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WO2023030434A1 - 前列腺特异性膜抗原的抑制剂及其医药用途 - Google Patents

前列腺特异性膜抗原的抑制剂及其医药用途 Download PDF

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WO2023030434A1
WO2023030434A1 PCT/CN2022/116453 CN2022116453W WO2023030434A1 WO 2023030434 A1 WO2023030434 A1 WO 2023030434A1 CN 2022116453 W CN2022116453 W CN 2022116453W WO 2023030434 A1 WO2023030434 A1 WO 2023030434A1
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membered
pharmaceutically acceptable
acceptable salt
formula
compound
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PCT/CN2022/116453
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English (en)
French (fr)
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王梦哲
周顺光
于亮
王利东
赵立博
孙纪云
郭飞虎
李心
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天津恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CA3230165A priority Critical patent/CA3230165A1/en
Priority to EP22863569.4A priority patent/EP4397322A1/en
Priority to JP2024513883A priority patent/JP2024532475A/ja
Priority to MX2024002552A priority patent/MX2024002552A/es
Priority to KR1020247009738A priority patent/KR20240055014A/ko
Priority to CN202280048584.2A priority patent/CN117615795A/zh
Priority to US18/687,804 priority patent/US20240366809A1/en
Priority to AU2022338842A priority patent/AU2022338842A1/en
Publication of WO2023030434A1 publication Critical patent/WO2023030434A1/zh

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Definitions

  • the disclosure belongs to the field of radiopharmaceuticals, in particular to an inhibitor of prostate specific membrane antigen (PSMA) and its medical use.
  • PSMA prostate specific membrane antigen
  • PCa Prostate cancer
  • RP radical prostatectomy
  • RT regional radiation therapy
  • PMSA prostate-specific membrane antigen
  • PSMA also known as folate hydrolase I (FOLH1) or glutamic acid carboxypeptidase II (GCPII)
  • FOLH1 folate hydrolase I
  • GCPII glutamic acid carboxypeptidase II
  • PSMA has two main enzymatic activities: the hydrolytic cleavage of ⁇ -linked glutamate from poly- ⁇ -glutamyl folate, and the protein of the neuropeptide N-acetyl-L-aspartate-L-glutamate (NAAG) hydrolysis.
  • PSMA is also upregulated (1000-fold above physiological levels) and strongly expressed in prostate cancer cells, especially in castration-resistant and metastatic prostate cancer, as well as in lymph node, bone, rectal and lung metastases in tumor tissue.
  • the expression level of PSMA in the neovascularization of tumor tissue was significantly increased, and the expression level was significantly correlated with the degree of tumor differentiation, metastasis tendency and sensitivity to hormone therapy.
  • Capromab (caprolumab) pendetide
  • ProstaScint TM which was approved by FDA in 1997 as an imaging agent for PSMA.
  • Capromab (7E11-C5) is a monoclonal antibody developed from the cell membrane of human prostate cancer cells LNCaP, labeled with indium-111 using diethylenetriaminepentaacetic acid (DTPA) as a chelator.
  • DTPA diethylenetriaminepentaacetic acid
  • Other second-generation drugs targeting PSMA monoclonal antibodies and antibody derivatives are currently in development, of which J591 is the most extensively studied to date.
  • This deimmunized monoclonal antibody has a high affinity with living cells expressing PSMA outside the cell membrane, which overcomes the main problems of Kaprozumab, such as the ability to effectively target PSMA only through the destruction of the cell membrane, and the long-term retention of radioactivity in non-target organs. limit. J591 has been successfully used in 111 In, 99m Tc, 89 Labeling and diagnosis of radioactive metal elements such as Zr, 90 Y, 177 Lu and 225 Ac.
  • antibodies have severe limitations as a routine clinical molecular imaging method, which requires a long metabolic time in vivo (usually 3-7 days) to reduce the background of blood circulation to achieve sufficient signal-to-noise ratio; its size also limits its tumor penetration.
  • PSMA inhibitors with low molecular weight and potential as radiopharmaceuticals were synthesized and evaluated. Compared with antibodies, low-molecular-weight ligands are easier to prepare on a large scale, and have good pharmacokinetic properties (such as bioavailability, biological half-life, etc.).
  • glutamate-phosphoramides Glutamic acid-ureido derivatives are two classes of chemical entities that have been extensively studied, and corresponding PSMA inhibitors have been investigated for nuclear medicine applications. Among these compounds, ureido derivative inhibitors are currently the most commonly used PSMA targeting molecules.
  • the FDA approved [ 18 F]DCFPyL for PET imaging of prostate cancer It not only has a short residence time in the blood, but also has a high binding affinity to PSMA and has high tumor uptake.
  • Another F-18-labeled radioligand, [ 18 F]PSMA-1007 has good binding and internalization properties in vitro and high specific uptake in vivo.
  • PSMA-1007 has a unique biodistribution compared to other known PSMA ligands, being almost exclusively excreted via the hepatobiliary route. This means that it is beneficial to identify lymph node metastasis of recurrent PCa from radioactivity in urine, or local recurrence from bladder.
  • Ga-68-labeled PSMA-specific tracer is [ 68 Ga]PSMA-11 (also known as [ 68 Ga]Glu-Urea-Lys(Ahx)-HBED-CC), which structurally contains urea Based on the pharmacophore and [ 68 Ga]HBED-CC complex, it can directly interact with the PSMA hydrophobic binding pocket S1.
  • [ 68 Ga]PSMA-11 is rapidly cleared in blood and non-target organs, has low accumulation in liver, and has high specific uptake in PSMA-high expressing organs and tumors. also, reported the synthesis and preclinical evaluation of ligands for PSMA-617.
  • PSMA-617 is an integrated ligand for diagnosis and treatment.
  • the chelating agent DOTA is coupled to the pharmacophore Glu-Urea-Lys through a naphthalene-containing linker.
  • Lu-177-labeled PSMA-617 has high binding affinity and internalization properties, higher rates of tumor uptake at later time points, lower accumulation in the spleen, and higher clearance from the kidney.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H;
  • R 1 and R 2 are each independently selected from H, C 1-4 alkyl, preferably both are H, and the C 1-4 alkyl is optionally substituted or unsubstituted by one or more substituent groups P ;
  • Each occurrence of Q, R 1 , R 2 may be the same or different;
  • R 4 is selected from H, C 1-6 alkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, the C 1-6 alkyl, 6-10 membered aryl, or 5-12 membered Heteroaryl is optionally substituted with one or more substituent groups P or unsubstituted;
  • Y is S or O, preferably O;
  • A is selected from -NR 4 (CO)-, -NR 4 (SO 2 )-, -NR 4 (CH 2 )- or absent;
  • the E is selected from 3-12 membered cycloalkyl groups, or or absent, the It is a heterocyclic group or a heteroaryl group containing one or more N atoms, wherein the 3-12 membered cycloalkyl group, heterocyclic group, and heteroaryl group are optionally substituted by one or more substituent groups P or not replaced;
  • W is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, the C 3-12 membered cycloalkyl, 3-12 membered Heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl are optionally substituted or unsubstituted by one or more substituent groups P;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)OR k , -C(S)R k , nitro , cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfide, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 Membered heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group, 8 to 12 membered fused ring aryl group and 5
  • R i and R j are each independently selected from hydrogen atom, hydroxyl, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R k is independently selected from hydrogen atom, C 1 ⁇ C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, -NR i R j , wherein said alkyl, alkoxy and haloalkyl are optionally selected from C 1 -C 6 alkyl, Halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, carboxyl, nitro, cyano, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylsulfide group, C 2 -C 6 One or more substituents in alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclic group, 6
  • a, b, e, g, h are each independently an integer of 0-6;
  • W is not naphthyl
  • R3 is selected from H or a chelating agent.
  • the A is -NH(CO)-, and E is selected from said It is a heterocyclic group containing one or more N atoms, the heterocyclic group is preferably a 3-12 membered heterocyclic group, more preferably a 3-8 membered monoheterocyclic group, most preferably
  • the A is -NH(CO)-
  • E is selected from said A heterocyclic group containing one or more N atoms is a 5-12-membered condensed heterocyclic group, preferably
  • the A is -NH(CO)-
  • E is selected from said A heteroaryl group containing one or more N atoms is a 5-12-membered condensed heteroaryl group, preferably
  • the A is -NH(CO)-
  • E is selected from a 3-12-membered cycloalkyl group, and is not cyclohexane, and the 3-12-membered cycloalkyl group is a 5-12-membered condensed Cycloalkyl, preferably
  • the A is -NH(CO)-, e is 1, and E is selected from 3-12 membered cycloalkyl groups, and the 3-12 membered cycloalkyl groups are spirocycloalkyl groups.
  • the A is -NH(CO)-, e is 1, E is selected from a 3-12 membered cycloalkyl group, and the 3-12 membered cycloalkyl group is a 5-12 membered single spiro ring alkyl.
  • the A is -NH(CO)-, e is 1, and E is selected from 3-12 membered cycloalkyl groups, and the 3-12 membered cycloalkyl groups are 3-membered/4-membered, 3-membered Yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/6 yuan monospirocyclane base.
  • the A is -NH(CO)-, e is 1, and E is selected from 3-12 membered cycloalkyl groups, and the 3-12 membered cycloalkyl groups are selected from
  • the A is -NH(CO)-, e is 1, and E is selected from 3-12 membered cycloalkyl groups, and the 3-12 membered cycloalkyl groups are
  • the A is -NH(CO)-
  • E is selected from 3-12 membered cycloalkyl groups, and the 3-12 membered cycloalkyl groups are bridged cycloalkyl groups.
  • the A is -NH(CO)-
  • E is selected from 3-12 membered cycloalkyl groups selected from
  • the A is -NH(CO)-, and E is selected from 3-12 membered cycloalkyl groups of In some embodiments, the A is -NH(CO)- and E is absent.
  • the a is 1, and the W is selected from phenyl or naphthyl.
  • said a is 1, and said W is naphthyl.
  • the Q is selected from H or a protecting group.
  • said Q is H.
  • each of the R 2 is independently H.
  • each of the R 1 is independently H.
  • h is selected from 1 or 2.
  • h is 1.
  • the g is selected from 3 or 4.
  • the g is 3.
  • the a is 1, the W is naphthyl, and Q, R 2 , and R 1 are each independently H.
  • the compound of formula (I) is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H, each occurrence may be the same or different;
  • E is selected from 3-12 membered cycloalkyl groups, or absent, the is a heterocyclic group containing one N atom, wherein the 3-12 membered cycloalkyl group and the heterocyclic group containing one N atom are optionally substituted or unsubstituted by one or more substituent groups P, and 3-12
  • the membered cycloalkyl group is not cyclohexane; the 3-12 membered cycloalkyl group is preferably a fused cycloalkyl group; the heterocyclic group containing one N atom is preferably a 6-membered ring;
  • W is selected from 6-10 membered aryl groups, and the 6-10 membered aryl groups are optionally substituted or unsubstituted by one or more substituent groups P;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto;
  • R3 is selected from H or a chelating agent.
