1H-benzo[F]indazol-5-YL derivatives as selective glucocorticoid receptor modulators
View Patent ↗The present invention encompasses compounds of Formula I: or pharmaceutically acceptable salts or hydrates thereof, which are useful as selective glucocorticoid receptor ligands for treating a variety of autoimmune and inflammatory diseases or conditions. Pharmaceutical compositions and methods of use are also included.
1. A compound represented by Formula I
or a pharmaceutically acceptable salt thereof, wherein:
n is 0;
J is NR 1 ;
K is NR 3 ;
L is C(R 5 )(R 6 );
X is a bond, —C(O)—, —N(R 14 )—, —N(R 14 )—C(O)—, or
R 1 , R 8 and R 10 are each independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 2-6 alkenyl,
(3) C 3-6 alkynyl,
(4) C 3-6 cycloalkyl,
(5) C 1-6 alkoxy,
(6) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(7) aryl,
(8) aralkyl,
(9) HET,
(10) —C 1-6 alkyl-HET,
(11) aryloxy,
(12) aroyloxy,
(13) aralkenyl,
(14) aralkynyl,
(15) hydrogen,
(16) hydroxy and
(17) C 1-6 alkyl-N(R 14 )—S(O) k —, wherein k is 0, 1 or 2,
wherein items (1) to (6) above and the alkyl portions of items (8), (10) and (17) above and the alkenyl portion of item (13) above and the alkynyl portion of item (14) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 , N(R 14 ) 2 , C 3-6 cycloalkyl and C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2, and
wherein items (7), (9), (11) and (12) above and aryl portion of items (8), (13) and (14) above and the HET portion of item (10) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-6 alkyl,
(e) C 2-6 alkenyl,
(f) C 3-6 alkynyl,
(g) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(h) aryl,
(i) aryl-S(O) k —, wherein k is 0, 1 or 2,
j) HET,
(k) aralkyl,
(l) aroyl,
(m) aryloxy,
(n) aralkoxy and
(o) CN,
wherein items (d) to (g) above and the alkyl portions of item (k) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 , and
wherein items (h), (i), (j), (l) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and C 1-4 alkyl,
or when X is a bond then R 8 and R 10 may be joined together to form a 4- to 8-membered monocylic ring, optionally containing 1-3 heteroatoms selected from O, S and N, and optionally containing 1 or 2 double bonds;
R 3 , R 5 and R 6 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halo,
(3) C 1-6 alkyl,
(4) C 2-6 alkenyl,
(5) C 3-6 alkynyl,
(6) C 3-6 cycloalkyl,
(7) C 1-6 alkoxy,
(8) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(9) aryl,
(10) aralkyl,
(11) HET and
(12) —C 1-16 alkyl-HET,
wherein items (3) to (8) above and the alkyl portions of items (10) and (12) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 , N(R 14 ) 2 and C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2; and
wherein items (9) and (11) and the aryl portion of items (10) and the HET portion of item (12) are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-6 alkyl,
(e) C 2-6 alkenyl,
(f) C 3-6 alkynyl and
(g) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
wherein items (d) to (g) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 ,
or R 1 and R 3 or R 3 and R 5 may be joined together to form a double bond;
R 7 is selected from the group consisting of:
(1) hydrogen,
(2) OR 13 ,
(3) C 1-4 alkyl,
(4) aryl and
(5) aralkyl,
wherein item (3) above and the alkyl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 , and
wherein item (4) above and the aryl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-6 alkyl,
(e) C 2-6 alkenyl and
(f) C 3-6 alkynyl,
wherein items (d) to (f) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 ;
Y is selected from the group consisting of:
(1) hydrogen,
(2) —O—R 9 ,
(3) —S(O) k —R 9 , wherein k is 0, 1 or 2,
(4) —C—W—R 9 , wherein W is O or S(O) k ,
(5) —N(R 15 ) 2 ,
(6) —S(O) k —N(R 15 ) 2 ,
(7) —N(R 15 )—S(O) k —N(R 15 ) 2 ,
(8) NO 2 ,
(9) —C(O)—R 15 ,
(10) —C(O)O—R 15 ,
(11) —CN,
(12) halo and
(13) —O—S(O) k —R 15 ,
