Heterobifunctional compounds and methods of treating disease

A compound represented by Formula II:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is phenyl substituted by cyano, halogen, and m occurrences of R4;
• R2 represents independently for each occurrence C1-4 alkyl;
• R3 is hydrogen or C1-4 alkyl;
• R4 is C1-4 alkyl;
• R5 represents independently for each occurrence C1-4 alkyl or halogen;
• A2 is
• R1A represents independently for each occurrence halogen or C1-4 alkyl;
• R2A is hydrogen or C1-4 alkyl;
• R3A represents independently for each occurrence C1-6 alkyl, —(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl;
• R4A represents independently for each occurrence C1-6 hydroxyalkyl, —(C1-6 alkylene)-(C1-6 alkoxyl), C1-6 alkyl, —(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl;
• X is C1-4 alkylene;
• R1B is hydrogen, halo, or C1-4 alkyl;
• R2B and R4B are independently hydrogen or C1-4 alkyl;
• R3B is halo;
• R5B is —C(O)N(R7B)(R8B) or —N(R7B)C(O)(R9B);
• R6B represents independently for each occurrence halo, C1-4 alkyl, or C1-4 haloalkyl;
• R7B and R8B are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl;
• or R7B and R8B are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom;
• R9B is C1-6 alkyl, —(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl;
• Y is —N(C1-4 alkyl)-, —N(H)—, or a 3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from oxygen and nitrogen;
• L is a linker;
• and
• k is 1,2,3, or 4;
• and
• m, n, p and t are independently 0, 1, or 2.

A compound represented by Formula I*:

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is phenyl substituted by cyano, halogen, and m occurrences of R4;
• R2 represents independently for each occurrence C1-4 alkyl;
• R3 is hydrogen or C1-4 alkyl;
• R4 is C1-4 alkyl;
• R5 represents independently for each occurrence C1-4 alkyl or halogen;
• A1 is a pyridazinylene, pyrimidinylene, pyrazinylene, or pyridinylene, each of which is substituted with n occurrences of R5;
• A2 is
• R1A represents independently for each occurrence halogen or C1-4 alkyl;
• R2A is hydrogen or C1-4 alkyl;
• R3A represents independently for each occurrence C1-6 alkyl, —(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl;
• R4A represents independently for each occurrence halo, C1-6 hydroxyalkyl, —(C1-6 alkylene)-(C1-6 alkoxyl), C1-6 alkyl, —(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl;
• X is C1-4 alkylene;
• R1B is hydrogen, halo, or C1-4 alkyl;
• R2B and R4B are independently hydrogen or C1-4 alkyl;
• R3B is halo;
• R5B is —C(O)N(R7B)(R8B) or —N(R7B)C(O)(R9B);
• R6B represents independently for each occurrence halo, C1-4 alkyl, or C1-4 haloalkyl;
• R7B and R8B are independently hydrogen, C1-6 alkyl, or C3-6 cycloalkyl;
• or R7B and R8B are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom;
• R9B is C1-6 alkyl, —(C1-6 alkylene)-(C3-6 cycloalkyl), or C3-6 cycloalkyl;
• R10B represents independently for each occurrence halo, C1-6 hydroxyalkyl, C1-4 alkyl, or oxo;
• R11B is hydrogen or C1-4 alkyl;
• W is —C(H)— or —N(R11B)—;
• Z is a bivalent, saturated or unsaturated, straight or branched C1-10 hydrocarbon chain, wherein 0-4 methylene units of the chain are independently replaced with —O—, —S—, —N(H)—, —N(C1-6 alkyl)-, —OC(O)—, —C(O)O—, or —C(O)—;
• L is a linker;
• and
• k is 1,2,3, or 4;
• and
• m, n, p, q, and t are independently 0, 1, or 2.

A compound represented by Formula III:

• or a pharmaceutically acceptable salt thereof, wherein:
• TPL is a group defined by Formula III-1 that is substituted by one occurrence of RIII-1A, wherein Formula III-1 is represented by:
• wherein:
• RIII-1A is a bond to L;
• R1 is phenyl substituted by cyano, halogen, and m occurrences of R4;
• R2 and R3 each represent independently for each occurrence hydrogen or C1-4 alkyl;
• R4 is C1-4 alkyl;
• R5 represents independently for each occurrence C1-4 alkyl or halogen;
• A1 is a pyridazinyl, pyrimidinyl, pyrazinyl, or pyridinyl, each of which is substituted with n occurrences of R5;
• Y is —N(R2) or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from oxygen and nitrogen;
• L is a linker;
• EPL is a moiety that binds to CDK;
• k is 1,2,3, or 4;
• and
• m and n are independently 0, 1, or 2.

A compound represented by Formula Ie:

• or a pharmaceutically acceptable salt wherein:
• A2 is
• L is one of the following:
• -(3-7 membered, monocyclic, saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(OCH2CH2)1-5—***, wherein *** is the point of attachment to A2;
• -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X3-(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-(C0-6 alkylene)-***, wherein *** is the point of attachment to A2, and X3 is C1-10 alkylene, —O—, —N(H)—, —N(C1-4 alkyl)-, or a bond;
• -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X1—***, wherein *** is the point of attachment to A2, and X1 is (i) C1-10 alkylene where 1 or 2 methylene groups are optionally replaced by —O—, —N(H)—, or —N(C1-4 alkyl)-, (ii) a 3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen, or (iii) -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatom s selected from nitrogen)-(C1-10 alkylene)-;
• or
• —N(C1-3 alkyl)-(C1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C1-6 alkylene)-N(H)SO2—***, -(5-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C1-6 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C0-6 alkylene)-O—***, -(5-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-(5-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)***, -(8-11 membered saturated fused bicyclic heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-(4-6 membered saturated heterocyclylene containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen)-(C0-4 alkylene)-***, or -(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-X1-(3-7 membered monocyclic saturated heterocyclic ring containing 1 or 2 heteroatoms selected from nitrogen)-C(O)—***, wherein *** is the point of attachment to A2, and X1 is (i) C1-10 alkylene where 1 or 2 methylene groups are optionally replaced by —O—, —N(H)—, or —N(C1-4 alkyl)-, wherein *** is the point of attachment to A2.