BENZIMIDAZOLE DERIVATIVES
Compounds, pharmaceutical compositions and methods are provided that are useful in the treatment of inflammatory and immune-related conditions or disorders. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, immune response regulation and cell proliferation. The subject compounds are 2-amino-imidazole derivatives.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein
R 1 is selected from the group consisting of H, (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, fluoro(C 1 -C 4 )alkyl, cycloalkyl(C 1 -C 8 )alkyl, heterocyclo(C 1 -C 8 )alkyl, aryl, aryl(C 1 -C 8 )alkyl, arylhetero(C 1 -C 8 )alkyl and heteroaryl;
R 2 is selected from the group consisting of (C 1 -C 8 )alkyl, hetero(C 1 -C 8 )alkyl, perfluoro(C 1 -C 4 )alkyl, aryl and heteroaryl;
Y is selected from the group consisting of C(O), S(O) m , S(O) 2 NR′, C(O)NR′, CR 3 R 4 , C(NR′), C(═CR 3 R 4 ), CR 3 (OR′) and CR 3 (NR′R″), wherein the subscript m is an integer selected from 1 to 2;
Z 1 and Z 2 are independently selected from the group consisting of H, halogen, CN, CO 2 R′, CONR′R″, (C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, perfluoro(C 1 -C 4 )alkyl, aryl, heteroaryl, NR′R″ and OR′, or Z 1 and Z 2 may be combined to an additional fused 5-, 6-, 7- or 8-membered cycloalkane, heterocycloalkane, aromatic or heteroaromatic ring;
R 3 and R 4 are independently selected from the group consisting of H, CN, CO 2 R′, CONR′R″, (C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, heteroaryl, NR′R″ and OR′;
R′ and R″ are independently selected from the group consisting of H, (C 1 -C 4 )alkyl, hetero(C 1 -C 4 )alkyl, aryl and aryl(C 1 -C 4 )alkyl;
alternatively, when R′ and R″ are attached to nitrogen, R′ and R″ may be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring; and
alternatively, when Y is CR 3 R 4 , C(NR′), C(═CR 3 R 4 ), CR 3 (OR′) or CR 3 (NR′R″), then R 3 , R 4 or R′ may be combined with R 2 to form a 5-, 6-, 7- or 8-membered ring containing from 0 to 3 heteroatoms selected from the group consisting of O, N, Si and S;
with the proviso that R 1 is not 3-(dialkylamino)propyl when Y is C(O) and Z 1 and Z 2 are combined to form an additional fused benzene ring.
2 .- 12 . (canceled)
13 . The compound of claim 1 , wherein Z 1 and Z 2 are combined to form an additional fused 6-membered cycloalkane, heteroaromatic or heterocycloalkane ring.
14 . The compound of claim 13 , wherein Z 1 and Z 2 are combined to form an additional fused benzene ring.
15 . The compound of claim 13 , wherein Z 1 and Z 2 are combined to form an additional fused cyclohexane ring.
16 . The compound of claim 13 , wherein Z 1 and Z 2 are combined to form an additional fused pyridine ring.
17 . The compound of claim 13 , wherein Z 1 and Z 2 are combined to form an additional fused tetrahydropyran ring.
18 . The compound of claim 1 , having the formula (II):
wherein
D, E, F and G are independently selected from the group consisting of CR′″ and N, wherein each R′″ is independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R 1 and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2, or R′″ may be combined with R 1 to form an additional 5-, 6-, 7- or 8-membered ring or an adjacent R′″ to form an additional fused 5-,6-, 7- or 8-membered ring.
19 . The compound of claim 18 , having the formula (IIa):
wherein
R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;
alternatively, R 5 , R 6 or R 7 may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7 and R 8 to form an additional fused 5-, 6-, 7- or 8-membered ring; and R 8 may be combined with R 7 to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1 to form an additional 5-, 6-, 7- or 8-membered ring.
