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US 9,440,953 B2Granted
Substituted amino triazoles useful as acidic mammalian chitinase inhibitors
AssigneeOncoArendi Therapeutics Sp. z o.o.
InventorsAdam Golebiowski, Robert Koralewski, Wojciech J. Czestkowski, Krzysztof Matyszewski, Sylwia Olejniczak, Jacek Olczak, Paul Beckett
Life of this patent
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Abstract
Disclosed are amino triazole compounds substituted by a carboxylate functional group or an bioisosteric polar functional group. Compounds having the carboxylate moiety or carboxylate bioisostere inhibit acidic mammalian chitinase. Also provided are methods of using the compounds to treat asthma reactions caused by allergens.
Claims33
A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
- wherein:
- X is N, and Z is CR10;
- or X is CR11, and Z is N;
- R1 is selected from the group consisting of Y, aryl substituted by Y, and alkyl substituted by Y;
- Y is —CO2H, —C(O)O(C1-C6)alkyl, —C(O)N(H)OH, —C(O)N(H)CN, —C(O)NH2, —C(O)NH((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, —C(O)NH(aryl), —C(O)N(aryl)((C1-C6)alkyl), —C(O)N(aryl)2, —C(O)NH((C1-C6)haloalkyl), —S(O)2NH2, —S(O)2NH((C1-C6)alkyl), —S(O)2NH((C1-C6)haloalkyl), —S(O)2NH(aryl), —S(O)2NHC(O)(C1-C6)alkyl, —S(O)2NHC(O)(C1-C6)haloalkyl, —S(O)2NHC(O)aryl, —N(H)S(O)2(C1-C6)alkyl, —N(H)S(O)2aryl, N(H)S(O)2(C1-C6)haloalkyl, —NHC(O)((C1-C6)alkyl), —NHC(O)((C1-C6)haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C1-C6)alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O)2(C1-C6)alkyl, —C(O)N(H)S(O)2aryl, C(O)N(H)S(O)2((C1-C6)haloalkyl), —P(O)(OH)2,
- R2, R3, R4, R5, R6, and R7 are each independently H, (C1-C6)alkyl, aryl(C1-C6)alkyl, or aryl;
- or R2, taken together with R6 or R7, forms a 5- or 6-membered ring;
- R8 is selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl;
- R9 is selected from the group consisting of OH, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl(C1-C6)alkyl, aryl, (C1-C6)alkoxyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, heteroaryl, and heteroaryl(C1-C6)alkyl;
- R10 and R11 are each independently selected from H and (C1-C6)alkyl;
- m is an integer from 0-5;
- n is an integer from 0-2;
- further wherein any occurrence of (C1-C6)alkyl, aryl(C1-C6)alkyl, aryl, (C3-C6)cycloalkyl, (C1-C6)alkoxyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, heteroaryl, or heteroaryl(C1-C6)alkyl is optionally and independently substituted by one or more substituents selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, —NH2, —NH((C1-C6)alkyl), —N((C1-C6)alkyl)2, —OH, (C3-C6)cycloalkyl, (C1-C6)alkoxyl, (C1-C6)haloalkoxyl, —SH, —S((C1-C6)alkyl), (C1-C6)hydroxyalkyl, and (C1-C6)alkoxy(C1-C6)alkyl, —CN, —CF3, —C(O)NH2, —C(O)NH(R12), —C(O)N(R12)2, —N(H)C(O)(R12), —N(R12)C(O)(R12), —S(O)2NH2, —S(O)2NH(R12), —S(O)2N(R12)2, —N(H)S(O)2(R12), —N(R12)S(O)2(R12), —NHC(O)NH2, —NHC(O)NH(R12), and —NHC(O)N(R12)2;
- and
- each occurrence of R12 is independently selected from the group consisting of (C1-C6)alkyl), aryl, and aryl(C1-C6)alkyl.
