - 274 wherein P 1b is P 10 .
290 . The compound of claim 289 wherein P 1b is:
291 . The compound of any one of claims 203 - 274 wherein P 1b is P 12 .
292 . The compound of any one of claims 203 - 274 wherein P 1b is P 15 .
293 . The compound of claim 292 wherein P 1a is selected from:
294 . The compound of any one of claims 203 - 274 wherein P 1a is P 18 .
295 . The compound of claim 294 wherein P 1b is:
296 . The compound of any one of claims 203 - 242 wherein at least one of P 1a and P 1b is:
297 . The compound of any one of claims 203 - 242 wherein at least one of P 1a and P 1b is selected from:
298 . The compound of any one of claims 203 - 242 wherein at least one of P 1a and P 1b is selected from:
299 . The compound of any one of claims 203 - 242 wherein at least one of P 1a and P 1b is selected from:
300 . The compound of any one of claims 203 - 242 wherein at least one of P 1a and P 1b :
301 . The compound of any one of claims 203 - 242 wherein at least one of P 1a and P 1b :
302 . The compound of any one of claims 203 - 242 wherein at least one of P 1a and P 1b is:
303 . The compound of any one of claims 203 - 242 wherein P 1a is
304 . The compound of any one of claims 203 - 242 and 303 wherein P 1b is
305 . The compound of any one of claims 203 - 242 and 303 wherein P 1a is
306 . The compound of any one of claims 203 - 242 and 305 wherein P 1b is
307 . A compound which is any one of formulae 26-102 as shown in Table 2 hereinabove, or a pharmaceutically acceptable salt or prodrug thereof.
308 . A compound which is any one of formulae 103-289 as shown in Table 3 hereinabove, or a pharmaceutically acceptable salt or prodrug thereof.
309 . A compound which is any one of formulae 290-539 as shown hereinabove, or a pharmaceutically acceptable salt or prodrug thereof.
310 . The compound of any one of claims 1 - 309 wherein:
E 1a is E 0 or E 1 , or E 1a -V 1a taken together are R 9a ; and
E 1b is E 0 or E 1 , or E 1b -V 1b taken together are R 9b .
311 . The compound of any one of claims 1 - 310 which is a prodrug or a pharmaceutically acceptable salt thereof.
312 . A pharmaceutical composition comprising the compound as described in any of claims 1 - 311 or a pharmaceutically acceptable salt, or prodrug thereof; and at least one pharmaceutically acceptable carrier.
313 . The pharmaceutical composition according to claim 312 for use in treating disorders associated with HCV.
314 . The pharmaceutical composition of claim 313 , further comprising at least one additional therapeutic agent.
315 . The pharmaceutical composition of claim 314 , wherein said additional therapeutic agent is selected from the group consisting of interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.
316 . The pharmaceutical composition according to claim 312 , further comprising a nucleoside analogue.
317 . The pharmaceutical composition according to claim 316 , further comprising an interferon or pegylated interferon.
318 . The pharmaceutical composition according to claim 316 , wherein said nucleoside analogue is selected from ribavirin, viramidine, levovirin, a L-nucleoside, and isatoribine and said interferon is α-interferon or pegylated interferon.
319 . A method of treating disorders associated with hepatitis C, said method comprising administering to an individual a pharmaceutical composition which comprises a therapeutically effective amount of the compound as described in any of claims 1 - 311 or a pharmaceutically acceptable salt, or prodrug thereof.
320 . A compound as described in any of claims 1 - 311 or a pharmaceutically acceptable salt, or prodrug thereof for use in medical therapy.
321 . Use of a compound as described in any one of claims 1 - 311 or a pharmaceutically acceptable salt, or prodrug thereof for preparing a medicament for treating hepatitis C or a hepatitis C associated disorder in an animal.
322 . A compound as described in any of claims 1 - 311 or a pharmaceutically acceptable salt, or prodrug thereof for use in the prophylactic or therapeutic treatment of hepatitis C or a hepatitis C associated disorder.
323 . A novel compound as described herein.
324 . A novel synthetic method as described herein.Cited by (0)
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