Selective bcl-xl protac compounds and methods of use

A compound of Formula (A):

• D-L-DSM (A),
• or an enantiomer, a diastereoisomer, and/or a pharmaceutically acceptable salt of any one of the foregoing, wherein:
• DSM is a degradation signaling compound covalently attached to the linker L;
• L is a linker that covalently attaches DSM to D;
• and
• D is a Bcl-xL inhibitor compound of Formula (I) or Formula (II) covalently attached to the
• linker L:
• or an enantiomer, a diastereoisomer, and/or a pharmaceutically acceptable salt of any one of the foregoing, wherein:
• R1 and R2 independently of one another represent a group selected from the group consisting of:
• hydrogen;
• a linear or branched C1-C6alkyl optionally substituted by a hydroxyl or a C1-C6alkoxy group;
• a C3-C6cycloalkyl;
• a trifluoromethyl;
• and a linear or branched C1-C6alkylene-heterocycloalkyl wherein the heterocycloalkyl group is optionally substituted by a linear or branched C1-C6alkyl group;
• or R1 and R2 form with the carbon atoms carrying them a C3-C6cycloalkylene group,
• R3 represents a group selected from the group consisting of:
• hydrogen;
• a C3-C6cycloalkyl;
• a linear or branched C1-C6alkyl;
• —X1—NRaRb;
• —X1—N+RaRbRc;
• —X1—O—Rc;
• —X1—COORc;
• —X1—PO(OH)2;
• —X1—SO2(OH);
• —X1—N3 and:
• —X1-≡CH,
• Ra and Rb independently of one another represent a group selected from the group consisting of:
• hydrogen;
• a heterocycloalkyl;
• —SO2-phenyl wherein the phenyl may be substituted by a linear or branched C1-C6alkyl;
• a linear or branched C1-C6alkyl optionally substituted by one or two hydroxyl groups;
• a C1-C6alkylene-SO2OH;
• a C1-C6alkylene-SO2O−;
• a C1-C6alkylene-COOH;
• a C1-C6alkylene-PO(OH)2;
• a C1-C6alkylene-NRdRe;
• a C1-C6alkylene-N+RdReRf;
• a C1-C6alkylene-phenyl wherein the phenyl may be substituted by a C1-C6alkoxy group;
• and the group:
• or Ra and Rb form with the nitrogen atom carrying them a cycle B1;
• or Ra, Rb and Rc form with the nitrogen atom carrying them a bridged C3-C8hetero cycloalkyl,
• Rc, Rd, Re, Rf, independently of one another represents a hydrogen or a linear or branched C1-C6alkyl group,
• or Rd and Re form with the nitrogen atom carrying them a cycle B2,
• or Rd, Re and Rf form with the nitrogen atom carrying them a bridged C3-C8hetero cycloalkyl,
• Het1 represents a group selected from the group consisting of:
• Het2 represents a group selected from the group consisting of:
• A1 is —NH—, —N(C1-C3alkyl), O, S or Se,
• A2 is N, CH or C(R5),
• G is selected from the group consisting of:
• —C(O)ORG3, —C(O)NRG1RG2, —C(O)RG2, —NRG1C(O)RG2, —NRG1C(O)NRG1RG2, —OC(O)NRG1RG2, —NRG1C(O)ORG3, —C(═NORG1)NRG1RG2, —NRG1C(═NCN)NRG1RG2, —NRG1S(O)2NRG1RG2, —S(O)2RG3, —S(O)2NRG1RG2, —NRG1S(O)2RG2, —NRG1C(═NRG2)NRG1RG2, —C(═S)NRG1RG2, —C(═NRG1)NRG1RG2, —C1-C6alkyl optionally substituted by a hydroxyl group, a halogen, —NO2, and —CN, in which:
• RG1 and RG2 at each occurrence are each independently selected from the group consisting of hydrogen, a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms, a C1-C6alkyl substituted by a hydroxyl, a C1-C6alkyl substituted by a C1-C6alkoxy group, a C2-C6alkenyl, a C2-C6alkynyl, a C3-C6cycloalkyl, phenyl and —(CH2)1-4-phenyl;
