IP Library › Granted Patent US 8,242,117

Granted Patent B2

US 8,242,117 · App. 12/950,649 · Granted Aug 14, 2012

5-membered heterocycle-based p38 kinase inhibitors

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Quick Facts

Patent No.: US 8,242,117
App. No.: 12/950,649
Granted: Aug 14, 2012
Kind: B2

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Abstract

Provided are 5-membered heterocycle-based p38 kinase inhibitors. Further provided are pyrazole and imidazole-based p38 kinase, including p38α and p38β kinase, inhibitors. Pharmaceutical compositions containing the compounds are also provided. Methods of use of the compounds and compositions are also provided, including methods of treatment, prevention, or amelioration of one or more symptoms of p38 kinase mediated diseases and disorders, including, but not limited to, inflammatory diseases and disorders.

Claims (68)

1. A method of treating or ameliorating one or more symptoms of p38 kinase-mediated diseases or disorders selected from the group consisting of rheumatoid arthritis, comprising administering to a subject in need thereof a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen, acyl or —P(O)(OH) 2 ;

R 2 is hydrogen, halo, alkyl, or alkylthio;

G is phenyl substituted with R 3 and R 4 ;

B is phenyl;

C is a pyrazole or imidazole;

D is C(O)NH(cyclopropyl);

R 3 is selected from the group consisting of:

(a) amino, alkylamino or dialkylamino;

(b) acylamino;

(d) heteroalkylcarbonyl;

(e) —Y-(alkylene)-R 9 where: Y is a single bond, —O—, —NH— or —S(O) n — (where n is an integer from 0 to 2); and R 9 is halo, cyano, optionally substituted phenyl, —COOH, —COR 10 , —COOR 11 , —CONR 12 R 13 , —SO 2 R 14 , —SO 2 NR 15 R 16 , —NHSO 2 R 17 or —NHSO 2 NR 18 R 19 , where R 10 is alkyl, R 11 is alkyl, and R 12 , R 13 , R 14 , R 15 , R 16 , R 17 R 18 and R 19 are, independently of each other, hydrogen or alkyl;

(f) —CONR 25 R 26 where R 25 and R 26 independently represent hydrogen, alkyl, heteroalkyl, or R 25 and R 26 together with the nitrogen to which they are attached form an optionally substituted heterocyclyl ring;

(g) —S(O) n R 27 where n is an integer from 0 to 2, and R 27 is alkyl, heteroalkyl, or —NR 28 R 29 where R 28 and R 29 are, independently of each other, hydrogen, alkyl or heteroalkyl;

(h) cycloalkylalkyl, cycloalkylalkenyl and cycloalkylalkynyl, all optionally substituted with alkyl, halo, hydroxy or amino;

(i) Z-alkylene-NR 30 R 31 or Z-alkylene-OR 32 where Z is —NH—, —N(lower alkyl)- or —O—, and R 30 , R 31 and R 32 are independently of each other, hydrogen, alkyl or heteroalkyl;

(j) —OC(O)-alkylene-CO 2 H or —OC(O)—NR′R″ where R′ and R″ are independently hydrogen or alkyl;

(k) hydrogen;

(l) halo;

(m) cyano;

(n) hydroxy;

(o) optionally substituted alkoxy;

(p) C(L)R 40 , where L is O; R 40 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phenyl, optionally substituted cycloalkyl, C(L)R 56 , halo, OR 55 , SR 55 , NR 57 R 58 or SiR 52 R 53 R 54 ; where R 52 , R 53 and R 54 are selected as in (i) or (ii) as follows (i) R 52 , R 53 and R 54 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR 55 or NR 62 R 63 ; or (ii) any two of R 52 , R 53 and R 54 together form alkylene, alkenylene, alkynylene, heteroalkylene; and the other is selected as in (i); R 55 is hydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl; R 56 is hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR 55 or NR 64 R 65 ; where R 64 and R 65 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR 66 or NR 62 R 63 , or R 64 and R 65 together form alkylene, alkenylene, alkynylene, heteroalkylene, where R 66 is hydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl; R 57 and R 58 are selected as in (i) or (ii) as follows (i) R 57 and R 58 are each independently hydrogen, optionally substituted alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR 55 , NR 67 R 68 or C(L)R 69 , where R 67 and R 68 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl or cycloalkyl, or together form alkylene, alkenylene, alkynylene, heteroalkylene; and R 69 is hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, OR 70 or NR 62 R 63 , where R 70 is alkyl, alkenyl, alkynyl, phenyl or cycloalkyl; or (ii) R 57 and R 58 together form alkylene, alkenylene, alkynylene, heteroalkylene, or alkylenoxyalkylene; R 62 and R 63 are each independently hydrogen, alkyl, alkenyl, alkynyl, phenyl, cycloalkyl, or R 62 and R 63 together form alkylene, alkenylene, alkynylene, heteroalkylene; and

(q) optionally substituted alkyl;

R 4 is selected from the group consisting of:

(a) hydrogen;

(b) halo;

(d) alkoxy; and

(e) hydroxy;

R 5 is selected from the group consisting of

(a) hydrogen;

(b) halo; and

R 6 is selected from the group consisting of:

(a) hydrogen;

(b) halo;

(d) alkoxy.

2. The method according to claim 1 , where C is an imidazole ring.

3. The method according to claim 1 , where C is a pyrazole ring.

4. The method according to claim 1 , wherein the compound is a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein the A ring is phenyl; and the hydrogen of the ring NH group is replaced by one of the —C(O)-A(R 3 )(R 4 ), —R 2 , or- B(D)(R 6 )(R 5 ) substituents, wherein A refers to the ring A and B refers to ring B in Formula II.

5. The method according to claim 1 , wherein the compound is a compound of formula III: