Targeted protein degradation using bifunctional compounds that bind ubiquitin ligase and target mcl-1 protein

The compound of any preceding claim, wherein

• R14 is —C1-6 alkyl, —SO2— or is absent
• R15 is piperazine, bridged piperazine, piperazine N-oxide, piperazine cation, —C1-6 alkyl-NH—,
• or is absent, wherein indicates attachment to R14 and indicates attachment to R16,
• R16 is —C1-6 alkyl, —C(O)—, —C(O)—NH—, —CH2—C(O)—NH— or is absent
• R17 is —CH2(C2H4—O)y, (C2H4—O)x, (C3H6—O)x, or is absent
• x is 1-6
• y is 2-6
• R18 is —C1-6 alkyl, piperazine, or is absent
• wherein at least one of R14-R18 is present.

The compound of any preceding claim, wherein

• R14 is —SO2—
• R15 is —C1-6 alkyl-NH—
• R16 is —C(O)—
• R17 is —CH2(C2H4—O)y, (C2H4—O)x or is absent
• R18 is —C2-4 alkyl.

The compound of any preceding claim, wherein

• R8 is H, R19, methyl, or —CH2CH2-morpholine;
• R9 is —C(O)OH or —C(O)NHR19,
• R10 is —C3H6O—R13,
• wherein R13 is
• tetraline, or naphthyl optionally substituted with fluorine;
• R11 is H, Cl, F or methyl,
• R12 is
• wherein R20 is Me, —CH2—O-bromobenzaldehyde, or

A compound of formula (I)

