Beta-carbolines useful for treating inflammatory disease
View Patent ↗This invention provides beta-carboline compounds of formula I: wherein Ring A is a substituted pyridinyl, pyrimidinyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl, pyranyl, tetrahydrofuranyl, cyclohexyl, cyclopentyl or thiomorpholinyl ring and R 1 , R 2 and R 3 are as described in the specification. The compounds are IKK-2 inhibitors that are useful for treating IKK-2-mediated diseases such as inflammatory diseases and cancer.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ring A is a morpholinyl ring that is substituted by (i) —C(R 9 ) 3 , —W-G, or -G, (ii) 0-4 R 6b and (iii) 0-1 oxo groups on a ring carbon;
each R 6a is independently selected from C 1-6 aliphatic, halo, alkoxy, or amino;
each R 6b is independently selected from C 1-3 aliphatic or —N(R 7 ) 2 , and two R 6b on the same or an adjacent carbon optionally are taken together with the intervening carbon(s) to form a 5-6 membered ring having 1-2 ring heteroatoms selected from N, O or S;
W is -Q-, -Q-C(O)—, —C(R 9 ) 2 —C(R 9 )(R 12 )—, or —C(R 9 ) 2 —[C(R 9 )(R 12 )] 2 —;
Q is —C(R 9 ) 2 — or —C(R 9 ) 2 C(R 9 ) 2—;
G is —OH, —NR 4 R 5 , —N(R 9 )CONR 4 R 5 , —N(R 9 )SO 2 (C 1-3 aliphatic), —N(R 9 )COCF 3 , —N(R 9 )CO(C 1-6 aliphatic), —N(R 9 )CO(heterocyclyl), —N(R 9 )CO(heteroaryl), —N(R 9 )CO(aryl), a 3-7 membered heterocyclyl ring, or a 5-6 membered heteroaryl, wherein each of the heteroaryl, aryl and heterocyclyl moieties of G is optionally substituted by 1-3 R 10 ;
R 1 is hydrogen, halo, C 1-3 aliphatic, amino, cyano, (C 1-3 alkyl) 1-2 amino, C 1-3 alkoxy, —CONH 2 , —NHCOCF 3 , or —CH 2 NH 2 ;
R 2 is hydrogen, halo, C 1-3 aliphatic, —CF 3 ;
R 3 is hydrogen, halo, C 1-6 aliphatic, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy, amino, cyano, or (C 1-6 alkyl) 1-2 amino;
R 4 is hydrogen, 3-7 membered heterocyclyl, or C 1-6 aliphatic;
R 5 is hydrogen, C 1-6 aliphatic group or a 3-7 membered heterocyclic ring having 1-2 ring heteroatoms selected from N, O, S, wherein R 5 is optionally substituted by halo, —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 8 , or —N(R 7 )C(O)N(R 7 ) 2 ;
each R 7 is independently selected from hydrogen or C 1-4 aliphatic, or two R 7 on the same nitrogen atom are taken together with the nitrogen to form a 5-6 membered heteroaryl or heterocyclyl ring;
each R 8 is independently selected from C 1-4 aliphatic;
each R 9 is independently selected from hydrogen or C 1-3 aliphatic;
each R 10 is independently selected from oxo, —R 11 , -T-R 11 , or —V-T-R 11 ;
each R 11 is independently selected from C 1-6 aliphatic, halo, —S(O) 2 N(R 7 ) 2 , —OR 7 , —CN, —SR 8 , —S(O) 2 R 8 , —C(O)R 7 , —CO 2 R 7 , —N(R 7 ) 2 , —C(O)N(R 7 ) 2 , —N(R 7 )C(O)R 7 , —N(R 7 )CO 2 R 7 , or —N(R 7 )C(O)N(R 7 ) 2 ;
T is a straight or branched C 1-4 alkylene chain;
V is —O—, —N(R 7 )—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, or —CO 2 —; and
R 12 is hydrogen, C 1-6 aliphatic, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl.
2. The compound of claim 1 where the —W-G or —C(R 9 ) 3 substituent on Ring A is ortho to the position where the beta-carboline portion is attached.
3. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
4. A compound of formula IV:
where R 14 is an amino protecting group or hydrogen;
R 1 is hydrogen, halo, C 1-3 aliphatic, amino, cyano, (C 1-3 alkyl) 1-2 amino, C 1-3 alkoxy, —CONH 2 , —NHCOCF 3 , or —CH 2 NH 2 ;
R 2 is hydrogen, halo, C 1-3 aliphatic, —CF 3 ; and
R 3 is hydrogen, halo, C 1-6 aliphatic, C 1-6 haloalkyl, C 1-6 alkoxy, hydroxy, amino, cyano, or (C 1-6 alkyl) 1-2 amino.
5. The compound of claim 4 , wherein the compound is represented by formula (S)—IV: