Fused tricyclic compounds for the treatment of inflammatory disorders

1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

E is phenyl, or is a monocyclic or bicyclic heteroaryl ring containing five to 10 ring atoms, wherein said heteroaryl ring contains from one to four heteroatoms selected from the group consisting of N, O, and S;

R 1 and R 2 are independently present or absent, and if present, are independently (C 1 -C 6 ) alkyl, halo, (C 1 -C 6 ) alkoxy, —CN, (C 1 -C 6 ) haloalkyl, azido, —C(═O)—(C 1 -C 6 )alkyl, —S(O)—(C 1 -C 6 )alkyl, or —S(O) 2 —(C 1 -C 6 )alkyl, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, carbamyl, —NH—C(═O)—(C 1 -C 6 ) alkyl, or hydroxyl;

M is —O—, —S(O)—, —S(O) 2 —, (C 1 -C 4 ) alkylene, (C 1 -C 4 ) alkenylene, (C 1 -C 4 )alkynylene, fluoro(C 1 -C 4 )alkylene, hydroxy(C 1 -C 4 )alkylene, or alkoxy(C 1 -C 4 )alkylene;

or M is absent, such that E is bonded directly to ring A;

X 1 is O or S;

R 9 is H, (C 1 -C 6 ) alkyl, or halo;

each occurrence of R 10 is independently H, (C 1 -C 3 ) alkyl, fluoro, (C 1 -C 3 ) fluoroalkyl, or (C 1 -C 3 ) alkoxy;

R 3 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or R 3 is a group of the formula -J-K,

wherein J is (C 1 -C 3 ) alkylene, —C(═O)—, or —C(═S)—;

K is (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl, heteroaryl, or heterocyclyl of K is unsubstituted or substituted with one to four moieties, wherein said moieties are the same or different, and wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CN, —OCF 3 , and R 25 ;

R 25 is (C 6 -C 10 ) aryl or 5- to 6-membered heteroaryl, wherein said aryl or heteroaryl of R 25 is unsubstituted or substituted with one to four moieties, wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, hydroxyl, (C 1 -C 6 ) alkoxy, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CF 3 , —OCF 3 , or —CN;

R 4 is absent, halo, —CN, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) fluoroalkyl;

wherein D is a heterocyclic or heteroaryl ring selected from the group consisting of:

wherein R 6 and R 7 are independently absent or present, and if present, are independently (C 1 -C 3 ) alkyl, (C 1 -C 3 ) fluoroalkyl, —CH 2 —O—(C 1 -C 3 )alkyl, —CH 2 CH 2 —O—(C 1 -C 3 )alkyl, or —CH 2 CH 2 CH 2 —O—(C 1 -C 3 )alkyl, and wherein R 6 and R 7 are substituted on a carbon atom;

R 18 is H, —CN, hydroxy, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) alkoxy; and

R 19 is H or (C 1 -C 3 ) alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is absent.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein D is

4. The compound of claim 1 having the Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein

R 1 and R 2 are independently absent or present, and if present are independently halo, (C 1 -C 6 ) alkoxy, —CN, (C 1 -C 6 ) haloalkyl, azido, acetyl, propionyl, butanoyl, —S(O)—(C 1 -C 4 )alkyl, or —S(O) 2 —(C 1 -C 4 )alkyl;

X 1 is O or S;

each occurrence of R 10 is independently H, (C 1 -C 3 ) alkyl, fluoro, (C 1 -C 3 ) fluoroalkyl, or (C 1 -C 3 ) alkoxy;

R 3 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 ) alkoxy(C 1 -C 6 )alkyl, or R 3 is a group of the formula -J-K,

wherein J is (C 1 -C 3 ) alkylene, —C(═O)—, or —C(═S)—;

K is (C 3 -C 10 ) cycloalkyl, (C 6 -C 10 ) aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl, heteroaryl, or heterocyclyl of K is unsubstituted or substituted with one to four moieties, wherein said moieties are the same or different, and wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CN, —OCF 3 , and R 25 ;

R 25 is (C 6 -C 10 ) aryl or 5- to 6-membered heteroaryl, wherein said aryl or heteroaryl of R 25 is unsubstituted or substituted with one to four moieties, wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, hydroxyl, (C 1 -C 6 ) alkoxy, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CF 3 , —OCF 3 , and —CN;

each occurrence of R 10 is independently H, (C 1 -C 3 ) alkyl, fluoro, (C 1 -C 3 ) fluoroalkyl, or (C 1 -C 3 ) alkoxy;

R 4 is absent, halo, cyano, (C 1 -C 3 ) alkyl, or (C 1 -C 3 ) fluoroalkyl;

