Heterocycle-containing lonp1 inhibitor compounds, uses and methods

A pharmaceutical composition comprising a compound according to Formula 1,

• or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or combinations thereof, and one or more pharmaceutically acceptable carrier, wherein:
• R1 is selected from the group consisting of:
• deuterium, C1-C4 alkyl, C1-C4 alkoxyl, C1-C4 oxoalkyl, C1-C5 alkyl-alkoxyl, wherein each alkyl, oxoalkyl or alkoxyl is optionally substituted with C3-C6 cycloalkyl, phenyl, phenoxy, or a 5- or 6-membered heteroaryl, wherein said phenyl, phenoxy, or heteroaryl are each optionally substituted with one or more substituent selected from deuterium, halogen, hydroxyl, CN, CO2H, CO2R8, CONR8R9, NR8R9, SR8, SO2NR8R9, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenyl, or a 5- or 6-membered heteroaryl;
• W is C1-C4 alkyl, optionally substituted with one or more of deuterium, halogen, hydroxyl, CN, methyl or ethyl;
• R2 is a 5 to 14 membered heterocyclic mono-, bi- or tricyclic ring optionally having one or more heteroatoms selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one or more substituent selected from deuterium, halogen, hydroxyl, CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxy;
• L is C(O), C(O)O, C(O)NR4, S(O)2, or a bond;
• R3 is C1-C4 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of deuterium, halogen, cyano, hydroxyl, C1-C4 alkoxyl, 5 or 6 membered aryl (e.g. phenyl) or 5 or 6 membered heteroaryl;
• or
• R3 is saturated or unsaturated cycloalkyl or saturated or unsaturated heterocycloalkyl having one or more heteroatoms selected from N, O and S, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, oxo, C1-C4 alkoxyl, or C1-C4 alkyl that is optionally substituted with one to three substituents selected from deuterium, halogen, cyano, hydroxyl, or C1-C4 alkoxyl;
• or
• R3 is aryl or heteroaryl having one or more heteroatoms selected from N, O and S, wherein aryl or heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, OR, CO2H, CO2R8, CONR8R9, NR8R9, SR8, SO2NR8R9, C1-C4 alkoxyl, or C1-C4 alkyl that is optionally substituted with one to three substituents selected from deuterium, halogen, cyano, hydroxyl, or C1-C4 alkoxyl;
• R4 is hydrogen, deuterium, or C1-C4 alkyl optionally substituted with one or more of halogen, hydroxyl and phenyl, wherein phenyl is optionally substituted with one or more substituent selected from halogen, hydroxyl and C1-C2 alkyl;
• R5 is selected from hydrogen, deuterium or C1-C2 alkyl;
• R6 is selected from hydrogen, deuterium or C1-C2 alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, methoxyl and phenyl;
• R7 is hydrogen, or R7 and R1, together with the boron atom to which —OR7 is attached form a 5-membered heteroalkyl ring;
• and
• R8 and R9 are each independently selected from hydrogen, deuterium, C1-C4 alkyl;
• C1-C4 haloalkyl, C1-C5 alkyl-alkoxyl, C3-C7 cycloalkyl, or R8 and R9 together with the N to which they are attached form 3 to 7 membered heterocyclic ring optionally having one or more additional heteroatoms selected from N, O and S, wherein the C3-C7 cycloalkyl or 3 to 7 membered heterocyclic ring is optionally substituted with one or more substituent selected from deuterium, halogen, hydroxyl, oxo, CN, C1-C4 alkyl, C1-C4 haloalkyl or C1-C4 alkoxyl.