• RG3 is selected from the group consisting of a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms, a C2-C6alkenyl, a C2-C6alkynyl, a C3-C6cycloalkyl, phenyl and —(CH2)1-4-phenyl;
• or RG1 and RG2, together with the atom to which each is attached are combined to form a C3-C8heterocycloalkyl;
• or in the alternative, G is selected from the group consisting of:
• wherein RG4 is selected from the group consisting of hydrogen, a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms, a C1-C6alkyl substituted by a hydroxyl, a C1-C6alkyl substituted by a C1-C6alkoxy group, a C2-C6alkenyl, a C2-C6alkynyl and a C3-C6cycloalkyl, and RG5 represents a hydrogen atom or a C1-C6alkyl group optionally substituted by 1 to 3 halogen atoms,
• R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, a hydroxyl or a methoxy group,
• R5 represents a group selected from the group consisting of:
• a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms;
• a C2-C6alkenyl;
• a C2-C6alkynyl;
• a halogen;
• and —CN,
• R6 represents a group selected from the group consisting of:
• hydrogen;
• a linear or branched —C1-C6alkylene-R8 group;
• a —C2-C6alkenyl;
• —X2—O—R7;
• —X2—NSO2—R7;
• —C═C(R9)—Y, —O—R7;
• a C3-C6cycloalkyl;
• a C3-C6heterocycloalkyl optionally substituted by a hydroxyl group;
• a C3-C6cycloalkylene-Y2—R7;
• a C3-C6heterocycloalkylene-Y2—R7 group, and
• a heteroarylene-R7 group optionally substituted by a linear or branched C1-C6alkyl group,
• R7 represents a group selected from the group consisting of:
• a linear or branched C1-C6alkyl group;
• a (C3-C6)cycloalkylene-R8;
• wherein Cy represents a C3-C8cycloalkyl,
• R8 represents a group selected from the group consisting of:
• hydrogen;
• a linear or branched C1-C6alkyl, —NR′aR′b;
• —NR′a—CO—OR′c;
• —NR′a—CO—R′c;
• —N+R′aR′bR′c;
• —O—R′c;
• —NH—X′2—N+R′aR′bR′c;
• —O—X′2—NR′aR′b;
• —X′2—NR′aR′b;
• —NR′c—X′2—N3 and
• —NR′c—X′2-≡CH,
• R9 represents a group selected from the group consisting of a linear or branched C1-C6alkyl, trifluoromethyl, hydroxyl, halogen, and a C1-C6alkoxy,
• R10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, —CF3 and methyl,
• R11 represents a group selected from the group consisting of hydrogen, a C1-C3alkylene-R8, a —O—C1-C3alkylene-R8, —CO—NRhRi and a —CH═CH—C1-C4alkylene-NRhRi, —CH═CH—CHO, a C3-C8cycloalkylene-CH2—R8, and a C3-C8heterocycloalkylene-CH2—R8,
• R12 and R13, independently of one another, represent a hydrogen atom or a methyl group,
• R14 and R15, independently of one another, represent a hydrogen or a methyl group, or R14 and R15 form with the carbon atom carrying them a cyclohexyl,
• Rh and Ri, independently of one another, represent a hydrogen or a linear or branched C1-C6alkyl group,
• X1 and X2 independently of one another, represent a linear or branched C1-C6alkylene group optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxyl, a halogen, and a C1-C6alkoxy,
• X′2 represents a linear or branched C1-C6alkylene,
• R′a and R′b independently of one another, represent a group selected from the group consisting of:
• hydrogen;
• a heterocycloalkyl;
• —SO2-phenyl wherein the phenyl may be substituted by a linear or branched C1-C6alkyl;
• a linear or branched C1-C6alkyl optionally substituted by one or two hydroxyl or C1-C6alkoxy groups;
• a C1-C6alkylene-SO2OH;
• a C1-C6alkylene-SO2O−;
