Patent EA-001203-B1 (EA)
Title: Substituted imidazoles having anti-cancer and cytokine inhibitory activity
Inventor: SELNIC HAROLD G
IPC: A61P37/00
Filed: 1996-10-02
Abstract: 1. A compound represented by formula I.    or a pharmaceutically acceptable salt thereof, wherein:  AR represents an aromatic group containing 6-10 atoms;  X and X' each independently represent -(CH2)m-Y-(CH2)n-, wherein m and n represent integers within the range of from 0-4, such that the sum of m and n is from 0-6; Y represents a member selected from the group consisting of: a direct bond; O; S(O)y, with y equal to 0, 1 or 2; NRq', with Rq' as defined below; C(O); OC(O); C(O)O; SOxNRq' with x equal to 1 or 2 and Rq' as defined below; NRq'SOx; C(O)NRq' and NRq'C(O);    represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms; and 0-1 O or S atoms; R<x> represents H, C1-6alkyl(Rq)3, OC1-6alkyl(Rq)3 or C(O)C1-6alkyl(Rq)3; each R and R" independently represents a member selected from the group consisting of: halo; hydroxy; C1-6alkyl(Rq)3; OC1-6alkyl(Rq)3; C3-8cycloalkyl(Rq)3; CN; CONH2; CONHC1-6alkyl(Rq)3; CON(C1-6alkyl(Rq)3)2; NH2; NHC1-6alkyl(Rq)3; N(C1-6alkyl(Rq)3)2; CO2H; CO2C1-6alkyl(Rq)3; C(O)C1-6alkyl(Rq)3; aryl(Rq)3; heteroaryl(Rq)3; CF3; SH; NO2; SOyC1-6alkyl(Rq)3, with y as defined above; SO2NH2; SO2NHC1-6alkyl(Rq)3; SO2N(C1-6alkyl(Rq)3)2; NHSO2C1-6alkyl(Rq)3, NHSO2aryl(Rq)3, NHSO2heteroaryl(Rq)3, N(Rq')C(O)C1-6alkyl(Rq)3; NRq'C(O)NH(C1-6alkyl(Rq)3); C2-4alkenyl(Rq)2-3 and C2-4alkynyl(Rq)1-3; each R' independently represents a member selected from the group consisting of: hydroxy; C1-6alkyl(Rq)3; C3-8cycloalkyl(Rq)3; OC1-6alkyl(Rq)3; OC3-8cycloalkyl(Rq)3; heterocyclyl(Rq)3; CN; NH(Rq"); NHC1-6alkyl(Rq)3; N(C1-6alkyl(Rq)3)2; NHC3-8cycloalkyl(Rq)3; N(C3-8cycloalkyl(Rq)3)2; CF3; SH; NO2; C2-4alkenyl(Rq)2-3, aryl(Rq)3 ,heteroaryl(Rq)3; C2-4alkynyl(Rq)1-3-OC(O)C3-8cycloalkyl(Rq)3; SO2NH2; SO2NHC1-6alkyl(Rq)3; SO2N(C1-6alkyl(Rq)3)2; NHSO2C1-6alkyl(Rq)3, NHSO2aryl(Rq)3, NHSO2heteroaryl(Rq)3,  -OC(O)heterocyclyl(Rq)3; N(Rq')C(O)C1-6alkyl(Rq)3; NRq'C(O)NH(C1-6alkyl(Rq)3); -OC(O)C1-6alkyl(Rq)3; -OC(O)aryl(Rq)3, -OC(O)heteroaryl(Rq)3; -C(=NRq')NH2; -C(=Nq')NHC1-6alkyl(Rq)3, -C(=Nq')N(C1-6alkyl(Rq)3)2; CONH2; CONHC1-6alkyl(Rq)3; CON(C1-6alkyl(Rq)3)2; CONHC3-8cycloalkyl(Rq)3; CON(C3-8cycloalkyl(Rq)3)2; CO2H; CO2C1-6alkyl(Rq)3; C(O)C1-6alkyl(Rq)3; CO2C3-8cycloalkyl(Rq)3; C(O)C3-8cycloalkyl(Rq)3; -[C(O)(CH2)j-CR<5>R<6>-(CH2)k-NR<7>]p-R<8>; -C(O)C3-8cycloalkyl(Rq)3; -C(O)heterocyclyl(Rq)3; -CON[C1-6alkyl(Rq)3][C3-8cycloalkyl(Rq)3]; -C(O)aryl(Rq)3, -C(O)heteroaryl(Rq)3;   and j and k independently represent integers of from 0-3; R<5> and R<6> are independently H, aryl, C1-6alkyl(Rq)3, or CR<5>R<6> in combination represents a 3, 4, 5 or 6 membered cycloalkyl or heterocyclyl group, an aryl group or a heteroaryl group; p represents 1, 2 or 3, with the proviso that when p represents 1, CR<5>R<6> represents a 3, 4, 5 or 6 membered cycloalkyl group or a heterocyclyl group, an aryl group or a heteroaryl group, and at least one of j and k is 1, 2 or 3;  R<7> and R<8> are independently H, C1-6alkyl or aryl;  R<9> represents H, a negative charge balanced by a positively charged group or a protecting group;  Rq represents a member selected from the group consisting of: Rq'; CN; CO2H; CO2C1-4alkyl; C(O)C1-4alkyl; NH(Rq"); aryl(R<a>)3; heteroaryl(R<a>)3; NHC1-4alkyl ; N(C1-4alkyl)2; CONH2; SH; S(O)yC1-6alkyl(R<a>)3; C(O)NHC1-6alkyl(R<a>)3; C(O)N(C1-6alkyl(R<a>)3)2; NHC(NH)NH2 ; -heteroalkyl(R<a>)3; -NHC(O)NH2;   and wherein   independently represent mono or bicyclic ring systems, non-aromatic or partially aromatic, containing from  5-10 ring atoms, 1-4 of which are N and 0-1 of which are O or S(O)y, with y equal to 0, 1 or 2, optionally containing 1-2 carbonyl groups; each R<a> independently represents a member selected from the group consisting of: H, C1-6alkyl, OC1-6alkyl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, aralkoxy, substituted aralkoxy, halo, hydroxy, CN, CONH2, CONHC1-6alkyl, CON(C1-6alkyl)2, CO2H, CO2C1-6alkyl, C(O)C1-6alkyl, phenyl, CF3, SN, NO2, SOyC1-6alkyl, with y as defined above; SO2NH2, SO2NC1-6alkyl, NHSO2(substituted aryl), NHSO2(substituted heteroaryl), NHSO2C1-6alkyl, NHSO2aryl, NHSO2heteroaryl, NH2, NHC1-6alkyl, N(C1-6alkyl)2, NHC(O)C1-6alkyl, NHC(O)NH(C1-6alkyl), C2-4alkenyl and C2-4alkynyl;  Rq' represents H, OH, C1-4alkyl, -OC1-4alkyl, aryl or C(O)C1-4alkyl, and  Rq" represents H, OH or OC1-4alkyl.  2. A compound in accordance with claim 1 wherein one or two R" are present, each independently representing a member selected from the group consisting of: NH2, NHC1-6alkyl(Rq)3, N(C1-6alkyl)2, N(Rq')C(O)C1-6alkyl(Rq)3 and NRqC(O)NHC1-6alkyl (Rq)3.  3. A compound in accordance with claim 1 wherein AR represents a phenyl ring unsubstituted or substituted with one or two R groups.  4. A compound in accordance with claim 3 wherein AR is phenyl and one or two R groups are present which are selected from the group consisting of: hydroxyl, halo, C1-6alkyl(Rq)3, OC1-6alkyl(Rq)3, NH2, CF3 and NO2.  5. A compound in accordance with claim 4 wherein each R represents halo, hydroxy or CF3.  6. A compound in accordance with claim 1 wherein: HETCy represents a 5-6 membered non-aromatic heterocycle with 1-2 nitrogen atoms contained therein.  7. A compound in accordance with claim 1 wherein each R' is selected from the group consisting of: C1-6alkyl(Rq)3, OC1-6alkyl(Rq)3, CN and NO2.  8. A compound in accordance with claim 1 wherein Rq is selected from Rq', CN,    Rq' represents H, C1-4alkyl, OH or aryl; Rq" represents H or OH;  represents a bicyclic partially aromatic group selected from phthalidyl and saccharinyl, and   represents piperidinyl.  9. A compound in accordance with claim 1 wherein each R' represents a member selected from the group consisting of:  -OC(O)C3-8cycloalkyl(Rq)3, -OC(O)heterocyclyl(Rq)3, N(Rq')C(O)C1-6alkyl(Rq)3, -N(Rq')C(O)NH(C1-6alkyl(Rq)3, -OC(O)C1-6alkyl(Rq)3,  -OC(O)aryl(Rq)3, -OC(O)heteroaryl(Rq)3, -O[C(O)(CH2)j-CR<5>R<6>-(CH2)k-NR<7>]pR<8>, and -[NR<7>-(CH2)kCR<5>R<6>-(CH2)j-(CO)]p-OR<9>. 10. A compound in accordance with claim 9 wherein Rq represents H, C1-4alkyl or OC1-4alkyl;  Rq" represents H or C1-4alkyl; p is 1 or 2; when p is 1, j represents 1, and k represents 0, 1 or 2; when p is 2, j represents 0 or 1, and k represents 0, 1 or 2;  R<5> and R<6> represent H or C1-6alkyl(Rq)3 or one of R<5> and R<6> represent aryl and the other is H or C1-6alkyl(Rq)3;  R<7> and R<8> represent H or C1-6alkyl(Rq)3, and R<9> represents H.  11. A compound in accordance with claim 1 wherein each R' represents a member selected from the group consisting of: CONH2; CONHC1-6alkyl(Rq)3; CON(C1-6alkyl(Rq)3)2; CONHC3-8cycloalkyl(Rq)3; CON(C3-8cycloalkyl(Rq)3)2; CO2H; CO2C1-6alkyl(Rq)3; C(O)C1-6alkyl(Rq)3; CO2C3-8cycloalkyl(Rq)3; C(O) C3-8cycloalkyl(Rq)3; -[C(O)(CH2)j-CR<5>R<6>-(CH2)k-NR<7>]p-R<8>; -C(O) C3-8cycloalkyl(Rq)3; -C(O)heterocyclyl(Rq)3; CON[C1-6alkyl(Rq)3][C3-8cycloalkyl(Rq)3]; C(O)aryl(Rq)3 and C(O)heteroaryl(Rq)3;  p represents 1, 2 or 3, and all other variables are as previously defined.  