12 more elements
A compound represented by formula (II) or a pharmaceutically acceptable salt thereof:
- wherein:
- X is NH or N(C(R1)(R2)(R3)), and Z is CR10;
- or X is CHR11 or C(R11)(C(R1)(R2)(R3)), and Z is N;
- R1, R2, R3, R4, R5, R6, and R7 are each independently H, (C1-C6)alkyl, aryl(C1-C6)alkyl, or aryl;
- or R2, taken together with R6 or R7, forms a 5- or 6-membered ring;
- R8 is selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl;
- R9 is selected from the group consisting of Y, aryl substituted by Y, and (C1-C6)alkyl substituted by Y;
- Y is —CO2H, —C(O)O(C1-C6)alkyl, —C(O)N(H)OH, —C(O)N(H)CN, —C(O)NH2, —C(O)NH((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, —C(O)NH(aryl), —C(O)N(aryl)((C1-C6)alkyl), —C(O)N(aryl)2, —C(O)NH((C1-C6)haloalkyl), —S(O)2NH2, —S(O)2NH((C1-C6)alkyl), —S(O)2NH((C1-C6)haloalkyl), —S(O)2NH(aryl), —S(O)2NHC(O)(C1-C6)alkyl, —S(O)2NHC(O)(C1-C6)haloalkyl, —S(O)2NHC(O)aryl, —N(H)S(O)2(C1-C6)alkyl, —N(H)S(O)2aryl, N(H)S(O)2(C1-C6)haloalkyl, —NHC(O)((C1-C6)alkyl), —NHC(O)((C1-C6)haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C1-C6)alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O)2(C1-C6)alkyl, —C(O)N(H)S(O)2aryl, C(O)N(H)S(O)2((C1-C6)haloalkyl), —P(O)(OH)2,
- R10 and R11 are each independently selected from H and (C1-C6)alkyl;
- m is an integer from 0-5;
- n is 1 or 2;
- further wherein any occurrence of (C1-C6)alkyl, aryl(C1-C6)alkyl, aryl, (C3-C6)cycloalkyl, (C1-C6)alkoxyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, heteroaryl, or heteroaryl(C1-C6)alkyl is optionally and independently substituted by one or more substituents selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, —NH2, —NH((C1-C6)alkyl), —N((C1-C6)alkyl)2, —OH, (C3-C6)cycloalkyl, (C1-C6)alkoxyl, (C1-C6)haloalkoxyl, —SH, —S((C1-C6)alkyl), (C1-C6)hydroxyalkyl, and (C1-C6)alkoxy(C1-C6)alkyl, —CN, —CF3, —C(O)NH2, —C(O)NH(R12), —C(O)N(R12)2, —N(H)C(O)(R12), —N(R12)C(O)(R12), —S(O)2NH2, —S(O)2NH(R12), —S(O)2N(R12)2, —N(H)S(O)2(R12), —N(R12)S(O)2(R12), —NHC(O)NH2, —NHC(O)NH(R12), and —NHC(O)N(R12)2;
- and
- each occurrence of R12 is independently selected from the group consisting of (C1-C6)alkyl), aryl, and aryl(C1-C6)alkyl.
11 more elements
A compound represented by formula (III) or a pharmaceutically acceptable salt thereof:
- wherein:
- X is NH or N(C(R1)(R2)(R3)), and Z is CR11);
- or X is CHR11 or C(R11)(C(R1)(R2)(R3)), and Z is N;
- R1, R2, R3, R4, R5, and R7 are each independently H, (C1-C6)alkyl, aryl(C1-C6)alkyl, or aryl;
- or R1 or R2, taken together with or R7, forms a 5- or 6-membered ring;
- R6 is selected from the group consisting of Y, aryl substituted by Y, and (C1-C6)alkyl substituted by Y;
- Y is —CO2H, —C(O)O(C1-C6)alkyl, —C(O)N(H)OH, —C(O)N(H)CN, —C(O)NH2, —C(O)NH((C1-C6)alkyl), —C(O)N((C1-C6)alkyl)2, —C(O)NH(aryl), —C(O)N(aryl)((C1-C6)alkyl), —C(O)N(aryl)2, —C(O)NH((C1-C6)haloalkyl), —S(O)2NH2, —S(O)2NH((C1-C6)alkyl), —S(O)2NH((C1-C6)haloalkyl), —S(O)2NH(aryl), —S(O)2NHC(O)(C1-C6)alkyl, —S(O)2NHC(O)(C1-C6)haloalkyl, —S(O)2NHC(O)aryl, —N(H)S(O)2(C1-C6)alkyl, —N(H)S(O)2aryl, N(H)S(O)2(C1-C6)haloalkyl, —NHC(O)((C1-C6)alkyl), —NHC(O)((C1-C6)haloalkyl), —NHC(O)(aryl), —NHC(O)NH(C1-C6)alkyl, —NHC(O)NHaryl, —C(O)N(H)S(O)2(C1-C6)alkyl, —C(O)N(H)S(O)2aryl, C(O)N(H)S(O)2((C1-C6)haloalkyl), —P(O)(OH)2,
- R8 is selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)haloalkyl, and (C3-C6)cycloalkyl;
- R9 is selected from the group consisting of OH, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl(C1-C6)alkyl, aryl, (C1-C6)alkoxyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, heteroaryl, and heteroaryl(C1-C6)alkyl;
- R10 and R11 are each independently selected from H and (C1-C6)alkyl;
- m is an integer from 0-5;
- n is an integer from 0-2;
- further wherein any occurrence of (C1-C6)alkyl, aryl(C1-C6)alkyl, aryl, (C3-C6)cycloalkyl, (C1-C6)alkoxyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, heteroaryl, or heteroaryl(C1-C6)alkyl is optionally and independently substituted by one or more substituents selected from the group consisting of halo, (C1-C6)alkyl, (C1-C6)haloalkyl, aryl, —NH2, —NH((C1-C6)alkyl), —N((C1-C6)alkyl)2, —OH, (C3-C6)cycloalkyl, (C1-C6)alkoxyl, (C1-C6)haloalkoxyl, —SH, —S((C1-C6)alkyl), (C1-C6)hydroxyalkyl, and (C1-C6)alkoxy(C1-C6)alkyl, —CN, —CF3, —C(O)NH2, —C(O)NH(R12), —C(O)N(R12)2, —N(H)C(O)(R12), —N(R12)C(O)(R12), —S(O)2NH2, —S(O)2NH(R12), —S(O)2N(R12)2, —N(H)S(O)2(R12), —N(R12)S(O)2(R12), —NHC(O)NH2, —NHC(O)NH(R12), and —NHC(O)N(R12)2;
- and
- each occurrence of R12 is independently selected from the group consisting of (C1-C6)alkyl), aryl, and aryl(C1-C6)alkyl.
12 more elements
Dependencies are inferred from the claim text.