20 . (canceled)
21 . The compound of claim 19 , wherein R 6 is selected from the group consisting of
22 .- 23 . (canceled)
24 . The compound of claim 18 , having the formula (IIb):
wherein
R 5 , R 6 and R 8 are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;
alternatively, R 6 may be combined with R 5 to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8 may be combined with R 1 to form an additional fused 5-, 6-, 7- or 8-membered ring.
25 . The compound of claim 18 , having the formula (IIc):
wherein
R 5 , R 6 and R 7 are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;
alternatively, R 6 may be combined with R 5 or R 7 to form an additional fused 5-, 6-, 7- or 8-membered ring.
26 . The compound of claim 1 , having the formula (III):
wherein
J, K, L and M are independently selected from the group consisting of CRaRb, NRa and O, wherein Ra and Rb are independently selected from the group consisting of H, halogen, CN, CO 2 R′, CONR′R″, (C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, heteroaryl, NR′R″ and OR′;
alternatively, J, K or L may be combined with an adjacent R group selected from R a and le to form an additional fused 5-, 6-, 7- or 8-membered ring and M may be combined with an adjacent R group selected from R a and R b to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1 to form an additional fused 5-, 6-, 7- or 8-membered ring.
27 .- 39 . (canceled)
40 . The compound of claim 39 1 , having the formula (IV):
wherein
R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;
alternatively, R 5 , R 6 or R 7 may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7 and R 8 to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8 may be combined with R 7 to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1 to form an additional 5-, 6-, 7- or 8-membered ring.
41 . A compound of claim 1 , having the formula (V):
whereinp
R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;
alternatively, R 5 , R 6 or R 7 may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7 and R 8 to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8 may be combined with R 7 to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1 to form an additional 5-, 6-, 7- or 8-membered ring.
42 . A compound of claim 1 , having the formula (VI):
wherein
R 5 , R 6 , R 7 and R 8 are independently selected from the group consisting of H, halogen, (C 1 C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, (C 1 -C 4 )heteroalkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, OC(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′, and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;
alternatively, R 5 , R 6 or R 7 may be combined with an adjacent R group selected from the group consisting of R 5 , R 6 , R 7 and R 8 to form an additional fused 5-, 6-, 7- or 8-membered ring and R 8 may be combined with R 7 to form an additional fused 5-, 6-, 7- or 8-membered ring or with R 1 to form an additional 5-, 6-, 7- or 8-membered ring.
43 .- 49 . (canceled)
50 . A compound of claim 40 , having the formula (VII):
wherein
R 9 , R 10 , R 11 , R 12 and R 13 are independently selected from the group consisting of H, halogen, (C 1 -C 4 )alkyl, perfluoro(C 1 -C 4 )alkyl, hetero(C 1 -C 4 )alkyl, aryl, aryl(C 1 -C 4 )alkyl, heteroaryl, CN, CO 2 R′, CONR′R″, NR′R″, NO 2 , OR′, SR′, C(O)R′, N(R″)C(O)R′, N(R″)CO 2 R′, N(R″)C(O)NR′R″, S(O) m NR′R″, S(O) m R′ and N(R″)S(O) m R′, wherein the subscript m is an integer from 1 to 2;
alternatively, R 9 , R 10 , R 11 , R 12 or R 13 may be combined with an adjacent R group selected from the group consisting of R 9 , R 10 , R 11 , R 12 and R 13 to form an additional fused 5-, 6-, 7- or 8-membered ring.
51 .- 53 . (canceled)
54 . The compound of claim 50 , having the formula (VIIc):
55 .- 62 . (canceled)
63 . The compound of claim 50 , having the formula (VIIa):
wherein
the subscript n is an integer from 1 to 5; and
X is selected from the group consisting of H, OR′, NR′R″, OC(O)R′, CO 2 R′, C(O)NR′R″, OC(O)NR′R″, NR″C(O)R′ and NR″CO 2 .
64 . (canceled)
65 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of any one of claims 1 , 13 - 19 , 21 , 24 - 26 , 40 - 42 , 50 , 54 and 63 .
66 .- 78 . (canceled)