• [MCL-1 ligand moiety]-[linker]-[ligase ligand moiety] (I)
• or a salt, solvate, hydrate, isomer or prodrug thereof,
• wherein [ligase ligand moiety] is:
• (a) Formula (IV)
• wherein:
• each of X1 and X2 is independently O or S;
• each of Q1 and Q2 is independently N or CR5, wherein at least one of Q1 and Q2 is N;
• each of E1, E2, E3 and E4 is independently N or CR′;
• n is 0, 1 or 2;
• L2 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)R′″, —C(O)OR′″, —C(O)NH2, —C(O)NHR′″, —C(O)NR′″2, —OR′″, —NR′″2, or —S(O)2R′;
• each R5 is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR′″, —NR″2, —NR′″C(O)R′″, —NR′″C(O)OR′″, —NO2, —CN, —C(O)R′″, —C(O)OR′″, —C(O)NH2, —C(O)NHR′″, —C(O)NR′″2, —OR′″, —OC(O)R′″, —OC(O)OR′″, —OC(O)NH2, —OC(O)NHR′″, —OC(O)NR′″2, —SR′″, —S(O)2R′″, —S(O)2OR′″, —S(O)2NH2, —S(O)2NHR′″, —S(O)2NR′″2;
• —O—R21, —NH—R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• each R′ is independently hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR′″, —NR′″2, —NR′″C(O)R′″, —NR′″C(O)OR′″, —NO2, —CN, —C(O)R′″, —C(O)OR′″, —C(O)NH2, —C(O)NHR′″, —C(O)NR′″2, —OR′″, —OC(O)R′″, —OC(O)OR′″, —OC(O)NH2, —OC(O)NHR′″, —OC(O)NR′″2, —SR′″, —S(O)2R′″, —S(O)2OR′″, S(O)2NH2, —S(O)2NHR′″, —S(O)2NR′″2, —R21, —O—R21, —NH—R21, —C(O)—R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• and
• each R′″ is independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, or benzyl;
• wherein R21 is a bond connected to R18 of the linker, and wherein Formula (IV) contains a single R21;
• or
• (b) Formula (Va) or (Vb):
• or a pharmaceutically acceptable salt or tautomer thereof,
• wherein
• each of X1 and X2 is independently O or S;
• Z1 is O, S or NR6;
• T is is C═O or SO2;
• R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• each of Y5, Y6, Y7, and Y8 is independently N or CR7, wherein at least one of Y5, Y6 and Y7 in Formula (Va) is CR7, and at least one of Y5, Y5 and Y8 in Formula (Vb) is CR7;
• n is 0, 1 or 2;
• L3 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)R″″, —CH2C(O)OR″″, —C(O)OR″″, —C(O)NH2, —C(O)NHR″″, —C(O)NR″″2, —OR″″, —NR″″2, or —S(O)2R″″;
• each R7 is independently hydrogen, halogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″″, —NR″″2, —CH2NR″″2, —NR″″C(O)R″″, —NR″″C(O)CH2NR″″2, —NR″″C(O)CH2-heterocycloalkyl, —NR″″C(O)CH(OH)R″″, —CH2NR″″C(O)OR″″, —NR″″C(O)OR″″, —NR″″SO2R″″, —NO2, —CN, —C(O)R″″, —C(O)OR″″, —C(O)NH2, —C(O)NHR″″, —C(O)NR″″2, —OR″″, —OC(O)R″″, —OC(O)OR″″, —OC(O)NH2, —OC(O)NHR″″, —OC(O)NR″″2, —NHC(S)NHR″″, SR″″, or —S(O)2R″″, —S(O)2OR″″, —S(O)2NH2, —S(O)2NHR″″, —S(O)2NR″″2, —O—R21, —NH—R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• each R″″ is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• R6 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″″, —NR″″2, —NR″″C(O)R″″, —N[C(O)R″″]2, —NR″″C(O)OR″″, —NO2, —CN, —C(O)R″″, —C(O)OR″″, —C(O)NH2, —C(O)NHR″″, —C(O)NR″″2, —OR″″, —OC(O)R″″, —OC(O)OR″″, —OC(O)NH2, —OC(O)NHR″″, —OC(O)NR″″2, —SR″″, or —S(O)2R″″, —S(O)2OR″″, —S(O)2NH2, —S(O)2NHR″″, —S(O)2NR″″2, —R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• wherein R21 is a bond connected to R18 of the linker, and wherein formula (Va) and formula (Vb) each contain a single R21;
