Cardiac sarcomere inhibitors
Inventors
Morgan, Bradley P. • VANDERWAL, Mark • Chuang, Chihyuan
Assignees
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Publication Number
US-12187712-B2
Publication Date
2025-01-07
Expiration Date
Abstract
Provided are compounds of Formula (I):or a pharmaceutically acceptable salt thereof, wherein R1, R2, Y1, Y2, L1, and G1 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention provides compounds of Formula (I), and pharmaceutically acceptable salts thereof, in which the structural variables R1, G1, R2, L1, Y1, and Y2 are defined by specified structural rules. The definitions include alternative arrangements for L1, Y1, and Y2 in which L1 is absent with Y1 as Rx and Y2 as Rz, or L1 is present with L2 absent, —O—, —NH—, or —OCH2—*, where * indicates attachment to Y2. The scaffold is further constrained by allowed values for R1, G1, and R2, including R1 as H or halo, G1 as —N— or —C(Rb)— with Rb as H or halo, and R2 as H or —CH3.
Y1 is defined through Rx and related substituent sets, with R1aa selected from H, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, and Rx including R1a, R1b, R1c1, R1c2, R1f, R1g, R1h1, and R1h2 each independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. Related sets R1d1, R1d2, R1d3, R1e1, and R1e2, and Rz-related substituents R2a, R2b1, R2b2, R2c, R2d1, R2g2, R2h, R2i, and R2j, are likewise defined by explicit allowed groups including H, halo, —OH, —CN, —NRcRd, alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NRcRd, with Rc and Rd each independently H or alkyl.
The disclosure includes conditional rules linking Y1 to specific substituent outcomes, including cases where R2 is —CH3, R1 is halo, and G1 is —C(Rb)— with Rb halo, and further restrictions when Y1 and Y2 are selected such that R2b1 falls within a defined group. It also includes an independent claim set of specifically enumerated substituted heteroaryl amines and related functionalized derivatives, including benzyl-linked 1,2,4-oxadiazolyl, isoxazolyl, thiazolyl, and oxazolyl motifs connected to pyrazine, pyridine, pyrimidine, and related heteroaryl cores.
Claims Coverage
The consolidated material includes two independent claim themes: one broad independent claim to compounds of Formula (I) or pharmaceutically acceptable salts, and one independent claim to an explicitly enumerated group of substituted heteroaryl amines and related functionalized derivatives. Across the claims, the coverage centers on defined scaffold variables, alternative linker arrangements, and conditional substituent constraints; there are 5 inventive features in the broad Formula (I) claim theme and 5 in the enumerated compound theme.
Formula (I) compound scaffold with defined substituent variables
A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is H or halo, G1 is —N— or —C(Rb)— with Rb being H or halo, R2 is H or —CH3, and L1, Y1, and Y2 are defined by either L1 absent with Y1=Rx and Y2=Rz, or L1 present with L2 absent, —O—, —NH—, or —OCH2—* indicating attachment to Y2.
Y1 substituent sets and ring/linker variable definitions
Y1 is Rx, where R1aa is H, alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl, and Rx includes R1a, R1b, R1c1, R1c2, R1f, R1g, R1h1, and R1h2 each independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, —C(O)O-alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl.
Rz and related substituent class constraints
Rz is defined through R2a, R2b1, R2b2, R2c, R2d1, R2g2, R2h, R2i, and R2j, each independently selected from H, halo, —OH, —CN, —NRcRd, alkyl, alkenyl, alkynyl, —O-alkyl, haloalkyl, cycloalkyl, and —C(O)NRcRd, with additional selections for R2e, R2f, R2g1, and R2g2 from the same general class set and Rc/Rd independently H or alkyl.
Conditional structural constraints linked to Y1
When Y1 is such that at least one of (a)-(c) applies, (a) R2 is —CH3, (b) R1 is halo, and (c) G1 is —C(Rb)— where Rb is halo; and when Y1 and Y2 are selected such that R2b1 falls within a specified group, the allowed embodiments are further constrained.
Enumerated oxadiazole-linked heteroaryl amine group
A compound selected from an explicitly listed group of substituted heteroaryl amines and related derivatives, including benzyl-linked 1,2,4-oxadiazolyl, isoxazolyl, thiazolyl, and oxazolyl motifs connected to pyrazine, pyridine, pyrimidine, and related heteroaryl amine cores.
Heteroaryl amine core with defined substitution patterns
The selected compounds include heteroaryl amine frameworks such as pyrazin-2-amine, pyrimidin-4-amine, pyrazin-2-carbonitrile, pyrimidine-4-carbonitrile, nicotinonitrile, isonicotinonitrile, and nicotinamide-like derivatives, with listed variants containing chloro, methyl, ethyl, trifluoromethyl, carbonitrile, and related substituents.
Functionalized derivatives within the selected compound set
The enumerated group includes related functionalized derivatives such as carbamate, benzamide, urea, and isonicotinamide-type structures, together with pharmaceutically acceptable salts.
Optional (R)-enantiomer inclusion
The selected compound set expressly includes (R)-enantiomer members for certain benzyl-linked azole-containing heteroaryl amines.
Asterisk-defined attachment of L2 to Y2
Where L1 is present, L2 is absent, —O—, —NH—, or —OCH2—*, with the asterisk indicating attachment to Y2.
Overall, the claim coverage is dominated by structural definitions for Formula (I) compounds with extensive conditional substituent rules, and by a separately enumerated set of substituted heteroaryl amines and related functionalized derivatives. The common scope is defined by the stated scaffold variables, linker definitions, and explicit substituent lists.
Stated Advantages
Improved therapeutic index and safety versus current sarcomere-targeting agents.
Documented Applications
Treating cardiac diseases including hypertrophic cardiomyopathy (HCM), including obstructive and nonobstructive HCM, and HFpEF, including conditions involving cardiac remodeling and diastolic dysfunction such as left ventricular hypertrophy and concentric remodeling.
Inhibiting the cardiac sarcomere by contacting it with a Formula (I) compound.
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