  • the W is phenyl or naphthyl.
  • the A is -N(CH 2 )-
  • E is selected from 3-12 membered cycloalkyl groups, preferably 3 - 12 membered cycloalkyl, more preferably cyclohexane, most preferably
  • the compound represented by formula (I) is a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H, each occurrence may be the same or different;
  • A is selected from -NH(SO 2 )- or -N(CH 2 )-;
  • E is selected from 3-12 membered cycloalkyl or does not exist, wherein said 3-12 membered cycloalkyl is optionally substituted by one or more substituent groups P or unsubstituted;
  • W is selected from 6-10 membered aryl groups, and the 6-10 membered aryl groups are optionally substituted or unsubstituted by one or more substituent groups P;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto;
  • R3 is selected from H or a chelating agent.
  • the W is naphthyl
  • the A does not exist, and E is selected from said It is a 5-12 membered condensed heterocyclic group containing one or more N atoms, preferably
  • the A does not exist, and E is selected from said is a 5-12 membered heteroaryl group containing one or more N atoms, preferably
  • the compound represented by the formula (I) is a compound represented by the formula (I-3) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H, each occurrence may be the same or different;
  • E from said It is a 5-12-membered condensed heterocyclic group or a 5-12-membered heteroaryl group containing one or more N atoms, and the 5-12-membered fused heterocyclic group or 5-
  • the 12-membered heteroaryl is optionally substituted or unsubstituted by one or more substituent groups P;
  • W is selected from 6-10 membered aryl groups, and the 6-10 membered aryl groups are optionally substituted or unsubstituted by one or more substituent groups P;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto, carbonyl;
  • e is selected from 0 or 1;
  • R3 is selected from H or a chelating agent.
  • the E is a 5-12 membered heteroaryl group containing one or more N atoms, and unsubstituted, preferably
  • the E is a 5-12 membered condensed heterocyclic group containing one or more N atoms, And the 5-12 membered condensed heterocyclic group containing one N atom is substituted by carbonyl, preferably
  • W in the compound represented by formula (I-3) or a pharmaceutically acceptable salt thereof is phenyl or naphthyl.
  • neither A nor E exists in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound represented by formula (I) is a compound represented by formula (I-4) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H, each occurrence may be the same or different;
  • W is selected from 6-10 membered aryl groups, 5-12 membered heteroaryl groups, the 6-10 membered aryl groups, 5-12 membered heteroaryl groups are optionally substituted by one or more substituent groups P or not replaced;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto;
  • R3 is selected from H or a chelating agent.
  • the W is selected from 6-10 membered aryl groups, preferably phenyl, naphthyl, biphenyl, phenylhydroxy, more preferably phenyl,
  • the W is selected from 5-12 membered heteroaryl, preferably 5-6 membered heteroaryl Or fused heteroaryl, more preferably indole, pyridine, imidazole, quinoline, most preferably
  • the present disclosure also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H;
  • R 1 and R 2 are independently selected from H, substituted or unsubstituted C 1-4 alkyl, preferably both are H;
  • Each occurrence of Q, R 1 , R 2 may be the same or different;
  • F is selected from -N(CH 2 ) n - or -(CH 2 ) m OG(CH 2 ) n -;
  • Y 1 and Y 2 are independently selected from S or O, preferably O;
  • g, h, n, m are each independently selected from an integer of 0-6;
  • G is selected from 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, the 3-12 membered cycloalkyl, 3-12 membered Heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl are optionally substituted or unsubstituted by one or more substituent groups P;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)OR k , -C(S)R k , nitro , cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfide, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 Membered heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group, 8 to 12 membered fused ring aryl group and 5
  • R i and R j are each independently selected from hydrogen atom, hydroxyl, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R k is independently selected from hydrogen atom, C 1 ⁇ C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, -NR i R j , wherein said alkyl, alkoxy and haloalkyl are optionally selected from C 1 -C 6 alkyl, Halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, carboxyl, nitro, cyano, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylsulfide group, C 2 -C 6 One or more substituents in alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclic group, 6
  • R3 is selected from H or a chelating agent.
  • the F is selected from -N(CH 2 ) n -.
  • said F is selected from -(CH 2 ) m OG(CH 2 ) n -, and said G is selected from 6 - 10-membered aryl, preferably phenyl.
  • the formula (II) is a compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H, each occurrence may be the same or different;
  • F is selected from -N(CH 2 ) n - or -(CH 2 ) m OG(CH 2 ) n -;
  • the G is selected from 6-10 membered aryl groups
  • n and m are each independently selected from an integer of 0-6;
  • R3 is selected from H or a chelating agent.
  • the G in the compound represented by formula (II-1) is phenyl.
  • the present disclosure also provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H;
  • R 1 and R 2 are independently selected from H, substituted or unsubstituted C 1-4 alkyl, preferably both are H;
  • Each occurrence of Q, R 1 , R 2 may be the same or different;
  • g, h, j are each independently selected from an integer of 0-6;
  • i is an integer selected from 1-3;
  • J is a linking group selected from the group consisting of C 1 -C 6 alkylene, C 3 -C 6 cycloalkylene, arylene, and heteroarylene, said C 1 -C 6 alkylene, C 3 -C 6 cycloalkylene, arylene, and heteroarylene are optionally substituted or unsubstituted by one or more substituent groups P;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)OR k , -C(S)R k , nitro , cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfide, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 Membered heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group, 8 to 12 membered fused ring aryl group and 5
  • R i and R j are each independently selected from hydrogen atom, hydroxyl, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R k is independently selected from hydrogen atom, C 1 ⁇ C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, -NR i R j , wherein said alkyl, alkoxy and haloalkyl are optionally selected from C 1 -C 6 alkyl, Halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, carboxyl, nitro, cyano, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylsulfide group, C 2 -C 6 One or more substituents in alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclic group, 6
  • the R 5 is selected from H or C 1 -C 4 alkyl
  • R3 is selected from H or a chelating agent.
  • i is selected from 2
  • J is selected from arylene base or heteroarylene, preferably pyridine or phenyl, more preferably
  • the compound represented by formula (III) is a compound represented by formula (III-1) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group, preferably H;
  • J is a linking group selected from the group consisting of arylene or heteroarylene, the arylene, and heteroarylene optionally being substituted or unsubstituted by one or more substituent groups P;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto, oxo, thio;
  • j is selected from an integer of 0-6;
  • R3 is selected from H or a chelating agent.
  • J is selected from pyridine or phenyl, preferably where each occurrence of J is different, j selected from 1.
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
  • Q is selected from H or a protecting group
  • R 1 and R 2 are each independently selected from H, C 1-4 alkyl, and the C 1-4 alkyl is optionally substituted or unsubstituted by one or more substituent groups P;
  • Each occurrence of Q, R 1 , R 2 may be the same or different;
  • Y 1 is S or O
  • T is selected from -NR 4 (CO)-, -NR 4 (SO 2 )-, -NR 4 (CH 2 )-;
  • R 4 is selected from H, C 1-6 alkyl, 6-10 membered aryl, or 5-12 membered heteroaryl, the C 1-6 alkyl, 6-10 membered aryl, or 5-12 membered Heteroaryl is optionally substituted with one or more substituent groups P or unsubstituted;
  • Ring A is selected from 3-12 membered nitrogen-containing heterocyclic groups, wherein said 3-12 membered nitrogen-containing heterocyclic groups are optionally substituted or unsubstituted by one or more substituent groups P;
  • W is selected from 6-10 membered aryl groups, 5-12 membered heteroaryl groups, the -10 membered aryl groups, 5-12 membered heteroaryl groups are optionally substituted by one or more substituent groups P or not replace;
  • the substituent group P is selected from C 1 -C 6 alkyl, halogen, deuterium, hydroxyl, mercapto, -NR i R j , oxo, thio, -C(O)R k , -C(O)OR k , -S(O)R k , -S(O)OR k , -S(O)(O)R k , -S(O)(O)OR k , -C(S)R k , nitro , cyano, C 1 -C 6 alkoxy, C 1 -C 6 alkylsulfide, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 Membered heterocyclic group, 6 to 10 membered aryl group, 5 to 10 membered heteroaryl group, 8 to 12 membered fused ring aryl group and 5
  • R i and R j are each independently selected from hydrogen atom, hydroxyl, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy;
  • R k is independently selected from hydrogen atom, C 1 ⁇ C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, hydroxyl, -NR i R j , wherein said alkyl, alkoxy and haloalkyl are optionally selected from C 1 -C 6 alkyl, Halogen, hydroxyl, mercapto, -NR i R j , oxo, thio, carboxyl, nitro, cyano, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkylsulfide group, C 2 -C 6 One or more substituents in alkenyl, C 2 -C 6 alkynyl, 3 to 10 membered cycloalkyl, 3 to 10 membered heterocyclic group, 6
  • y, z, g, h are each independently an integer of 0-6;
  • R3 is selected from H or a chelating agent.
  • Q in the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof is a protecting group, specifically a hydroxyl protecting group, as a hydroxyl protecting group, including As all the groups, for example, groups described in W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 16-366, 2007, John Wiley & Sons, INC. can be mentioned.
  • C 1-6 alkyl C 2-6 alkenyl, aryl C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, acyl, C 1-6 6 alkoxycarbonyl, C 1-6 alkylsulfonyl, arylsulfonyl, tetrahydrofuryl, tetrahydropyranyl or silyl, etc.
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, wherein T is -NH(CO)-, ring A is a 5-12 membered nitrogen-containing spiroheterocycle base.
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, wherein T is -NH(CO)-, ring A is selected from 5-12 membered nitrogen-containing single spiro heterocyclyl.
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, wherein T is -NH(CO)-, ring A is selected from 3-membered/4-membered, 3-membered/ 5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/6 yuan nitrogen-containing single spiro heterocycle base.
  • T is -NH(CO)-
  • ring A is selected from 3-membered/4-membered, 3-membered/ 5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan
  • the T is -NH(CO)-, and ring A is selected from
  • the T is -NH(CO)-, and ring A is selected from
  • the T is -NH(CO)-
  • ring A is
  • the W is selected from 6-10 membered aryl groups.
  • W is naphthyl
  • the Y 1 is O.
  • the R 1 and R 2 are each independently H.
  • the Q is selected from H or a protecting group.
  • y and h are each independently selected from 0, 1 or 2.
  • the y is 1.
  • h is 1.
  • the g is selected from 3 or 4.
  • the g is 3.
  • the z is selected from 0 or 1.
  • z is 0.
  • the aforementioned chelating agent is selected from:
  • the aforementioned chelating agent is In some embodiments, the aforementioned compounds are selected from Table 1 below:
  • the chelating agent previously described in this disclosure comprises a radionuclide.
  • the aforementioned radionuclide is selected from 18 F, 11 C, 68 Ga, 124 I, 89 Zr, 64 Cu, 86 Y, 99m Tc, 111 In, 123 I, 90 Y, 125 I, 131 I , 177 Lu, 211 At, 153 Sm, 186 Re, 188 Re, 67 Cu, 212 Pb, 225 Ac, 213 Bi, 212 Bi, 212 Pb or 67 Ga.
