US 2026/0284242 A1Published application

Protease-activated receptor-2 (par2) targeted therapeutics and uses thereof

AssigneeRadionetics Oncology, Inc.

InventorsJunjie LIU, Yunfei ZHU, Yifeng XIONG

Life of this patent

Estimating the term…

Abstract

Described herein are radiotherapeutics that target tumor cells expressing the Protease-Activated Receptor-2 (PAR2) and their use in the treatment and/or diagnosis of cancer.

Claims30

Dependent claims

A compound of Formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:
L9 is an optional linker that is attached to any one of X5, X6, X7, or X8;
Rb is:
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA);
2,2′,2″-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (PSC);
1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A);
1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A);
α,α′,α″,α′″-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA);
1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (DOTAM);
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrapropionic acid (DOTPA);
2,2′,2″-(10-(2-amino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid;
benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA);
2,2′,2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA);
6,6′-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diyl)bis(methylene))dipicolinic acid (macropa);
2,2′,2″,2′-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (crown);
6,6′-((ethane-1,2-diylbis((carboxymethyl)azanediyl))bis(methylene))dipicolinic acid (H4octapa);
H4octapa-benzyl;
or
3,6,9,12-tetrakis(carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA);
Ra is —C(═O)—R10;
R10 is an aryl, heteroaryl, or partially unsaturated bicyclic heterocyclic ring, each optionally substituted with 1 to 3 substituents that are each independently selected from the group consisting of halo, —C1-C6 alkyl, alkoxy, —OH, —NH2, —NH—C1-C6 alkylene-R11, or —O—C1-C6 alkylene-R11, or —R11;
wherein any saturated carbon of R10 is optionally substituted with oxo (═O);
R11 is an aryl or heteroaryl optionally substituted with 1 to 3 substituents that are each independently selected from the group consisting of —F, —Cl, —Br, —C1-C3 alkyl, —CF3, —CN, —OCH3, —NH2, or —NO2;
X1 is
R1 is -L1-R1b;
L1 is absent, —CH2—, or —CHPh-;
R1b is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 3,3-difluorocyclohexyl, 3,3-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, cyclooctyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl, perfluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4,5-trichlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3,4-bis(trifluoromethyl)phenyl, 4-vinylphenyl, 4-tert-butylphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-aminophenyl, 4-carbamoylphenyl, 4-ureidophenyl, 4-acetylphenyl, 4-azidophenyl, 4-(azidomethyl)phenyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 3-cyclopropylphenyl, [1,1′-biphenyl]-4-yl, 4′-fluoro-[1,1′-biphenyl], 4′-methyl-[1,1′-biphenyl]-4-yl, piperidin-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 1H-indol-3-yl, 2,3-dihydrobenzofuran-6-yl, naphthalen-1-yl, or adamantan-1-yl;
wherein each R1b is optionally additionally substituted with 1 or more —F, —Br, —Cl, —I, —CF3, or —C1-C6 alkyl;
R1a is hydrogen or methyl;
or R1 and R1a are taken together with the carbon atoms to which they are attached to form:
X2 is
R2 is -L2-R2b;
L2 is absent;
R2b is methyl, pent-3-yl, tert-butyl, 1,1,1,3,3,3-hexafluoropropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 3,3-difluorocyclohexyl, 3,3-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, cyclooctyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl, perfluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4,5-trichlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3,4-bis(trifluoromethyl)phenyl, 4-vinylphenyl, 4-tert-butylphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-aminophenyl, 4-carbamoylphenyl, 4-ureidophenyl, 4-acetylphenyl, 4-azidophenyl, 4-(azidomethyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 3-cyclopropylphenyl, [1,1′-biphenyl]-4-yl, 4′-fluoro-[1,1′-biphenyl], 4′-methyl-[1,1′-biphenyl]-4-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 1H-indol-3-yl, 2,3-dihydrobenzofuran-6-yl, naphthalen-1-yl, or adamantan-1-yl;
