Claims for Patent: RE50050

Summary for Patent: RE50050

Title:	Pyrimidinedione compounds
Abstract:	Provided are novel pyrimidine dione compounds and pharmaceutically acceptable salts thereof, that are useful for the treatment of hypertrophic cardiomyopathy (HCM) and conditions associated with left ventricular hypertrophy or diastolic dysfunction. The synthesis and characterization of the compounds and pharmaceutically acceptable salts thereof, are described, as well as methods for treating HCM and other forms of heart disease.
Inventor(s):	Johan Oslob, Robert Anderson, Danielle Aubele, Marc Evanchik, Jonathan Charles Fox, Brian Kane, Puping Lu, Robert McDowell, Hector Rodriguez, Yonghong Song, Arvinder Sran
Assignee:	Myokardia Inc
Application Number:	US17/699,114
Patent Claims:	1. A compound having the formula: or a pharmaceutically acceptable salt thereof, wherein R1 is a member selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C4 alkyl, 4- to 7-membered heterocycloalkyl, phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl-C1-C4 alkyl, wherein each R1 is optionally substituted with from 1-3 Ra; R2 is a member selected from the group consisting of phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl-C1-C4 alkyl, wherein each R2 is optionally substituted with from 1-5 Rb; R3 is a member selected from the group consisting of C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl wherein each R3 is optionally substituted with from 1-3 Rc; R4 is H; X is a member selected from the group consisting of H and F; each Ra is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenyl, phenyl-C1-C4 alkyl, phenyl-C1-C4 alkoxy, phenoxy, —CORa1, —CO2Ra1, —SO2Ra1, —SO2NRa1Ra2, and —CONRa1Ra2, wherein each Ra1 and Ra2 is independently selected from the group consisting of H, C1-C4 alkyl and phenyl, or optionally Ra1 and Ra2 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; each Rb is independently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenoxy, phenyl-C1-C4 alkoxy, methylenedioxy, difluoromethylenedioxy, —CORb1, —CO2Rb1, —SO2Rb1, —SO2NRb1Rb2, CONRb1Rb2, NRb1Rb2, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted with oxo, wherein each Rb1 and Rb2 is independently selected from the group consisting of H and C1-C4 alkyl or optionally Rb1 and Rb2 when attached to a nitrogen atom are combined to form a 4- to 6-membered ring; and each Rc is independently selected from the group consisting of halo, hydroxyl and C1-C2 alkoxy, wherein R1 is selected from the group consisting of C3-C4 alkyl, C3-C5 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein each R1 is optionally substituted with from 1-2 Ra. 2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, R1 is a member selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein each R′ is optionally substituted with from 1-3 Ra; R2 is phenyl, which is optionally substituted with from 1-5 Rb; R3 is a member selected from the group consisting of C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl wherein each R3 is optionally substituted with from 1-2 Rc; R4 is H; X is a member selected from the group consisting of H and F; each Ra is independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 alkoxy, —CORa1, —CO2Ra1, —SO2Ra1, —SO2NRa1Ra2, and —CONRa1Ra2, wherein each Ra1 and Ra2 is independently selected from the group consisting of H and C1-C4 alkyl or optionally Ra1 and Ra2 when attached to a nitrogen atom are combined to form a 4- to 6-membered ring; each Rb is independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 alkoxy, —CORb1, —CO2Rb1, —SO2Rb1, —SO2NRb1Rb2, CONRb1Rb2, NRb1Rb2, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted with oxo, wherein each Rb1 and Rb2 is independently selected from the group consisting of H and C1-C4 alkyl or optionally Rb1 and Rb2 when attached to a nitrogen atom are combined to form a 4- to 6-membered ring; and each Rc is independently selected from the group consisting of halo and C1-C2 alkoxy. 3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is H. 4. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C3-C4 alkyl, C3-C5 cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein each R1 is optionally substituted with from 1-2 Ra. 5. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R1 is optionally substituted with from 1-3 Ra. 6. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C3-C4 alkyl, C3-C5 cycloalkyl, and 4- to 6-membered heterocycloalkyl. 7. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is 4- to 6-membered heterocycloalkyl, optionally substituted with from 1-2 Ra selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, —CORa1, —CO2Ra1, —SO2Ra1, —SO2NRa1Ra2, and —CONRa1Ra2, wherein each Ra1 and Ra2 is independently selected from the group consisting of H and C1-C4 alkyl. 8. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of cyclobutyl, isopropyl, isobutyl, 1-methoxypropan-2-yl, cyclopentyl, cyclohexyl, 4-tetrahydropyranyl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, and 1-methyl-3-pyrazolyl. 9. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is optionally substituted with from 1-2 Rb. 10. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl, 3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, and 3-(1,2,4-triazol-1-yl)phenyl. 11. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxyalkyl, and C3-C4 cycloalkyl. 12. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and 2-methoxymethyl. 13. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl. 14. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is isopropyl; R2 is optionally substituted with 1-2 Rb; and R3 is methyl. 15. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is 4- to 6-membered heterocycloalkyl, optionally substituted with from 1-2 Ra selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, —CORa1, —CO2Ra1, —SO2Ra1, —SO2NRa1Ra2, and —CONRa1Ra2, wherein each Ra1 and Ra2 is independently selected from the group consisting of H and C1-C4 alkyl; R2 is optionally substituted with 1-2 Rb; and R3 is methyl. 16. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R1 is optionally substituted with from 1-3 Ra; R2 is optionally substituted with from 1-2 Rb; and R3 is methyl. 17. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 18. A compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 19. A compound of the formula or a pharmaceutically acceptable salt thereof. 20. A compound having the structure 21. A pharmaceutically acceptable salt of a compound having the structure 22. A pharmaceutical composition comprising: the compound according to claim 20; and a pharmaceutically acceptable excipient. 23. A pharmaceutical composition comprising: the pharmaceutically acceptable salt according to claim 21; and a pharmaceutically acceptable excipient.