• a C1-C6alkylene-COOH;
• a C1-C6alkylene-PO(OH)2;
• a C1-C6alkylene-NR′dR′e;
• a C1-C6alkylene-N+R′dR′eR′f;
• a C1-C6alkylene-O—C1-C6alkylene-OH;
• a C1-C6alkylene-phenyl wherein the phenyl may be substituted by a hydroxyl or a C1-C6alkoxy group;
• and the group:
• or R′a and R′b form with the nitrogen atom carrying them a cycle B3,
• or R′a, R′b and R′c form with the nitrogen atom carrying them a bridged C3-C8 hetero cycloalkyl,
• R′c, R′d, R′e, R′f, independently of one another, represents a hydrogen or a linear or branched C1-C6alkyl group,
• or R′d and R′e form with the nitrogen atom carrying them a cycle B4,
• or R′d, R′e and R′f form with the nitrogen atom carrying them a bridged C3-C8 Dheterocycloalkyl,
• Y1 represents a linear or branched C1-C4alkylene,
• Y2 represents a bond, —O—, —O—CH2—, —O—CO—, —O—SO2—, —CH2—, —CH2—O, —CH2—CO—, —CH2—SO2—, —C2H5—, —CO—, —CO—O—, —CO—CH2—, —CO—NH—CH2—, —SO2—, —SO2—CH2—, —NH—CO—, or —NH—SO2—,
• m=0, 1 or 2,
• B1, B2, B3 and B4, independently of one another, represents a C3-C6heterocycloalkyl group, which group can:
• (i) be a mono- or bi-cyclic group, wherein bicyclic group includes fused, bridged or spiro ring system, (ii) can contain, in addition to the nitrogen atom, one or two hetero atoms selected independently from oxygen, sulphur and nitrogen, (iii) be substituted by one or two groups selected from the group consisting of:
• fluorine, bromine, chlorine, a linear or branched C1-C6alkyl, hydroxyl, —NH2, oxo and piperidinyl,
• wherein one of the R3 and R8 groups, if present, is covalently attached to the linker, and wherein the valency of an atom is not exceeded by virtue of one or more substituents bonded thereto;
• or
• or an enantiomer, a diastereoisomer, and/or a pharmaceutically acceptable salt of any one of the foregoing, wherein:
• n=0, 1 or 2,
• ------ represents a single or a double bond,
• A4 and A5 independently of one another represent a carbon or a nitrogen atom,
• Z1 represents a bond, —N(R)—, or —O—, wherein R represents a hydrogen or a linear or branched C1-C6alkyl,
• R1 represents a group selected from the group consisting of:
• hydrogen;
• a linear or branched C1-C6alkyl optionally substituted by a hydroxyl or a C1-C6alkoxy group;
• a C3-C6cycloalkyl;
• trifluoromethyl;
• and a linear or branched C1-C6alkylene-heterocycloalkyl wherein the heterocycloalkyl group is optionally substituted by a linear or branched C1-C6alkyl group;
• R2 represents a hydrogen or a methyl;
• R3 represents a group selected from the group consisting of:
• hydrogen;
• a linear or branched C1-C4alkyl;
• —X1—NRaRb;
• —X1—N+RaRbRc;
• —X1—O—Rc;
• —X1—COORc;
• —X1—PO(OH)2;
• —X1—SO2(OH);
• —X1—N3 and:
• X1-≡CH,
• Ra and Rb independently of one another represent a group selected from the group consisting of:
• hydrogen;
• a heterocycloalkyl;
• —SO2-phenyl wherein the phenyl may be substituted by a linear or branched C1-C6alkyl;
• a linear or branched C1-C6alkyl optionally substituted by one or two hydroxyl groups;
• a C1-C6alkylene-SO2OH;
• a C1-C6alkylene-SO2O−;
• a C1-C6alkylene-COOH;
• a C1-C6alkylene-PO(OH)2;
• a C1-C6alkylene-NRdRe;
• a C1-C6alkylene-N+RdReRf;
• a C1-C6alkylene-phenyl wherein the phenyl may be substituted by a C1-C6alkoxy group;
• and the group:
• or Ra and Rb form with the nitrogen atom carrying them a cycle B1;