R 9 is selected from the group consisting of: hydrogen, C 1-12 alkyl and aryl, wherein C 1-12 alkyl and aryl are optionally substituted from one up to the maximum number of substituents with halo, or when Y is OR 9 then R 8 and R 9 may be joined together to form a carbonyl group;
each R 11 and R 12 is independently selected from the group consisting of:
(1) halo,
(2) C 1-16 alkyl,
(3) C 2-6 alkenyl,
(4) C 1-6 alkoxy and
(5) hydroxy,
wherein items (2) to (4) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 12 , N(R 13 ) 2 and C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2;
each R 13 and R 14 is independently selected from the group consisting of hydrogen and C 1-4 alkyl and C 2-4 alkenyl, each of said C 1-4 alkyl and C 2-4 alkenyl optionally substituted from one up to the maximum number of substitutable positions with substituent independently selected from the group consisting of: halo, C 1-4 alkoxy, aryl, C 3-6 cycloalkyl, CN and C 1-4 alkyl-S(O) k , wherein k is 0, 1 or 2;
each R 15 is independently selected from the group consisting of: hydrogen, C 1-6 alkyl, aryl and C 1-12 alkoxycarbonyl, wherein said C 1-6 alkyl and C 1-12 alkoxycarbonyl are optionally substituted from one up to the maximum number of substitutable positions with halo and said aryl is optionally substituted from one up to the maximum number of substitutable positions with halo and C 1-4 alkyl, optionally substituted with 1-3 halo groups; and
HET is a 5- to 10-membered aromatic, partially aromatic or non-aromatic mono- or bicyclic ring, containing 1-4 heteroatoms selected from O, S and N, and optionally substituted with 1-2 oxo groups.
2. A compound according to claim 1 represented by Formula I
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
n is 0;
J is NR 1 ;
K is NR 3 ;
L is C(R 5 )(R 6 );
X is a bond, —C(O), —N(R 14 )—, —N(R 14 )—C(O)—, or
R 1 , R 8 and R 10 are each independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 2-6 alkenyl,
(3) C 3-6 alkynyl,
(4) C 3-6 cycloalkyl,
(5) C 1-6 alkoxy,
(6) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(7) aryl,
(8) aralkyl,
(9) HET,
(10) —C 1-16 alkyl-HET,
(11) aryloxy,
(12) aroyloxy,
(13) aralkenyl,
(14) aralkynyl,
(15) hydrogen,
(16) hydroxy and
(17) C 1-6 alkyl-N(R 14 )—S(O) k —, wherein k is 0, 1 or 2,
wherein items (1) to (6) above and the alkyl portions of items (8), (10) and (17) above and the alkenyl portion of item (13) above and the alkynyl portion of item (14) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 , N(R 14 ) 2 , C 3-6 cycloalkyl and C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2, and
wherein items (7), (9), (11) and (12) above and aryl portion of items (8), (13) and (14) above and the HET portion of item (10) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-6 alkyl,
(e) C 2-6 alkenyl,
(f) C 3-6 alkynyl,
(g) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(h) aryl,
(i) aryl-S(O) k —, wherein k is 0, 1 or 2,
(j) HET,
(k) aralkyl,
(l) aroyl,
(m) aryloxy,
(n) aralkoxy and
(o) CN,
wherein items (d) to (g) above and the alkyl portions of item (k) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 , and
wherein items (h), (i), (j), (l) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and C 1-4 alkyl,
or when X is a bond then R 8 and R 10 may be joined together to form a 4- to 8-membered monocylic ring, optionally containing 1-3 heteroatoms selected from O, S and NR 14 , and optionally containing 1 or 2 double bonds;
R 3 , R 5 and R 6 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halo,
(3) C 1-6 alkyl,
(4) C 2-6 alkenyl,
(5) C 3-6 alkynyl,
(6) C 3-6 cycloalkyl,
(7) C 1-6 alkoxy,
(8) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(9) aryl,
(10) aralkyl,
(11) HET and
(12) —C 1-6 alkyl-HET,
wherein items (3) to (8) above and the alkyl portions of items (10) and (12) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 , N(R 14 ) 2 and C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2; and
wherein items (9) and (11) and the aryl portion of items (10) and the HET portion of item (12) are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-6 alkyl,
