Macrocyclic 2-amino-but-3-enamides as inhibitors of mcl-1

A compound of Formula (I)

• wherein
• R1a and R1b are each independently selected from the group consisting of hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkenyl, Het1, Ar1, Het2, and Cy1, wherein said C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl or C3-7cycloalkenyl is optionally substituted with one or two R2,
• or R1a and R1b are taken together to form together with the N-atom to which they are attached a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2, and wherein said heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of oxo, ORf, SRf, NRdRc, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORf, SRf, CN and halo;
• or R1a and R1b are taken together to form together with the N-atom to which they are attached a 6- to 11-membered bicyclic fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2, and wherein said heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of oxo, ORf, SRf, NRdRe, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORf, SRf, CN and halo;
• each R2 is independently selected from the group consisting of ORf, SRf, CN, halo, CF3, NRmRn, SO2Rc, C(═O)Rc, C(═O)ORd, C(═O)NRdRc, SO2NRdRc, C3-7cycloalkyl, C3-7cycloalkenyl, Het1, Ar1, Het2, and Cy1 wherein said C3-7cycloalkyl or C3-7cycloalkenyl is optionally substituted with one or two substituents each independently selected from the group consisting of ORf, SRf, CN, halo and NRdRc;
• Rc is selected from the group consisting of C1-6alkyl, C3-7cycloalkyl, Het1, Ar1 and Het2,
• Rm and Rn are each independently selected from the group consisting of hydrogen, methyl, C2-7alkyl, C3-7cycloalkyl, Het1, Ar1, and let2, wherein said C2-7alkyl or C3-7cycloalkyl is optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRgRh, CN, halo, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN, NRgRh and halo;
• Rd and Rc are each independently selected from the group consisting of hydrogen, methyl, C2-7alkyl, C3-7cycloalkyl, Het1, Ar1, and Het2, wherein said C2-7alkyl or
• C3-7cycloalkyl is optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRgRh, CN, halo, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN, NRgRh and halo;
• or Rd and Re are taken together to form together with the N-atom to which they are attached a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2, and wherein said heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRgRh, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN and halo;
• or Rd and Re are taken together to form together with the N-atom to which they are attached a fused 6- to 11-membered bicyclic fully saturated heterocyclyl containing one N-atom and optionally one or two additional heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2, and wherein said heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRgRh, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN and halo;
• n is 1 or 2;
• Rf is selected from the group consisting of hydrogen, C1-6alkyl, CF3, C3-7cycloalkyl, Het1, Ar1, Het2, wherein said C1-6alkyl or C3-7cycloalkyl is optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN, halo, NRmRn, SO2Rc, C(═O)Rc, C(═O)ORd, C(═O)NRdRc, SO2NRdRe, C3-7cycloalkyl, Het1, Ar1 and Het2;
• Rg and Rh are each independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;
• or Rg and Rh are taken together to form together with the N-atom to which they are attached a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one N-atom and optionally one additional heteroatom selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2;
• Het1 represents a 4- to 7-membered monocyclic fully saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2, and wherein said heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRjRk, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN and halo;
• Het2 represents a 5- to 6-membered monocyclic aromatic ring containing one, two, three or four heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2, and wherein said aromatic ring is optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRjRk, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN and halo;
• Cy1 represents a 6- to 11-membered bicyclic fully saturated ring system optionally containing one or two heteroatoms each independently selected from O, S, and N, wherein said S-atom might be substituted to form S(═O) or S(═O)2, and wherein said ring system is optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRjRk, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN and halo;
• Ar1 represents phenyl optionally substituted with one or two substituents each independently selected from the group consisting of ORi, SRi, NRgRh, CN, halo, CF3, and C1-4alkyl optionally substituted with one substituent selected from the group consisting of ORi, SRi, CN and halo;
• Ri represents hydrogen, C1-6alkyl or C3-7cycloalkyl;
• Rj and Rk are each independently selected from the group consisting of hydrogen, C1-6alkyl and C3-7cycloalkyl;
• R3 represents hydrogen, C1-4alkyl or C1-4alkyl-OH;
• R4 represents hydrogen or methyl;
• R5 represents —(C═O)-phenyl, —(C═O)-Het4 or —(C═O)-Het3;
• wherein said phenyl, Het3 or Het4 are optionally substituted with one or two substituents selected from methyl or methoxy;
• Het4 represents a C-linked 4- to 7-membered monocyclic fully saturated heterocyclyl containing one or two heteroatoms each independently selected from O, S, and N;
• wherein said S-atom might be substituted to form S(═O) or S(═O)2;
• Het3 represents a C-linked 5- or 6-membered monocyclic aromatic ring containing one, two or three heteroatoms each independently selected from O, S, and N;
• Y represents O or CH2;
• X1 represents CR6;
• X2 represents CR7;
• X3 represents CR8;
• R6, R7 and R8 each independently represent hydrogen, fluoro or chloro;
• X4 represents O or NR5;
• or a pharmaceutically acceptable salt, or a solvate thereof.