US 8,946,197 B2 · Transglutaminase TG2 inhibitors, pharmaceutical compositions, and methods of use thereof

Abstract

Certain compounds and pharmaceutically acceptable salts are provided herein. Also provided are pharmaceutical compositions comprising at least one compound or pharmaceutically acceptable salt therein and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain disease states responsive to the inhibition of transglutaminase TG2 activity are described. These disease states include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one compound or pharmaceutically acceptable salt thereof as a single active agent or administering at least one compound or pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents.

A compound of Formula II

or a pharmaceutically acceptable salt thereof, wherein
U is N or CH;
R1 is chosen from hydrogen, —Ra, —ORb, —SRb, —NRbRc, halo, cyano, nitro, —COR b, —CO2Rb, —CONRbRc, —OCORb, —OCO2Ra, —OCONRbRc, —NRcCORb, —NRcCO2Ra, —NRcCONRbRc, —CO2Rb, —CONR bRc, —NRcCORb, —SORa, —SO2Ra —SO2NRbRc, and —NRcSO2Ra,
where Ra is chosen from optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
Rb is chosen from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
and
Rc is chosen from hydrogen and optionally substituted C1-C4 alkyl;
or
Rb and Rc, and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group;
and
where each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C1-C4 alkyl, aryl, heteroaryl, aryl-C1-C4 alkyl-, heteroaryl-C1-C4 alkyl-, C1-C4 haloalkyl-, —OC1-C4 alkyl, —OC1-C4 alkylphenyl, —C1-C4 alkyl-OH, —OC1-C4 haloalkyl, halo, —OH, —NH2, —C1-C4 alkyl-NH2, —N(C1-C4 alkyl)(C1-C4 alkyl), —NH(C1-C4 alkyl), —N(C1-C4 alkyl)(C1-C4 alkylphenyl), —NH(C1-C4 alkylphenyl), cyano, nitro, oxo (as a substitutent for heteroaryl), —CO2H, —C(O)OC1-C4 alkyl, —CON(C1-C4 alkyl)(C1-C4 alkyl), —CONH(C1-C4 alkyl), —CONH2, —NHC(O)(C1-C4 alkyl), —NHC(O)(phenyl), —N(C1-C4 alkyl)C(O)(C1-C4 alkyl), —N(C1-C4 alkyl)C(O)(phenyl), —C(O)C1-C4 alkyl, —C(O)C1-C4 phenyl, —C(O)C1-C4 haloalkyl, —OC(O)C1-C4 alkyl, —SO2(C1-C4 alkyl), —SO2(phenyl), —SO2(C1-C4 haloalkyl), —SO2NH2,—SO2NH(C1-C4 alkyl), —SO2NH(phenyl), —NHSO2(C1-C4 alkyl), —NHSO2(phenyl), and —NHSO2(C1-C4 haloalkyl);
R2 is chosen from hydrogen and optional substituted alkyl;
R3,R4,and R5 are independently chosen from hydrogen, halo, and optional substituted alkyl or R3 taken together with R4 forms a bond and R5 is chosen from hydrogen and optionally substituted alkyl;
m is 0, 1, or 2;
p is 0, 1, or 2;
W is —CH or N;
R9 is chosen from
hydrogen,
lower alkyl optionally substituted with optionally substituted amino, cycloalkyl, heterocycloalkyl, heteroaryl, or alkoxy, each of which, excluding optionally substituted amino, is optionally substituted with one or more groups chosen from lower alkoxy and halo,
cycloalkyl optionally substituted with optionally substituted amino, heterocycloalkyl, heteroaryl, or alkoxy, each of which, excluding optionally substituted amino, is optionally substituted with one or more groups chosen from lower alkoxy and halo,
—NR12R13 wherein R12 and R13 are independently chosen from hydrogen, lower alkyl, aralkyl, heteroaralkyl, —C(O)R14, —C(O)OR14, and —C(O)NR14R14 wherein for each occurrence R14 is chosen from hydrogen, lower alkyl, cycloalkyl, aralkyl, aryl, heterocycloalkyl, heteroaralkyl, and heteroaryl,
phenyl optionally substituted with one or more groups chosen from halo, lower alkyl, CF3, lower alkoxy, and phenyl,
aralkyl optionally substituted with one or more groups chosen from lower alkyl, lower alkoxy, alkylenedioxy, and phenyl,
heteroaryl optionally substituted with one or more groups chosen from halo, heteroaryl, lower alkyl, CF3, and lower alkoxy, and
—X—Y—C(O)—Z—(CH2)r—R11 wherein
X is absent or is —CH2—;
Y is absent or Y is chosen from —CH2—or —NR12—;
Z is absent or Z is chosen from —O —and —NR12—;
r is 0, 1, 2, or 3;
and
R11 is chosen from optionally substituted amino, lower alkyl, lower alkenyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each of which, excluding optionally substituted amino, is optionally substituted with one or more groups chosen from halo, lower alkyl, lower alkoxy, CF3, and phenoxy;
and
for each occurrence, R10 is chosen from optionally substituted lower alkyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryl, and optionally substituted aryl.

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Transglutaminase TG2 inhibitors, pharmaceutical compositions, and methods of use thereof

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Transglutaminase TG2 inhibitors, pharmaceutical compositions, and methods of use thereof

Life of this patent

Abstract

Claims50