Claims for Patent: 9,585,883

Summary for Patent: 9,585,883

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):	Oslob; Johan (Sunnyvale, CA), Anderson; Robert (Brisbane, CA), Aubele; Danielle (San Mateo, CA), Evanchik; Marc (San Jose, CA), Fox; Jonathan Charles (San Francisco, CA), Kane; Brian (Oakland, CA), Lu; Puping (Foster City, CA), McDowell; Robert (San Francisco, CA), Rodriguez; Hector (Brisbane, CA), Song; Yonghong (Foster City, CA), Sran; Arvinder (Fremont, CA)
Assignee:	MYOKARDIA, INC. (South San Francisco, CA)
Application Number:	14/883,152
Patent Claims:	1. A method of treating hypertrophic cardiomyopathy (HCM), comprising administering to a subject in need thereof an effective amount of a compound having the formula: ##STR00218## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is a member selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkyl-C.sub.1-C.sub.4 alkyl, 4-to 7-membered heterocycloalkyl, phenyl, phenyl-C.sub.1-C.sub.4 alkyl, 5-to 6-membered heteroaryl and 5-to 6-membered heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.1 is optionally substituted with from 1-3 R.sup.a; R.sup.2 is a member selected from the group consisting of phenyl, phenyl-C.sub.1-C.sub.4 alkyl, 5-to 6-membered heteroaryl and 5-to 6-membered heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.2 is optionally substituted with from 1-5 R.sup.b; R.sup.3 is a member selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl, and 4-to 7-membered heterocycloalkyl wherein each R.sup.3 is optionally substituted with from 1-3 R.sup.c; R.sup.4 is H; X is a member selected from the group consisting of H and F; each R.sup.a is independently selected from the group consisting of halo, CN, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, phenyl, phenyl-C.sub.1-C.sub.4 alkyl, phenyl-C.sub.1-C.sub.4 alkoxy, phenoxy, --COR.sup.a1, --CO.sub.2R.sup.a1,--SO.sub.2R.sup.a1, --SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein each R.sup.a1and R.sup.a2 is independently selected from the group consisting of H, C.sub.1-C.sub.4 alkyl and phenyl, or optionally R.sup.a1 and R.sup.a2 when attached to a nitrogen atom are combined to form a 4-to 6-membered ring; each R.sup.b is independently selected from the group consisting of halo, CN, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.l-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, phenoxy, phenyl-C.sub.1-C.sub.4 alkoxy, methylenedioxy, difluoromethylenedioxy, --COR.sup.b1, --CO.sub.2R.sup.b1, --SO.sub.2R.sup.b1,---SO.sub.2NR.sup.b1R.sup.b2, CONR.sup.b1R.sup.b2, NR.sup.b1R.sup.b2, 5-to 6-membered heteroaryl, and 5-to 6-membered heterocyclyl optionally substituted with oxo, wherein each R.sup.b1 and R.sup.b2 is independently selected from the group consisting of H and C.sub.1-C.sub.4 alkyl or optionally R.sup.b1 and R.sup.b2 when attached to a nitrogen atom are combined to form a 4-to 6-membered ring; and each R.sup.c is independently selected from the group consisting of halo, hydroxyl and C.sub.1-C.sub.2 alkoxy. 2. A method in accordance with claim 1, wherein, R.sup.1 is a member selected from the group consisting of C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, 4-to 7-membered heterocycloalkyl, phenyl, and 5-to 6-membered heteroaryl, wherein each R.sup.1 is optionally substituted with from 1-3 R.sup.a; R.sup.2 is phenyl, which is optionally substituted with from 1-5 R.sup.b; R.sup.3 is a member selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl, and 4-to 7-membered heterocycloalkyl wherein each R.sup.3 is optionally substituted with from 1-2 R.sup.c; R.sup.4 is H; X is a member selected from the group consisting of H and F; each R.sup.a is independently selected from the group consisting of halo, CN, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, --COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1, --SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein each R.sup.a1and R.sup.a2 