IP Library › Granted Patent US 12685789

Granted Patent B2

US 12685789 · App. 19/002,144 · Granted Jul 21, 2026

Neuropeptide Y1 receptor (NPY1R) targeted therapeutics and uses thereof

Inventors: Yifeng Xiong (San Diego, CA); Junjie Liu (San Diego, CA); Yunfei Zhu (San Diego, CA)

Assignee: RADIONETICS ONCOLOGY, INC.

A61K51/0497 C07B59/002 A61K2121/00 C07B2200/05

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Quick Facts

Patent No.: US 12685789
App. No.: 19/002,144
Granted: Jul 21, 2026
Kind: B2

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Abstract

Described herein are radiotherapeutics that target tumor cells expressing the neuropeptide Y 1 receptor (NPY 1 R) and their use in the treatment and/or diagnosis of cancer.

Claims (155)

1 . A compound of Formula (If), or a pharmaceutically acceptable salt thereof:

wherein,

R 2 is —OH, —NH 2 , —C(═O)NH 2 or —CH 2 NHC(═O)NH 2 ;

R 3a , R 3b , R 3c , and R 3d are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, substituted or unsubstituted —C 1 -C 6 alkyl, and substituted or unsubstituted —C 1 -C 6 alkoxy;

R 4 is H, —C(═O)R 10 , —C(═O)NHR 10 or —C(═O)N(CH 3 )R 10 ;

R 10 is substituted or unsubstituted —C 1 -C 6 alkyl, substituted or unsubstituted 2 to 6-membered heteroalkyl, or —(CH 2 ) t NHC(═O)(CH 2 ) u CH 3 ;

t is 1, 2, 3, 4, 5, or 6;

u is 1, 2, 3, or 4;

R 6 is —Z A —L A —R A ;

Z A is absent, —C 1 -C 6 alkylene-, —C 1 -C 6 alkylene-O—, —O—C 1 -C 6 alkylene-, —C(═O)NR 12 —, —NR 12 C(═O)—, —O—, or —NR 12 —;

L A is a linker;

R A is a chelating moiety or a radionuclide complex thereof; and

R 12 is H or unsubstituted —C 1 -C 4 alkyl;

wherein R A is selected from the group consisting of:

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);

p-hydroxy-benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (p-OH-Bn-DOTA);

6,6′-(((pyridine-2,6-diylbis(methylene))bis((carboxymethyl) azanediyl))bis(methylene))dipicolinic acid (H 4 pypa);

H 4 pypa-benzyl;

6,6′,6″,6″-(((pyridine-2,6-diylbis(methylene))bis (azanetriyl))tetrakis(methylene))tetrapicolinic acid (H 4 py 4 pa);

H 4 py 4 pa-benzyl;

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 (H 4 octapa);

H 4 octapa-benzyl; and

3,6,9,12-tetrakis (carboxymethyl)-3,6,9,12-tetraazatetradecanedioic acid (TTHA);

or a radionuclide complex thereof;

wherein the radionuclide of the chelator-radionuclide complex is:

111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 69-gallium ( 69 Ga), 71-gallium ( 71 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), 177-lutetium ( 177 Lu), 204-lead ( 204 Pb), 206-lead ( 206 Pb), 207-lead ( 207 Pb), 208-lead ( 208 Pb), 212-lead ( 212 Pb), 63-copper ( 63 Cu), 64-copper ( 64 Cu), 65-copper ( 65 Cu), or 67-copper ( 67 Cu).

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

Z A is C 1 -C 6 alkylene, —O—, —NH—, —N(—CH 3 )—, or —NHC(═O).

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein

R 3a , R 3b , R 3c , and R 3d are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, —CH 3 , —CF 3 , and —OCH 3 ; and

Z A is —CH 2 —, —O—, —NH—, —N(—CH 3 )—, or —NHC(═O)—.