wherein each R2b is optionally additionally substituted with 1 or more —F, —Br, —Cl, —I or —C1-C6 alkyl;
R2a is hydrogen or methyl;
or R2 and R2a are taken together with the carbon atoms to which they are attached to form:
R4b is H, —C(═NH)NH2, —C(═O)CH(CH3)NCH3, —CH2C(═O)NHC1-C10 alkyl-NH2, or —C(═O)CH2NHC1-C10 alkyl;
X5 is absent, -L5-, alanine (Ala), lysine (Lys), ornithine (Orn), β3-homolysine, γ-glutamic acid (γ-Glu), leucine (Leu), phenylalanine (Phe), 4-azidophenylalanine (Phe(4-N3)), norleucine (Nle), 2-aminoheptanoic acid, 2-amino-6-azidohexanoic acid, N6-acetyl-lysine, N6-(pent-4-ynoyl)-lysine, N6-octanoyl-lysine, tyrosine (Tyr), N6-palmitoyl-Lys, N6-(15-carboxypentadecanoyl)-Lys, N6-(16-oxo-16-((2-(N—N—N-trimethyl-amino)ethyl)amino)hexadecanoyl)-Lys, N6-(4-fluorobenzoyl)-Lys, β3-homolysine, 3-amino-alanine (H-Dap-OH), 4-fluorophenylalanine (Phe(4-F)), 4-iodophenylalanine (Phe(4-I)), 4-nitrophenylalanine (Phe(4-NO2)), (4-fluorobenzamido)methylglycine, 4-aminomethylphenylalanine (Phe(4-CH2NH2)), 4-azidomethylphenylalanine (Phe(4-CH2N3)), 4-amino-1-((3-fluoro-4-methylbenzyl)glycyl)piperidine-4-carboxylic acid, 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, proline (Pro), hydroxyproline (Hyp), piperidine-2-carboxylic acid, isoindoline-1-carboxylic acid, or (4-(aminomethyl)-1H-1,2λ2,3λ2-triazol-1-yl)methyl)-glycine;
X6 is absent, -L6-, lysine (Lys), ornithine (Orn), (4-fluorobenzamido)methylglycine, N6-(4-fluorobenzoyl)-Lys, 4-amino-1-(methylglycyl)piperidine-4-carboxylic acid, or 4-amino-1-(N-carbamimidoyl-N-methylglycyl)piperidine-4-carboxylic acid;
X7 is absent, -L7-, lysine (Lys), ornithine (Orn), glutamic acid (Glu), norleucine (Nle), or
R17 is —CH3 or —I;
z is 1, 2, or 3;
and
X8 is absent, lysine (Lys), or glutamic acid (Glu).
L5, L6, and L7 are each independently —NR15-L13-L14-C(═O)— or substituted or unsubstituted piperazinylene-;
L13 is absent, —C1-C6 alkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted cyclohexylene, —(CH2CH2O)y—, or —(CH2CH2NR16)y—;
L14 is absent, —C1-C6 alkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted cyclohexylene;
R15 and R16 are each independently selected from H or —C1-C4 alkylene;
and
y is 1, 2, 3, 4, 5, or 6;
wherein the compound of Formula (VIII) is optionally substituted with —C(═O)—C1-C14 alkylene-R12, wherein R12 is H, —CH3, —COOH, —OH, —NH2, or —NHCH2CH2N(CH3)3;
wherein any free —NH— of a peptide bond is optionally independently substituted with —CH3 or —CH2CH3;
wherein any alpha position of any amino acid is optionally independently substituted with —CH3 or —CH2CH3;
and
wherein the C-terminal end of the compound of Formula (VIII) may be either —COOH or —CONH2;
wherein the radionuclide of the radionuclide complex is:
111-indium (111In), 115-indium (115In), 67-gallium (67Ga), 68-gallium (68Ga), 69-gallium (69Ga), 71-gallium (71Ga), 99m-technetium (99mTc), 195m-platinum (195mPt), 225-actinium (225Ac), 213-bismuth (213Bi), 223-radium (223Ra), 211-astatine (211At), aluminium-[18F]fluoride ([18F]AlF), 90-yttrium (90Y), 175-lutetium (175Lu), 177-lutetium (177Lu), 161-terbium (161Tb), 186-rhenium (186Re), 188-rhenium (188Re), 204-lead (204Pb), 206-lead (206Pb), 207-lead (207Pb), 208-lead (208Pb), 212-lead (212Pb), 63-copper (63Cu), 64-copper (64Cu), 65-copper (65Cu), 67-copper (67Cu), 153-samarium (153Sm), 89-strontium (89Sr), 198-gold (198Au), 169-erbium (169Er), 165-dysprosium (165Dy), 99m-technetium (99mTc), 89-zirconium (89Zr), 52-manganese (52Mn), 60-cobalt (60Co), 103-palladium (103Pd), 137-cesium (137Cs), 169-ytterbium (169Yb), 192-iridium (192Ir), or 226-radium (226Ra).

