Indole carboxamides as IKK2 inhibitors

1. A compound according to formula (I):

wherein:

R1 is the group —YZ;

Y is a bond, C 1 -C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;

Z is optionally substituted aryl or optionally substituted heteroaryl,

where said aryl and heteroaryl are optionally substituted with one to three substituents each independently selected from the group consisting of: halo, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, heteroaryl optionally substituted with one to three C 1 -C 6 alkyl groups; —N(Rb)SO 2 Re, N(Rb)C(O)Ra, —C(O)NRaRb, —C(O)NRfRg, —C(O)H, —SO 2 Ri, —NRaRb, —SO 2 NRaRb, SO 2 NRfRg, —ORc, —SRb, —N(Rb)C(O)NRaRb, —N(Rb)C(O)NRfRg, and N(Rb)C(O)ORd, where said C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: —CN, —NRaRb—N(Rb)SO 2 Re, —C(O)Ra, —C(O)NRaRb, —SO 2 Ri, SO 2 NRaRb, C 3 -C 6 cycloalkyl, —ORc, —SRb, phenyl, and heterocycloalkyl optionally substituted with one or two C 1 -C 6 alkyl groups;

R2 is an optionally substituted 4-10 member heterocycloalkyl containing S, S═O, or S(O) 2 as member atom(s) and the remaining member atoms are carbon, said 4-10 member heterocycloalkyl being optionally substituted with one to three substituents each independently selected from the group consisting of OH, C 1 -C 6 alkyl, and phenyl; or

R2 is the bicyclo group of formula (II):

wherein A is a bridging group selected from: —CH 2 —CH 2 — or —CH 2 —X—CH 2 and connects carbon atoms 1 or 2 to carbon atoms 3 or 4; X is O, NR5, or S(O) n ; R5 is H, C 1 -C 6 alkyl, or —SO 2 NRaRb; and each n is independently 0, 1, or 2;

R3 and R4 are each independently H or fluoro;

m is 0 or 1;

each Ra is independently selected from the group consisting of: H, C 2 -C 6 alkenyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one to three substituents independently selected from the group consisting of: halo, CN, C(O)NH 2 , N(CH 3 ) 2 , SO 2 Ri, —C(O)ORb, —N(Rb)C(O)Rb, —ORc, —SRc, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heterocycloalkyl, phenyl, and heteroaryl; phenyl, phenyl substituted with one to three substituents independently selected from the group consisting of: halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , heteroaryl, —ORc, and

—NRfRg; heteroaryl, heteroaryl substituted with one to three substituents independently selected from the group consisting of: halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , heteroaryl, —ORc, and —NRfRg; C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted with one to three substituents independently selected from the group consisting of: halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , heteroaryl, —ORc, and —NRfRg; heterocycloalkyl, and heterocycloalkyl substituted with one to three substituents independently selected from the group consisting of: halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, NH 2 , heteroaryl, —ORc, and —NRfRg;

each Rb is independently selected from the group consisting of: H, C 1 -C 6 alkyl, and C 3 -C 7 cycloalkyl;

each Rc is independently selected from the group consisting of: H, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one to three substituents independently selected from the group consisting of: OH, C 3 -C 6 cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl; C 1 -C 6 haloalkyl, C 1 -C 6 haloalkyl substituted with one to three substituents independently selected from the group consisting of: OH, C 3 -C 6 cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl; C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl substituted with one to three C 1 -C 3 alkyl groups; heterocycloalkyl, heterocycloalkyl substituted with one to three C 1 -C 3 alkyl groups; aryl, aryl substituted with one to three substituents independently selected from the group consisting of: halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and OH; heteroaryl, and heteroaryl substituted with one to three substituents independently selected from the group consisting of: halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and OH;

each Rd is independently an optionally substituted C 1 -C 3 alkyl, where said C 1 -C 3 alkyl is optionally substituted with one to three substituents selected from the group consisting of: C 3 -C 6 cycloalkyl, optionally substituted phenyl, and optionally substituted heteroaryl; and where said phenyl and heteroaryl are optionally substituted with one to three substituents selected from the group consisting of: halo, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

each Re is independently selected from the group consisting of: C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with one substituent selected from the group consisting of: phenyl, heteroaryl, heterocycloalkyl, and NRaRb; phenyl, phenyl substituted with one to three substituents selected from the group consisting of: halo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and ORh; heteroaryl, heteroaryl substituted with one to three substituents selected from the group consisting of: halo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and, ORh; C 5 -C 7 cycloalkyl, C 5 -C 7 cycloalkyl substituted with one to three substituents selected from the group consisting of: halo, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; heterocycloalkyl, and heterocycloalkyl substituted with one to three substituents selected from the group consisting of: halo, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;