(e) C 2-6 alkenyl,
(f) C 3-6 alkynyl and
(g) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
wherein items (d) to (g) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 ,
or R 1 and R 3 or R 3 and R 5 may be joined together to form a double bond;
R 7 is selected from the group consisting of:
(1) hydrogen,
(2) OR 13 ,
(3) C 1-4 alkyl,
(4) aryl and
(5) aralkyl,
wherein item (3) above and the alkyl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 , and
wherein item (4) above and the aryl portion of item (5) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-16 alkyl,
(e) C 2-6 alkenyl and
(f) C 3-6 alkynyl,
wherein items (d) to (f) above are optionally substituted with from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 ;
Y is selected from the group consisting of:
(1) hydrogen,
(2) —O—R 9 ,
(3) —S(O) k —R 9 , wherein k is 0, 1 or 2,
(4) —C—W—R 9 , wherein W is O or S(O) k ,
(5) —N(R 15 ) 2 ,
(6) —S(O) k —N(R 15 ) 2 ,
(7) —N(R 15 )—S(O) k —N(R 15 ) 2 ,
(8) NO 2 ,
(9) —C(O)—R 15 ,
(10) —C(O)O—R 15 ,
(11) —CN,
(12) halo and
(13) —O—S(O) k —R 15 ,
R 9 is selected from the group consisting of: hydrogen, C 1-12 alkyl and aryl, wherein C 1-12 alkyl and aryl are optionally substituted from one up to the maximum number of substituents with halo, or when Y is OR 9 then R 8 and R 9 may be joined together to form a carbonyl group;
each R 11 and R 12 is independently selected from the group consisting of:
(1) halo,
(2) C 1-6 alkyl,
(3) C 2-6 alkenyl,
(4) C 1-16 alkoxy and
(5) hydroxy,
wherein items (2) to (4) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 12 , N(R 13 ) 2 and C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2;
each R 13 and R 14 is independently selected from the group consisting of hydrogen and C 1-4 alkyl, optionally substituted from one up to the maximum number of substitutable positions with halo; and
each R 15 is independently selected from the group consisting of: hydrogen, C 1-6 alkyl, aryl and C 1-12 alkoxycarbonyl, wherein said C 1-6 alkyl and C 1-12 alkoxycarbonyl are optionally substituted from one up to the maximum number of substitutable positions with halo and said aryl is optionally substituted from one up to the maximum number of substitutable positions with halo and C 1-4 alkyl, optionally substituted with 1-3 halo groups.
3. The compound according to claim 2 wherein:
R 3 and R 5 are joined together to form a double bond.
4. The compound according to claim 2 wherein the optional double bond shown in ring A of the compound of Formula I is present.
5. The compound according to claim 2 wherein R 1 is aryl or HET, said aryl or HET optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-6 alkyl,
(e) C 2-6 alkenyl,
(f) C 3-6 alkynyl,
(g) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(h) aryl,
(i) aryl-S(O) k —, wherein k is 0, 1 or 2,
(j) HET,
(k) aralkyl,
(l) aroyl,
(m) aryloxy,
(n) aralkoxy and
(o) CN,
wherein items (d) to (g) above and the alkyl portions of item (k) are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 , and
wherein items (h), (i), (j), (l) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and C 1-14 alkyl.
6. The compound according to claim 5 wherein R 1 is phenyl, optionally substituted with 1-3 halo groups.
7. The compound according to claim 2 wherein Y is OR 9 .
8. The compound according to claim 7 wherein R 9 is hydrogen.
9. The compound according to claim 2 wherein R 7 is methyl.
10. The compound according to claim 2 wherein R 8 is hydrogen or methyl.
11. The compound according to claim 2 wherein X is a bond.
12. The compound according to claim 2 wherein R 10 is selected from the group consisting of:
(1) C 1-6 alkyl,
(2) C 2-6 alkenyl,
(3) C 3-6 alkynyl,
(4) C 3-6 cycloalkyl,
(5) C 1-6 alkoxy,
(6) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
wherein items (1) to (6) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 , N(R 14 ) 2 , C 3-6 cycloalkyl and C 1-6 alkyl-S(O) k , wherein k is 0, 1 or 2.