• wherein when Z1 is O, then Y6 is CR7 and
• wherein when the compound is of Formula (Va), then
• (i) when each of Y5, Y6 and Y7 is CR7, then at least one of R7 is not H;
• (ii) when Z1 is NR6, then Y6 and Y7 are CR7;
• (iii) when Z1 is S, then Y5 is not C—OMe and Y6 is not C—OMe;
• (iv) when Z1 is S and Y5 is C—NHCOMe, then Y7 is not C—CH2NR″″C(O)OR″″;
• (v) when Z1 is S and Y5 is N, then Y6 is not C—H, C-aryl or C—C(O)OR″″;
• and
• (vi) when Z1 is S and Y6 is N, then Y7 is C—NH2, C—NHR″″, C—NR″″2, C—NR″″C(O)OR″″, C—CH2NR″″C(O)OR″″, C-haloalkyl, C-tButyl, C—OR″″, C—COOR″″ or C—SR″″;
• wherein when Y7 is C—NH2, C—NHR″″ or C—NR″″2, then Y5 is C—H;
• and when the compound is of Formula (Vb), then:
• (vii) when each of Y5, Y6 and Y8 is CR7, then at least one of R7 is not H;
• (viii) when Z1 is S, then Y5 is not C—COOH or C—NHC(O)Me, and Y8 is not C—Br;
• (ix) when Z1 is S and Y6 is C—Br, then Y8 is C—OR″″
• (x) when Z1 is S, Y5 is N and Y6 is C—H or C—NH2, then Y8 is not C—H
• (xi) when Z1 is S and Y5 is N, then Y6 is not C— halogen, C-alkyl, C-cycloalkyl, C-aryl, C-heteroaryl, C—CH2NH2, C—COOalkyl, or C—NHC(O)alkyl;
• (xii) when Z1 is NR6, then Y5, Y6 and Y8 are CR7, or
• (c) Formula (IIa) or (IIb):
• wherein
• each of X1 and X2 is independently O or S;
• Z is O, S or NR2;
• T is C═O or SO2;
• Y3 is N or CR;
• Y4 is N or CR;
• indicates a single or double bond, wherein
• when each is a double bond, each of W1, W2, W3 and W4 is independently N or CRa, wherein at least one of W1, W2, W3 and W4 is N, and
• when each is a single bond, W1, W2, W3 and W4 are each CRa2 and Y4 is CR;
• n is 0, 1 or 2;
• L is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)Rh, —C(O)ORh, —C(O)NH2, —C(O)NHRh, —C(O)NRh2, —ORh, —NRh2, or —S(O)2Rh;
• each R is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHRh, —NRh2, —NRhC(O)Rh, —NRhC(O)CH2Rh, —NRhC(O)CH(OH)Rh, —NRhC(O)ORh, —NRhSO2Rh, —NO2, —CN, —C(O)Rh, —C(O)ORh, —C(O)NH2, —C(O)NHRh, —C(O)NRh2, —ORh, —OC(O)Rh, —OC(O)ORh, —OC(O)NH2, —OC(O)NHRh, —OC(O)NRh2, —SRh, or —S(O)2Rh, —S(O)2ORh, —S(O)2NH2, —S(O)2NHRh, or —S(O)2NRh2;
• each Ra is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHRh, —NRh2, —NRhC(O)Rh, —NRhC(O)CH(OH)Rh, —NRhC(O)ORh, —NRhSO2Rh, —NO2, —CN, —C(O)Rh, —C(O)ORh, —C(O)NH2, —C(O)NHRh, —C(O)NRh2, —ORh, —OC(O)Rh, —OC(O)ORh, —OC(O)NH2, —OC(O)NHRh, —OC(O)NRh2, —SRh, —S(O)2Rh, —S(O)2ORh, —S(O)2NH2, —S(O)2NHRh, —S(O)2NRh2, —O—R21, —NH—R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• each Rh is independently hydrogen, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• R2 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHRh, —NRh2, —NRhC(O)Rh, —N[C(O)Rh]2, —NRhC(O)ORh, —NO2, —CN, —C(O)Rh, —C(O)ORh, —C(O)NH2, —C(O)NHRh, —C(O)NRh2, —ORh, —OC(O)Rh, —OC(O)ORh, —OC(O)NH2, —OC(O)NHRh, —OC(O)NRh2, —SRh, —S(O)2Rh, —S(O)2ORh, —S(O)2NH2, —S(O)2NHRh, or —S(O)2NRh2;