4 . The compound of claim 3 , wherein the compound has the structure of Formula (Iz) or Formula (Iaa), or a pharmaceutically acceptable salt thereof:

5 . The compound of claim 2 , wherein the compound has the following structure, or a pharmaceutically acceptable salt thereof:

6 . A compound that has the following structure, or a pharmaceutically acceptable salt thereof:

or a radionuclide complex thereof;

wherein,

R 1 is H;

R 2 is —OH;

each R 3 is independently selected from the group consisting of H, F, Cl, Br, I, —CN, —CH 3 , —CF 3 , and —OCH 3 ;

R 4 is —C(═O)NHR 10 ;

R 10 is unsubstituted —C 1 -C 6 alkyl or —(CH 2 ) t NHC(═O)(CH 2 ) u CH 3 ;

t is 1, 2, 3, or 4;

u is 1 or 2;

Z A is absent, —C 1 -C 6 alkylene-, —C 1 -C 6 alkylene-O—, —O—C 1 -C 6 alkylene-, —C(═O)NR 12 -, —NR 12 C(═O)—, —O—, or —NR 12 -;

L A is a linker:

R 9 is H;

R 12 is H or unsubstituted —C 1 -C 4 alkyl;

n is 0, 1, 2, 3, or 4;

m is 0; and

p is 0;

wherein the radionuclide of the chelator-radionuclide complex is:

7 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —OH;

R 3a and R 3d are F or Cl and R 3b and R 3c are H;

R 4 is —C(═O)NHR 10 ;

R 10 is unsubstituted —C 1 -C 6 alkyl or —(CH 2 ) t NHC(═O)(CH 2 ) u CH 3 ;

t is 1, 2, 3, or 4; and

u is 1 or 2.

8 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R A is:

1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA);

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); or

benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Bn-DOTA);

or a radionuclide complex thereof.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R A is

or a radionuclide complex thereof.

10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein L A is independently selected from -L 2 -, -L 3 -, -L 4 -, -L 5 -, -L 6 -, -L 7 -, -L 2 -L 3 -, -L 2 -L 7 -, -L 4 -L 7 -, -L 2 -L 4 -L 7 -, -L 2 -L 6 -L 7 -, -L 2 -L 3 -L 4 -L 7 -, -L 2 -L 4 -L 5 -L 7 -, -L 2 -L 4 -L 6 -L 7 -, or -L 2 -L 4 -L 5 -L 6 -L 7 -;

L 2 is absent, substituted or unsubstituted —C 1 -C 20 alkylene-NR 16 —, substituted or unsubstituted —C 1 -C 20 alkylene-NR 16 C(═O)—, or —(CH 2 CH 2 O) w —CH 2 CH 2 —;

each R 16 is independently selected from H and C 1 -C 4 alkyl;

w is 1, 2, 3, 4, 5, or 6;

L 3 is absent or a natural or unnatural amino acid or peptide that is formed from two or more independently selected natural and unnatural amino acids, wherein when two or more amino acids are present then the N atom of the amide linking the amino acids is optionally substituted with —C 1 -C 6 alkyl;

L 4 is absent, substituted or unsubstituted 2 to 10-membered heteroalkylene, —(CH 2 ) v -, —(CH 2 CH 2 O) v —CH 2 CH 2 —, —C(═O)CH 2 CH 2 —, —(CH 2 ) v —NR 17 C(═O)—, —CH 2 CH 2 C(═O)NHCH 2 CH 2 —, —CH 2 CH 2 —C(═O)NH—(CH 2 CH 2 O) v CH 2 CH 2 —, —(CH 2 ) x —NR 17 —(CH 2 ) v -, —NHC(═O)NH—O—(CH 2 ) v -, —NHC(═O)NH—(CH 2 ) v -, —(CH 2 ) x —NHC(═O)NH—(CH 2 ) v -, —(CH 2 ) x —NHC(═O)—(CH 2 ) v -, —(CH 2 ) x —C(═O)NH—(CH 2 ) v -, —CH 2 CH(═OH) CH 2 —CH(OH)—CH 2 CH 2 —, —CH 2 CH(═OH)CH 2 —CH(OH)—CH 2 CH 2 —NHC(═O)CH 2 CH 2 C(═O)—NHCH 2 CH 2 —, or —NHC(═O)CH 2 —O—NH—C(═O)(CH 2 ) v -;

each R 17 is H or —C 1 -C 6 alkyl;

each x is independently 1, 2, 3, 4, 5, or 6;

each v is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

L 5 is absent, —O—, or —NR 13 C(═O); R 13 is H or —C 1 -C 4 alkyl;

L 6 is absent or -L 8 -L 9 -L 10 -;

