Substituted pyrido[3′,4′:4,5]pyrrolo[3,2-b][1,6]naphthyridines as CK2 inhibitors
Novel pyrido[3′,4′:4,5]pyrrolo[3,2-b][1,6]naphthyridine compounds of the formula as shown below, a method of synthesizing said compounds, a pharmaceutical composition comprising said compounds and a suitable carrier, and a method of using the compounds. The pyrido[3′,4′:4,5]pyrrolo[3,2-b][1,6]naphthyridine compounds, identified as CK2 inhibitors, are useful as anticancer and/or antitumor agents, and as agents for treating other kinase-associated conditions including inflammation, pain, and certain immunological disorders, and other types of diseases such as diabetes, viral infection, neurodegenerative diseases.
1. A compound having the formula I:
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R is (CH 2 ) 2-3 NR 3 R 4 , (CH 2 ) 1-2 Ar, C(O)—(CH 2 ) 2-3 NR 3 R 4 , C(O)Ar, NH(CH 2 ) 2-3 NR 3 R 4 , NH(CH 2 ) 0-2 Ar, NHC(O)—(CH 2 ) 2-3 NR 3 R 4 , NHC(O)Ar, NHS(O) 2 Ar, S(o0 2 —(CH 2 ) 2-3 NR 3 R 4 , S(O) 2 Ar, or Ar;
Ar is aryl or 5- or 6-membered heteroaryl, wherein the aryl or 5- or 6-membered heteroaryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cyanoalkyl, C(O)R 1 , C(O)NR 1 R 2 , C(O)OR 1 , NR 1 R 2 , NHC(O)R 1 , NHC(O)NHR 1 , NHC(O)OR 1 , NHS(O) 2 R 1 , NHS(O) 2 NHR 1 , OR 1 , S(O) 2 NR 1 R 2 , C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, and C 3 -C 6 cyanocycloalkyl;
each R 1 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, or C 3 -C 6 cyanocycloalkyl;
each R 2 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, or C 3 -C 6 cyanocycloalkyl;
each R 3 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, or C 3 -C 6 cyanocycloalkyl; and
each R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cyanoalkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, or C 3 -C 6 cyanocycloalkyl; or
any R 3 and R 4 , taken together with the nitrogen atom to which they are attached, independently forms a nitrogen-containing heterocyclyl, wherein each nitrogen-containing heterocyclyl is optionally and independently substituted with one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, OH, and OC 1 -C 6 alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is NH(CH 2 ) 3 NR 3 R 4 , NH(CH 2 ) 0-3 Ar, or Ar, wherein the Ar of NH(CH 2 ) 0-2 Ar is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cyanoalkyl, C(O)R 1 , C(O)NR 1 R 2 , C(O)OR 1 , NR 1 R 2 , NHC(O)R 1 , NHC(O)NHR 1 , NHC(O)OR 1 , NHS(O) 2 R 1 , NHS(O) 2 NHR 1 , OR 1 , S(O) 2 NR 1 R 2 , C 3 -C 6 cycloalkyl, C 3 -C 6 halocycloalkyl, and C 3 -C 6 cyanocycloalkyl.
3. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is NH(phenyl), wherein the phenyl of NH(phenyl) is substituted with one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C(O)NR 1 R 2 , OH, and OC 1 -C 6 alkyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is NH(phenyl), wherein the phenyl of NH(phenyl) is substituted with one, two, or three substituents independently selected from the group consisting of Cl, C 1 -C 3 alkyl, CF 3 , C(O)N(CH 3 ) 2 , OH, and OCH 3 .
5. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R is NH(CH 2 ) 3 NR 3 R 4 ;
R 3 is C 1 -C 6 alkyl; and
R 4 is C 1 -C 6 alkyl; or
R 3 and R 4 , taken together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclyl, wherein each nitrogen-containing heterocyclyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 trihaloalkyl, OH, and OC 1 -C 6 alkyl.
6. The compound of claim 5 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R 3 is CH 3 ; and
R 4 is CH 3 ; or
R 3 and R 4 , taken together with the nitrogen atom to which they are attached, form 4-methylpiperazin-1-yl.
7. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is NHCH 2 (phenyl), wherein the phenyl of NHCH 2 (phenyl) is substituted with one Cl substituent.
8. The compound of claim 2 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R is NH-(2-methylpyridin-4-yl).
9. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutically acceptable composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.
11. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.