Glucocorticoid receptor modulators

A compound of formula I

• 62
• an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;
• wherein m is 1 or 2;
• ——— represents an optional bond;
• A is selected from the group consisting of
• 63
• G, H and I together with 2 carbon atoms from the A-ring or 2 carbon atoms from the B-ring form a 5-membered heterocyclic ring comprising one or more N, O or S atoms;
• provided that there is at most one of O and S per ring;
• J, K, L and M together with 2 carbon atoms from the B-ring forms a 6-membered heterocyclic ring comprising 1 or more N atoms;
• X is a) absent, b) —CH2—, c) —CH(OH)— or d) —C(O)—;
• R1 is a) —H, b) —Z—CF3, c) —(C1-C6)alkyl, d) —(C2-C6)alkenyl, e) —(C2-C6)alkynyl, f) —CHO, g) —CH═N—OR12, h) —Z—C(O)OR12, i) —Z—C(O)—NR12R13, j) —Z—C(O)—NR12—Z-het, k) —Z—NR12R13, l) —Z—NR12het, m) —Z-het, n) —Z—O-het, o) —Z-aryl′, p) —Z—O-aryl′, q) —CHOH-aryl′ or r) —C(O)-aryl′ wherein aryl′ in substituents o) to r) is substituted independently with 0, 1 or 2 of the following:
• —Z—OH, —Z—NR12R13, —Z—NR12-het, —C(O)NR12R13, —C(O)O(C1-C6)alkyl, —C(O)OH, —C(O)-het, —NR12—(C(O)—C1-C6)alkyl, —NR12—C(O)—(C2-C6)alkenyl, —NR12—C(O)—(C2-C6)alkynyl, —NR12—C(O)—Z-het, —CN, —Z-het, —O—(C1-C3)alkyl-C(O)—NR12R13, —O—(C1-C3)alkyl-C(O)O(C1-C6)alkyl, —NR12—Z—C(O)O(C1-C6)alkyl, —N(Z—C(O)O(C1-C6)alkyl)2, —NR12—Z—C(O)—NR12R13, —Z—NR12—SO2—R13, —NR12—SO2-het, —C(O)H, —Z—NR12—Z—O(C1-C6)alkyl, —Z—NR12—Z—NR12R13, —Z—NR12—(C3-C6)cycloalkyl, —Z—N(Z—O(C1-C6)alkyl)2, —SO2R12, —SOR12, —SR12, —SO2NR12R13, —O—C(O)—(C1-C4)alkyl, —O—SO2—(C1-C4)alkyl, -halo or —CF3;
• Z for each occurrence is independently a) —(C0-C6)alkyl, b) —(C2-C6)alkenyl or c) —(C2-C6)alkynyl;
• R2 is a) —H, b) -halo, c) —OH, d) —(C1-C6)alkyl substituted with 0 or 1 —OH, e) —NR12R13, f) —Z—C(O)O(C1-C6)alkyl, g) —Z—C(O)NR12R13, h) —O—(C1-C6)alkyl, i) —Z—O—C(O)—(C1-C6)alkyl, j) —Z—O—(C1-C3)alkyl-C(O)—NR12R13, k) —Z—O—(C1-C3)alkyl-C(O)—O(C1-C6)alkyl, l) —O—(C2-C6)alkenyl, m) —O—(C2-C6)alkynyl, n) —O—Z-het, o) —COOH, p) —C(OH)R12R13 or q) —Z—CN;
• R3 is a) —H, b) —(C1-C10)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom is substituted with 0, 1 or 2 Ry, c) —(C2-C10)alkenyl substituted with 0, 1 or 2 Ry, d) —(C2-C10)alkynyl wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0, 1 or 2 Ry, e) —CH═C═CH2, f) —CN, g) —(C3-C6)cycloalkyl, h) —Z-aryl, i) —Z-het, j) —C(O)O(C1-C6)alkyl, k) —O(C1-C6)alkyl, l) —Z—S—R12, m) —Z—S(O)—R12, n) —Z—S(O)2—R12, o) —CF3p) —NR12O—(C1-C6)alkyl or q) —CH2ORy;
• provided that one of R2 and R3 is absent when there is a double bond between CR2R3 (the 7 position) and the F moiety (the 8 position) of the C-ring;
• Ry for each occurrence is independently a) —OH, b) -halo, c) —Z—CF3, d) —Z—CF(C1-C3 alkyl)2, e) —CN, f) —NR12R13, g) —(C3-C6)cycloalkyl, h) —(C3-C6)cycloalkenyl, i) —(C0-C3)alkyl-aryl, j) -het or k) —N3;