12. A compound in accordance with claim 1 wherein each R' independently represents a member selected from the group consisting of: CONH2; CONHC1-6alkyl(Rq)3; CON(C1-6alkyl(Rq)3)2; CO2H; CO2C1-6alkyl(Rq)3; C(O)C1-6alkyl(Rq)3; -[C(O)(CH2)j-CR<5>R<6>-(CH2)k-NR<7>]p-R<8>; C(O)aryl(Rq)3 and C(O)heteroaryl(Rq)3;  Rq is Rq', CN,   or   Rq' represents; H, C1-4alkyl, OH or aryl;     represents a bicyclic partially aromatic group selected from phthalidyl and saccharinyl, and    represents piperidinyl.  13. A compound in accordance with claim 12 wherein R' represents a member selected from the group consisting of: CONH2; CO2H; CO2C1-6alkyl(Rq)3; C(O)C1-6alkyl(Rq)3; and -[C(O)(CH2)j-CR<5>R<6>-(CH2)k-NR<7>]p-R<8>; Rq represents H, C1-4alkyl or OC1-4alkyl; p represents 1; j represents 0 or 1; k represents 0, 1 or 2; and each R<7> and R<8> preferably represents H or C1-6alkyl(Rq)3.  14. A compound in accordance with claim 1 wherein R<x> is H or C1-6alkyl(Rq)3.  15. A compound in accordance with claim 1 wherein X' represents a direct bond.  16. A compound in accordance with claim 1 wherein X represents -(CH2)m-Y-(CH2)n-, Y represents a direct bond, O, S or C(O); m represents 0 or 1 and n represents 0 or 1.  17. A compound in accordance with claim 16 wherein X represents a direct bond.  18. A compound in accordance with claim 1 wherein: AR represents phenyl or naphthyl; X and X' represent -(CH2)m-Y-(CH2)n-, wherein m and n are zero and Y is a bond; HETCy represents a pyrrolidinyl or piperidinyl group; one or two R groups are present and are selected from the group consisting of: halo, hydroxy, C1-6alkyl(Rq)3, OC1-6alkyl(Rq)3, CN, NH2, CO2H, CF3, NO2 and CO2NH2; one or two R' groups are present and are selected from the group consisting of C1-6alkyl(Rq)3, OC1-6alkyl(Rq)3, CN and NO2; Rq represents Rq', CN, CO2H, NH(Rq''),    or   Rq' represents H, C1-4alkyl, OH or phenyl;  Rq" represents H or OH,     represents phthalidyl or saccharinyl, and     represents piperidinyl. 19. A compound in accordance with claim 1 wherein:  AR represents an aromatic group containing 6-10 atoms;  X and X' each independently represent -(CH2)m-Y-(CH2)n-, wherein m and n represent integers within the range of from 0-4, such that the sum of m and n is from 0-6; Y represents; a member selected from the group consisting of: a direct bond; O; S(O)y, with y equal to 0, 1 or 2; NRq', with Rq' as defined below; C(O); OC(O); C(O)O; SOxNRq' with x equal to 1 or 2, and Rq' as defined below; NRq'SOx; C(O)NRq' and NRq'C(O);    represents a 4 to 10 membered non-aromatic heterocycle containing at least one N atom, and optionally containing 1-2 additional N atoms and 0-1 O or S atom;  R<x> represents; H, C1-6alkyl(Rq)3, OC1-6alkyl(Rq)3 or C(O)C1-6alkyl(Rq)3; each R independently represents a member selected from the group consisting of: halo; hydroxy; C1-6alkyl(Rq)3; OC1-6alkyl(Rq)3; C3-8cycloalkyl(Rq)3; CN; CONH2; CONHC1-6alkyl(Rq)3; CON(C1-6alkyl(Rq)3)2; NH2; N