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US 11,529,350 B2Granted
Tyrosine kinase non-receptor 1 (TNK1) inhibitors and uses thereof
AssigneeSumitomo Pharma Oncology, Inc.
InventorsAdam Siddiqui-Jain, Jeyaprakashnarayanan Seenisamy, Steven L. Warner, Clifford J. Whatcott, David J. Bearss
Life of this patent
Estimating the term…
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.
Claims51
A compound represented by the following 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 —H, halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR20R21 or —NR20R21;
- R20 and R21 are each independently —H or (C1-C6)alkyl;
- 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;
- R2 is —NR13R14;
- R13 and R14 are each independently —H or (C1-C6)alkyl, or taken together with the N to which they are attached, form a (C3-C7)heterocyclyl optionally substituted with one or more R30;
- R30, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R3 is —H, halo, cyano or (C1-C6)alkyl;
- R4 is —H, (C1-C6)alkyl, hydroxy(C1-C6)alkyl or —C(O)(C1-C6)alkyl;
- R5 is —H;
- and
- R6 is —H, halo, (C1-C6)alkoxy, (C1-C6)haloalkoxy or (C3-C7)cycloalkoxy;
- or
- R5 and R6, taken together with their intervening atoms, form a (C6)aryl or (C5-C6)heteroaryl optionally substituted with one or more R40, or (C5-C8)carbocyclyl or (C5-C8)heterocyclyl optionally substituted with one or more R50;
- R40, for each occurrence, is optionally and independently halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R50, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R7 is halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR17R18 or —NR17R18;
- R17 and R18 are each independently —H or (C1-C6)alkyl;
- R8, for each occurrence, is independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- m is 0 or 1, provided that if R9 is halo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy, m is 0;
- and
- n is 0, 1 or 2.
22 more elements
A compound of any of the following structural formulas:
- or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition, comprising a therapeutically effective amount of a compound represented by the following 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 —H, halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR20R21 or —NR20R21;
- R20 and R21 are each independently —H or (C1-C6)alkyl;
- 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;
- R2 is —NR13R14;
- R13 and R14 are each independently —H or (C1-C6)alkyl, or taken together with the N to which they are attached, form a (C3-C7)heterocyclyl optionally substituted with one or more R30;
- R30, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R3 is —H, halo, cyano or (C1-C6)alkyl;
- R4 is —H, (C1-C6)alkyl, hydroxy(C1-C6)alkyl or —C(O)(C1-C6)alkyl;
- R5 is —H;
- and
- R6 is —H, halo, (C1-C6)alkoxy, (C1-C6)haloalkoxy or (C3-C7)cycloalkoxy;
- or
- R5 and R6, taken together with their intervening atoms, form a (C6)aryl or (C5-C6)heteroaryl optionally substituted with one or more R40, or (C5-C8)carbocyclyl or (C5-C8)heterocyclyl optionally substituted with one or more R50;
- R40, for each occurrence, is optionally and independently halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R50, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R7 is halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR17R18 or —NR17R18;
- R17 and R18 are each independently —H or (C1-C6)alkyl;
- R8, for each occurrence, is independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- m is 0 or 1, provided that if R9 is halo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy, m is 0;
- and
- n is 0, 1 or 2, and
- one or more pharmaceutically acceptable carriers.
23 more elements
A pharmaceutical combination, comprising a therapeutically effective amount of a compound represented by the following 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 —H, halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR20R21 or —NR20R21;
- R20 and R21 are each independently —H or (C1-C6)alkyl;
- R1 is halo, —CN, —C(O)NR10R11, —C(O)(C1-C6)alkyl, —OR12 or —NR10R11;
- R10 and RH are each independently —H or (C1-C6)alkyl;
- R12 is —H or (C1-C6)alkyl;
- R2 is —NR13R14;
- R13 and R14 are each independently —H or (C1-C6)alkyl, or taken together with the N to which they are attached, form a (C3-C7)heterocyclyl optionally substituted with one or more R30;
- R30, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R3 is —H, halo, cyano or (C1-C6)alkyl;
- R4 is —H, (C1-C6)alkyl, hydroxy(C1-C6)alkyl or —C(O)(C1-C6)alkyl;
- R5 is —H;
- and
- R6 is —H, halo, (C1-C6)alkoxy, (C1-C6)haloalkoxy or (C3-C7)cycloalkoxy;
- or
- R5 and R6, taken together with their intervening atoms, form a (C6)aryl or (C5-C6)heteroaryl optionally substituted with one or more R40, or (C5-C8)carbocyclyl or (C5-C8)heterocyclyl optionally substituted with one or more R50;
- R40, for each occurrence, is optionally and independently halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R50, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R7 is halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR17R18 or —NR17R18;
- R17 and R18 are each independently —H or (C1-C6)alkyl;
- R8, for each occurrence, is independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- m is 0 or 1, provided that if R9 is halo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy, m is 0;
- and
- n is 0, 1 or 2, and
- a therapeutically effective amount of one or more other therapeutic agents.
23 more elements
A method of improving intestinal barrier function in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by the following 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 —H, halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR20R21 or —NR20R21;
- R20 and R21 are each independently —H or (C1-C6)alkyl;
- 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;
- R2 is —NR13R14;
- R13 and R14 are each independently —H or (C1-C6)alkyl, or taken together with the N to which they are attached, form a (C3-C7)heterocyclyl optionally substituted with one or more R30;
- R30, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R3 is —H, halo, cyano or (C1-C6)alkyl;
- R4 is —H, (C1-C6)alkyl, hydroxy(C1-C6)alkyl or —C(O)(C1-C6)alkyl;
- R5 is —H;
- and
- R6 is —H, halo, (C1-C6)alkoxy, (C1-C6)haloalkoxy or (C3-C7)cycloalkoxy;
- or
- R5 and R6, taken together with their intervening atoms, form a (C6)aryl or (C5-C6)heteroaryl optionally substituted with one or more R40, or (C5-C8)carbocyclyl or (C5-C8)heterocyclyl optionally substituted with one or more R50;
- R40, for each occurrence, is optionally and independently halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R50, for each occurrence, is optionally and independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- R7 is halo, hydroxy, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, —C(O)NR17R18 or —NR17R18;
- R17 and R18 are each independently —H or (C1-C6)alkyl;
- R8, for each occurrence, is independently halo, oxo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- m is 0 or 1, provided that if R9 is halo, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy, m is 0;
- and
- n is 0, 1 or 2, and
- a therapeutically effective amount of one or more other therapeutic agents.
23 more elements
Dependencies are inferred from the claim text.