Cdk8/19 dual inhibitors and methods of use thereof

A compound of Formula (Ia), or a pharmaceutically acceptable salt or stereoisomer thereof:

• wherein:
• R1 is halogen, —CN, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)OR5, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• R2 is fluoro, chloro, or bromo and R3 is hydrogen, fluoro, chloro, iodo, —CN, —OH, —ORa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —S(═O)(═NRb)Rb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• or
• R3 is fluoro, chloro, or bromo and R2 is hydrogen, fluoro, chloro, iodo, —CN, —OH, —ORa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —S(═O)(═NRb)Rb, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• X is N or CR4;
• R4 is hydrogen, halogen, —CN, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• W is —N—;
• Z is —N— or —CRZ1—;
• RZ1 is hydrogen, halogen, —SF5, —CN, —NO2, —OH, —ORa, —NRcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• each R5 is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SF5, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —S(═O)(═NRb)Rb, —NRcRd, —NRDC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —N═S(═O)(Rb)2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —P(═O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R5a;
• or two R5 on the same atom are taken together to form an oxo;
• each R5a is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O)Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SF5, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —S(═O)(═NRb)Rb, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —N═S(═O)(Rb)2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —P(═O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• or two R5a on the same atom are taken together to form an oxo;
• n is 0, 1, 2, 3, 4, 5, or 6;
• Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• each R6 is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O) Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SF5, —SH, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRcRd, —S(═O)(═NRb)Rb, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRbC(═O)ORb, —NRbS(═O)2Ra, —N═S(═O)(Rb)2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —P(═O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R6a;
• or two R6 on the same atom are taken together to form an oxo;
• or two R6 on the same atom are taken together to form ═NH;
• each R6a is independently halogen, —CN, —NO2, —OH, —ORa, —OC(═O) Ra, —OC(═O)ORb, —OC(═O)NRcRd, —SF5, —SH, —SRa, —S(═O)Ra, —S(═O) ¿Ra, —S(═O)2NRcRd, —S(═O)(═NRb)Rb, —NRcRd, —NRbC(═O)NRcRd, —NRbC(═O)Ra, —NRDC(═O)ORb, —NRbS(═O)2Ra, —N═S(═O)(Rb)2, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —P(═O)(Rb)2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
• wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• or two R6a on the same atom are taken together to form an oxo;
• m is 0, 1, 2, 3, 4, 5, or 6;
• each Ra is independently C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• each Rb is independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• Rc and Rd are each independently hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;
• or Rc and Rd are taken together with the atom to which they are attached to form a heterocycloalkyl optionally substituted with one or more R;
• and
• L is absent or C1-C3 alkylene optionally substituted with one or more R;
• each R is independently halogen, —CN, —OH, —SF5, —SH, —S(═O) C1-C3alkyl, —S(═O)2C1-C3alkyl, —S(═O)2NH2, —S(═O)2NHC1-C3alkyl, —S(═O)2N(C1-C3alkyl)2, —S(═O)(═NC1-C3alkyl)(C1-C3alkyl), —NH2, —NHC1-C3alkyl, —N(C1-C3alkyl)2, —N═S(═O)(C1-C3alkyl)2, —C(═O)C1-C3alkyl, —C(═O)OH, —C(═O)OC1-C3alkyl, —C(═O)NH2, —C(═O)NHC1-C3alkyl, —C(═O)N(C1-C3alkyl)2, —P(═O)(C1-C3alkyl)2, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, or C3-C6cycloalkyl.