Therapeutic compounds and compositions
Inventors
Chrusciel, Robert A. • Gadwood, Robert C. • Hayward, Neil J. • Melnick, Michael J. • Navia, Manuel A. • Poel, Toni J. • Stassen, Frans L. • Stewart, Catherine A.
Assignees
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Publication Number
US-9499532-B2
Publication Date
2016-11-22
Expiration Date
Abstract
The present invention provides compounds and compositions that inhibit Factor XIa or kallikrein and methods of using these compounds and composition.
Core Innovation
The invention relates to compounds of formula (II) and pharmaceutically acceptable salts thereof. The compounds are defined by substituent variables R1, R2, R3, R4, R5, R6, R7, A, X, and Y, with broad option sets for functional groups and ring systems. The structural definition includes substitution-count constraints such as 0-3 occurrences of —NH2 or R6 on defined ring substituents, and conditional rules for R6, including cases where two R6 groups form a 5-7-membered ring.
A key structural element is the connector/group X, which is defined as one of several carbonyl/heteroatom-containing groups, including —C(O)O—, —OC(O)—, —C(O)S(O)2—, —S(O)2C(O)—, —C(O)N(R5)—, or —N(R5)C(O)—. The backbone linking unit A is defined as a bond, C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene. Y is defined as cycloalkyl, heteroaryl, or heterocyclyl substituted with 0-3 occurrences of —NH2 or R6, with alternative conditions where Y can be substituted C1-6 alkyl or phenyl having 1-2 occurrences of R6.
The disclosure includes compound embodiments and exemplified structures within the formula (II) scaffold, including variants with heteroaryl and phenyl substituents, halogen substitution, carboxylic acid or ester-like functionality, amide-related carbonyl motifs, and sulfonyl/sulfone-like motifs. The accompanying content also describes chemical structure depictions and related compound families, while maintaining the same formula-based structural framework.
Claims Coverage
The consolidated claim coverage includes two independent claim types: a compound of formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising such a compound with pharmaceutically acceptable excipients. The independent compound claim is defined by multiple inventive structural features, including a formula-based scaffold with variable substituents, a defined linkage A, a restricted functional group set X, a ring or aryl selection Y, conditional substitution rules for R6, and integer constraints q and n; subclass selection through formula (IIa) and integer m is also described in the inputs.
Formula (II) compound with defined substituent scope
A compound of formula (II) or a pharmaceutically acceptable salt thereof, with R1 to R7, A, X, and Y defined by broad but constrained structural options, including bond or C1-6/C2-6 linkers for A, carbonyl- or carboxylic-derived groups for X, and cycloalkyl, heteroaryl, heterocyclyl, C1-6 alkyl, or phenyl options for Y.
Conditional R6 substitution and ring formation
Conditional rules define R6 when it substitutes R4, R5, R7, or Y, including halo, hydroxy, cyano, nitro, C1-6 alkyl, C1-6 alkoxy, aryl, heteroaryl, aralkyl, cycloalkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, haloalkoxy, and the option for two R6 groups to form a 5-7-membered ring.
Formula (IIa) subclass selection with integer m
The compound of formula (II) is selected from formula (IIa), with formula (IIa) defined by substituents R1, R2, R3, R4, R7, and Y and integer m selected from 1 to 6.
Pharmaceutical composition comprising formula (II) compound
A pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients.
The claims are directed to a broad formula (II) compound class defined by variable substituents and linkage options, plus a pharmaceutical composition containing that compound class. The coverage is driven by the defined X and A linkers, ring and heteroaryl selection for Y, and the substitution-count and conditional R6 rules.
Stated Advantages
Reducing thrombosis and/or angioedema while minimizing bleeding risk.
Documented Applications
Reducing stroke risk and embolism risk through Factor XIa inhibition, including prophylaxis and reduction of recurrence risk in ischemic events, transient ischemic event, non-central nervous system systemic embolism, deep vein thrombosis, and pulmonary embolism contexts.
Therapeutic targeting of Factor XIa and kallikrein for disorders associated with blood coagulation, including thromboembolic disorders and hereditary angioedema.
Treatment or risk reduction for thromboembolic conditions identified in the document: deep vein thrombosis, stroke, myocardial infarction, unstable angina, atrial fibrillation, and pulmonary embolism.
Therapeutic use for angioedema, including hereditary angioedema.
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