Substituted glutarimides as CDK inhibitors

A compound represented by formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• each is independently a single or double bond;
• A is absent;
• W is —NR17— or —X2C(O)X3—;
• X is —C(O)—;
• X′ is —N—;
• X″ is absent;
• X2 is absent;
• X3 is —NR18—;
• X6 is absent;
• Y is —(CR22R23)h—;
• Z is —(CR24R25)i—;
• R1 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C(O)H, C(O)C1-6 hydrocarbyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl, wherein the C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C(O)C1-6 hydrocarbyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl is optionally substituted;
• each R2 is independently H, F, Cl, Br, I, CN, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C(O)H, C(O)C1-6 hydrocarbyl, C(O)NH2, C(O)NHC1-6 hydrocarbyl, C(O)N(C1-6 hydrocarbyl)2, NR27R28, OR26, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C(O)C1-6 hydrocarbyl, C(O)NHC1-6 hydrocarbyl, C(O)N(C1-6 hydrocarbyl)2, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R3 is independently H, F, Cl, Br, I, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NR30R31, OR29, X6C(O)jR33, X6S(O)jR32, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclic hydrocarbyl, and heterocyclic hydrocarbyl is optionally and independently substituted;
• each R5 is independently FI, F, Cl, Br, I, CN, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C(O)H, C(O)C1-6 hydrocarbyl, C(O)NH2, C(O)NHC1-6 hydrocarbyl, C(O)N(C1-6 hydrocarbyl)2, NR27R28, OR26, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C(O)C1-6 hydrocarbyl, C(O)NHC1-6 hydrocarbyl, C(O)N(C1-6 hydrocarbyl)2, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R6 is independently H, F, Cl, Br, I, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NR30R31, OR29, X6C(O)jR33, X6S(O)jR32, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein each heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl is optionally and independently substituted;
• R7 is H, F, Cl, Br, I, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NR30R31, OR29, X6C(O)jR33, X6S(O)jR32, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl is optionally substituted;
• R8 is C3-8 cycloalkyl or C3-8 cycloalkenyl, wherein the C3-8 cycloalkyl or C3-8 cycloalkenyl is optionally substituted;
• R9 is FI, F, Cl, Br, I, CN, NO2, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NR30R31, OR29, X6C(O)jR33, X6S(O)jR32, cyclic hydrocarbyl, or heterocyclic hydrocarbyl, wherein the heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, cyclic hydrocarbyl, or heterocyclic hydrocarbyl is optionally substituted;
• R10 is X6C(O)NH2, X6C(O)NH(C1-6 alkyl), or X6C(O)N(C1-6 alkyl)2;
• R17 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl, wherein the C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl is optionally substituted;
• R18 is H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl, wherein the C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein the C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl is optionally substituted;
• each R22 is independently H, CN, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, OH, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, and phenyl is optionally and independently substituted;
• each R23 is independently H, CN, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, OH, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, and phenyl is optionally and independently substituted;
• each R24 is independently H, CN, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, OH, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, and phenyl is optionally and independently substituted;
• each R25 is independently H, CN, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, OH, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, or phenyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, OC1-8 alkyl, OC2-8 alkenyl, OC2-8 alkynyl, OC3-8 cycloalkyl, OC3-8 cycloalkenyl, Ophenyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C1-8 heterocyclic hydrocarbyl, and phenyl is optionally and independently substituted;
• each R26 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R27 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R28 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl independently contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R29 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R30 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R31 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R32 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• each R33 is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, C3-8 cyclic hydrocarbyl, or C1-8 heterocyclic hydrocarbyl, wherein each C1-8 heterocyclic hydrocarbyl contains one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and further wherein each C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cyclic hydrocarbyl, and C1-8 heterocyclic hydrocarbyl is optionally and independently substituted;
• a is 0, 1, 2, 3, 4, or 5;
• b is 0, 1, 2, or 3;
• c is 0;
• d is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
• e is 0, 1, 2, or 3;
• h is 0, 1, 2, 3, 4, 5, or 6;
• i is 1, 2, 3, 4, 5, or 6;
• and
• j is 0, 1, or 2;
• wherein the optional substituents for R1, R2, R3, R5, R6, R7, R8, R9, R17, R18, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, and R33 are independently selected from the group consisting of F, Cl, Br, I, CN, C1-6 halohydrocarbyl, C(O)H, C(O)C1-6 hydrocarbyl, NH2, NH(C1-6 hydrocarbyl), N(C1-6 hydrocarbyl)2, OH, O(C1-6 hydrocarbyl), and S(O)2C1-6 hydrocarbyl.