• and
• R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• R21 is a bond connected to R18 of the linker, and wherein formula (IIa) and formula (IIb) each contain a single R21;
• wherein when each is a double bond, Z is NR2, R2 is hydrogen, and each Ra is hydrogen, then W4 is CRa;
• wherein
• [MCL-1 ligand moiety] is a compound of Formula (A), Formula (B) or Formula (C)
• wherein
• is a single bond or a double bond;
• R8 is H, R19, or C1-C6 alkyl optionally substituted with morpholine;
• R9 is —C(O)OH, —C(O)OC1-C6alkyl, —C(O)NH2, —C(O)OR19 or —C(O)NHR19,
• R10 is —C2-5alkyl-O—R13 or —C2-5alkyl-NMe-R13, wherein R13 is phenyl, naphthyl or tetraline, wherein the phenyl, naphthyl or tetraline is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and —O(C1-C6 alkyl);
• or wherein the tetraline is optionally substituted with a bridging —CH2— group;
• or wherein the naphthyl is optionally substituted with —O— or —S—,
• R11 is H, halogen or C1-C6 alkyl,
• R12 is H,
• wherein R20 is Me, —CH2—OMe, —CH2—O-bromobenzaldehyde, or
• or when R12 is
• and R10 is —O-naphthyl substituted with —O— or —S—, then R20 is
• wherein indicates attachment to —O— or —S— of R10;
• and wherein
• R19 is a bond connected to R14 of the linker;
• R23 is —C(O)OH or —C(O)OC1-C6alkyl;
• Z2 is N or C, wherein when Z2 is N, then is a single bond;
• and when Z2 is C, then is a double bond,
• R24 is furan optionally substituted with at least one halogen,
• each R25 is independently phenyl substituted with —OR28 and optionally further substituted with at least one substituent selected from halogen and C1-C6 alkyl;
• R26 is —C(O)OR19 or —C(O)NHR19;
• and
• each R28 is independently —C1-3alkyl-(N-alkyl piperazine) or —C1-3alkyl-(N-haloalkylpyrazole)
• and wherein each of Formula (A), Formula (B) and Formula (C) contains a single R19;
• and wherein [linker] has the following formula
• R14—R15—R16—R17—R18
• wherein
• R14 is —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —C1-6 alkyl-N(C1-6 alkyl)-, —C(O)—, —SO2— or is absent
• R15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C1-6 alkyl-NH—, —C1-6 alkyl-N(C1-6 alkyl)-, -cycloalkyl-NH—, -heterocycloalkyl-NH— or is absent
• R16 is —C1-6alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH2—C(O)—, —CH2—C(O)—NH—, —CH2—C(O)O— or is absent
• R17 is —CH2(C2H4—O)y, (C2H4—O)x, (C3H6—O)x, or is absent
• x is 1-10
• y is 2-10
• R18 is —C1-6 alkyl, heterocycloalkyl, or is absent
• wherein at least one of R14-R18 is present.