  • the aforementioned radionuclide is68Ga .
  • the aforementioned radionuclide is177Lu .
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which is
  • the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof provided by the application is,
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which is
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which is
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which is
  • the chelating agent contains a radionuclide, which is68Ga .
  • the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which is
  • the chelating agent contains a radionuclide, and the radionuclide is 177 Lu.
  • the present disclosure further provides a preparation method of a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (IV) is a compound represented by formula v or a pharmaceutically acceptable salt thereof, including The step of de-tert-butyl compound shown in formula v-5:
  • the preparation method of the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof further comprises: condensation reaction of the compound represented by formula v-3 and the compound represented by formula v-4 to obtain formula v- 5 steps for the compound shown,
  • the preparation method of the compound shown in formula (IV) or its pharmaceutically acceptable salt comprises the preparation step of the compound shown in formula (IV) or its pharmaceutically acceptable salt, further comprises the compound shown in formula (IV) or its The step of complexing a chelating agent with a radionuclide in a pharmaceutically acceptable salt.
  • the present disclosure provides a method for preparing a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
  • the compounds can be labeled with the aforementioned radionuclides.
  • the present disclosure also provides isotopically substituted, preferably deuterated, compounds of the aforementioned compounds.
  • the present disclosure also provides a pharmaceutical composition, comprising at least one of the aforementioned compounds or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01%-99.99% of the aforementioned compound based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable carriers, diluents or excipients.
  • the present disclosure also provides the use of the aforementioned compounds, or pharmaceutically acceptable salts and isotopic substitutions thereof, in the manufacture of compositions for imaging in a patient.
  • the present disclosure also provides the use of the aforementioned compounds or their pharmaceutically acceptable salts and their isotope substitutions in the preparation of medicaments for diagnosing and/or treating and/or preventing PSMA-mediated diseases or conditions.
  • the present disclosure also provides the aforementioned compounds or their pharmaceutically acceptable salts and their isotope substitutions in the preparation for the diagnosis and/or treatment and/or prevention of tumors and cancers, wherein the tumors and cancers are preferably prostate cancer and / or its transfer.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a linear or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylp
  • alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkylene refers to a saturated straight or branched chain aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, which are A linear or branched chain group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms.
  • alkylene examples include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), etc.
  • Alkylene groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment.
  • alkenylene refers to a group comprising linear alkenes having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and having at least one double bond in any position. groups, including, for example, vinylidene, allylene, propenylene, butenylene, prenylene, butadienylene, pentenylene, pentylene Alkenyl, hexenylene, hexadienylene, etc.
  • alkynylene includes linear alkynylene groups having 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, and having at least one triple bond in any position. groups, including, for example, ethynylene, propynylene, butynylene, pentynylene, hexynylene, and the like.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 12 carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl. "Carbocycle” refers to the ring system in a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocarbocycle refers to the ring system in a spirocycloalkyl.
  • Non-limiting examples of spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused carbocycle refers to the ring system in a fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthalene base, benzocycloheptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 6 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl and pyrrolidinyl.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Heterocycle" refers to a ring system in a heterocyclyl group.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5 to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (wherein m is an integer from 0 to 2), the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiroheterocyclyl can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl.
  • Spiroheterocycle refers to the ring system in a spiroheterocyclyl group.
  • Non-limiting examples of spiroheterocyclyls include:
  • fused heterocyclyl refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bond, but none of the rings has a fully conjugated ⁇ -electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer from 0 to 2), and the remaining ring
  • the atom is carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocycle refers to a ring system within a fused heterocyclyl group.
  • fused heterocyclic groups include:
  • bridged heterocyclyl refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete shared bond.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring where the ring bonded to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • Heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 10 membered, having a conjugated pi-electron system, such as benzene base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is the aryl ring.
  • “Aromatic ring” refers to a ring system in an aryl group. Non-limiting examples of aryl groups include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate, preferably phenyl.
  • fused ring aryl can be an unsaturated aromatic condensed ring structure containing 8-14 ring atoms connected by two or more ring structures sharing two adjacent atoms.
  • the number of atoms is preferably 8-12.
  • it includes all unsaturated condensed ring aryl groups, such as naphthalene, phenanthrene, etc., and also includes partially saturated condensed ring aryl groups, such as benzo 3-8 membered saturated monocyclic cycloalkyl, benzo 3-8 membered partially saturated monocyclic ring alkyl.
  • fused aromatic ring refers to a ring system in a fused aromatic group.
  • condensed ring aryl group examples include 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 12 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine group, etc., preferably imidazolyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl or thiazolyl.
  • heteroaryl may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring.
  • Heteroaryl refers to a ring system in a heteroaryl group.
  • Non-limiting examples of heteroaryl groups include:
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • fused heteroaryl may contain 5-14 ring atoms (including at least one heteroatom), which is formed by connecting two or more ring structures with two adjacent atoms.
  • Aromatic condensed ring structure, including carbon atoms, nitrogen atoms and sulfur atoms can be oxo, preferably "5-12 membered fused heteroaryl", “7-12 membered fused heteroaryl”, “9-12 membered Fused heteroaryl” etc., such as benzofuryl, benzoisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazole, indazolyl, benzotri Azolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinolinyl Azolinyl
  • Fused heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the removal of a hydrogen atom from the parent ring atom, or 2 residues derived from the same or two different ring atoms of the parent A residue derived from a hydrogen atom, namely "divalent cycloalkyl", “divalent heterocyclyl", “arylene”, “heteroarylene”.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,
  • alkylthio refers to -S-(alkyl) and -S-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio.
  • Alkylthio groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alk Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , One or more substituents in heterocycloalkylthio.
  • hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
  • deuteroalkyl refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.
  • hydroxyl refers to a -OH group.
  • a carbon atom is linked to an oxygen atom by a double bond, where a ketone or aldehyde group is formed.
  • a carbon atom is double bonded to a sulfur atom to form a thiocarbonyl group -C(S)-.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • aldehyde refers to -CHO.
  • carboxylate refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl halide refers to a compound containing the group -C(O)-halogen.
  • sulfonyl refers to -S(O)(O)-.
  • an "isostere” of a chemical group is another chemical group that exhibits the same or similar properties.
  • tetrazole is an isostere of a carboxylic acid because it mimics the properties of a carboxylic acid, even though the two have very different molecular formulas. Tetrazole is one of many possible isosteric substitutions for carboxylic acids.
  • Other expected carboxylic acid isosteres include -SO3H , -SO2HNR , -PO2 (R) 2 , -PO3 (R) 2 , -CONHNHSO2R , -COHNSO2R , and -CONRCN, wherein R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl as defined herein.
  • carboxylic acid isosteres may comprise 5- to 7-membered carbocyclic or heterocyclic rings comprising any combination of CH2 , O, S, or N in any chemically stable oxidation state, wherein the Any one atom of the ring structure is optionally substituted at one or more positions. It is contemplated, and also contemplated, that when chemical substituents are added to the carboxy isostere, the compound retains the properties of the carboxy isostere. It is expected that when the carboxy isosteres are optionally substituted with one or more moieties selected from R as defined above, then the degree of substitution (substitution) and the position of substitution are selected so that they do not eliminate the carboxylic acid of the compound Electron isosteric properties.
  • Optional or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • the bond configuration is not specified, i.e. the key can be or both Two configurations.
  • the bond If the configuration is not specified, it can be the Z configuration or the E configuration, or both configurations.
  • Tautomers are structural isomers of organic compounds that are readily interconvertible through a chemical reaction known as tautomerization. This reaction often results in the formal transfer of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds. Some common tautomeric pairs are: keto-enol, lactam-lactim. An example of a lactam-lactim equilibrium is between A and B as shown below.
  • the chelate ring (DOTA-like ring) complexes metal ions, it will form two conformations of square antiprism (SAP) and twisted tetragonal antiprism (TSAP) in solution, which can be rotated by the vertical arm of the chelate ring Or ring inversion to form tautomers; in addition, the inversion of the side chain connecting the chelating ring will also form tautomers.
  • SAP square antiprism
  • TSAP twisted tetragonal antiprism
  • Atoms capable of being isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. They can be replaced by isotopes 2 H(D), 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, respectively.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to mean deuterium having an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (ie, at least 45 % deuterium incorporation).
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein or a physiologically pharmaceutically acceptable salt or prodrug thereof and other chemical components, as well as other components such as a physiologically acceptable carrier and excipient.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm).
  • the determination of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is four Methylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • MS was determined by Shimadzu 2010Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
  • HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200LC high pressure liquid chromatography (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um chromatographic column; use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate for thin-layer chromatography silica gel plate, and the specification of silica gel plate used for thin-layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the specifications
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui chemical companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), the developer used for reaction, the eluent system of the column chromatography that purifies compound adopts and the developer system of thin-layer chromatography comprise: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: petroleum ether/ethyl acetate/methanol, the volume ratio of the solvent is determined according to the polarity of the compound Adjustment can also be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine and acetic acid.
  • TLC thin-layer chromatography
  • EtOAc(EA) ethyl acetate
  • DCM dichloromethane
  • THF tetrahydrofuran
  • DIPEA N,N-diisopropylethylamine
  • PPTS pyridinium p-toluenesulfonate
  • Boc tert-butoxycarbonyl, MeOH: methanol
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • DIEA N,N-diisopropylethyl amine.
  • the resin was washed 3 times with DMF, 300 mL each time.
  • the resin was blocked for 8 hours, and the peptide resin was shrunk and dried with methanol to obtain the product S-1 (8.75 mmol).
  • the product S-1 (7mmol) was swelled with 150mL DMF, then added 200mL 20% DBLK (20% piperidine/DMF solution, purchased from Anaiji Company) for deprotection for 10min, and then added 200mL 20% DBLK was deprotected for 10 minutes, the Kaiser test detected the blue color of the resin, and the resin was dried, and the resin was washed with DMF until neutral to obtain the product S-2.
  • DBLK 20% piperidine/DMF solution, purchased from Anaiji Company
  • the product S-2 (7 mmol) was added to the glutamyl isocyanate reaction solution, and the reaction was slowly stirred in a constant temperature oscillator for 18 hours.
  • the Kaiser test detected that the resin was colorless.
  • the resin was transferred to a solid-phase reaction column, and the reaction solution was drained.
  • the resin was washed 3 times with DMF, 300 mL each time, to obtain the product Product S-3.
  • the product S-3 (7mmol) was added to the reaction column, phenylsilane (4.6g, 42mmol), tetrakistriphenylphosphine palladium (0.81g, 0.7mmol) were dissolved in 180mL DCM, and the solution Add it into the reaction column, react with nitrogen gas bubbling for 0.5h, drain the solvent, and repeat the above steps twice, the resin is blue-black as detected by the Kaiser test, after the reaction is complete, drain the solvent, wash with DMF three times, drain, and then After being shrunk three times with methanol, it was vacuum-dried at 30°C for 2 h to obtain the product S-4 (22.2 g, 7 mmol) for future use.
  • resin compound S-4 (4.0 g, 1.28 mmol) was swollen with dichloromethane (purchased from Sinopharm Group Chemical Reagent Co., Ltd.) for 0.5 h, drained, washed with DMF three times and drained for later use.
  • lysate TFA trifluoroacetic acid
  • peptide resin compound 4 under stirring Reaction 2h.
  • the resin was removed by suction filtration, and the filtrate was concentrated by rotary evaporation.
  • the concentrated solution was added to 100 mL of isopropyl ether, filtered by suction, and dried under reduced pressure to obtain 0.40 g of crude peptide with a yield of 60.9%. Purification by high-pressure preparative liquid chromatography gave the title product Compound a (105 mg, yield: 26.2%).
  • step 1
  • step 1
  • Boc-L-tyrosine methyl ester compound g-1 0.5g, 2.78mmol
  • pyridine 1.2mL, 14.61mmol
  • trifluoromethanesulfonate After the addition of acid anhydride (2.4 mL, 14.10 mmol), the reaction was naturally raised to room temperature and stirred for 3 hours. TLC monitored the completion of the reaction.
  • reaction solution was washed successively with 100mL saturated sodium bicarbonate solution, 100mL 1N HCL, and 100mL saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain compound g-2 (0.84g, yield: 99.0%).
  • compound g-3 (0.51g, 1.4mmol) was dissolved in 1.5mL THF and 1mL water, lithium hydroxide was added, and the reaction was completed overnight at room temperature.
  • the resin compound S-4 (1.1 g, 0.38 mmol) prepared in Example 1 was swollen with DCM for 0.5 h, drained and washed with DMF three times for later use.
  • step 1
  • resin compound S-4 (1.7 g, 0.65 mmol) was swelled with DCM for 0.5 h, drained and washed with DMF three times for later use.
  • Boc-3-(4-pyridyl)-L-alanine (0.54g, 2.01mmol), HATU (0.76g, 2.01mmol), HOBt (0.27g, 2.01mmol), DIEA (0.52g, 4.02mmol ), DMF (15mL) was added to the reaction bottle, shaken to dissolve, and the resin swollen in advance was added to the reaction bottle, and the reaction was shaken for 2 hours.
  • the Kaiser test detected that the resin was colorless. Drain the reaction solution, wash the resin three times with DMF, then shrink it with methanol and dry it for later use.
  • the title product compound j-1 was obtained.
  • step 1
  • Fmoc-L-tyrosine tert-butyl ester (5.0 g, 10.9 mmol) was dissolved in 50 mL of DMF, potassium carbonate (1.81 g, 13.1 mmol) was added, and the reaction was stirred at room temperature for 12 h.
  • Boc-glycine (2.29g, 13.1mmol) and HATU (4.98g, 13.1mmol) were added, the ice bath was lowered to 0°C, DIEA was added dropwise, and the reaction was stirred at room temperature for 2h.
  • compound O-2 (4.2g, 9.0mmol) was dissolved in 50mL THF and 50ml water, and the ice bath was lowered to 0°C, and an aqueous solution of lithium hydroxide was slowly added, and the reaction was completed at room temperature for 2h.
  • step 1
  • compound q-1 (3g, 11.94mmol) was dissolved in 60mL of dichloromethane, and EDCI (5.49g, 28.66mmol) (1-(3-dimethylaminopropyl)-3-ethylcarbon Diimine hydrochloride, purchased from McLean), DMAP (4.37g, 35.82mmol), stirred for 20min under N2 atmosphere, added compound q-2 (2.17g, 14.33mmol), stirred at room temperature for 16-18h .
  • Resin compound S-4 (2.11 g, 0.68 mmol) was swelled with DMF (20 mL) for 30 min at room temperature.
  • Compound q-4 (760mg, 2.05mmol), HATU (779mg, 2.05mmol), HOBt (277mg, 2.05mmol), DIEA (529mg, 4.09mmol) were dissolved in DMF (15mL) and added to the swellable resin to react at room temperature for 2.5 h. Take a small amount of resin and wash it with DMF (2mL ⁇ 3) after suction filtration, and then use ninhydrin to develop it into colorless. After the reaction resin is suction filtered, use DMF (50mL ⁇ 3), DCM (50mL ⁇ 3), isopropyl Wash with ether (50mL ⁇ 3) to obtain wet resin compound q-5.
  • step 1
  • r-3 (200mg, 0.42mmoL) was dissolved in TFA (5mL), and reacted overnight at 33°C after addition. The reaction solution was evaporated to dryness and purified by high-pressure preparative liquid chromatography to obtain the title product r (71.5 mg, yield: 50.7%).
  • step 1
  • N-E-benzyloxycarbonyl-L-lysine tert-butyl ester hydrochloride (10 g, 0.03 mol) and DIEA (3.84 g, 0.03 mol) in 120 mL of DCM, cool to -10°C to 0°C, Stir for 0.5h, add triphosgene (4.4g, 0.015mol), add DIEA (19.2g, 0.149mol) dropwise at -10°C to 0°C, dropwise, keep warm for 3h, add L-glutamic acid di Tert-butyl ester hydrochloride (10 g, 0.039 mol), naturally raised to room temperature and stirred overnight. TLC monitored the completion of the reaction.
  • t-3 (9.8g, 15.8mmol) was dissolved in 100mL methanol solution, stirred to dissolve, and Pd/C (4.9g water content 58%) was added.
  • the reaction flask was replaced with nitrogen gas three times and hydrogen gas three times, and the reaction was stirred at room temperature for 5 h, and the reaction was completed by TLC monitoring.
  • the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure and evaporated to dryness to obtain t-4 (6.2 g, yield: 80.7%).
  • 6-Boc-6-azaspiro[2.5]octane-1-carboxylic acid 145mg, 0.57mmol
  • HATU 216mg, 0.57mmoL
  • DIEA 226mg, 1.75mmoL
  • DCM 4mL
  • step 1
  • DOTA 1636mg, 2.86mmol
  • HATU 1087mg, 2.86mmol
  • DIEA N,N-diisopropylethylamine, 851mg, 6.6mmol
  • DCM 10mL
  • v-2 (800mg, 1.01mmol) was dissolved in 12mL THF and 10mL water, and lithium hydroxide (73mg, 3.2mmol) was added, and reacted at room temperature overnight.
  • step 1
  • w-3 (4.0g, 8.5mmol) was dissolved in 20mL THF and 10mL water, lithium hydroxide (0.62g, 25.6mmol) was added, and the addition was completed and reacted overnight at room temperature.
  • w-6 (0.86g, 1.1mmol) was dissolved in 2mL ethyl acetate, and 4M HCl/EA solution (8mL, 32mmol) was added with stirring, and the reaction was stirred for 2h. TLC monitored the completion of the reaction. The reaction solution was concentrated under reduced pressure to constant weight to obtain the title product w-7 (0.82 g, yield: 95.3%).
  • the total reaction volume is 400 ⁇ L, 15nmol compound v, 15mCi 177 Lu, add 321 ⁇ L acetic acid-sodium acetate buffer (0.1M, pH4.5) to a 1.5mL centrifuge tube, then add 15 ⁇ L compound v solution to obtain 7 ⁇ L 177 LuCl 3 ( Activity: 15.23mCi; placed on a constant temperature mixer, oscillating, reaction temperature 95°C, reaction time 15min, activity: 15.15mCi, HPLC results >99%.
  • Multifunctional microplate reader SPARK, TECAN
  • PSMA inhibitors can bind to PSMA enzyme to prevent PSMA enzyme from decomposing the substrate N-Acetyl-Asp-Glu.
  • the binding ability of PSMA inhibitors to PSMA enzymes was evaluated by detecting the change of ultraviolet absorption produced by the decomposition degree of the substrate, and the activity of the compounds was evaluated according to the IC 50 size.
  • Buffer 1 50 mM HEPES, 0.1 M NaCl, pH 7.5 was used to prepare 0.4 ⁇ g/ml rhPSMA solution and 40 ⁇ M substrate N-Acetyl-Asp-Glu.
  • PSMA-617 as a positive control.
  • Buffer 1 50 mM HEPES, 0.1 M NaCl, pH 7.5 was used to prepare 0.4 ⁇ g/ml rhPSMA solution and 40 ⁇ M substrate N-Acetyl-Asp-Glu.
  • PSMA-617 as a positive control.
  • the time point of the experiment was 2 hours, and the animals were killed by dislocation of the neck. A total of 3 animals were collected, and tissue samples were collected, including blood, heart, lung, liver, spleen, kidney, stomach, intestine, bone, meat, brain, salivary gland, large intestine, pancreas,
  • tissue samples were collected, including blood, heart, lung, liver, spleen, kidney, stomach, intestine, bone, meat, brain, salivary gland, large intestine, pancreas.
  • For tumors first weigh the net weight of the tissue, and then use a ⁇ -counter to count the radioactivity of the tissue. Determine the distribution of labeled compounds in different tissues and organs of mice.
  • the test sample was accurately diluted 100 times, and 0.1 mL was taken in a counting tube as a standard 1% ID (i.e. one percent of the dose), and the 1% ID standard and Radioactive counting of biological samples. Biodistribution data were expressed as radioactive counts per gram of tissue or organ as
  • Each mouse was administered with 50 ⁇ Ci/100 ⁇ L, blood was collected through the orbit at 0.083, 0.25, 0.5, 1, 2, and 4 h after administration, and 4 animals were collected at each time point in pre-weighed sample tubes, weighed and weighed. Record the weight of the blood sample, and then count the radioactivity with a ⁇ -counter. At the same time, the test sample is accurately diluted 100 times, and 0.1 mL is taken in a counting tube as a standard 1% ID (i.e. one percent of the dose), and the 1% ID standard and biological Radioactive counts of samples. Blood data are expressed as radioactive counts per gram of blood as a percentage of the total administered dose (radioactive counts) (%ID/g). Pharmacokinetic parameter calculations were performed based on blood drug concentration data.
  • the blood half-life of 68 Ga-v (Example 9) in mice is 0.13h (7.8min), and the half-life of the elimination phase is 0.758h respectively.
  • the time for complete metabolism is estimated according to 5 half-lives. metabolism.

