Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
Inventors
Siddiqui-Jain, Adam • Seenisamy, Jeyaprakashnarayanan • Warner, Steven L. • Whatcott, Clifford J. • Bearss, David J.
Assignees
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Publication Number
US-11529350-B2
Publication Date
2022-12-20
Expiration Date
Abstract
Provided herein is a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., X1, X2, R2, R3, R4, R5, R6, R7, R8, m, n) are as described herein. Compounds of Formula I, pharmaceutically acceptable salts thereof, pharmaceutical compositions of either of the foregoing, and combinations of any of the foregoing can be used to treat tyrosine kinase non-receptor 1 (TNK1)-mediated diseases, disorders and conditions.
Core Innovation
The invention provides compounds represented by structural formulas, or pharmaceutically acceptable salts thereof, in which X1 is —N— and X2 is —C(R9)—, or X1 is —C(R9)— and X2 is —N—. The structural definition specifies R9 as H, halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR20R21, or —NR20R21, with R20 and R21 each independently —H or (C1-C6)alkyl. The invention also defines additional substituent ranges including R1, R2, R3, R4, R5, R6, R7, and R8, together with m and n.
R1 is halo, —CN, —C(O)NR10R11, —C(O)(C1-C6)alkyl, —OR12, or —NR10R11, with R10 and R11 each independently —H or (C1-C6)alkyl and R12 as —H or (C1-C6)alkyl. R2 is —NR13R14, with R13 and R14 each independently —H or (C1-C6)alkyl, or taken together with the N to which they are attached to form a (C3-C7)heterocyclyl optionally substituted with one or more R30. R30, R40, and R50 are optionally and independently halo, oxo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy.
The invention further includes options in which R5 and R6 taken together with intervening atoms form a (C6)aryl or (C5-C6)heteroaryl optionally substituted with one or more R40, or a (C5-C8)carbocyclyl or (C5-C8)heterocyclyl optionally substituted with one or more R50. The compounds are constrained by m being 0 or 1, with an explicit condition on m when R9 is in a substituted class, and n being 0, 1, or 2. The same structural framework is used to define pharmaceutical compositions, pharmaceutical combinations, and a method for improving intestinal barrier function in a subject in need thereof.
Claims Coverage
The provided content includes independent claims covering a structurally defined compound family, pharmaceutical compositions, pharmaceutical combinations, and a method of improving intestinal barrier function. Across these independent claims, the inventive features are centered on the variable structural formula with X1/X2, R9, R1/R10/R11/R12, R2/R13/R14/R30, R5/R6/R40/R50, and the index constraints m and n.
Defined compound structural formula and pharmaceutically acceptable salt
A compound represented by a structural formula, or a pharmaceutically acceptable salt thereof, wherein X1 is —N— and X2 is —C(R9)—, or X1 is —C(R9)— and X2 is —N—; R9 is selected from H, halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR20R21, or —NR20R21; and R20 and R21 are each independently —H or (C1-C6)alkyl.
Substitution constraints on R1 and R2
R1 is halo, —CN, —C(O)NR10R11, —C(O)(C1-C6)alkyl, —OR12, or —NR10R11; R10 and R11 are each independently —H or (C1-C6)alkyl; R12 is —H or (C1-C6)alkyl; and R2 is —NR13R14, where R13 and R14 are each independently —H or (C1-C6)alkyl, or taken together with the N to form a (C3-C7)heterocyclyl optionally substituted with one or more R30.
Additional ring and aryl substitution options
R5 and R6, taken together with intervening atoms, form a (C6)aryl or (C5-C6)heteroaryl optionally substituted with one or more R40, or a (C5-C8)carbocyclyl or (C5-C8)heterocyclyl optionally substituted with one or more R50; R30, R40, and R50 are optionally and independently halo, oxo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, or (C1-C6)haloalkoxy.
Index constraints on m and n
m is 0 or 1, with an explicit condition on m when R9 is in a substituted class, and n is 0, 1, or 2.
Pharmaceutical composition containing the structural-formula compound
A pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the structural formula or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers.
Pharmaceutical combination including other therapeutic agents
A pharmaceutical combination comprising a therapeutically effective amount of the compound represented by the structural formula or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents.
Method for improving intestinal barrier function
A method of improving intestinal barrier function in a subject in need thereof, comprising administering a therapeutically effective amount of the compound represented by the structural formula or a pharmaceutically acceptable salt thereof.
Compound of specified structural formulas
A compound of any of the following structural formulas, or a pharmaceutically acceptable salt thereof.
The independent claims are directed to a structure-defined compound family with constrained variable substituents and limited index parameters, and extend that family to compositions, combinations, and a method of improving intestinal barrier function in a subject.
Stated Advantages
Improve intestinal barrier function in a subject.
Documented Applications
A method of improving intestinal barrier function in a subject in need thereof.
Pharmaceutical compositions comprising a therapeutically effective amount of the compound with one or more pharmaceutically acceptable carriers.
Pharmaceutical combinations comprising a therapeutically effective amount of the compound together with one or more other therapeutic agents.
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