Indazole carboxamides and their use
The invention is directed to novel indazole carboxamide derivatives. Specifically, the invention is directed to compounds according to Formula I: wherein R1 and Z are defined below, and to pharmaceutically-acceptable salts thereof. The compounds of the invention are inhibitors of IKK2 and can be useful in the treatment of disorders associated with inappropriate IKK2 (also known as IKKβ) activity, such as rheumatoid arthritis, asthma, and COPD (chronic obstructive pulmonary disease). Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting IKK2 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
1. A compound according to Formula (I):
wherein:
Z is optionally substituted thienyl
wherein the thienyl is optionally substituted with one or more substituent independently selected from the group consisting of: halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted heterocycloalkyl, CN, N(Rb)SO 2 Re, N(Rb)C(O)Ra, C(O)NRaRb, C(O)NRxRy, SO 2 NRaRb, SO 2 NRxRy, ORc, N(Rb)C(O)NRaRb, N(Rb)C(O)NRxRy, N(Rb)C(O)ORd, where said C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are optionally substituted with one or more substituent selected from the group consisting of: NRaRb, C 3 -C 6 cycloalkyl, ORc, phenyl, and heterocycloalkyl optionally substituted with one or two C 1 -C 6 alkyl groups;
R1 is —WX;
W is a bond; and
X is optionally substituted piperidinyl
optionally substituted with one or more substituent independently selected from the group consisting of: halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, ORc, C(O)Rg, C(O)ORf, N(Rb)SO 2 Re, N(Rb)C(O)Ra, C(O)NRaRb, SO 2 NRaRb, SO 2 Re, and heterocycloalkyl, where said C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are optionally substituted with one phenyl group;
each Ra is independently selected from the group consisting of: H, optionally substituted C 1 -C 3 alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted C 3 -C 7 cycloalkyl, and optionally substituted heterocycloalkyl, where said C 1 -C 3 alkyl is optionally substituted with one or more substituent selected from the group consisting of: halo, ORc, C 1 -C 6 haloalkyl, phenyl, and heteroaryl; and where said phenyl, heteroaryl, C 3 -C 7 cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituent selected from the group consisting of: halo, ORc, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
each Rb is independently selected from the group consisting of: H and optionally substituted C 1 -C 3 alkyl, where said C 1 -C 3 alkyl is optionally substituted with one or more ORc groups;
each Rc is independently selected from the group consisting of: H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 3 -C 7 cycloalkyl, optionally substituted heterocycloalkyl, and optionally substituted aryl, optionally substituted heteroaryl, where said C 1 -C 6 alkyl and C 1 -C 6 haloalkyl are optionally substituted with one or more substituent selected from the group consisting of: C 3 -C 6 cycloalkyl, phenyl, heterocycloalkyl, and heteroaryl; and where said aryl and heteroaryl are optionally substituted with one or more substituent selected from the group consisting of: halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl and OH; and where said C 3 -C 7 cycloalkyl and heterocycloalkyl are optionally substituted with one or more C 1 -C 3 alkyl groups;
each Rd is independently optionally substituted C 1 -C 3 alkyl, where said C 1 -C 3 alkyl is optionally substituted with one or more substituent selected from the group consisting of: C 3 -C 6 cycloalkyl; phenyl optionally substituted with one or more substituent selected from the group consisting of: halo, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; and heteroaryl optionally substituted with one or more substituent 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: optionally substituted C 1 -C 6 alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted C 5 -C 7 cycloalkyl, and optionally substituted heterocycloalkyl, where said C 1 -C 6 alkyl is optionally substituted with one substituent selected from the group consisting of: ORc, trifluoromethyl, phenyl, heteroaryl, heterocycloalkyl optionally substituted with ORc or heterocycloalkyl, and NRaRb; where said phenyl and heteroaryl are optionally substituted with one or more substituent selected from the group consisting of: halo, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, N(Rb)C(O)Ra, and ORh; and where said C 5 -C 7 cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituent selected from the group consisting of: halo, C 1 -C 6 alkyl optionally substituted with ORc, and C 3 -C 6 cycloalkyl;
each Rf is independently selected from the group consisting of: H and optionally substituted C 1 -C 4 alkyl, where said C 1 -C 4 alkyl is optionally substituted with one or more substituent selected from the group consisting of: C 3 -C 6 cycloalkyl; phenyl optionally substituted with one or more substituent selected from the group consisting of: halo, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; and heteroaryl optionally substituted with one or more substituent selected from the group consisting of: halo, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
each Rg is independently selected from the group consisting of: optionally substituted C 1 -C 3 alkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted C 3 -C 7 cycloalkyl, and optionally substituted heterocycloalkyl, where said C 1 -C 3 alkyl is optionally substituted with one or more substituent selected from the group consisting of: halo and C 1-6 haloalkyl; and where said phenyl, heteroaryl, C 3 -C 7 cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituent selected from the group consisting of: halo, C 1-6 alkyl, and C 1 -C 6 haloalkyl;
each Rh is independently selected from the group consisting of: H, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
Rx and Ry taken together with the nitrogen atom to which they are attached form a ring having from 5 to 7 member atoms wherein said ring optionally contains one additional heteroatom as a member atom, said ring is saturated or unsaturated but not aromatic, and said ring is optionally substituted with one or two C 1 -C 3 alkyl substituent;
or a pharmaceutically-acceptable salt thereof.
2. A compound according to claim 1 wherein X is optionally substituted piperidinyl.
3. A compound according to claim 2 wherein X is piperidinyl substituted with C(O)Rg, C(O)ORf, or SO 2 Re.
4. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically-acceptable excipient.
5. A compound selected from:
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-thienyl)-1H-indazole-7-carboxamide;
3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-thienyl)-1H-indazole-7-carboxamide;
3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide;
3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide;
3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide;
3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide;
3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-5-(2-thienyl)-1H-indazole-7-carboxamide; and
3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide; or a pharmaceutically acceptable salt thereof.