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Abstract

前列腺特异性膜抗原的抑制剂及其医药用途。具体而言，属于放射性药物领域，涉及一种式(IV)所示化合物或其药学上可接受的盐。

Description

前列腺特异性膜抗原的抑制剂及其医药用途 技术领域
本公开属于放射性药物领域，具体涉及前列腺特异性膜抗原(PSMA)的抑制剂及其医药用途。
背景技术
前列腺癌(PCa)目前已成为男性第二大常见癌症，发病率和死亡率仅次于肺癌，全世界每年有近160万新病例。虽然2018年与前列腺癌相关的死亡有36.6万人，但在许多发达国家，前列腺癌死亡率一直在下降，这主要归功于前列腺特异性抗原(PSA)血液检测的广泛使用。PSA被认为使PCa筛查发生了革命性的变化，因为它是初始治疗(如根治性前列腺切除术(RP)或局部放疗(RT))后复发疾病的有效检测指标。这种被定义为生化复发(BCR)的疾病状态，其特征就是PCa初始治疗后PSA水平上升。
在过去的几十年里，新的诊断/预后工具尤其是影像学检查，在临床实践中被引入，以更好地支持前列腺癌患者的诊疗，并克服检测PSA水平的一些限制。目前的临床成像方法包括经直肠超声(TRUS)，用于活检指导和近距离放疗粒子放置，磁共振成像(MRI)和计算机断层扫描(CT)用于前列腺癌分期和转移扩散检测，骨显像用于骨转移评估。这些传统的成像技术在检测早期/微小的复发或转移，如淋巴结和硬化骨转移的敏感性和特异性较差。在过去几年中，放射性成像方法与放射性药物的使用在泌尿生殖系统疾病，特别是PCa诊疗中发挥了突出的作用。
新的检测手段有助于疾病分期诊断和分类，对于监测复发和评价疗效无疑是至关重要的。随着利用不断的科学发现和技术改进，研究人员研究了新的生物化学途径，以及可能作为疾病治疗靶点的细胞结构。其中，前列腺特异性膜抗原(PMSA)作为药物，尤其是放射性药物的特异性作用靶点的重要性不断增加。
PSMA，也称为叶酸水解酶I(FOLH1)或谷氨酸羧肽酶II(GCPII)，是一种750氨基酸的II型跨膜糖蛋白，在健康人体组织中有一定表达，如泪腺和唾液腺、附睾、卵巢、正常人类前列腺上皮、神经中枢系统(CNS)以及小肠空肠刷状边界内的星形胶质细胞和Schwann细胞。PSMA具有两种主要的酶活性:从聚γ-谷氨酰叶酸水解裂解γ-联谷氨酸，和神经肽N-乙酰-L-天冬氨酸-L-谷氨酸(NAAG)的蛋白质水解。除了酶的功能外，PSMA还在前列腺癌细胞中上调(高于生理水平1000倍)并强烈表达，特别是在去势抵抗性和转移性前列腺癌中，以及在淋巴结、骨、直肠和肺转移肿瘤组织中。PSMA在肿瘤组织的新生血管中表达水平显著增加,而且表达水平与肿瘤分化程度、转移趋势和对激素治疗的敏感程度显著相关。研究证实PSMA在几乎所有前列腺癌组织中都有高表达，这使得PSMA具有高灵敏度和高特异性靶向前列腺癌转移病灶的潜力，是一种理想的生物标志物，同时可用于癌症晚期的放射性核素靶向治疗。在过去几十年，靶向PSMA开发新型放射性药物主要有如下两个不同的方向。
起初，研究主要集中在PSMA的大分子蛋白结构上，提供针对PSMA表位的特异性单克 隆抗体。第一个临床应用的PSMA靶向放射示踪剂是[ 111In]capromab(卡普罗单抗)pendetide，商标为ProstaScint TM，1997年被FDA批准用作PSMA的显像剂。Capromab(7E11-C5)是一种单克隆抗体，由人前列腺癌细胞LNCaP细胞膜开发而来，用二乙三胺五乙酸(DTPA)作为螯合剂，标记了铟-111。其它以PSMA为靶点的单克隆抗体和抗体衍生物的第二代药物目前也在开发中，其中J591是迄今为止研究最广泛的。这种去免疫的单克隆抗体与细胞膜外表达PSMA的活细胞具有高亲和力，克服了卡普罗单抗的只能通过细胞膜的破坏来有效靶向PSMA以及放射性在非靶器官的长时间滞留等主要限制。J591通过与金属螯合剂1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)偶联，已成功地用于 111In、 99mTc、 89Zr、 90Y、 177Lu和 225Ac等放射性金属元素的标记和诊疗。但是抗体作为临床常规分子影像手段具有严重局限性，其需要较长的体内代谢时间(通常3-7天)降低血液循环的背景，以实现足够的信噪比；其大小也限制了它的肿瘤穿透性。
随着PSMA晶体结构的解析，以PSMA的酶活性为出发点，各种低分子量且具有作为放射性药物潜力的PSMA抑制剂被合成和评价。相对于抗体，低分子量配体更易于大规模制备，且具有良好的药代动力学特性(如生物利用度、生物半衰期等)。其中，谷氨酸-磷酰胺类
Figure PCTCN2022116453-appb-000001
谷氨酸-脲基衍生物
Figure PCTCN2022116453-appb-000002
是两类被广泛研究的化学实体，相应的PSMA抑制剂已被研究用于核医学应用。在这些化合物中，脲基衍生物类抑制剂是目前最常用的PSMA靶向分子。2021年，FDA批准[ 18F]DCFPyL用于前列腺癌PET显像，它不仅在血液中滞留时间短，而且对PSMA的结合亲和力高，具有较高的肿瘤摄取。另一种F-18标记的放射性配体，[ 18F]PSMA-1007在体外具有良好的结合和内化特性，在体内具有较高的特异性摄取。此外，与其他已知的PSMA配体相比，PSMA-1007具有独特的生物分布，几乎完全经肝胆途径排泄。这意味着有利于从尿液的放射性中鉴别复发PCa的淋巴结转移，或从膀胱中鉴别局部复发。Ga-68标记的PSMA特异性示踪剂最广泛使用的是[ 68Ga]PSMA-11(也称为[ 68Ga]Glu-Urea-Lys(Ahx)-HBED-CC),结构上包含以脲为基础的药效团和[ 68Ga]HBED-CC复合物，能够直接与PSMA疏水结合袋S1相互作用。[ 68Ga]PSMA-11在血液和非靶器官中快速清除，在肝脏中低积累，在PSMA高表达器官和肿瘤中具有高特异性摄取。此外，
Figure PCTCN2022116453-appb-000003
等人报道了PSMA-617的配体的合成和临床前评价。PSMA-617是一种诊疗一体化配体，螯合剂DOTA通过含萘linker偶联到药效团Glu-Urea-Lys上。Lu-177标记的PSMA-617具有高结合亲和力和内化性质，在较晚的时间点具有较高的肿瘤摄取率，脾脏积累较低，且从肾脏的清除效率较高。
虽然目前已有文献报道了大量PSMA抑制剂的开发，但前列腺癌患者对于更好的PSMA靶向药物仍有很高的需求。因此开发出一种体内稳定且具有更高亲和力和特异性的PSMA抑制剂，具有重要的科研价值和广阔的应用前景。
发明内容
本公开提供一种式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000004
其中：
Q选自H或保护基团，优选H；
R 1、R 2各自独立地选自H、C 1-4烷基，优选均为H，所述C 1- 4烷基任选被一个或多个取代基团P取代或未取代；
Q、R 1、R 2的每次出现可以是相同或不同的；
R 4选自H、C 1- 6烷基、6-10元芳基、或5-12元杂芳基，所述C 1- 6烷基、6-10元芳基、或5-12元杂芳基任选被一个或多个取代基团P取代或未取代；
Y 1是S或O，优选O；
A选自-NR 4(CO)-、-N R 4(SO 2)-、-N R 4(CH 2)-或不存在；
所述E选自3-12元环烷基，或
Figure PCTCN2022116453-appb-000005
或不存在，所述
Figure PCTCN2022116453-appb-000006
为包含一个或多个N原子的杂环基、或杂芳基，其中所述的3-12元环烷基、杂环基、杂芳基任选被一个或多个取代基团P取代或未取代；
当A选自-NR 4(CO)-或不存在时，E不为环己烷；
W选自3-12元环烷基、3-12元杂环烷基、6-10元芳基、5-12元的杂芳基，所述C 3-12环烷基、3-12元杂环烷基、6-10元芳基、5-12元的杂芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基、-NR iR j、氧代、硫代、-C(O)R k、-C(O)OR k、-S(O)R k、-S(O)OR k、-S(O)(O)R k、-S(O)(O)OR k、-C(S)R k、硝基、氰基、C 1-C 6烷氧基、C 1-C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基、5至10元杂芳基、8至12元稠环芳基和5至12元稠杂芳基；
R i、R j各自独立地选自氢原子、羟基、C 1～C 6烷基、C 1～C 6烷氧基；R k独立地选自氢原子、C 1～C 6烷基、C 1～C 6卤代烷基、C 1～C 6烷氧基、羟基、-NR iR j，其中所述的烷基、烷氧基、卤代烷基任选被选自C 1～C 6烷基、卤素、羟基、巯基、-NR iR j、氧代、硫代、羧基、硝基、氰基、C 1～C 6烷氧基、C 1～C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元 杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；
a、b、e、g、h各自独立地为0-6的整数；
当A和E均不存在时，W不为萘基；
R 3选自H或螯合剂。
在一些实施方案中，所述A为-NH(CO)-，E选自
Figure PCTCN2022116453-appb-000007
所述
Figure PCTCN2022116453-appb-000008
为包含一个或多个N原子的杂环基，所述杂环基优选3-12元杂环基，更优选3-8元单杂环，最优选
Figure PCTCN2022116453-appb-000009
在一些实施方案中，所述A为-NH(CO)-，E选自
Figure PCTCN2022116453-appb-000010
所述
Figure PCTCN2022116453-appb-000011
为包含一个或多个N原子的杂环基为5-12元的稠杂环基，优选
Figure PCTCN2022116453-appb-000012
在一些实施方案中，所述A为-NH(CO)-，E选自
Figure PCTCN2022116453-appb-000013
所述
Figure PCTCN2022116453-appb-000014
为包含一个或多个N原子的杂芳基为5-12元的稠杂芳基，优选
Figure PCTCN2022116453-appb-000015
在一些实施方案中，所述A为-NH(CO)-，E选自3-12元环烷基，且不为环己烷，所述3-12元环烷基为5-12元稠环烷基，优选
Figure PCTCN2022116453-appb-000016
Figure PCTCN2022116453-appb-000017
在一些实施方案中，所述A为-NH(CO)-，e为1，E选自3-12元环烷基，所述3-12元环烷基为螺环烷基。
在一些实施方案中，所述A为-NH(CO)-，e为1，E选自3-12元环烷基，所述3-12元环烷基为5-12元的单螺环烷基。
在一些实施方案中，所述A为-NH(CO)-，e为1，E选自3-12元环烷基，所述3-12元环烷基为为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元单螺环烷基。
在一些实施方案中，所述A为-NH(CO)-，e为1，E选自3-12元环烷基，所述3-12元环 烷基选自
Figure PCTCN2022116453-appb-000018
Figure PCTCN2022116453-appb-000019
在一些实施方案中，所述A为-NH(CO)-，e为1，E选自3-12元环烷基，所述3-12元环烷基为
Figure PCTCN2022116453-appb-000020
在一些实施方案中，所述A为-NH(CO)-，E选自3-12元环烷基，所述3-12元环烷基为桥环烷基。
在一些实施方案中，所述A为-NH(CO)-，E选自3-12元环烷基选自
Figure PCTCN2022116453-appb-000021
Figure PCTCN2022116453-appb-000022
在一些实施方案中，所述A为-NH(CO)-，E选自3-12元环烷基为
Figure PCTCN2022116453-appb-000023
在一些实施方案中，所述A为-NH(CO)-，E不存在。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述a为1，所述W选自苯基或萘基。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述a为1，所述W为萘基。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述Q选自H或保护基团。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述Q为H。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述R 2各自独立地为H。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述R 1各自独立地为H。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述h选自1或2。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述h为1。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述g选自3或4。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述g为3。
在一些实施方案中，本公开提供的式(I)所示化合物或其药学上可接受的盐，所述a为1，所述W为萘基，Q、R 2、R 1各自独立地为H。
在一些实施方案中，所述式(I)化合物为式(I-1)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000024