55 more elements

A compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein:
m is 1 or 2;
Ra is —C(═O)—R10;
R10 is an aryl, heteroaryl, or partially unsaturated bicyclic heterocyclic ring, each optionally substituted with 1 to 3 substituents that are each independently selected from the group consisting of halo, —C1-C6 alkyl, alkoxy, —OH, —NH2, —NH—C1-C6 alkylene-R11, or —O—C1-C6 alkylene-R11, or —R1;
wherein any saturated carbon of R10 is optionally substituted with oxo (═O);
R11 is an aryl or heteroaryl optionally substituted with 1 to 3 substituents that are each independently selected from the group consisting of —F, —Cl, —Br, —C1-C3 alkyl, —CF3, —CN, —OCH3, —NH2, or —NO2;
R1 is -L1-R1b;
L1 is absent, —CH2—, or —CHPh-;
R1b is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 3,3-difluorocyclohexyl, 3,3-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, cyclooctyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl, perfluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4,5-trichlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3,4-bis(trifluoromethyl)phenyl, 4-vinylphenyl, 4-tert-butylphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-aminophenyl, 4-carbamoylphenyl, 4-ureidophenyl, 4-acetylphenyl, 4-azidophenyl, 4-(azidomethyl)phenyl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 3-cyclopropylphenyl, [1,1′-biphenyl]-4-yl, 4′-fluoro-[1,1′-biphenyl], 4′-methyl-[1,1′-biphenyl]-4-yl, piperidin-1-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 1H-indol-3-yl, 2,3-dihydrobenzofuran-6-yl, naphthalen-1-yl, or adamantan-1-yl;
wherein each R1b is optionally additionally substituted with 1 or more —F, —Br, —Cl, —I, —CF3, or —C1-C6 alkyl;
R1a is hydrogen or methyl;
or R1 and R1a are taken together with the carbon atoms to which they are attached to form:
R2 is -L2-R2b;
L2 is absent, —CH2—, or —CHPh-;
R2b is methyl, pent-3-yl, tert-butyl, 1,1,1,3,3,3-hexafluoropropan-2-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-fluorocyclohexyl, 4-fluorocyclohexyl, 3,3-difluorocyclohexyl, 3,3-dimethylcyclohexyl, 4,4-difluorocyclohexyl, 4,4-dimethylcyclohexyl, cycloheptyl, cyclooctyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl, perfluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4,5-trichlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3,4-bis(trifluoromethyl)phenyl, 4-vinylphenyl, 4-tert-butylphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-aminophenyl, 4-carbamoylphenyl, 4-ureidophenyl, 4-acetylphenyl, 4-azidophenyl, 4-(azidomethyl)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2,3-dihydro-1H-inden-1-yl, 2,3-dihydro-1H-inden-2-yl, 3-cyclopropylphenyl, [1,1′-biphenyl]-4-yl, 4′-fluoro-[1,1′-biphenyl], 4′-methyl-[1,1′-biphenyl]-4-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 1H-indol-3-yl, 2,3-dihydrobenzofuran-6-yl, naphthalen-1-yl, or adamantan-1-yl;
wherein each R2b is optionally additionally substituted with 1 or more —F, —Br, —Cl, —I or —C1-C6 alkyl;
R2a is hydrogen or methyl;
or R2 and R2a are taken together with the carbon atoms to which they are attached to form:
X3 is glycine, (S)-alanine (Ala), (S)-trifluoromethylalanine, (S)-homoalanine, (S)-Glu, (S)-Gln, (S)-Orn, (S)-lysine (Lys), (S)-serine (Ser), (S)—N-methylalanine (N-Me-Ala), 2-amino-2-methylpropanoic acid (AIB), 1-aminocyclopropane-1-carboxylic acid (ACC), norleucine (Nle), (S)-3-aminoalanine, (S)-2-amino-6-azidohexanoic acid, (S)-2-amino-6-(4-hexyl-1H-1,2,3-triazol-1-yl)hexanoic acid, (S)-2-amino-6-(4-((2-methoxyethoxy)methyl)-1H-1,2,3-triazol-1-yl)hexanoic acid, (S)-2-amino-6-(4-(cyclopentylmethyl)-1H-1,2,3-triazol-1-yl)hexanoic acid, (S)-2-amino-6-(4-benzyl-1H-1,2,3-triazol-1-yl)hexanoic acid, (S)-proline (Pro), (S)-cyclopropylglycine, or (S)-biphenylalanine (Bip);
X4 is
X6 is absent, -L6-, lysine (Lys), ornithine (Orn), (4-fluorobenzamido)methylglycine, N6-(4-fluorobenzoyl)-Lys, 4-amino-1-(methylglycyl)piperidine-4-carboxylic acid, or 4-amino-1-(N-carbamimidoyl-N-methylglycyl)piperidine-4-carboxylic acid;
X7 is absent, -L7-, lysine (Lys), ornithine (Orn), glutamic acid (Glu), norleucine (Nle), or
R17 is —CH3 or —I;
z is 1, 2, or 3;
and
L6 and L7 are each independently —NR15-L13-L14-C(═O)— or substituted or unsubstituted piperazinylene-;
L13 is absent, —C1-C6 alkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted cyclohexylene, —(CH2CH2O)y—, or —(CH2CH2NR16)y—;
L14 is absent, —C1-C6 alkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted cyclohexylene;
R15 and R16 are each independently selected from H or —C1-C4 alkylene;
and
y is 1, 2, 3, 4, 5, or 6;
wherein the compound of Formula (IX) is optionally substituted with —C(═O)—C1-C14 alkylene-R12, wherein R12 is H, —CH3, —COOH, —OH, —NH2, or —NHCH2CH2N(CH3)3;
wherein any free —NH— of a peptide bond is optionally independently substituted with —CH3 or —CH2CH3;
wherein any alpha position of any amino acid is optionally independently substituted with —CH3 or —CH2CH3;
and
wherein the C-terminal end of the compound of Formula (IX) may be either —COOH or —CONH2;
wherein the radionuclide of the radionuclide complex is:
an Auger electron-emitting radionuclide that is 111-indium (111In), 115-indium (115In), 67-gallium (67Ga), 68-gallium (68Ga), 69-gallium (69Ga), 71-gallium (71Ga), 99m-technetium (99mTc), 195m-platinum (195mPt) 225-actinium (225Ac), 213-bismuth (213Bi), 223-radium (223Ra), 211-astatine (211At), aluminium-[18F]fluoride ([18F]AlF), 90-yttrium (90Y), 175-lutetium (175Lu), 177-lutetium (177Lu), 161-terbium (161Tb), 186-rhenium (186Re), 188-rhenium (188Re), 204-lead (204Pb), 206-lead (206Pb), 207-lead (207Pb), 208-lead (208Pb), 212-lead (212Pb), 63-copper (63Cu), 64-copper (64Cu), 65-copper (65Cu), 67-copper (67Cu), 153-samarium (153Sm), 89-strontium (89Sr), 198-gold (198Au), 169-erbium (169Er), 165-dysprosium (165Dy), 99m-technetium (99mTc), 89-zirconium (89Zr), 52-manganese (52Mn), 60-cobalt (60Co), 103-palladium (103Pd), 137-cesium (137Cs), 169-ytterbium (169Yb), 192-iridium (192Ir), or 226-radium (226Ra).

35 more elements

Dependencies are inferred from the claim text.

patentgrep

Loading patent…

Back to results