• or R2 and R3 are taken together to form a) ═CHR11, b) ═NOR11, c) ═O, d) ═N—NR12, e) ═N—NR12—C(O)—R12, f) oxiranyl or g) 1,3-dioxolan-4-yl;
• R4 and R5 for each occurrence are independently a) —H, b) —CN, c) —(C1-C6)alkyl substituted with 0 to 3 halo, d) —(C2-C6)alkenyl substituted with 0 to 3 halo, e) —(C2-C6)alkynyl substituted with 0 to 3 halo, f) —O—(C1-C6)alkyl substituted with 0 to 3 halo, g) —O—(C2-C6)alkenyl substituted with 0 to 3 halo, h) —O—(C2-C6)alkynyl substituted with 0 to 3 halo, i) halo, j) —OH, k) (C3-C6)cycloalkyl or l) (C3 -C6)cycloalkenyl;
• or R4 and R5 are taken together to form ═O;
• R6 is a) —H, b) —CN, c) —(C1-C6)alkyl substituted with 0 to 3 halo, d) —(C2-C6)alkenyl substituted with 0 to 3 halo, e) —(C2-C6)alkynyl substituted with 0 to 3 halo or f) —OH;
• R7 and R16 for each occurrence are independently a) —H, b) -halo, c) —CN, d) —(C1-C6)alkyl substituted with 0 to 3 halo, e) —(C2-C6)alkenyl substituted with 0 to 3 halo or f) —(C2-C6)alkynyl substituted with 0 to 3 halo;
• provided that R7 is other than —CN or -halo when D is NR7;
• or R7 and R16 are taken together to form ═O;
• R8, R9, R14 and R15 for each occurrence are independently a) —H, b) -halo, c) (C1-C6)alkyl substituted with 0 to 3 halo, d) —(C2-C6)alkenyl substituted with 0 to 3 halo, e) —(C2-C6)alkynyl substituted with 0 to 3 halo, f —CN, g) —(C3-C6)cycloalkyl, h) —(C3-C6)cycloalkenyl, i) —OH, j) —O—(C1-C6)alkyl, k) —O—(C1-C6)alkenyl, l) —O—(C1-C6)alkynyl, m) —NR12R13, n) —C(O)OR12 or o) —C(O)NR12R13;
• or R8 and R9 are taken together on the C-ring to form ═O;
• provided that when m is 2, only one set of R8 and R9 are taken together to form ═O;
• or R14 and R15 are taken together to form ═O;
• provided that when R14 and R15 are taken together to form ═O, D is other than CR7 and E is other than C;
• R10 is a) —(C1-C10)alkyl substituted with 0 to 3 substituents independently selected from -halo, —OH and —N3, b) —(C2-C10)alkenyl substituted with 0 to 3 substituents independently selected from -halo, —OH and —N3, c) —(C2-C10)alkynyl substituted with 0 to 3 substituents independently selected from -halo, —OH and —N3, d) -halo, e) —Z—CN, f) —OH, g) —Z-het, h) —Z—NR12R13, i) —Z—C(O)-het, j) —Z—C(O) —(C1-C6)alkyl, k) —Z—C(O)—NR12R13, l) —Z—C(O) —NR12—Z—CN, m) —Z—C(O)—NR12—Z-het, n) —Z—C(O) —NR12—Z-aryl, o) —Z—C(O) —NR12—Z—NR12R13, p) —Z—C(O)—NR12—Z—O(C1-C6)alkyl, q) —(C0-C6)alkyl-C(O)OH, r) —Z—C(O)O(C1-C6)alkyl, s) —Z—O—(C0-C6)alkyl-het, t) —Z—O—(C0-C6)alkyl-aryl, u) —Z—O—(C1-C6)alkyl substituted with 0 to 2 