其中：
Q选自H或保护基团，优选H，每次出现可以是相同或不同的；
E选自3-12元环烷基、
Figure PCTCN2022116453-appb-000025
或不存在，所述
Figure PCTCN2022116453-appb-000026
为包含一个N原子的杂环基，其中所述的3-12元环烷基、包含一个N原子的杂环基任选被一个或多个取代基团P取代或未取代，且3-12元环烷基不为环己烷；所述3-12元环烷基优选稠环烷基；所述包含一个N原子的杂环基优选6元环；
W选自6-10元芳基，所述6-10元芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(I-1)所示化合物或其药学上可接受的盐中，所述W为苯基或萘基。
在一些实施方案中，所述的式(I)所示化合物或其药学上可接受的盐，中所述A为-NH(SO 2)-，E选自C 3-12环烷基，优选3-8元环烷基，更优选环己烷，最优选
Figure PCTCN2022116453-appb-000027
Figure PCTCN2022116453-appb-000028
在一些实施方案中，所述式(I)所示化合物或其药学上可接受的盐中，所述A为-N(CH 2)-，E选自3-12元环烷基，优选3-12元环烷基，更优选环己烷，最优选
Figure PCTCN2022116453-appb-000029
在一些实施方案中，所述的式(I)所示化合物为式(I-2)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000030
其中：
Q选自H或保护基团，优选H，每次出现可以是相同或不同的；
A选自-NH(SO 2)-或-N(CH 2)-；
E选自3-12元环烷基或不存在，其中所述的3-12元环烷基任选被一个或多个取代基团P取代或未取代；
W选自6-10元芳基，所述6-10元芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(I-2)所示化合物或其药学上可接受的盐中，所述W为萘基。
在一些实施方案中，所述的式(I)所示化合物或其药学上可接受的盐中，所述A不存在，E选自
Figure PCTCN2022116453-appb-000031
所述
Figure PCTCN2022116453-appb-000032
为包含一个或多个N原子的5-12元的稠杂环基，优选
Figure PCTCN2022116453-appb-000033
在一些实施方案中，所述的式(I)所示化合物或其药学上可接受的盐中，所述A不存在，E选自
Figure PCTCN2022116453-appb-000034
所述
Figure PCTCN2022116453-appb-000035
为包含一个或多个N原子的5-12元的杂芳基，优选
Figure PCTCN2022116453-appb-000036
在一些实施方案中，所述式(I)所示化合物为式(I-3)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000037
其中：
Q选自H或保护基团，优选H，每次出现可以是相同或不同的；
E选自
Figure PCTCN2022116453-appb-000038
所述
Figure PCTCN2022116453-appb-000039
为包含一个或多个N原子的5-12元的稠杂环基或5-12元的杂芳基，所述包含一个或多个N原子的5-12元的稠杂环基或5-12元的杂芳基任选被一个或多个取代基团P取代或未取代；
W选自6-10元芳基，所述6-10元芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基、羰基；
e选自0或1；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(I-3)所示化合物或其药学上可接受的盐中，所述E为包含一个或多个N原子的5-12元的杂芳基，且未被取代，优选
Figure PCTCN2022116453-appb-000040
在一些实施方案中，所述的式(I-3)所示化合物或其药学上可接受的盐中，所述E为包含一个或多个N原子的5-12元的稠杂环基，且所述包含一个N原子的5-12元的稠杂环基被羰基取代，优选
Figure PCTCN2022116453-appb-000041
在一些实施方案中，所述的式(I-3)所示化合物或其药学上可接受的盐中所述W为苯基或萘基。
在一些实施方案中，所述的式(I)所示化合物或其药学上可接受的盐中所述A、E均不 存在。
在一些实施方案中，所述的式(I)所示化合物为式(I-4)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000042
其中：
Q选自H或保护基团，优选H，每次出现可以是相同或不同的；
W选自6-10元芳基、5-12元的杂芳基，所述6-10元芳基、5-12元的杂芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(I-4)所示化合物或其药学上可接受的盐中，所述W选自6-10元芳基，优选苯基、萘基、联苯、苯羟基，更优选苯基、
Figure PCTCN2022116453-appb-000043
Figure PCTCN2022116453-appb-000044
在一些实施方案中，所述的式(I-4)所示化合物或其药学上可接受的盐中，所述W选自5-12元的杂芳基，优选5-6元杂芳基或稠杂芳基，更优选吲哚、吡啶、咪唑、喹啉，最优选
Figure PCTCN2022116453-appb-000045
Figure PCTCN2022116453-appb-000046
本公开还提供了一种式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000047
其中：
Q选自H或保护基团，优选H；
R 1、R 2独立地选自H、取代或未取代的C 1-4烷基，优选均为H；
Q、R 1、R 2的每次出现可以是相同或不同的；
F选自-N(CH 2) n-或-(CH 2) mOG(CH 2) n-；
Y 1、Y 2独立地选自S或O，优选O；
g、h、n、m各自独立地选自0-6的整数；
G选自3-12元环烷基、3-12元杂环烷基、6-10元芳基、5-12元的杂芳基，所述3-12元环烷基、3-12元杂环烷基、6-10元芳基、5-12元的杂芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基、-NR iR j、氧代、硫代、-C(O)R k、-C(O)OR k、-S(O)R k、-S(O)OR k、-S(O)(O)R k、-S(O)(O)OR k、-C(S)R k、硝基、氰基、C 1-C 6烷氧基、C 1-C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基、5至10元杂芳基、8至12元稠环芳基和5至12元稠杂芳基；
R i、R j各自独立地选自氢原子、羟基、C 1～C 6烷基、C 1～C 6烷氧基；R k独立地选自氢原子、C 1～C 6烷基、C 1～C 6卤代烷基、C 1～C 6烷氧基、羟基、-NR iR j，其中所述的烷基、烷氧基、卤代烷基任选被选自C 1～C 6烷基、卤素、羟基、巯基、-NR iR j、氧代、硫代、羧基、硝基、氰基、C 1～C 6烷氧基、C 1～C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(II)所示化合物或其药学上可接受的盐中，所述F选自-N(CH 2) n-。
在一些实施方案中，所述的式(II)所示化合物或其药学上可接受的盐中所述F选自-(CH 2) mOG(CH 2) n-，所述G选自6-10元芳基，优选苯基。
在一些实施方案中，所述的式(II)为式(II-1)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000048
其中：
Q选自H或保护基团，优选H，每次出现可以是相同或不同的；
F选自-N(CH 2) n-或-(CH 2) mOG(CH 2) n-；
所述G选自6-10元芳基；
n、m各自独立地选自0-6的整数；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(II-1)所示化合物中所述G为苯基。
本公开还提供一种式(III)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000049
其中：
Q选自H或保护基团，优选H；
R 1、R 2独立地选自H、取代或未取代的C 1-4烷基，优选均为H；
Q、R 1、R 2的每次出现可以是相同或不同的；
g、h、j各自独立地选自0-6的整数；
i选自1-3的整数；
J是选自由C 1-C 6亚烷基、C 3-C 6亚环烷基、亚芳基、以及亚杂芳基组成的组的连接基，所述C 1-C 6亚烷基、C 3-C 6亚环烷基、亚芳基、以及亚杂芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基、-NR iR j、氧代、硫代、-C(O)R k、-C(O)OR k、-S(O)R k、-S(O)OR k、-S(O)(O)R k、-S(O)(O)OR k、-C(S)R k、硝基、氰基、C 1-C 6烷氧基、C 1-C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基、5至10元杂芳基、8至12元稠环芳基和5至12元稠杂芳基；
R i、R j各自独立地选自氢原子、羟基、C 1～C 6烷基、C 1～C 6烷氧基；R k独立地选自氢原子、C 1～C 6烷基、C 1～C 6卤代烷基、C 1～C 6烷氧基、羟基、-NR iR j，其中所述的烷基、烷氧基、卤 代烷基任选被选自C 1～C 6烷基、卤素、羟基、巯基、-NR iR j、氧代、硫代、羧基、硝基、氰基、C 1～C 6烷氧基、C 1～C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；
K选自由-NR 5-(C＝O)-、-NR 5-(C＝S)-、-(C＝O)-NR 5-、和-(C＝S)-NR 5-组成的组；
所述R 5选自H或C 1-C 4烷基；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(III)所示化合物或其药学上可接受的盐中所述i选自2，K选自-NH-(C＝O)-，J选自亚芳基或亚杂芳基，优选吡啶或苯基，更优选
Figure PCTCN2022116453-appb-000050
在一些实施方案中，所述的式(III)所示化合物为式(III-1)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000051
其中：
Q选自H或保护基团，优选H；
J是选自由亚芳基或亚杂芳基组成的组的连接基，所述亚芳基、以及亚杂芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基、氧代、硫代；
其中Q、J的每次出现能够是相同的或不同的；
j选自0-6的整数；
R 3选自H或螯合剂。
在一些实施方案中，所述的式(III)所示化合物或其药学上可接受的盐中所述J选自吡啶或苯基，优选
Figure PCTCN2022116453-appb-000052
其中J的每次出现是不同的，j选自1。
本公开提供一种式(IV)所示化合物或其药学上可接受的盐，
Figure PCTCN2022116453-appb-000053
其中：
Q选自H或保护基团；
R 1、R 2各自独立地选自H、C 1-4烷基，所述C 1- 4烷基任选被一个或多个取代基团P取代或未取代；
Q、R 1、R 2的每次出现可以是相同或不同的；
Y 1是S或O；
T选自-NR 4(CO)-、-NR 4(SO 2)-、-N R 4(CH 2)-；
R 4选自H、C 1- 6烷基、6-10元芳基、或5-12元杂芳基，所述C 1- 6烷基、6-10元芳基、或5-12元杂芳基任选被一个或多个取代基团P取代或未取代；
环A选自3-12元含氮杂环基，其中所述的3-12元含氮杂环基任选被一个或多个取代基团P取代或未取代；
W选自6-10元芳基、5-12元的杂芳基，所述-10元芳基、5-12元的杂芳基任选地被一个或多个取代基团P取代或未取代；
所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基、-NR iR j、氧代、硫代、-C(O)R k、-C(O)OR k、-S(O)R k、-S(O)OR k、-S(O)(O)R k、-S(O)(O)OR k、-C(S)R k、硝基、氰基、C 1-C 6烷氧基、C 1-C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基、5至10元杂芳基、8至12元稠环芳基和5至12元稠杂芳基；
R i、R j各自独立地选自氢原子、羟基、C 1～C 6烷基、C 1～C 6烷氧基；R k独立地选自氢原子、C 1～C 6烷基、C 1～C 6卤代烷基、C 1～C 6烷氧基、羟基、-NR iR j，其中所述的烷基、烷氧基、卤代烷基任选被选自C 1～C 6烷基、卤素、羟基、巯基、-NR iR j、氧代、硫代、羧基、硝基、氰基、C 1～C 6烷氧基、C 1～C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；
y、z、g、h各自独立地为0-6的整数；
R 3选自H或螯合剂。
在一些实施方案中，式(IV)所示化合物或其药学上可接受的盐中Q为保护基团，具体可选羟基保护基，作为羟基保护基，包括通常可作为羟基的保护基使用的所有基团，可列举出例如W.Greene等，Protective Groups in Organic Synthesis，第4版，第16～366页，2007年，John Wiley&Sons，INC.中记载的基团。作为具体例子，可列举出C 1-6烷基、C 2-6链烯基、 芳基C 1-6烷基、C 1-6烷氧基C 1-6烷基、酰基、C 1-6烷氧基羰基、C 1-6烷基磺酰基、芳基磺酰基、四氢呋喃基、四氢吡喃基或硅烷基等。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述T为-NH(CO)-，环A为5-12元的含氮螺杂环基。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述T为-NH(CO)-，环A选自5-12元的含氮单螺杂环基。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述T为-NH(CO)-，环A选自3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元含氮单螺杂环基。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述T为-NH(CO)-，环A选自
Figure PCTCN2022116453-appb-000054
Figure PCTCN2022116453-appb-000055
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述T为-NH(CO)-，环A选自
Figure PCTCN2022116453-appb-000056
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述T为-NH(CO)-，环A为
Figure PCTCN2022116453-appb-000057
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述W选自6-10元芳基。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述W为萘基。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述Y 1是O。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述R 1和R 2各自独立地为H。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述Q 选自H或保护基团。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述Q为H。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述y和h各自独立地选自0、1或2。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述y为1。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述h为1。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述g选自3或4。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述g为3。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述z选自0或1。
在一些实施方案中，本公开提供的式(IV)所示化合物或其药学上可接受的盐，所述z为0。
在一些实施方案中，前述螯合剂选自：
Figure PCTCN2022116453-appb-000058
Figure PCTCN2022116453-appb-000059
Figure PCTCN2022116453-appb-000060
在一些实施方案中，前述螯合剂为
Figure PCTCN2022116453-appb-000061
在一些实施方案中，前述螯合剂为
Figure PCTCN2022116453-appb-000062
在一些实施方案中，前述化合物选自下表1：
表1
Figure PCTCN2022116453-appb-000063
Figure PCTCN2022116453-appb-000064
Figure PCTCN2022116453-appb-000065
Figure PCTCN2022116453-appb-000066
Figure PCTCN2022116453-appb-000067
Figure PCTCN2022116453-appb-000068
在一些实施方案中，本公开前述所述螯合剂包含放射性核素。
在一些实施方案中，前述放射性核素选自 18F、 11C、 68Ga、 124I、 89Zr、 64Cu、 86Y、 99mTc、 111In、 123I、 90Y、 125I、 131I、 177Lu、 211At、 153Sm、 186Re、 188Re、 67Cu、 212Pb、 225Ac、 213Bi、 212Bi、 212Pb或 67Ga中的至少一种。
在一些实施方案中，前述放射性核素为 68Ga。
在一些实施方案中，前述放射性核素为 177Lu。
在一些实施方案中，本公开提供一种式(IV)所示化合物或其药学上可接受的盐，其为
Figure PCTCN2022116453-appb-000069
可选的实施方案中，本申请提供的式(IV)所示化合物或其药学上可接受的盐，其为，
Figure PCTCN2022116453-appb-000070
在一些实施方案中，本公开提供一种式(IV)所示化合物或其药学上可接受的盐，其为
Figure PCTCN2022116453-appb-000071
在一些实施方案中，本公开提供一种式(IV)所示化合物或其药学上可接受的盐，其为
Figure PCTCN2022116453-appb-000072
在一些实施方案中，本公开提供一种式(IV)所示化合物或其药学上可接受的盐，其为
Figure PCTCN2022116453-appb-000073
所述螯合剂包含放射性核素，所述放射性核素为 68Ga。
在一些实施方案中，本公开提供一种式(IV)所示化合物或其药学上可接受的盐，其为 为
Figure PCTCN2022116453-appb-000074
所述螯合剂包含放射性核素，所述放射性核素为 177Lu。
本公开进一步提供一种式(IV)所示化合物或其药学上可接受的盐的制备方法，所示式(IV)所示化合物为式v所示化合物或其药学上可接受的盐，包括式v-5所示化合物脱叔丁基的步骤：
Figure PCTCN2022116453-appb-000075
可选的实施方案中，式(IV)所示化合物或其药学上可接受的盐的制备方法进一步包括：式v-3所示化合物与式v-4所示化合物发生缩合反应得到式v-5所示化合物的步骤，
Figure PCTCN2022116453-appb-000076
式(IV)所示化合物或其药学上可接受的盐的制备方法，包括式(IV)所示化合物或其药学上可接受的盐的制备步骤，进一步包括式(IV)所示化合物或其药学上可接受的盐中螯合剂与放射性核素络合的步骤。
可选的实施方案中，本公开提供一种式(IV)所示化合物或其药学上可接受的盐的制备方法，
所述式(IV)所示化合物或其药学上可接受的盐为
Figure PCTCN2022116453-appb-000077
包括将
Figure PCTCN2022116453-appb-000078
通过常规拆分得到单一异构体的步骤。
在一些实施方案中，所述的化合物可以被前述的放射性核素标记。
本公开还提供了前述化合物的同位素取代物，优选氘代化合物。
本公开还提供了一种药物组合物，包括至少一种前述化合物或其可药用的盐，以及药学上可接受的载体、稀释剂或赋形剂。
在某些实施方式中，所述的药物组合物的单位剂量为0.001mg-1000mg。
在某些实施方式中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的前述化合物。在某些实施方式中，所述的药物组合物含有0.1％-99.9％的前述化合物。在某些实施方式中，所述的药物组合物含有0.5％-99.5％的前述化合物。在某些实施方式中，所述的药物组合物含有1％-99％的前述化合物。在某些实施方式中，所述的药物组合物含有2％-98％的前述化合物。
在某些实施方式中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方式中，所述的药物组合物含有0.1％-99.9％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方式中，所述的药物组合物含有0.5％-99.5％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方式中，所述的药物组合物含有1％-99％的药学上可接受的载体、稀释剂或赋形剂。在某些实施方式中，所述的药物组合物含有2％-98％的药学上可接受的载体、稀释剂或赋形剂。
本公开还提供前述的化合物或其药学上可接受的盐及其同位素取代物在制备用于在患者中成像的组合物中的用途。
本公开还提供前述的化合物或其药学上可接受的盐及其同位素取代物在制备用于诊断和/或治疗和/或预防PSMA介导的疾病或病症的药物中的用途。
本公开还提供前述的化合物或其药学上可接受的盐及其同位素取代物在制备用于诊断和 /或治疗和/或预防肿瘤和癌症中的用途，其中所述肿瘤和癌症优选前列腺癌和/或其转移。
术语解释：
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“亚烷基”指饱和的直链或支链脂肪族烃基，其具有2个从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH 2-)、1,1-亚乙基(-CH(CH 3)-)、1,2-亚乙基(-CH 2CH 2)-、1,1-亚丙基(-CH(CH 2CH 3)-)、1,2-亚丙基(-CH 2CH(CH 3)-)、1,3-亚丙基(-CH 2CH 2CH 2-)、1,4-亚丁基(-CH 2CH 2CH 2CH 2-)等。亚烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代。
术语“亚链烯基”指包含具有2至8个碳原子，优选地具有2至6个碳原子，更优选地具有2至4个碳原子并在任何位置具有至少一个双键的线性链烯基，包括例如亚乙烯基、亚烯丙基(allylene)、亚丙烯基、亚丁烯基、亚异戊二烯基(prenylene)、亚丁二烯基(butadienylene)、亚戊烯基、亚戊二烯基、亚己烯基、亚己二烯基等。
术语“亚链炔基”包括具有2至8个碳原子，优选地具有2至6个碳原子，更优选地具有2至4个碳原子且在任何位置具有至少一个叁键的线性亚链炔基，包括例如亚乙炔基、亚丙炔基、亚丁炔基、亚戊炔基、亚己炔基等。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳 原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。“碳环”指的是环烷基中的环系。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。“螺碳环”指的是螺环烷基中的环系。螺环烷基的非限制性实例包括：
Figure PCTCN2022116453-appb-000079
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠碳环”指的是稠环烷基中的环系。稠环烷基的非限制性实例包括：
Figure PCTCN2022116453-appb-000080
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2022116453-appb-000081
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷 基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至6个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。“杂环”指的是杂环基中的环系。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元或6元/6元单螺杂环基。“螺杂环”指的是螺杂环基中的环系。螺杂环基的非限制性实例包括：
Figure PCTCN2022116453-appb-000082
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。“稠杂环”指的是稠杂环基中的环系。稠杂环基的非限制性实例包括：
Figure PCTCN2022116453-appb-000083
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环 原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2022116453-appb-000084
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022116453-appb-000085
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。“芳环”指的是芳基中的环系。芳基非限制性实例包括：
Figure PCTCN2022116453-appb-000086
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基，优选苯基。
