Compounds comprising a fibroblast activation protein ligand and use thereof

A compound comprising a cyclic peptide

• of formula (I)
• and an N-terminal modification group A attached to Xaa1,
• wherein
• the peptide sequence is drawn from left to right in N to C-terminal direction,
• Xaa1 is a residue of an amino acid of formula (II)
• wherein
• R1a is —NH—
• R1b is H or CH3,
• n=0 or 1,
• the N-terminal modification group A is covalently attached to the nitrogen atom of Xaa1,
• the carbonyl group of Xaa1 is covalently attached to the nitrogen of Xaa2,
• and the sulfur atom of Xaa1 is covalently attached as thioether to Yc;
• Xaa2 is a residue of an amino acid of formula (III), (IV) or (XX)
• wherein
• R2a, R2b and R2c are each and independently selected from the group consisting of (C1-C2)alkyl and H, wherein said (C1-C2)alkyl may be substituted by a substituent selected from the group consisting of OH, NH2, halogen, (C5-C7)cycloalkyl,
• p=0, 1 or 2
• v=1 or 2
• w=1, 2 or 3 and
• the amino acid of formula (IV) may be substituted by one or two substituents selected from the group consisting of methyl, OH, NH2 and F, at indicated ring positions 3 and 4;
• Xaa3 is a residue of an amino acid of formula (V) or (XX)
• wherein
• X3 is selected from the group consisting of CH2, CF2, CH—R3b, S, O and NH,
• p=1 or 2
• v=1 or 2
• w=1, 2 or 3,
• R3a is H, methyl, OH, NH2 or F,
• R3b is methyl, OH, NH2 or F;
• Xaa4 is a residue of an amino acid of formula (VI)
• wherein
• R4a is selected from the group consisting of H, OH, COOH, CONH2, X4 and —NH—CO—X4, wherein X4 is selected from the group consisting of (C1-C6)alkyl, (C5-C6)aryl and (C5-C6)heteroaryl, and X4 may be substituted by one or two substituents selected from the group consisting of methyl, CONH2, halogen, NH2 and OH;
• q=1, 2 or 3, wherein optionally, one or two hydrogens of said one, two, or three CH2-groups are each and individually substituted by methyl, ethyl, (C5-C6)aryl or (C5-C6)heteroaryl,
• R4b is methyl or H;
• Xaa5 is a residue of an amino acid of structure (VII)
• wherein
• R5 is selected from the group of OH and NH2, and
• r=1, 2 or 3;
• Xaa6 is an amino acid selected from the group consisting of an aromatic L-α-amino acid and a heteroaromatic L-α-amino acid;
• Xaa7 is a residue of an amino thiol or an amino acid of formula (IX),
• wherein
• R7a is —CO—, —COOH, —CONH2, —CH2—OH, —(CO)—NH—R7b, —(CO)—(NR7c)—R7b or H, wherein R7b and R7c are each and independently (C1-C4)alkyl and
• t is 1 or 2;
• Yc is a structure of formula (X)
• linking the S atom of Xaa1 and the S atom of Xaa7 under the formation of two thioether linkages thus forming a cyclic structure of formula (XXI)
• wherein
• the substitution pattern of the aromatic group in formula (X) is ortho, meta or para, preferably meta,
• n=0 or 1,
• t=1 or 2,
• Y1 is C—H,
• Y2 is C—Rc1,
• Rc1 is CH2—Rc2 or H and
• Rc2 is a structure of formula (XIId) or (XXIIc)
• wherein
• u=1,
• Rc4 is H
• Z is a chelator optionally comprising a linker;
• and
• wherein the N-terminal modification group A is a blocking group Abl, wherein the blocking group Abl is Ra1—NH—C(O)—;
• wherein Ra1 is (C1-C8)alkyl optionally substituted by up to two substituents each and independently selected from the group consisting of OH, F, COOH, (C3-C8)cycloalkyl, aryl, heteroaryl and (C3-C8)heterocycle, and wherein in (C1-C8)alkyl one of the —CH2-groups is optionally replaced by —S— or —O—.

