A compound selected from Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein: R 1 is H, D, F, Cl, CN, NH 2, -NHCH 3, -N(CH 3) 2, -H, -OCH 3, -OCH 2 CH 3,-OCH 2 CH 2 OH, heteroaryl selected from imidazolyl and pyrazolyl, heterocyclyl selected from oxetanyl and azetidinyl, and C 1 -C 3 alkyl; R 2, R 3 and R 4 are independently selected from H, D, F, Cl, -NH 2, -NHCH 3,-N(CH 3) 2, -OH, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 OH, and C 1 -C 3 alkyl; R 5 is optionally substituted C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, -(C 6 -C 20 aryl)-(C 2 -C 20 heterocyclyl), -(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl), -(C 1 -C 20 heteroaryl)-(C 1 -C 6 alkyl), or -(C 1 -C 20 heteroaryl)-C(=O)-(C 2 -C 20 heterocyclyl); R 6 is H, F, -NH 2, -OH, or optionally substituted C 1 -C 3 alkyl; X is S, S(=O), S(=O) 2, N, NR 6, O, or CR 7; R 7 is independently selected from H, D, F, Cl, -CH 3, -CH 2 CH 3, -CN, -CH 2 F,-CHF 2, -CF 3, -NH 2, -OH, and -OCH 3; Y 1 and Y 2 are independently selected from CR 6 and N; Z 1, Z 2, Z 3, and Z 4 are independently selected from C, CR 7, and N; Z 5 is selected from -C(R 3) 2 -, -C(=O)-, -N(R 6)-, -C(R 3) 2 C(R 3) 2 -, -C(R 3) 2 C(=O)-,-CR 3 =CR 3 -, -CR 3 =N-, -N(R 6)C(R 3) 2 -, -N(R 6)C(R 3) 2 C(R 3) 2 -, and -OC(R 3) 2 C(R 3) 2 -; one of Z 1 and Z 2, or X and Z 1, where X is not S, S(=O), or S(=O) 2, forms a five-, six-, or seven-membered aryl, carbocyclyl, heterocyclyl or heteroaryl ring; where alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from D, F, Cl, Br, I, -CH 3, -CH 2 CH 3,-CH 2 CH(CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -C(CH 3) 2 OH, -CH CH(CH 3) 2,-C(CH 3) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3, -CH 2 OP 2, -CN, -CH 2 F, -CHF 2, -CF 3,-CO 2 H, -COCH 3, -CO 2 CH 3, -CO 2 C(CH 3) 3, -COCH CH 3, -CONH 2, -CONHCH 3,-CON(CH 3) 2, -C(CH 3) 2 CONH 2, -NO 2, -NH 2, -NHCH 3, -N(CH 3) 2, -NHCOCH 3,-N(CH 3)COCH 3, -NHS 2 CH 3, -N(CH 3)C(CH 3) 2 CONH 2, -N(CH 3)CH 2 CH 2 S 2 CH 3, =O, -OH, -OCH 3, -OCH 2 CH 2 N(CH 3) 2, -OP 2, -S 2 N(CH 3) 2, -SCH 3, -CH 2 OCH 3,-S 2 CH 3, cyclopropyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, oxetanyl, and morpholino; and wherein the group: forms the structures: where the wavy line indicates the site of attachment. R 1 is H, D, F, Cl, CN, NH 2, -NHCH 3, -N(CH 3) 2, -H, -OCH 3, -OCH 2 CH 3,-OCH 2 CH 2 OH, heteroaryl selected from imidazolyl and pyrazolyl, heterocyclyl selected from oxetanyl and azetidinyl, and C 1 -C 3 alkyl; R 2, R 3 and R 4 are independently selected from H, D, F, Cl, -NH 2, -NHCH 3,-N(CH 3) 2, -OH, -OCH 3, -OCH 2 CH 3, -OCH 2 CH 2 OH, and C 1 -C 3 alkyl; R 5 is optionally substituted C 6 -C 20 aryl, C 3 -C 12 carbocyclyl, C 2 -C 20 heterocyclyl, C 1 -C 20 heteroaryl, -(C 6 -C 20 aryl)-(C 2 -C 20 heterocyclyl), -(C 1 -C 20 heteroaryl)-(C 2 -C 20 heterocyclyl), -(C 1 -C 20 heteroaryl)-(C 1 -C 6 alkyl), or -(C 1 -C 20 heteroaryl)-C(=O)-(C 2 -C 20 heterocyclyl); R 6 is H, F, -NH 2, -OH, or optionally substituted C 1 -C 3 alkyl; X is S, S(=O), S(=O) 2, N, NR 6, O, or CR 7; R 7 is independently selected from H, D, F, Cl, -CH 3, -CH 2 CH 3, -CN, -CH 2 F,-CHF 2, -CF 3, -NH 2, -OH, and -OCH 3; Y 1 and Y 2 are independently selected from CR 6 and N; Z 1, Z 2, Z 3, and Z 4 are independently selected from C, CR 7, and N; Z 5 is selected from -C(R 3) 2 -, -C(=O)-, -N(R 6)-, -C(R 3) 2 C(R 3) 2 -, -C(R 3) 2 C(=O)-,-CR 3 =CR 3 -, -CR 3 =N-, -N(R 6)C(R 3) 2 -, -N(R 6)C(R 3) 2 C(R 3) 2 -, and -OC(R 3) 2 C(R 3) 2 -; one of Z 1 and Z 2, or X and Z 1, where X is not S, S(=O), or S(=O) 2, forms a five-, six-, or seven-membered aryl, carbocyclyl, heterocyclyl or heteroaryl ring; where alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from D, F, Cl, Br, I, -CH 3, -CH 2 CH 3,-CH 2 CH(CH 3) 2, -CH 2 OH, -CH 2 CH 2 OH, -C(CH 3) 2 OH, -CH CH(CH 3) 2,-C(CH 3) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3, -CH 2 OP 2, -CN, -CH 2 F, -CHF 2, -CF 3,-CO 2 H, -COCH 3, -CO 2 CH 3, -CO 2 C(CH 3) 3, -COCH CH 3, -CONH 2, -CONHCH 3,-CON(CH 3) 2, -C(CH 3) 2 CONH 2, -NO 2, -NH 2, -NHCH 3, -N(CH 3) 2, -NHCOCH 3,-N(CH 3)COCH 3, -NHS 2 CH 3, -N(CH 3)C(CH 3) 2 CONH 2, -N(CH 3)CH 2 CH 2 S 2 CH 3, =O, -OH, -OCH 3, -OCH 2 CH 2 N(CH 3) 2, -OP 2, -S 2 N(CH 3) 2, -SCH 3, -CH 2 OCH 3,-S 2 CH 3, cyclopropyl, azetidinyl, 1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, oxetanyl, and morpholino; and wherein the group: forms the structures: where the wavy line indicates the site of attachment.