Thiazolopyridyl Amide Derivatives as DNA Polymerase Theta Inhibitors

The compound of formula (I):

• or a N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof,
• wherein:
• ring CyA is a 5- to 12-membered heteroaromatic ring comprising 1 to 4 heteroatoms selected from N, O, or S as ring member(s);
• R1 is —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR1a, —SO2R1a, —SO2NR1aR1b, —P(O)R1aR1b, —COR1a, —CO2R1a, —CONR1aR1b, —NR1aR1b, —NR1aCOR1b, —NR1aCO2R1b, —NR1aCONR1bR1c, or —NR1aSO2R1b;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R1d;
• R1a, R1b and R1c are each independently selected from hydrogen, —C1-8alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R1f;
• or
• (R1a and R1b), (R1b and R1c) or (R1a and R1c), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R1f;
• R1d and R1f are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR1g, —SO2R1g, —SO2NR1gR1h, —P(O)R1gR1h, —COR1g, —CO2R1g, —CONR1gR1h, —NO2, —NR1gR1h, —NR1gCOR1h, —NR1gCO2R1h, —NR1gCONR1hR1i, or —NR1gSO2R1h;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R1j;
• or
• two R1d or two R1f, together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R1k;
• R1g, R1h and R1i are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• R1j and R1k are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR1l, —SO2R1l, —SO2NR1lR1m, —COR1l, —CO2R1l, —CONR1lR1m, —NO2, —NR1lR1m, —NR1lCOR1m, —NR1′CO2R1m, —NR1lCONR1mR1n, or —NR1lSO2R1m;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl
• R1l, R1m and R1n are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• R2 is hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R2a;
• R2a is each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR2b, —SO2R2b, —SO2NR2bR2c, —COR2b, —CO2R2b, —CONR2bR2c, —NO2, —NR2bR2c, —NR2bCOR2c, —NR2bCO2R2c, —NR2bCONR2cR2d or —NR2bSO2R2c;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R2e;
• or
• two R2a, together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R2f;
• R2b, R2c and R2d are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• R2e and R2f are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, —C1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
• wherein each of said —C1-8alkyl, —C2-8 alkenyl, —C2-8alkynyl, —C1-8alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• R3 and R4 are each independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR3a, —SO2R3a, —SO2NR3aR3b, —COR3a, —CO2R3a, —CONR3aR3b, —NR3aR3b, —NR3aCOR3b, —NR3aCO2R3b, —NR3aCONR3bR3c, or —NR3aSO2R3b;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R3d;
• R3a, R3b and R3c are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R3f;
• or
• (R3a and R3b), (R3b and R3c) or (R3a and R3c), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R3f;
• R3d and R3f are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR3g, —SO2R3g, —SO2NR3gR3h, —COR3g, —CO2R3g, —CONR3gR3h, —NO2, —NR3gR3h, —NR3gCOR3h, —NR3gCO2R3h, —NR3gCONR3h, R3i, or —NR3gSO2R3h;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• R3g, R3h and R3i are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• R5 is halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR5a, —SR5a, —SO2R5a, —P(O)R5aR5b, —SO2NR5aR5b, —COR5a, —CO2R5a, —CONR5aR5b, —NR5aR5b, —NR5aCOR5b, —NR5aCO2R5b, —NR5aCONR5bR5c, or —NR5aSO2R5b;
• wherein each of said —C1-8alkyl, —C2-8 alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R5d;
• R5a, R5b and R5c are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R5f;
• or
• (R5a and R5b), (R5b and R5c) or (R5a and R5c), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R5f;
• R5d and R5f are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR5g, —SO2R5g, —SO2NR5gR5h, —COR5g, —CO2R5g, —CONR5gR5h, —NO2, —P(O)R5gR5h, —NR5gR5h, —NR5gCOR5h, —NR5gCO2R5h, —NR5gCONR5hR5i or —NR5gSO2R5h;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R5j;
• or
• two R5d or two R5f, together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent R5k;
• R5g, R5h and R5i are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• or
• (R5g and R5h), (R5h and R5i) or (R5g and R5i), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8 alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroary;
• R5j and R5k are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —OR5l, —SO2R5l, —SO2NR5lR5m, —COR5l, —CO2R5l, —CONR5lR5m, —NO2, —NR5lR5m, —NR5lCOR5l, —NR5lCO2R5m, —NR5lCONR5mR5n, or —NR5lSO2R5m;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl
• R5l, R5m and R5n are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• Rz, at each of its occurrences, is independently hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —ORza, —SO2Rza, —SO2NRzaRzb, —CORza, —CO2Rza, —CONRzaRzb, —NRzaRzb, —NRzaCORzb, —NRzaCO2Rzb, —NRzaCONRzbRzc, or —NRzaSO2Rzb;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent Rzd;
• Rza, Rzb and Rzc are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent Rzf;
• or
• (Rza and Rzb), (Rzb and Rzc) or (Rza and Rzc), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent Rzf;
• Rzd and Rzf are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN, —ORzg, —SO2Rzg, —SO2NRzgRzh, —CORzg, —CO2Rzg, —CONRzgRzh, —NO2, —NRzgRzh, —NRzgCORzh, —NRzgCO2Rzh, —NRzgCONRzhRzi, or —NRzgSO2Rzh;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent Rzj;
• or
• two Rzd or two Rzf, together with the atom(s) to which they are attached, form a 3- to 12-membered ring, said ring comprising 0, 1 or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur as ring member(s), said ring is optionally substituted with at least one substituent Rzk;
• Rzg, Rzh and Rzi are each independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• Rzj and Rzk are each independently selected from hydrogen, halogen, —C1-8alkyl, —C2-8alkenyl, —C2-8 alkynyl, —C1-8alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, —CN;
• wherein each of said —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —C1-8alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent halogen, hydroxy, —C1-8alkyl, -haloC1-8alkyl, —C1-8alkoxy, —C2-8 alkenyl, —C2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;
• n1 is 0, 1, 2, 3, 4, 5, 6, 7 or 8.