each Rf and Rg is independently taken together with the nitrogen atom to which they are attached forming a ring having from 4 to 7 member atoms wherein said ring optionally contains one additional heteroatom as a member atom, said ring being saturated or unsaturated but not aromatic, and said ring being optionally substituted with one or two C 1 -C 3 alkyl substituents;

each Rh is independently selected from the group consisting of: H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and

each Ri is independently selected from the group consisting of: C 3 -C 7 cycloalkyl, OH, and C 1 -C 3 alkyl optionally substituted with one OH; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein Y is a bond; or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 wherein m is 0; or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 wherein R3 and R4 are both H; or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 wherein R2 is the group of formula (III):

optionally substituted with one to three substituents each independently selected from the group consisting of OH, C 1 -C 6 alkyl, and phenyl; and wherein p is 0, 1, or 2 and q is 1, 2, or 3; or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 wherein R2 is

optionally substituted with one to three substituents each independently selected from the group consisting of OH, C 1 -C 3 alkyl, and phenyl; or R2 is the bicyclo group

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 wherein R2 is

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 wherein Z is optionally substituted phenyl; or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 wherein Z is phenyl optionally substituted with one to three substituents each independently selected from the group consisting of halo, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted heteroaryl, —N(Rb)SO 2 Re, —NRbC(O)Ra, —C(O)NRaRb, —C(O)H, —NRaRb, and —ORc; wherein said C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of: —CN, —NRaRb, and —ORc;

each Ra, Rb, and Rc is independently selected from the group consisting of H and C 1 -C 6 alkyl; and

each Re is C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 wherein Z is optionally substituted heteroaryl; or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 10 wherein Z is an optionally substituted heteroaryl selected from the group consisting of thienyl, furanyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, indazolyl, 2,3-dihydrobenzofuranyl, and benzothienyl; or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 10 wherein Z is optionally substituted with one to three substituents each independently selected from the group consisting of halo, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, —NRaRb, —SO 2 NRaRb, —SO 2 NRfRg, —ORc, and heteroaryl optionally substituted with one to three C 1 -C 6 alkyl groups; where said C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are optionally substituted with one to three substituents each independently selected from the group consisting of —CN, —NRaRb, —SO 2 Ri, —SO 2 NRaRb, C 3 -C 6 cycloalkyl, —ORc, —SRb, and heterocycloalkyl optionally substituted with one or two C 1 -C 6 alkyl groups;

each Ra is independently selected from the group consisting of C 1 -C 6 alkyl and C 1 -C 6 alkyl substituted with one to three —ORc groups;

each Rb and Rc is independently selected from the group consisting of H and C 1 -C 6 alkyl;

each Rf and Rg is independently taken together with the nitrogen atom to which they are attached forming a ring having from 4 to 7 member atoms wherein said ring optionally contains one additional heteroatom as a member atom, said ring being saturated or unsaturated but not aromatic, and said ring being optionally substituted with one or two C 1 -C 3 alkyl substituents; and

each Ri is independently selected from the group consisting of C 3 -C 7 cycloalkyl and C 1 -C 3 alkyl optionally substituted with one OH; or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

14. A method of treating a disorder mediated by inappropriate IKK2 activity wherein the disorder is rheumatoid arthritis, asthma, rhinitis, or chronic obstructive pulmonary disease comprising administering an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

15. A compound which is 5-{5-[(Dimethylamino)methyl]-3-thienyl}-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide; or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a compound according to claim 15 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

17. A compound which is 3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1H-indole-7-carboxamide; or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to claim 17 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

19. A compound according to claim 10 wherein Z is a thienyl group.

20. A pharmaceutical composition comprising a compound according to claim 19 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

21. A compound selected from:

5-{5-[(Dimethylamino)methyl]-3-thienyl}-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide;

3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-{[methyl(1-methylethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide;

3-(1,1-Dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-{[ethyl(methyl) amino]methyl}-3-thienyl)-1 H-indole-7-carboxamide;

5-{5-[(diethylamino)methyl]-3-thienyl}-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide;

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to claim 21 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

23. A compound selected from:

3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1H-indole-7-carboxamide;

3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-[5-(1-pyrrolidinylmethyl)-2-thienyl]-1H-indole-7-carboxamide;

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a compound according to claim 23 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.