Therapeutic compounds and compositions
Inventors
Chenard, Bertrand L. • Xu, Yuelian • Stassen, Frans L. • Hayward, Neil J. • TENG, ZHIYAO
Assignees
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Publication Number
US-11691962-B2
Publication Date
2023-07-04
Expiration Date
Abstract
The present invention provides compounds that inhibit Factor XIa or kallikrein and pharmaceutically acceptable salts thereof and compositions thereof. The present invention also provides methods of using these compounds and compositions.
Core Innovation
The invention is directed to compounds of formula (II), or pharmaceutically acceptable salts thereof, defined by substituent variables R1 through R10 together with integer parameters m and n. The compound family includes allowed groups such as hydrogen, C1-6 alkyl, C1-6 haloalkyl, halo, cyano, and —OR6, as well as optional ring formation when R4 and R5 are taken together with the carbon atom to which they are attached.
A specific structural condition is included for a pyridyl unit when Rx is —O. In that case, the nitrogen atom of the pyridyl ring is positively charged and Rx is negatively charged, thereby forming a pyridyl N-oxide. The formula (II) definition further specifies choices for R2 as an optionally substituted 5-membered heteroaryl or optionally substituted 5-membered heterocyclyl, while R3 and R6 define allowable substituent types in terms of hydrogen, C1-6 alkyl, and C1-6 haloalkyl.
The disclosed family is supported by chemical structure depictions for a series of specific formula-(II) compounds, showing variations in substituents across multiple numbered compounds. The structures include a central bicyclic/fused-ring and amide or urea-like carbonyl motif context, with variations in fluorine, hydrogen, methyl, and heteroaryl differences among the numbered compounds, including aminopyridyl-containing members and fluorinated aryl substituents.
Claims Coverage
The independent claim is directed to a compound of formula (II), or a pharmaceutically acceptable salt, with detailed structural substituent definitions for R1 through R10 and ring or charge conditions, including a pyridyl N-oxide condition when Rx is —O. The main inventive features are the formula-defined chemical scaffold, the enumerated substituent allowances, the optional ring formation for R4 and R5, and the explicit constraints on m and n.
Compound of formula (II) and pharmaceutically acceptable salt
A compound of formula (II) or a pharmaceutically acceptable salt thereof, defined by the variable substituent framework for R1 through R10 and the parameters m and n.
Substituent definitions for R1 through R6
R1 is hydrogen or —NR8R9; Ra is C1-6 alkyl, C1-6 haloalkyl, halo, cyano, or —OR6; Rb is hydrogen or C1-6 alkyl; R2 is optionally substituted 5-membered heteroaryl or optionally substituted 5-membered heterocyclyl; R3 is hydrogen, C1-6 alkyl, or C1-6 haloalkyl; R4 is C1-6 alkyl, C1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one, two, or three occurrences of halo, C1-6 alkyl, C1-6 haloalkyl, cyano, or —OR6; and R5 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, cycloalkyl, or aryl, optionally substituted with one, two, or three occurrences of halo, C1-6 alkyl, C1-6 haloalkyl, cyano, or —OR6.
Ring formation condition for R4 and R5
R4 and R5, taken together with the carbon atom to which they are attached, form a ring.
Carbonyl substituents for R8 and R9 and definition of R10
Each R8 and R9 is independently hydrogen, C1-6 alkyl, —C(O)R10, or —C(O)OR10; and R10 is C1-6 alkyl or C1-6 haloalkyl.
Pyridyl N-oxide charge condition when Rx is O
Rx is —O or absent, wherein when Rx is —O, the nitrogen atom of the pyridyl ring is positively charged and Rx is negatively charged, thereby forming a pyridyl N-oxide.
Parameter constraints on m and n
m is 0, 1, 2, or 3; and n is 0 or 1, wherein if n is 0, then R5 is hydrogen and R4 is absent.
Overall, claim coverage centers on a formula-(II) chemical entity, or pharmaceutically acceptable salt, defined by specific enumerated substituent allowances for R1 through R10, an optional ring-formation constraint for R4 and R5, an explicit pyridyl N-oxide charge condition when Rx is —O, and explicit constraints on m and n.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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