Rx, v) —Z—O—C1-C6)alkyl-CH(O), w) —Z—O—(C1-C6)alkyl-NR12-het, x) —Z—O—Z-het-Z-het, y) —Z—O—Z-het-Z—NR12R13, z) —Z—O—Z-het-C(O)-het, a1) —Z—O—Z—C(O)-het, b1) —Z—O—Z—C(O)-het-het, c1) —Z—O—Z—C(O)—(C1-C6)alkyl, d1) —Z—O—Z—C(S)—NR12R13, e1) —Z—O—Z—C(O)—NR12R13, f1) —Z—O—Z—(C1-C3)alkyl-C(O) —NR12R13, g1) —Z—O—Z—C(O)—O(C1-C6)alkyl, h1) —Z—O—Z—C(O)—OH, i1) —Z—O—Z—C(O)—NR12—O(C1-C6)alkyl, j1) —Z—O—Z—C(O)—NR12—OH, k1) —Z—O—Z—C(O)—NR12—Z—NR12R13, l1) —Z—O—Z—C(O)—NR12—Z-het, m1) —Z—O—Z—C(O)—NR12—SO2—(C1-C6)alkyl, n1) —Z—O—Z—C(═NR12)(NR12R13), o1) —Z—O—Z—C(═NOR12)(NR12R13), p1) —Z—NR12—C(O)—O—Z—NR12R13, q1) —Z—S—C(O)—NR12R13, r1) —Z—O—SO2—(C1-C6)alkyl, S1) —Z—O—SO2-aryl, t1) —Z—O—SO2—NR12R13, u1) —Z—O—SO2—CF3, v1) —Z—NR12C(O)OR13 or w1) —Z—NR12C(O)R13;
• or R9 and R10 are taken together on the moiety of formula A-5 to form a) ═O or b) ═NOR12;
• R11 is a) —H, b) —(C1-C5)alkyl, c) —(C3-C6)cycloalkyl or d) —(C0-C3)alkyl-aryl;
• R12 and R13 for each occurrence are each independently a) —H, b) —(C1-C6)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom is substituted with 0 to 6 halo, c) —(C2-C6)alkenyl substituted with 0 to 6 halo or d) —(C1-C6)alkynyl wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0 to 6 halo;
• or R12 and R13 are taken together with N to form het;
• or R6 and R14 or R15 are taken together to form 1,3-dioxolanyl;
• aryl is a) phenyl substituted with 0 to 3 Rx, b) naphthyl substituted with 0 to 3 Rx or c) biphenyl substituted with 0 to 3 Rx;
• het is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;
• and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle;
• and the nitrogen may be in the oxidized state giving the N-oxide form;
• and substituted with 0 to 3 Rx;
• Rx for each occurrence is independently a) -halo, b) —OH, c) —(C1-C6)alkyl, d) —(C2-C6)alkenyl, e) —(C2-C6)alkynyl, f) —O(C1-C6)alkyl, g) —O(C2-C6)alkenyl, h) —O(C2-C6)alkynyl, i) —(C0-C6)alkyl-NR12R13, j) —C(O)—NR12R13, k) —Z—SO2R12, l)—Z—SOR12, m) —Z—SR12, n) —NR12—SO2R13, o) —NR12—C(O)—R13, p) —NR12—OR13, q) —SO2—NR12R13, r) —CN, s) —CF3, t) —C(O)(C1-C6)alkyl, u) ═O, v) —Z—SO2-phenyl or w) —Z—SO2-het′;
• aryl′ is phenyl, naphthyl or biphenyl;
• het′ is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;
• and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle;
• provided that:
• 1) X—R1 is other than hydrogen or methyl;
• 2) when R9 and R10 are substituents on the A-ring, they are other than mono- or di-methoxy;
• 3) when R2 and R3 are taken together to form ═CHR11 or ═O wherein R11 is —O(C1-C6)alkyl, then —X—R1 is other than (C1-C4)alkyl;
• 4) when R2 and R3 taken together are C═O and R9 is hydrogen on the A-ring;
• or when R2 is hydroxy, R3 is hydrogen and R9 is hydrogen on the A-ring, then R10 is other than —O—(C1-C6)alkyl or —O—CH2-phenyl at the 2-position of the A-ring;
• 5) when X—R1 is (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl, R9 and R10 are other than mono-hydroxy or ═O, including the diol form thereof, when taken together;
• and
• 6) when X is absent, R1 is other than a moiety containing a heteroatom independently selected from N, O or S directly attached to the juncture of the B-ring and the C-ring.