Pyrimidines for degrading bruton's tyrosine kinase

Abstract

The present invention provides for compounds of formula (I)  (I)wherein R1, R2, R3, R4A, R4b, and R5, are as defined herein, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of CLL.(Fig. 1)

Claims

Claim 1. A compound of formula (I):whereinR1 is selected from the group consisting of hydrogen, C1-C3 alkyl, CN, C1-C3 haloalkyl, halo, CH2OCH3, CH2OH, and CH2CN;R2 and R3 are each independently selected from the group consisting of hydrogen and halo;R4a and R4b are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, and CH2OCH3;R5 is selected from the group consisting of hydrogen, halo, and C1-C3 alkyl;or a pharmaceutically acceptable salt thereof. Claim 2. The compound of claim 1, wherein R4a is H and R4b is methyl, or a pharmaceutically acceptable salt thereof. Claim 3. The compound of any one of claims 1-2, wherein R1 is methyl, or a pharmaceutically acceptable salt thereof.Claim 4. The compound of any one of claims 1-3, wherein R2 is hydrogen, or a pharmaceutically acceptable salt thereof. Claim 5. The compound of any one of claims 1-4, wherein R3 is hydrogen, or a pharmaceutically acceptable salt thereof. Claim 6. The compound of any one of claims 1-5, wherein R5 is hydrogen, or a pharmaceutically acceptable salt thereof. Claim 7. A compound which is , or a pharmaceutically acceptable salt thereof. Claim 8. A compound, which is a pharmaceutically acceptable salt of Claim 9. A compound which isClaim 10. The compound of claim 1, selected from the group consisting of3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-4-yl)-2- methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1-yl)-3- fluorophenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1-yl)-3- fluorophenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1-yl)-3- fluorophenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-ethylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diazinan-1-yl)phenyl]ethyl}- 2,2-dimethylpiperazin-1-yl)pyridin-2-yl]amino}pyrimidin-4-yl)-2-methylphenyl]ethyl}- 1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-3-fluoro-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-4-yl)-3-fluoro-2- methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-{(1R)-1-[4-(6-{[5-(4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}piperazin-1-yl)pyridin-2-yl]amino}pyrimidin-4-yl)-5-fluoro-2- methylphenyl]ethyl}-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-(propan-2-yl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{2-chloro-4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4- yl]phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2R)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-(methoxymethyl)piperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]- 2-methylphenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide;3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- (trifluoromethyl)phenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; and3-tert-butyl-N-[(1R)-1-{4-[6-({5-[(2S)-4-{2-[4-(2,4-dioxo-1,3-diazinan-1- yl)phenyl]ethyl}-2-methylpiperazin-1-yl]pyridin-2-yl}amino)pyrimidin-4-yl]-2- fluorophenyl}ethyl]-1,2,4-oxadiazole-5-carboxamide; or a pharmaceutically acceptable salt thereof. Claim 11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.  

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