D is a group of the formula:

wherein R 6 and R 7 are independently absent or present, and if present are independently (C 1 -C 3 ) alkyl, (C 1 -C 3 ) fluoroalkyl, —CH 2 —O—(C 1 -C 3 )alkyl, —CH 2 CH 2 —O—(C 1 -C 3 ) alkyl, —CH 2 CH 2 CH 2 —O—(C 1 -C 3 ) alkyl, and wherein R 6 and R 7 are substituted on a carbon atom;

R 18 is H, —CN, hydroxy, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) alkoxy; and

R 19 is H or (C 1 -C 3 ) alkyl.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 3 is -J-K, wherein J is (C 1 -C 3 ) methylene, K is 3- to 6-membered cycloalkyl or phenyl, wherein said cycloalkyl or phenyl of K is unsubstituted or is substituted with one to two moieties, wherein said moieties are the same or different, and wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CN, —OCF 3 , and R 25 ; and

R 25 is phenyl or 5- to 6-membered heteroaryl, wherein said phenyl or heteroaryl of R 25 is unsubstituted or substituted with one to four moieties, wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, hydroxyl, (C 1 -C 6 ) alkoxy, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CF 3 , —OCF 3 , and —CN.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein R 25 is pyridyl or pyrimidyl, wherein said pyridyl or pyrimidyl is unsubstituted or substituted with one to four moieties, wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, hydroxyl, (C 1 -C 6 ) alkoxy, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CF 3 , —OCF 3 , and —CN.

7. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein D is

8. The compound of claim 1 having the Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein

R 1 is halo or cyano;

X 1 is O or S;

R 3 is H, (C 1 -C 6 ) alkyl, halo(C 1 -C 6 )alkyl, or (C 1 -C 6 ) alkoxy(C 1 -C 6 )alkyl, or R 3 is a group of the formula -J-K,

wherein J is (C 1 -C 3 ) alkylene, —C(═O)—, or —C(═S)—;

K is (C 3 -C 10 )cycloalkyl, (C 6 -C 10 ) aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl, wherein said cycloalkyl, aryl, heteroaryl, or heterocyclyl of K is unsubstituted or substituted with one to four moieties, wherein said moieties are the same or different, and wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CN, —OCF 3 , and R 25 ;

R 25 is (C 6 -C 10 ) aryl or 5- to 6-membered heteroaryl, wherein said aryl or heteroaryl of R 25 is unsubstituted or substituted with one to four moieties, wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, hydroxyl, (C 1 -C 6 ) alkoxy, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CF 3 , —OCF 3 , or —CN;

Q 1 is N or C(R 18 );

R 18 is H, —CN, hydroxy, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) alkoxy; and

R 19 is H or (C 1 -C 3 ) alkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, methyl, ethyl, propyl, butyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl; or

R 3 is -J-K, wherein J is methylene, K is 3- to 6-membered cycloalkyl or phenyl, wherein said cycloalkyl or phenyl of K is unsubstituted or is substituted with one to two moieties, wherein said moieties are the same or different, and wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CN, —OCF 3 , and R 25 ;

R 25 is phenyl or 5- to 6-membered heteroaryl, wherein said phenyl or heteroaryl of R 25 is unsubstituted or substituted with one to four moieties, wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, hydroxyl, (C 1 -C 6 ) alkoxy, halo, amino, (C 1 -C 6 ) alkylamino, di(C 1 -C 6 )alkylamino, —CF 3 , —OCF 3 , and —CN.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, methyl, 2,2-difluoroethyl, methoxymethyl; or

R 3 is —CH 2 —K, wherein K is cyclopropyl, phenyl, or phenyl substituted with one to two moieties, wherein said moieties are the same or different, and wherein said moieties are selected from the group consisting of halo, amino, and R 25 ;

wherein R 25 is phenyl or 5- to 6-membered heteroaryl, wherein said phenyl or heteroaryl of R 25 is unsubstituted or substituted with one moiety, wherein said moiety is selected from the group consisting of (C 1 -C 6 ) alkoxy and amino.

11. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Q 1 is N.

12. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein Q 1 is C(R 18 ), wherein R 18 is H, —CN, hydroxy, (C 1 -C 6 ) alkyl, or (C 1 -C 6 ) alkoxy.

13. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein

R 3 is H, methyl, 2,2-difluoroethyl, methoxymethyl; or —CH 2 —K,

wherein K is cyclopropyl, phenyl, or phenyl substituted with one to two moieties, wherein said moieties are the same or different, and wherein said moieties are selected from the group consisting of (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, halo, —CN, —OCF 3 , and R 25 ;

R 25 is phenyl, pyridyl, or pyrimidyl, wherein said phenyl, pyridyl, or pyrimidyl of R 25 is unsubstituted or substituted with one moiety, wherein said moiety is selected from the group consisting of (C 1 -C 6 ) alkoxy or amino;

Q 1 is N or C(H); and

R 19 is H or methyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following compounds:

15. A pharmaceutical composition, comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A method of treating an inflammatory disorder selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, psoriasis, asthma, and chronic obstructive pulmonary disorder, comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.