A compound comprising a cyclic peptide

• of formula (I)
• and an N-terminal modification group A attached to Xaa1,
• wherein
• the peptide sequence is drawn from left to right in N to C-terminal direction,
• Xaa1 is a residue of an amino acid of formula (II)
• wherein
• R1a is —NH—
• R1b is H or CH3,
• n=0 or 1,
• the N-terminal modification group A is covalently attached to the nitrogen atom of Xaa1,
• the carbonyl group of Xaa1 is covalently attached to the nitrogen of Xaa2,
• and the sulfur atom of Xaa1 is covalently attached as thioether to Yc;
• Xaa2 is a residue of an amino acid of formula (III), (IV) or (XX)
• wherein
• R2a, R2b and R2c are each and independently selected from the group consisting of (C1-C2)alkyl and H, wherein said (C1-C2)alkyl may be substituted by a substituent selected from the group consisting of OH, NH2, halogen, (C5-C7)cycloalkyl,
• p=0, 1 or 2
• v=1 or 2
• w=1, 2 or 3 and
• the amino acid of formula (IV) may be substituted by one or two substituents selected from the group consisting of methyl, OH, NH2 and F, at indicated ring positions 3 and 4;
• Xaa3 is a residue of an amino acid of formula (V) or (XX)
• wherein
• X3 is selected from the group consisting of CH2, CF2, CH—R3b, S, O and NH,
• p=1 or 2
• v=1 or 2
• w=1, 2 or 3,
• R3a is H, methyl, OH, NH2 or F,
• R3b is methyl, OH, NH2 or F;
• Xaa4 is a residue of an amino acid of formula (VI)
• wherein
• R4a is selected from the group consisting of H, OH, COOH, CONH2, X4 and —NH—CO—X4, wherein X4 is selected from the group consisting of (C1-C6)alkyl, (C5-C6)aryl and (C5-C6)heteroaryl, and X4 may be substituted by one or two substituents selected from the group consisting of methyl, CONH2, halogen, NH2 and OH;
• q=1, 2 or 3, wherein optionally, one or two hydrogens of said one, two, or three CH2-groups are each and individually substituted by methyl, ethyl, (C5-C6)aryl or (C5-C6)heteroaryl,
• R4b is methyl or H;
• Xaa5 is a residue of an amino acid of structure (VII)
• wherein
• R5 is selected from the group of OH and NH2, and
• r=1, 2 or 3;
• Xaa6 is an amino acid selected from the group consisting of an aromatic L-α-amino acid and a heteroaromatic L-α-amino acid;
• Xaa7 is a residue of an amino thiol or an amino acid of formula (IX),
• wherein
• R7a is —CO—, —COOH, —CONH2, —CH2—OH, —(CO)—NH—R7b, —(CO)—(NR7c)—R7b or H, wherein R7b and R7c are each and independently (C1-C4)alkyl and
• t is 1 or 2;
• Yc is a structure of formula (X)
• linking the S atom of Xaa1 and the S atom of Xaa7 under the formation of two thioether linkages thus forming a cyclic structure of formula (XXI)
• wherein
• the substitution pattern of the aromatic group in formula (X) is meta,
• n=0 or 1,
• t=1 or 2,
• Y1 is C—H or N,
• Y2 is C—Rc1,
• Rc1 is H;
• wherein the N-terminal modification group A is an amino acid Aaa,
• wherein
• the amino acid Aaa is an L-amino acid residue of structure (XIV):
• wherein
• Ra2 is selected from the group consisting of (C1-C6)alkyl and modified (C1-C6)alkyl, wherein in modified (C1-C6)alkyl one —CH2— group is replaced by —S— or —O—,
• the amino acid Aaa is covalently attached to a linker, wherein the linker is covalently linked to a chelator Z, wherein the linker consists (a) of a first linker or (b) of a first linker and a second linker, wherein
• if the linker consists of the first linker, the first linker is covalently linked to the chelator and the amino acid Aaa, and
• if the first linker consists of a first linker and a second linker, the first linker is covalently linked to the amino acid Aaa and to the second linker, and the second linker is covalently linked to the chelator,
• the first linker is selected from the group consisting of Ttds and PEG6, preferably the first linker is Ttds,
• the second linker is selected from the group consisting of PPAc and PEG6, preferably the second linker is PPAc.

A compound comprising a cyclic peptide

• of formula (I)
• and an N-terminal modification group A attached to Xaa1,
• wherein
• the peptide sequence is drawn from left to right in N to C-terminal direction,
• Xaa1 is a residue of an amino acid of formula (II)
• wherein
• R1a is —NH—
• R1b is H or CH3,
• n=0 or 1,
• the N-terminal modification group A is covalently attached to the nitrogen atom of Xaa1,
• the carbonyl group of Xaa1 is covalently attached to the nitrogen of Xaa2,
• and the sulfur atom of Xaa1 is covalently attached as thioether to Yc;
• Xaa2 is a residue of an amino acid of formula (III), (IV) or (XX)
• wherein
• R2a, R2b and R2c are each and independently selected from the group consisting of (C1-C2)alkyl and H, wherein said (C1-C2)alkyl may be substituted by a substituent selected from the group consisting of OH, NH2, halogen, (C5-C7)cycloalkyl,
• p=0, 1 or 2
• v=1 or 2
• w=1, 2 or 3 and
• the amino acid of formula (IV) may be substituted by one or two substituents selected from the group consisting of methyl, OH, NH2 and F, at indicated ring positions 3 and 4;
• Xaa3 is a residue of an amino acid of formula (V) or (XX)
• wherein
• X3 is selected from the group consisting of CH2, CF2, CH—R3b, S, O and NH,
• p=1 or 2
• v=1 or 2
• w=1, 2 or 3,
• R3a is H, methyl, OH, NH2 or F,
• R3b is methyl, OH, NH2 or F;
• Xaa4 is a residue of an amino acid of formula (VI)
• wherein
• R4a is selected from the group consisting of H, OH, COOH, CONH2, X4 and —NH—CO—X4, wherein X4 is selected from the group consisting of (C1-C6)alkyl, (C5-C6)aryl and (C5-C6)heteroaryl, and X4 may be substituted by one or two substituents selected from the group consisting of methyl, CONH2, halogen, NH2 and OH;
• q=1, 2 or 3, wherein optionally, one or two hydrogens of said one, two, or three CH2-groups are each and individually substituted by methyl, ethyl, (C5-C6)aryl or (C5-C6)heteroaryl,
• R4b is methyl or H;
• Xaa5 is a residue of an amino acid of structure (VII)
• wherein
• R5 is selected from the group of OH and NH2, and
• r=1, 2 or 3;
• Xaa6 is an amino acid selected from the group consisting of an aromatic L-α-amino acid and a heteroaromatic L-α-amino acid;
• Xaa7 is a residue of an amino thiol or an amino acid of formula (IX),
• wherein
• R7a is —CO—, —COOH, —CONH2, —CH2—OH, —(CO)—NH—R7b, —(CO)—(NR7c)—R7b or H, wherein R7b and R7c are each and independently (C1-C4)alkyl and
• t is 1 or 2;
• Yc is a structure of formula (X)
• linking the S atom of Xaa1 and the S atom of Xaa7 under the formation of two thioether linkages thus forming a cyclic structure of formula (XXI)
• wherein
• the substitution pattern of the aromatic group in formula (X) is meta,
• n=0 or 1,
• t=1 or 2,
• Y1 is C—H
• Y2 is C—Rc1,
• Rc1 is CH2—R2 and
• Rc2 is a structure of formula (XIId)
• wherein
• u=1, 2, 3, 4, 5 or 6, preferably u=1,
• Rc4 is H or methyl,
• Z is a chelator optionally comprising a linker, and
• wherein the N-terminal modification group A is a blocking group Abl, wherein the blocking group Abl is selected from the group consisting of Ra11—C(O)—, wherein Ra11 is C4 alkyl or C5 alkyl, wherein in each and any one of C4 alkyl and C5 alkyl individually and independently one of the —CH2-groups is optionally replaced by —O— or —S—.