13. The compound according to claim 2 wherein R 1 is selected from the group consisting of:
(1) phenyl
(2) naphthyl,
(3) benzyl,
(4) phenethyl,
(5) phenoxy,
(6) benzoyl and
(7) benzoyloxy,
wherein the aryl portions of items (1) to (7) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of:
(a) halo,
(b) OR 13 ,
(c) N(R 14 ) 2 ,
(d) C 1-6 alkyl,
(e) C 2-6 alkenyl,
(f) C 3-6 alkynyl,
(g) C 1-6 alkyl-S(O) k —, wherein k is 0, 1 or 2,
(h) aryl,
(i) aryl-S(O) k —, wherein k is 0, 1 or 2,
(j) HET,
(k) aralkyl,
(l) aroyl,
(m) aryloxy,
(n) aralkoxy and
(o) CN,
wherein items (d) to (g) above and the alkyl portions of item (k) are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and N(R 14 ) 2 , and
wherein items (h), (i), (j), (l) and (m) above and the aryl portions of items (k) and (n) above are optionally substituted from one up to the maximum number of substitutable positions with a substituent independently selected from the group consisting of: halo, OR 13 and C 1-4 alkyl.
14. The compound according to claim 1 wherein R 10 is HET or —C 1-4 alkyl-HET wherein HET is selected from the group consisting of:
(1) pyridine,
(2) thiophene and
(3) furan,
or benzofused analogs of (1) to (3) above.
15. A compound according to claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the above.
16. A compound according to claim 1 selected from one of the following tables:
or a pharmaceutically acceptable salt of any of the above.
17. A compound according to claim 1 of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
n is 0,
R 8 is hydrogen or methyl,
R 9 is hydrogen or methyl or
R 8 and R 9 may be joined together with the oxygen atom shown in Formula III to form a carbonyl group;
R 10 is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl or benzofuryl,
(5) thienyl or benzothienyl, or the S,S-dioxide thereof,
(6) benzyl
(7) quinoline,
(8) thiazoyl or benzothienyl, and
(9) phenylsulfonylmethyl or phenylsulfonylmethyl, wherein
groups (1) to (9) are optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) trifluoromethoxy,
(d) —N(R 14 ), wherein each R 14 is independently hydrogen or C 1-4 alkyl,
(e) pyrrolyl,
(f) methoxy, ethoxy or isopropoxy, each optionally substituted with a substituent selected from; methoxy, benzyl, cyclopropylmethyl, cyano, methylthio, methylsulfinyl and methylsulfonyl,
(g) methyl,
(h) vinyl and
(i) hydroxy, and
R 11 is hydrogen or halo.
18. A compound according to claim 1 of formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
n is 0,
R 10 is selected from the group consisting of:
(1) —CH(OR 13 )-aryl, wherein aryl is phenyl or naphthyl,
(2) —CH(OR 13 )—HET, and
(3) —CH(OR 13 )—C 1-4 alkyl or —CH(OR 13 )—C 2-4 alkenyl, said —CH(OR 13 )—C 1-14 alkyl or H(OR 13 )—C 2-4 alkenyl optionally substituted with phenylsulfonyl,
R 13 is hydrogen or methyl,
HET is selected from the group consisting of:
(1) pyridyl,
(2) furyl or benzofuryl,
(3) thienyl or benzothienyl, or the S,S-dioxide thereof,
(4) benzyl,
(5) quinoline,
(6) thiazolyl or benzothiazolyl,
said aryl of HET are optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(a) halo,
(b) trifluoromethyl,
(c) trifluoromethoxy,
(d) —N(R 14 ), wherein each R 14 is independently hydrogen or
(e) C 1-4 alkyl,
(f) pyrrolyl,
(g) methoxy, ethoxy or isopropoxy, each optionally substituted with a substituent selected from; methoxy, benzyl, cyclopropylmethyl, cyano, methylthio, methylsulfinyl and methylsulfonyl,
(h) methyl,
(i) vinyl and
(j) hydroxy, and
R 11 is hydrogen or halo.
19. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.
20. A compound according to claim 1 administered at a dose of 0.01 mg to 10 mg per kg of body weight.
21. A pharmaceutically acceptable salt of the compound according to claim 1 .