L 8 is absent, —(CH 2 ) r -, —(CH 2 ) r —NR 14 —, or substituted or unsubstituted heterocycloalkylene;

r is 0, 1, 2, or 3;

L 9 is substituted or unsubstituted cycloalkylene, substituted or unsubstituted cycloalkenylene, substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted arylene;

L 10 is absent, —(CH 2 ) q -, —NR 15 —(CH 2 ) q -, or —C(═O)—(CH 2 ) q -; q is 1, 2, 3, 4, 5 or 6;

R 14 and R 15 are each independently selected from H or —C 1 -C 6 alkyl; and

L 7 is —NH—.

11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein L 2 is substituted or unsubstituted —C 1 -C 20 alkylene-NH— or substituted or unsubstituted —C 1 -C 20 alkylene —NHC(═O)—;

L 3 is absent or L 3 is a natural amino acid, an unnatural amino acid, or peptide that is formed from two or more independently selected amino acids selected from the group consisting of alanine (Ala), 3-(2-Naphthyl)-alanine (2-Nal), arginine (Arg), asparagine (Asn), aspartate (Asp), cysteine (Cys), cysteic acid, glutamine (Gln), glutamate (Glu), gamma-Carboxyglutamate (Gla), glycine (Gly), histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), hydroxylysine (Hyl), ornithine (Orn), methionine (Met), phenylalanine (Phe), p-phenyl phenylalanine (Bip), proline (Pro), hydroxyproline (Hyp), serine (Ser), homoserine (Hse), sarcosine (Sar), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), and valine (Val), wherein when two or more amino acids are present then the N atom of the amide linking the amino acids is optionally substituted with —CH 3 ;

L 4 is —(CH 2 ) v -, —(CH 2 CH 2 O) v —CH 2 CH 2 —, —(CH 2 ) v —NR 17 C(═O)—, —CH 2 CH 2 C(═O)NHCH 2 CH 2 —, —CH 2 CH 2 —C(═O)NH—(CH 2 CH 2 O) v CH 2 CH 2 —, —(CH 2 ) v —NR 17 —(CH 2 ) v -, —NH(C═O)NH—O—(CH 2 ) v -, —NHC(═O)NH—(CH 2 ) v -, —(CH 2 ) x —NHC(═O)NH—(CH 2 ) v -, —CH 2 CH(OH)CH 2 —CH(OH)—CH 2 CH 2 —, —CH 2 CH(OH)CH 2 —CH(OH)—CH 2 CH 2 —NHC(═O)CH 2 CH 2 C(═O)—NHCH 2 CH 2 —, or —NHC(═O)CH 2 —O—NH—C(═O)(CH 2 ) v -;

v is 1, 2, 3, 4, 5, or 6;

L 6 is absent or -L 8 -L 9 -L 10 -;

L 8 is absent, —(CH 2 ) r -, or —(CH 2 ) r —NR 14 —;

r is 1 or 2;

L 9 is substituted or unsubstituted 4 to 6-membered heterocycloalkylene, an unsubstituted or substituted C 4 -C 8 cycloalkylene, an unsubstituted or substituted C 4 -C 8 cycloalkenylene, or unsubstituted phenylene; and

L 10 is absent, —(CH 2 ) q -, —NH—(CH 2 ) q -, or —C(═O)—(CH 2 ) q -.

12 . The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein L 9 is azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, or

13 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

-L 2 -L 3 -R A ;

L 2 is unsubstituted —C 1 -C 6 alkylene-NH—; and L 3 is a natural or unnatural amino acid, wherein the N atom of the amide linking the amino acids is optionally substituted with —CH 3 .

14 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

-L A -R A is -L 2 -L 7 -R A ;

L 2 is —(CH 2 CH 2 O) w —CH 2 CH 2 —; and

L 7 is —NH—.