• or Ra, Rb and Rc form with the nitrogen atom carrying them a bridged C3-C8 heterocycloalkyl,
• Rc, Rd, Re, Rf, independently of one another represents a hydrogen or a linear or branched C1-C6alkyl group,
• or Rd and Re form with the nitrogen atom carrying them a a cycle B2,
• or Rd, Re and Rf form with the nitrogen atom carrying them a bridged C3-C8 heterocycloalkyl,
• Het1 represents a group selected from the group consisting of:
• Het2 represents a group selected from the group consisting of:
• A1 is —NH—, —N(C1-C3alkyl), O, S or Se,
• A2 is N, CH or C(R5),
• G is selected from the group consisting of:
• —C(O)ORG3, —C(O)NRG1RG2, —C(O)RG2, —NRG1C(O)RG2, —NRG1C(O)NRG1RG2, —OC(O)NRG1RG2, —NRG1C(O)ORG3, —C(═NORG1)NRG1RG2, —NRG1C(═NCN)NRG1RG2, —NRG1S(O)2NRG1RG2, —S(O)2RG3, —S(O)2NRG1RG2, —NRG1S(O)2RG2, —NRG1C(═NRG2)NRG1RG2, —C(═S)NRG1RG2, —C(═NRG1)NRG1RG2, —C1-C6alkyl optionally substituted by a hydroxyl group, halogen, —NO2, and —CN, in which:
• RG1 and RG2 at each occurrence are each independently selected from the group consisting of hydrogen, a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms, a C1-C6alkyl substituted by a hydroxyl, a C1-C6alkyl substituted by a C1-C6alkoxy group, a C2-C6alkenyl, a C2-C6 alkynyl, a C3-C6cycloalkyl, phenyl and —(CH2)1-4-phenyl;
• RG3 is selected from the group consisting of a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms, a C2-C6alkenyl, a C2-C6alkynyl, a C3-C6cycloalkyl, phenyl and —(CH2)1-4-phenyl;
• or RG1 and RG2, together with the atom to which each is attached are combined to form a C3-C8heterocycloalkyl;
• or in the alternative, G is selected from the group consisting of:
• wherein RG4 is selected from the group consisting of hydrogen, a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms, a C1-C6alkyl substituted by a hydroxyl, a C1-C6alkyl substituted by a C1-C6alkoxy group, a C2-C6 alkenyl, a C2-C6alkynyl and a C3-C6cycloalkyl, and RG5 represents a hydrogen atom or a C1-C6alkyl group optionally substituted by 1 to 3 halogen atoms,
• R4 represents a hydrogen, fluorine, chlorine or bromine atom, a methyl, a hydroxyl or a methoxy group,
• R5 represents a group selected from the group consisting of:
• a C1-C6alkyl optionally substituted by 1 to 3 halogen atoms;
• a C2-C6alkenyl;
• a C2-C6alkynyl;
• a halogen;
• and —CN,
• R6 represents a group selected from the group consisting of:
• hydrogen;
• a linear or branched —C1-C6alkylene-R8 group;
• a —C2-C6alkenyl;
• —X2—O—R7;
• —X2—NSO2—R7;
• —C═C(R9)—Y1—O—R7;
• a C3-C6cycloalkyl;
• a C3-C6heterocycloalkyl optionally substituted by a hydroxyl group;
• a C3-C6cycloalkylene-Y2—R7;
• a C3-C6heterocycloalkylene-Y2—R7 group, and
• a heteroarylene-R7 group optionally substituted by a linear or branched C1-C6alkyl group,
• R7 represents a group selected from the group consisting of:
• a linear or branched C1-C6alkyl group;
• a (C3-C6)cycloalkylene-R8;
• wherein Cy represents a C3-C8cycloalkyl,
• R8 represents a group selected from the group consisting of:
• hydrogen;
• a linear or branched C1-C6alkyl, —NR′aR′b;
• —NR′a—CO—OR′c;
• —NR′a—CO—R′c;
• —N+R′aR′bR′c;
• —O—R′c;
• —NH—X′2—N+R′aR′bR′c;
• —O—X′2—NR′aR′b, —X′2—NR′aR′b, —NR′c—X′2—N3 and
• —NR′c—X′2-≡CH,