is independently selected from the group consisting of H and C.sub.1-C.sub.4 alkyl or optionally R.sup.a1 and R.sup.a2 when attached to a nitrogen atom are combined to form a 4-to 6-membered ring; each R.sup.b is independently selected from the group consisting of halo, CN, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, --COR.sup.b1, --CO.sub.2R.sup.b1, --SO.sub.2R.sup.b1, --SO.sub.2NR.sup.b1R.sup.b2, CONR.sup.b1R.sup.b2, NR.sup.b1R.sup.b2, 5-to 6-membered heteroaryl, and 5-to 6-membered heterocyclyl optionally substituted with oxo, wherein each R.sup.b1 and R.sup.b2 is independently selected from the group consisting of H and C.sub.1-C.sub.4 alkyl or optionally R.sup.b1 and R.sup.b2 when attached to a nitrogen atom are combined to form a 4-to 6-membered ring; and each R.sup.c is independently selected from the group consisting of halo and C.sub.1-C.sub.2 alkoxy. 3. A method in accordance with claim 1, wherein X is H. 4. A method in accordance with claim 1, wherein R.sup.1 is selected from the group consisting of C.sub.3-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl, and 4-to 6-membered heterocycloalkyl, wherein each le is optionally substituted with from 1-2 R.sup.a. 5. A method in accordance with claim 1, wherein R.sup.1 is selected from the group consisting of phenyl and 5-to 6-membered heteroaryl, wherein each R.sup.1 is optionally substituted with from 1-3 R.sup.a. 6. A method in accordance with claim 1, wherein R.sup.1 is selected from the group consisting of C.sub.3-C.sub.4 alkyl, C.sub.3-C.sub.5 cycloalkyl, and 4-to 6-membered heterocycloalkyl. 7. A method in accordance with claim 1, wherein R.sup.1 is 4-to 6-membered heterocycloalkyl, optionally substituted with from 1-2 R.sup.a selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, --COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1, --SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein each R.sup.a1 and R.sup.2 is independently selected from the group consisting of H and C.sub.1-C.sub.4 alkyl. 8. A method in accordance with claim 1, wherein R.sup.1 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 method in accordance with claim 1, wherein R.sup.2 is optionally substituted with from 1-2 R.sup.b. 10. A method in accordance with claim 1, wherein R.sup.2 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 method in accordance with claim 1, wherein R.sup.3 is selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyalkyl, and C.sub.3-C.sub.4 cycloalkyl. 12. A method in accordance with claim 1, wherein R.sup.3 is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and 2-methoxymethyl. 13. A method in accordance with claim 1, wherein R.sup.3 is methyl. 14. A method in accordance with claim 1, wherein R.sup.1 is isopropyl; R.sup.2 is optionally substituted with 1-2 R.sup.b; and R.sup.3 is methyl. 15. A method in accordance with claim 1, wherein R.sup.1 is 4-to 6-membered heterocycloalkyl, optionally substituted with from 1-2 R.sup.a selected from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, --COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1, --SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein each R.sup.a1 and R.sup.a2 is independently selected from the group consisting of H and C.sub.1-C.sub.4 alkyl; R.sup.2 is optionally substituted with 1-2 R.sup.b; and R.sup.3 is methyl. 16. A method in accordance with claim 1, wherein R.sup.1 is selected from the group consisting of phenyl and 5-to 6-membered heteroaryl, wherein each R.sup.1 is optionally substituted with from 1-3 R.sup.a; R.sup.2 is optionally substituted with from 1-2 R.sup.b; and R.sup.3 is methyl. 17. A method in accordance with claim 1, wherein said compound is selected from the group consisting of: ##STR00219## ##STR00220## or a pharmaceutically acceptable salt thereof. 18. A method in accordance with claim 1, wherein said compound is ##STR00221## or a pharmaceutically acceptable salt thereof.