The compound of any one of claims 48-978, wherein

• R8 is H, R19, methyl, or —CH2CH2-morpholine;
• R9 is —C(O)OH or —C(O)NHR19,
• R10 is —C3H6O—R13,
• wherein R13 is
• tetraline, or naphthyl optionally substituted with fluorine;
• R11 is H, Cl, F or methyl,
• R12 is
• wherein R20 is Me, —CH2—O-bromobenzaldehyde, or

A compound of formula (I)

• [MCL-1 ligand moiety]-[linker]-[ligase ligand moiety] (I)
• or a salt, solvate, hydrate, isomer or prodrug thereof,
• wherein [ligase ligand moiety] is:
• (a) Formula (11):
• wherein:
• each of X1 and X2 is independently O or S;
• T is C═O or SO2;
• R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• n is 0, 1 or 2;
• L4 is hydrogen, alkyl, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)H, —C(O)R″, —C(O)OH, —C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —NH2, —NHR″, —NR″2, —S(O)2H or —S(O)2R″;
• Ry is selected from
• wherein indicates attachment to T,
• Z3 is O, S or NR3;
• U is O, S, NRb or CRb2;
• each of Y1, Y2 and Y3 is independently N or CRd;
• each Rd is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″, —NR″2, —NHC(O)R″, —NR″C(O)R″, NHC(O)CH(OH)R″, —NR″C(O)CH(OH)R″, —NHC(O)OR″, —NR″C(O)OR″, —NHSO2R″, —NR″SO2R″, —NO2, —CN, —C(O)H, C(O)R″, —C(O)OH, —C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —OC(O)H, —OC(O)R″, —OC(O)OH, —OC(O)OR″, —OC(O)NH2, —OC(O)NHR″, —OC(O)NR″2, —SH, —SR″, —S(O)2H, —S(O)2R″, —S(O)2OH, —S(O)2OR″, —S(O)2NH2, —S(O)2NHR″, —S(O)2NR″2, —O—R21, —NH—R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• each Rb is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″, —NR″2, —NHC(O)R″, —NR″C(O)R″, NHC(O)CH(OH)R″, —NR″C(O)CH(OH)R″, —NHC(O)OR″, —NR″C(O)OR″, —NHSO2R″, —NR″SO2R″, —NO2, —CN, —C(O)H, C(O)R″, —C(O)OH, —C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —OC(O)H, —OC(O)R″, —OC(O)OH, —OC(O)OR″, —OC(O)NH2, —OC(O)NHR″, —OC(O)NR″2, —SH, —SR″, —S(O)2H, —S(O)2R″, —S(O)2OH, —S(O)2OR″, —S(O)2NH2, —S(O)2NHR″, or —S(O)2NR″2;
• each R3 is independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″, —NR″2, —NHC(O)R″, —NR″C(O)R″, NHC(O)CH(OH)R″, —NR″C(O)CH(OH)R″, —NHC(O)OR″, —NR″C(O)OR″, —NHSO2R″, —NR″SO2R″, —NO2, —CN, —C(O)H, C(O)R″, —C(O)OH, —C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —OC(O)H, —OC(O)R″, —OC(O)OH, —OC(O)OR″, —OC(O)NH2, —OC(O)NHR″, —OC(O)NR″2, —SH, —SR″, —S(O)2H, —S(O)2R″, —S(O)2OH, —S(O)2OR″, —S(O)2NH2, —S(O)2NHR″, —S(O)2NR″2, —R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• each R″ is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• R21 is a bond connected to R18 of the linker, wherein Formula (II) contains a single R21;
• wherein,
• (i) when Rv is
• then Y2 is CRd;
• and
• (ii) when Rv is
• then Rb in CRb2 is not hydrogen
• or
• (b) Formula (III):
• wherein:
• each of X1 and X2 is independently O or S;
• T is C═O or SO2;
• R1 is hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• n is 0, 1 or 2;
• L1 is hydrogen, alkenyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)H, —C(O)R″, —C(O)OH, —C(O)OR″, —CH2C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —NH2, —NHR″, —NR″2, —S(O)2H or —S(O)2R″;
• Rx is selected from
• wherein indicates attachment to T,
• Z4 is O, S or NR4;
• V is CRf2, NR4 or S;
• each of G1, G2, G3 and G4 is independently N or CRc,
• each of Y1 and Y2 is independently N or CRf,
• each Rf is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, fused aryl-cycloalkyl, fused aryl-heterocycloalkyl, heteroaryl, heteroaryl substituted with at least one aryl group, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″, —NR″2, —NHC(O)R″, —NR″C(O)R″, NHC(O)CH(OH)R″, —NR″C(O)CH(OH)R″, —NHC(O)OR″, —NR″C(O)OR″, —NHSO2R″, —NR″SO2R″, —NO2, —CN, —C(O)H, C(O)R″, —C(O)OH, —C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —OC(O)H, —OC(O)R″, —OC(O)OH, —OC(O)OR″, —OC(O)NH2, —OC(O)NHR″, —OC(O)NR″2, —SH, —SR″, —S(O)2H, —S(O)2R″, —S(O)2OH, —S(O)2OR″, —S(O)2NH2, —S(O)2NHR″, —S(O)2NR″2, —R21, —O—R21, —NH—R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• or when Y1 and Y2 are CRf then each Rf, together with the carbon atom to which it is attached, forms a 5- or 6-membered ring;