• R9 represents a group selected from the group consisting of a linear or branched C1-C6alkyl, trifluoromethyl, hydroxyl, a halogen, and a C1-C6alkoxy,
• R10 represents a group selected from the group consisting of hydrogen, fluorine, chlorine, bromine, —CF3 and methyl,
• R11 represents a group selected from the group consisting of hydrogen, a halogen, a C1-C3alkylene-R8, a —O—C1-C3alkylene-R8, —CO—NRhRi and a —CH═CH—C1-C4alkylene-NRhRi, —CH═CH—CHO, a C3-C8cycloalkylene-CH2—R8, and a C3-C8heterocycloalkylene-CH2—R8,
• R12 and R13, independently of one another, represent a hydrogen atom or a methyl group,
• R14 and R15, independently of one another, represent a hydrogen or a methyl group, or R14 and R15 form with the carbon atom carrying them a cyclohexyl,
• Rh and Ri, independently of one another, represent a hydrogen or a linear or branched C1-C6alkyl group,
• X1 represents a linear or branched C1-C4alkylene group optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxyl, a halogen, and a C1-C6alkoxy,
• X2 represents a linear or branched C1-C6alkylene group optionally substituted by one or two groups selected from the group consisting of trifluoromethyl, hydroxyl, a halogen, and a C1-C6alkoxy,
• X′2 represents a linear or branched C1-C6alkylene,
• R′a and R′b independently of one another, represent a group selected from the group consisting of:
• hydrogen;
• a heterocycloalkyl;
• —SO2-phenyl wherein the phenyl may be substituted by a linear or branched C1-C6alkyl;
• a linear or branched C1-C6alkyl optionally substituted by one or two hydroxyl or C1-C6alkoxy groups;
• a C1-C6alkylene-SO2OH;
• a C1-C6alkylene-SO2O−;
• a C1-C6alkylene-COOH;
• a C1-C6alkylene-PO(OH)2;
• a C1-C6alkylene-NR′dR′e;
• a C1-C6alkylene-N+R′dR′eR′f;
• a C1-C6alkylene-O—C1-C6alkylene-OH;
• a C1-C6alkylene-phenyl wherein the phenyl may be substituted by a hydroxyl or a C1-C6alkoxy group;
• and the group:
• or R′a and R′b form with the nitrogen atom carrying them a cycle B3, or R′a, R′b and R′c form with the nitrogen atom carrying them a bridged C3-C8 heterocycloalkyl,
• R′c, R′d, R′e, R′f, independently of one another, represents a hydrogen or a linear or branched C1-C6alkyl group,
• or R′d and R′e form with the nitrogen atom carrying them a cycle B4,
• or R′d, R′e and R′f form with the nitrogen atom carrying them a bridged C3-C8 heterocycloalkyl,
• Y1 represents a linear or branched C1-C4alkylene,
• Y2 represents a bond, —O—, —O—CH2—, —O—CO—, —O—SO2—, —CH2—, —CH2—O, —CH2—CO—, —CH2—SO2—, —C2H5—, —CO—, —CO—O—, —CO—CH2—, —CO—NH—CH2—, —SO2—, —SO2—CH2—, —NH—CO—, or —NH—SO2—,
• m=0, 1 or 2,
• B1, B2, B3 and B4, independently of one another, represents a C3-C6heterocycloalkyl group, which group can:
• (i) be a mono- or bi-cyclic group, wherein bicyclic group includes fused, bridged or spiro ring system, (ii) can contain, in addition to the nitrogen atom, one or two hetero atoms selected independently from oxygen, sulphur and nitrogen, (iii) be substituted by one or two groups selected from the group consisting of:
• fluorine, bromine, chlorine, a linear or branched C1-C6alkyl, hydroxyl, —NH2, oxo and piperidinyl,
• wherein one of the R3, R8 and G groups, if present, is covalently attached to the linker, and wherein the valency of an atom is not exceeded by virtue of one or more substituents bonded thereto.