15 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

-L A -R A is -L 2 -L 4 -L 7 -R A ,

L 2 is unsubstituted —C 1 -C 6 alkylene- or unsubstituted —C 1 -C 6 alkylene-NHC(═O)—;

L 4 is —(CH 2 ) v —, —(CH 2 CH 2 O) v —CH 2 CH 2 —, —(CH 2 ) v —NR 17 —(CH 2 ) v , —NHC(═O)NH—O—(CH 2 ) v —NHC(═O)CH 2 —O—NH—C(═O)(CH 2 ) v —, —CH 2 CH(═OH) CH 2 —CH(OH)—CH 2 CH 2 —, —CH 2 CH 2 C(═O)NHCH 2 CH 2 —, —CH 2 CH 2 —C(═O)NH—(CH 2 CH 2 O) v CH 2 CH 2 —, or —CH 2 CH(—OH)CH 2 —CH(OH)—CH 2 CH 2 —NHC(═O)CH 2 CH 2 C(═O)—NHCH 2 CH 2 ; and

L 7 is —NH—.

16 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

-L A -R A is -L 2 -L 6 -L 7 -R A ;

L 2 is unsubstituted —C 1 -C 6 alkylene-, unsubstituted —C 1 -C 6 alkylene-NH—, or unsubstituted —C 1 -C 6 alkylene-NHC(═O)—;

L 6 is -L 8 -L 9 -L 10 -; and

L 7 is —NH—.

17 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein L A is:

18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H;

R 2 is —OH;

R 3a and R 3d are F or Cl and R 3b and R 3c are H;

R 4 is —C(═O)NHR 10 ;

R 10 is unsubstituted —C 1 -C 6 alkyl or —(CH 2 ) t NHC(═O)(CH 2 ) u CH 3 ;

t is 1, 2, 3, or 4; u is 1 or 2;

R 6 is —Z A -L A -R A ;

and

Z A is —O—, —NH—, —N(—CH 3 )—, —NHC(—O)— or —CH 2 —.

19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein -L A -R A is:

or a radionuclide complex thereof.

20 . A compound that has one of the following structures, or a pharmaceutically acceptable salt thereof:

or a radionuclide complex thereof;

wherein the radionuclide of the chelator-radionuclide complex is:

21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (If) has one of the following structures, or a pharmaceutically acceptable salt thereof:

or a radionuclide complex thereof.

22 . The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein the compound comprises a chelator-radionuclide complex and the radionuclide of the chelator-radionuclide complex is: 225-actinium ( 225 Ac), 212-lead ( 212 Pb), or 177-lutetium ( 177 Lu).

23 . The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein: the compound comprises a chelator-radionuclide complex and the radionuclide of the chelator-radionuclide complex is 111-indium ( 111 In), 115-indium ( 115 In), 67-gallium ( 67 Ga), 68-gallium ( 68 Ga), 225-actinium ( 225 Ac), 175-lutetium ( 175 Lu), or 177-lutetium ( 177 Lu).

24 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

25 . A method for the treatment of cancer comprising administering to a mammal with cancer an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof; wherein the compound comprises a chelator-radionuclide complex and the radionuclide of the chelator-radionuclide complex is:

an α-emitting radionuclide that is 225-actinium ( 225 Ac), or 212-lead ( 212 Pb); or

a β-emitting radionuclide that is 177-lutetium ( 177 Lu), 64-copper ( 64 Cu), or 67-copper ( 67 Cu).

26 . The method of claim 25 , wherein the cancer is breast cancer, kidney cancer, ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, nephroblastoma, or adrenal gland tumors.

27 . A method of killing tumors in a mammal that overexpress the neuropeptide Y 1 receptor (NPY 1 R) comprising administering to the mammal a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound comprises a chelator-radionuclide complex and the radionuclide of the chelator-radionuclide complex is:

an α-emitting radionuclide that is 225-actinium ( 225 Ac), 213-bismuth ( 213 Bi), 223-radium ( 223 Ra), or 212-lead ( 212 Pb); or

a β-emitting radionuclide that is 90-yttrium ( 90 Y), 177-lutetium ( 177 Lu), 64-copper ( 64 Cu), 67-copper ( 67 Cu), or 153-samarium ( 153 Sm).

28 . The method of claim 27 , wherein the mammal has been diagnosed with breast cancer, kidney cancer, ovarian cancer, melanoma, gastrointestinal stromal tumor (GIST), Ewing's sarcoma, nephroblastoma, or adrenal gland tumors.

29 . A compound that has one of the following structures, or a pharmaceutically acceptable salt thereof:

or a radionuclide complex thereof;

wherein the radionuclide of the chelator-radionuclide complex is: