3,4-disubstituted 3-cyclobutene-1,2-diones and use thereof

A compound of Formula I or a pharmaceutically acceptable salt thereof, including an enantiomer, a diastereoisomer, a tautomer thereof:

• wherein
• R1 is selected from
• i) 6 to 12 membered aryl optionally substituted with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• ii) 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• iii) 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• iv) 5 to 12 membered heteroaryl optionally with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• v) tri-C1-5 alkylsilyl, and
• vi) C1-10 alkyl optionally substituted with at least one group selected from OR6, 6 to 12 membered aryl, 3 to 11 membered cycloalkyl, —CO2R6, —C(O)NR6R7, halo, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, C2-5 alkenyl, and C2-5 alkynyl;
• R2 is selected from hydrogen, C1-5 alkyl, C2-5 alkenyl, and C2-5 alkynyl;
• or R1 and R2 together with the carbon to which they are attached form
• i) a 6 to 12 membered aryl optionally with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• ii) a 3 to 11 membered cycloalkyl optionally with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• iii) a 5 to 12 membered heteroaryl optionally with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, CD3, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W, or
• iv) a 4 to 12 membered heterocyclyl optionally with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• provided that R3 is absent when the carbon to which R1 and R2 are attached is part of an aromatic or double bond;
• R3 is selected from
• i) hydrogen, deuterium, —CO2R6, —NR6R7, —C(O)NR6R7, —OR6, CD2CD3, halo, C2-5 alkenyl, C2-5 alkynyl, sulfonate, phosphonate,
• ii) 6 to 12 membered aryl optionally substituted with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• iii) 3 to 11 membered cycloalkyl optionally with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• iv) 4 to 12 membered heterocyclyl optionally with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• v) 5 to 12 membered heteroaryl optionally substituted with at least one group selected from C1-6 alkyl, C2-6 alkoxyalkyl, C2-6 alkenyl, —NR6R7, C1-6 alkyl-C(O)O—, —C(O)O—C1-6 alkyl, C(O)NR6R7, —NR6C(O)R7, halo, OR6, R6S(O)2O— (sulfonate), phosphonate, 6 to 12 membered aryl optionally substituted with at least one group selected from W, 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W, 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W, and
• vi) C1-5 alkyl optionally substituted with at least one group selected from OR6, 6 to 12 membered aryl, 3 to 11 membered cycloalkyl, —CO2R6, —C(O)NR6R7, halo, 5 to 12 membered heteroaryl, 4 to 12 membered heterocyclyl, —Si(C1-6 alkyl), C2-5 alkenyl, and C2-5 alkynyl;
• R4 is selected from —CO2R6, —C(O)NR6R7, —NR6C(O)R7, —NR6CO2R7, —NR6C(O)NR6R7, —NR7SO2R6, —NR7SO2NR6R7, C1-6 hydroxyalkyl, C1-6 haloalkyl, halo, CN, —SO2NR6R7, and —SO2R6;
• R5 is selected from hydrogen, C1-6 alkyl, —OR6, halo, —NR6R7, CN, C1-6haloalkyl, and —NO2;
• R6 and R7 are independently selected from
• i) hydrogen,
• ii) C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C2-6 alkoxyalkyl, aralkyl, CD3,
• iii) C2-5 alkenyl, C2-5 alkynyl,
• iv) 6 to 12 membered aryl optionally substituted with at least one group selected from W,
• v) 3 to 11 membered cycloalkyl optionally substituted with at least one group selected from W,
• vi) 5 to 12 membered heteroaryl optionally substituted with at least one group selected from W, and
• vii) 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W,
• or R6 and R7 together with the nitrogen to which they are attached form a 4 to 12 membered heterocyclyl optionally substituted with at least one group selected from W;
• W is selected from C1-6 alkyl, C2-5 alkenyl, C2-5 alkynyl, halo, C1-6 alkoxy, and hydroxyl;
• with the provisos:
• a) that when R1 is 6 to 12 membered aryl optionally substituted as described above or 5 to 12 membered heteroaryl optionally substituted as described above, R3 is not a 4 or 5 membered heterocyclyl optionally substituted as described above, and that when R3 is 6 to 12 membered aryl optionally substituted as described above or 5 to 12 membered heteroaryl optionally substituted as described above, R1 is not a 4 or 5 membered heterocyclyl optionally substituted as described above;
• b) that when any of R1, R2, or R3 are C1-5 alkyl or C1-10 alkyl, and R4 is —SO2NR6R7, R5 is not hydrogen;
• c) that when either R1 or R3 is 4 or 5 membered heterocyclyl optionally substituted as described above, R2 is not C1-10 alkyl;
• d) that when either R1 or R3 is 5 to 12 membered heteroaryl optionally substituted as described above, and R4 is —SO2NR6R7, then neither R6 or R7 in the —SO2NR6R7 is hydrogen or 5 to 12 membered heteroaryl optionally substituted as described above;
• e) that when R1 and R2 together with the carbon to which they are attached form a 6 to 12 membered aryl optionally substituted as described above, and R4 is —SO2NR6R7, R5 is not C1-6 alkyl or CN and both R6 and R7 in the —SO2NR6R7 are C1-6 alkyl;
• and
• f) that when R1 and R2 together with the carbon to which they are attached form a 4 to 12 membered heterocyclyl optionally substituted as described above, R3 is not hydrogen.