• each Rc is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aryl substituted with at least one —OR″, heteroaryl, benzyl, haloalkyl, haloalkenyl, —NH2, —NHR″, —NR″2, —CH2NH2, —NHC(O)R″, —NR″C(O)R″, NHC(O)CH(OH)R″, —NR″C(O)CH(OH)R″, —NHC(O)OR″, —NR″C(O)OR″, —NHSO2R″, —NR″SO2R″, —NO2, —CN, —C(O)H, C(O)R″, —C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —OC(O)H, —OC(O)R″, —OC(O)OH, —OC(O)OR″, —OC(O)NH2, —OC(O)NHR″, —OC(O)NR″2, —SH, —SR″, —S(O)2H, —S(O)2R″, —S(O)2OH, —S(O)2OR″, —S(O)2NH2, —S(O)2NHR″, —S(O)2NR″2, —O—R21, —NH—R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• each R4 is independently hydrogen, halogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, benzyl, haloalkyl, haloalkenyl, —C(O)H, C(O)R″, —C(O)OH, —C(O)OR″, —C(O)NH2, —C(O)NHR″, —C(O)NR″2, —OH, —OR″, —NH2, —NHR″, —NR″2, —S(O)2H, —S(O)2R″, —R21, —C(O)—NH—R21, or —CH2—NH—C(O)—R21;
• and
• each R″ is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl;
• R21 is a bond connected to R18 of the linker, wherein Formula (III) contains a single R21;
• wherein, when n=2, each Rc is hydrogen, and each of G1, G2, G3 and G4 is CRc, then C═X1 may be replaced by CH;
• and wherein:
• (i) when Rx is
• and Z4 is NH, then L1 is hydrogen, —CH2C(O)OR″, or —OR″;
• (ii) when Rx is
• Z4 is NR4, Y1 is CRf, and Y2 is N, then R4 is not alkyl and at least one of R2 and R is not H;
• (iii) when Rx is
• Z4 is NR4, and Y1 and Y2 are CRf, then at least one of G1, G2 and G3 is N;
• (iv) when Z4 is NR4, and Y1 and Y2 are CRf, then Rx is not
• (v) when Rx is
• Z4 is NR4, and Y1 or Y2 is N, then R4 is not alkyl;
• (vi) when Rx is
• then n=1 or 2;
• and
• (vii) when Rx is
• wherein
• [MCL-1 ligand moiety] is a compound of Formula (A), Formula (B) or Formula (C)
• wherein
• is a single bond or a double bond;
• R8 is H, R19, or C1-C6 alkyl optionally substituted with morpholine;
• R9 is —C(O)OH, —C(O)OC1-C6alkyl;
• —C(O)NH2;
• —C(O)OR19 or —C(O)NHR19,
• R10 is —C2-5alkyl-O—R13 or —C2-5alkyl-NMe-R3, wherein R13 is phenyl, naphthyl or tetraline, wherein the phenyl, naphthyl or tetraline is optionally substituted with at least one substituent selected from halogen, C1-C6 alkyl and —O(C1-C6 alkyl);
• or wherein the tetraline is optionally substituted with a bridging —CH2— group;
• or wherein the naphthyl is optionally substituted with —O— or —S—,
• R11 is H, halogen or C1-C6 alkyl,
• R12 is H,
• wherein R20 is Me, —CH2—OMe, —CH2—O-bromobenzaldehyde, or
• or when R12 is
• and R10 is —O-naphthyl substituted with —O— or —S—, then R20 is
• wherein indicates attachment to —O— or —S— of R10;
• and wherein
• R19 is a bond connected to R14 of the linker;
• R23 is —C(O)OH or —C(O)OC1-C6alkyl;
• Z2 is N or C, wherein when Z2 is N, then is a single bond;
• and when Z2 is C, then is a double bond,
• R24 is furan optionally substituted with at least one halogen,
• each R25 is independently phenyl substituted with —OR28 and optionally further substituted with at least one substituent selected from halogen and C1-C6 alkyl;
• R26 is —C(O)OR19 or —C(O)NHR19;
• and
• each R28 is independently —C1-3alkyl-(N-alkyl piperazine) or —C1-3alkyl-(N-haloalkylpyrazole)
• and wherein each of Formula (A), Formula (B) and Formula (C) contains a single R19;
• and wherein [linker] has the following formula
• R14—R15—R16—R17—R18
• wherein
• R14 is —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, C1-6 alkyl-N(C1-6 alkyl)-, —C(O)—, —SO2— or is absent
• R15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C1-6 alkyl-NH—, —C1-6 alkyl-N(C1-6 alkyl)-, -cycloalkyl-NH—, -heterocycloalkyl-NH— or is absent
• R16 is —C1-6alkyl, —C(O)—, —C(O)—NH—, —C(O)O—, —CH2—C(O)—, —CH2—C(O)—NH—, —CH2—C(O)O— or is absent
• R17 is —CH2(C2H4—O)y, (C2H4—O)x, (C3H6—O)x, or is absent
• x is 1-10
• y is 2-10
• R18 is —C1-6 alkyl, heterocycloalkyl, or is absent
• wherein at least one of R14-R18 is present