Thienopyrimidine inhibitors of atypical protein kinase C
The present application provides a compound of formula (I) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.
1. A compound, or a pharmaceutically acceptable salt thereof, of formula I:
wherein,
R 1 , R 2 , and R 11 are independently chosen from H and C 1-6 alkyl optionally substituted by 1-13 R 19 ;
R 3 is chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 19 , C 7-11 arylalkyl optionally substituted by 1-9 R 19 , C 6-7 cycloalkylalkyl optionally substituted by 1-6 R 19 , and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R 19 ;
R 4 , R 5 , and R 6 are H;
R 7 is selected from H and C 1-6 alkyl optionally substituted by 1-3 R 19 ;
R 8 is selected from C 2-6 alkynyl optionally substituted by 1-3 R 19 ;
R 12 , R 13 , R 14 , and R 15 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , halogen, —NR 22 R 23 , —NR 24 C(═O)R 20 , —R 24 C(═O)NR 22 R 23 , —OR 20 , and —S(═O) 2 NR 22 R 23 ;
R 19 at each occurrence is independently chosen from C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —C(═O)OR 30 and —OR 30 ; and
R 20 , R 22 , R 23 , R 24 , and R 30 at each occurrence are independently chosen from H and C 1-6 alkyl.
2. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein R 1 and R 2 are H.
3. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein R 11 is H.
4. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein R 1 , R 2 and R 11 are H.
5. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein R 3 is selected from C 1-6 alkyl optionally substituted by 1-13 R 19 and C 7-11 arylalkyl optionally substituted by 1-9 R 19 .
6. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein R 7 is H.
7. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein R 19 is selected from C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, halogen and —OR 30 .
8. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 wherein R 12 , R 13 , R 14 , and R 15 are independently chosen from H and halogen.
9. The compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Structure
Name
(S)-N*1*-[7-(3-Methoxy-prop- 1-ynyl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine
4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-but-3-yn-1-ol
4-[4-((S)-2-Amino-3-phenyl- propylamino)-6-methyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-7-yl]-2-methyl-but- 3-yn-2-ol
4-[4-((S)-2-Amino-3-phenyl- propylamino)-6-tert-butyl-2- pyridin-4-yl-thieno[3,2- d]pyrimidin-7-yl]-2-methyl-but- 3-yn-2-ol
3-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-prop-2-yn-1- ol
1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-ylethynyl]- cyclobutanol
(S)-4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-but-3-yn-2-ol
4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-(3-fluoro- pyridin-4-yl)-thieno[3,2- d]pyrimidin-7-yl]-2-methyl-but- 3-yn-2-ol
4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]-2- methyl-but-3-yn-2-ol
4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- but-3-yn-2-ol
3-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- prop-2-yn-1-ol
S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- pent-1-yn-3-ol
(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]-4- methyl-hept-1-yn-3-ol
(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]-3- methyl-pent-1-yn-3-ol
(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- 3,4-dimethyl-pent-1-yn-3-ol
1-[4-(2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]-3- ethyl-pent-1-yn-3-ol
(S)-1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- hex-1-yn-3-ol
1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7- ylethynyl]-cyclopentanol
4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- but-3-yn-1-ol
1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7- ylethynyl]-cyclopropanol
(S)-4-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- but-3-yn-2-ol
(R)-4-[4-((S)-2-Amino-3- phenyl-propylamino)-2-pyridin- 4-yl-thieno[3,2-d]pyrimidin-7- yl]-but-3-yn-2-ol
5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- pent-4-yn-1-ol
5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- pent-4-yn-2-ol
5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]-2- methyl-pent-4-yn-2-ol
1-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7- ylethynyl]-cyclobutanol
(S)-5-[4-((S)-2-Amino-3-phenyl- propylamino)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-7-yl]- pent-4-yn-2-ol
(S)-N*1*-[7-((R)-3-Fluoro-but- 1-ynyl)-2-pyridin-4-yl- thieno[3,2-d]pyrimidin-4-yl]-3- phenyl-propane-1,2-diamine
(S)-N*1*-[7-(3-Fluoro-prop-1- ynyl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidin-4-yl]-3-phenyl- propane-1,2-diamine
(S)-N*1*-[7-(4-Fluoro-but-1- ynyl)-2-pyridin-4-yl-thieno[3,2- d]pyrimidine.
10. A pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein Formula I is:
wherein,
R 1 , R 2 , and R 11 are independently chosen from H and C 1-6 alkyl optionally substituted by 1-13 R 19 ;
R 3 is chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 19 , C 7-11 arylalkyl optionally substituted by 1-9 R 19 , C 6-7 cycloalkylalkyl optionally substituted by 1-6 R 19 , and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R 19 ;
R 4 , R 5 , and R 6 are H;
R 7 is selected from H and C 1-6 alkyl optionally substituted by 1-3 R 19 ;
R 8 is selected from C 2-6 alkynyl optionally substituted by 1-3 R 19 ;
R 12 , R 13 , R 14 , and R 15 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , halogen, —NR 22 R 23 , —NR 24 C(═O)R 20 , —NR 24 C(═O)NR 22 R 23 , —OR 20 , and —S(═O) 2 NR 22 R 23 ;
R 19 at each occurrence is independently chosen from C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, halogen, —C(═O)OR 30 and —OR 30 ; and
R 20 , R 22 , R 23 , R 24 , and R 30 at each occurrence are independently chosen from H and C 1-6 alkyl.