术语“稠环芳基”可以是含有8-14个环原子由两个或两个以上环状结构彼此共用两个相邻的原子连接起来形成的不饱和的具有芳香性的稠环结构，环原子优选8-12个。例如包括全部不饱和稠环芳基，例如萘、菲等，还包括部分饱和稠环芳基，例如苯并3-8元饱和单环环烷基、苯并3-8元部分饱和单环环烷基。“稠芳环”指的是稠环芳基中的环系。稠环芳基具体实例如2,3-二氢-1H-茚基、IH-茚基、1,2,3,4-四氢萘基、1,4-二氢萘基等。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至12元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、吡唑基、嘧啶基或噻唑基；更优选为吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。“杂芳环”指的是杂芳基中的环系。杂芳基非限制性实例包括：
Figure PCTCN2022116453-appb-000087
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“稠杂芳基”可以是含有5-14个环原子(其中至少含有一个杂原子)由两个或两个以上环状结构彼此共用两个相邻的原子连接起来形成的不饱和的具有芳香性的稠环结构，同时包括碳原子、氮原子和硫原子可以被氧代，优选"5-12元稠杂芳基"、"7-12元稠杂芳基"、"9-12元稠杂芳基"等，例如苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。“稠杂芳环”指的是稠杂芳基中的环系。
稠杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
上述环烷基、杂环基、芳基和杂芳基具有1个从母体环原子上除去一个氢原子所衍生的残基，或2个从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷硫基”指-S-(烷基)和-S-(非取代的环烷基)，其中烷基的定义如上所述。烷硫基的非限制性实例包括：甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基、环己硫基。烷硫基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基中的一个或多个取代基所取代。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指被卤素取代的烷基，其中烷基如上所定义。
术语“氘代烷基”指被氘原子取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“氧代”指＝O基团。例如，碳原子与氧原子通过双键连接，其中形成酮或醛基。
术语“硫代”指＝S基团。例如，碳原子与硫原子通过双键连接，形成硫代羰基-C(S)-。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羧基”指-C(O)OH。
术语“醛基”指-CHO。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
术语“磺酰基”指-S(O)(O)-。
术语“亚磺酰基”指-S(O)-。
化学基团的“电子等排体”为表现出相同或相似性质的其它化学基团。例如，四唑是羧酸的电子等排体，因为其模拟羧酸的性质，即使这两者具有非常不同的分子式。四唑是羧酸的许多可能的电子等排替换物中的其中一种。其他可预期的羧酸电子等排体包括-SO 3H、-SO 2HNR、-PO 2(R) 2、-PO 3(R) 2、-CONHNHSO 2R、-COHNSO 2R和-CONRCN，其中R选自如本文所定义的氢、烷基、烯基、炔基、环烷基、芳基、杂芳基和杂环基。此外，羧酸电子等排体可包含5元至7元碳环或杂环，所述杂环包含在任何化学稳定氧化态情况下的CH 2、O、S或N的任何组合，其中所述环结构的任何一种原子在一个或多个位置处被任选取代。可以预期的是，还应预期，当将化学取代基添加至羧基电子等排体时，化合物保留羧基电子等排体的性质。预期的是，当羧基电子等排体被选自如以上所定义的R的一个或多个部分任选取代时，则选择取代度(substitution)和取代位置，以使其不会消除化合物的羧酸电子等排性质。类似地，还应预期，如果一个或多个R取代基会破坏化合物的羧酸电子等排性质，则此类取代基在碳环或杂环羧酸电子等排体上的位置不是位于使化合物的羧酸电子等排性质保持完整或为完整的一个或多个原子处的取代。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须 存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本公开所述化合物的化学结构中，键
Figure PCTCN2022116453-appb-000088
并未指定构型，即键
Figure PCTCN2022116453-appb-000089
可以为
Figure PCTCN2022116453-appb-000090
Figure PCTCN2022116453-appb-000091
或者同时包含
Figure PCTCN2022116453-appb-000092
两种构型。本公开所述化合物的化学结构中，键
Figure PCTCN2022116453-appb-000093
并未指定构型，即可以为Z构型或E构型，或者同时包含两种构型。
虽然为简便起见将全部上述结构式画成某些异构体形式，但是本公开可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。
互变异构体是有机化合物的结构异构体，通过被称为互变异构化的化学反应容易相互转化。这种反应常导致氢原子或质子的形式迁移，伴随着单键和邻近的双键的转换。一些常见的互变异构对为：酮-烯醇、内酰胺-内酰亚胺。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022116453-appb-000094
另外，因为螯合环(DOTA类似环)络合金属离子后会在溶液中会形成四方反棱柱(SAP)和扭曲的四方反棱柱(TSAP)两种构象，其可以通过螯合环垂臂旋转或环翻转形成互变异构体；另外，连接螯合环侧链的翻转同样也会形成互变异构体。具体如期刊(Dalton Trans.2018,47(31):10360；Dalton Trans.2016,45(11),4673；Nature Communication 2018,9:857；Bioconjugate Chem.2015,26(2),338.)中解释。
Figure PCTCN2022116453-appb-000095
本公开中的所有化合物可以被画成A型或B型。所有的互变异构形式在本公开的范围内。化合物的命名不排除任何互变异构体。
本公开所述化合物或其可药用盐、或其异构体的任何同位素标记的衍生物都被本公开所覆盖。能够被同位素标记的原子包括但不限于氢、碳、氮、氧、磷、氟、氯、碘等。它们可分别被同位素同位素 2H(D)、 3H、 11C、 13C、 14C、 15N、 18F、 31P、 32P、 35S、 36Cl和 125I等代 替。除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少3000倍的丰度的氘(即，至少45％的氘掺入)。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上药学上可接受的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
附图说明
图1.PSMA-617、化合物v和x酶活实验对比。
图2. 68Ga-v和68Ga-x在LnCaP荷瘤鼠中的2h生物分布。
图3. 68Ga-PSMA-617和 68Ga-v(实施例9)在正常鼠中血液代谢曲线。
具体实施方式
以下将结合实施例更详细地解释本公开，本公开的实施例仅用于说明本公开的技术方案，本公开的实质和范围并不局限于此。若无特殊说明，本公开使用原料均为正常市售产品。
NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Shimadzu 2010Mass Spectrometer或Agilent 6110A MSD质谱仪。
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱；薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，D：石油醚/乙酸乙酯/甲醇，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
下述实验中所用缩写代表的含义如下:
EtOAc(EA):乙酸乙酯；DCM:二氯甲烷；THF:四氢呋喃；DIPEA:N,N-二异丙基乙胺；PPTS：对甲基苯磺酸吡啶盐；Boc：叔丁氧羰基，MeOH:甲醇；HATU：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；DIEA：N,N-二异丙基乙胺。
实施例1
Figure PCTCN2022116453-appb-000096
(((S)-5-((S)-2-(4-(氨基甲基)哌啶-1-甲酰氨基)-3-(2-萘基)丙酰氨基)-1-羧基戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000097
步骤1(制备树脂化合物S-4)：
Figure PCTCN2022116453-appb-000098
将所需原料及树脂取出，放入干燥器平衡至室温。称取25g Wang Resin(sub＝0.38mmol/g，8.75mmol)(王树脂，购自西安蓝晓科技有限公司)放入500mL单口烧瓶中，加入250mL DMF，置于振荡器振摇30min。加入Fmoc-Lys(Alloc)-OH(19.8g,43.75mmol)(N-[(9H-芴-9-甲氧基)羰基]-N'-[(2-丙烯氧基)羰基]-L-赖氨酸，购自吉尔生化公司)、DIC(5.5g，43.75mmol)、HOBt(13.0g，43.75mmol)(1-羟基苯并三唑，购自迈瑞尔公司)、DMAP(0.11g，0.875mmol)(4-二甲氨基吡啶，购自安耐吉)置于振荡器室温反应23h。将树脂转入固相反应柱，抽除反应液。树脂用DMF洗涤3次，每次300mL。树脂以吡啶：乙酸酐＝1:1(V:V)150mL对树脂进行封闭。树脂封闭8h，肽树脂用甲醇收缩干燥，得到产物S-1(8.75mmol)。
室温下，将产物S-1(7mmol)用150mL DMF溶胀，后加入200mL 20％DBLK(20％哌啶/DMF溶液，购自安耐吉公司)脱保护10min，抽干后再加入200mL 20％DBLK脱保护10min，Kaiser test检测树脂蓝色，抽干，用DMF洗涤树脂至中性，得到产物S-2。
室温下，将产物S-2(7mmol)加入到谷氨酰基异氰酸酯反应液内，在恒温振荡器缓慢搅拌反应18h，Kaiser test检测树脂为无色。将树脂转入固相反应柱，抽干反应液。树脂用DMF洗涤3次，每次300mL，得到产物产物S-3。
室温下，将用产物S-3(7mmol)加入到反应柱中，将苯硅烷(4.6g，42mmol)、四三苯基膦钯(0.81g，0.7mmol)溶于180mL DCM中，将此溶液加入到反应柱中，氮气鼓泡反应0.5h，抽干溶剂，再重复操作上述步骤2次，通过Kaiser test检测树脂呈蓝黑色，反应完毕， 抽干溶剂，用DMF洗涤三次，抽干，再用甲醇收缩三次后，30℃真空干燥2h，得到产物S-4(22.2g，7mmol)备用。
步骤2：
室温下，将树脂化合物S-4(4.0g，1.28mmol)用二氯甲烷(购自国药基团化学试剂有限公司)溶胀0.5h，抽干，DMF洗涤三次抽干备用。
称取Fmoc-2-NAL-OH(1.68g，3.84mmol)(Fmoc-3-(2-萘基)-L-丙氨酸，购自迈瑞尔公司)、HOBt(0.52g，3.84mmol)(1-羟基苯并三唑，购自迈瑞尔公司)、HATU(1.46g，3.84mmol)2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯购自麦克林公司)、DIEA(1.01g，7.68mmol)(N,N-二异丙基乙胺，购自安耐吉)，用DMF(25mL)(N,N-二甲基甲酰胺，购自安耐吉)溶解后加入至放有化合物S-4的固相反应柱中，反应2h，Kaiser test检测树脂无色。抽干反应液，用DMF洗涤树脂三次，得到标题产物a-1。
步骤3：
室温下，向放有a-1的固相反应柱中加入40mL 20％DBLK(20％哌啶/DMF溶液，购自安耐吉公司)脱保护10min，抽干后再加入40mL 20％DBLK脱保护10min，Kaiser test检测树脂蓝色，抽干用DMF洗涤树脂至中性，得到产物化合物a-2。
步骤4：
室温下，将化合物a-2(1.0mmol)、三光气(0.2g，0.68mmoL)加至6mL DCM溶液中，降温至0℃，滴加DIEA(0.65g，5mmol)，加毕，保温反应2h，Kaiser test检测树脂无色，加入4-Boc-氨甲基哌啶，升至室温反应3h，抽干反应液，用DMF(N,N-二甲基甲酰胺)洗涤树脂三次，再用甲醇收缩三次后，30℃真空干燥2h，得到产物化合物a-3备用。
步骤5：
室温下，配制裂解液(裂解液TFA(三氟乙酸)：H 2O：Tis(三异丙基硅烷，购自麦克林公司)＝95：2.5：2.5)40mL，搅拌下加入肽树脂化合物4反应2h。之后抽滤，除掉树脂，滤液旋蒸浓缩，将浓缩液加入到100mL异丙醚中，抽滤，减压烘干，得到粗肽0.40g，产率60.9％。高压制备液相色谱法纯化，得到标题产物化合物a(105mg，产率：26.2％)。
MS m/z(ESI):657.3[M+1] +
1H NMR(400MHz,Deuterium Oxide)δ7.82(t,J＝9.1Hz,3H),7.64(s,1H),7.46(s,2H),7.37(d,J＝8.4Hz,1H),4.51(t,J＝8.1Hz,1H),4.14(s,1H),3.85(dd,J＝30.1,11.1Hz,2H),3.71(d,J＝13.8Hz,1H),3.22(dd,J＝13.6,7.5Hz,1H),3.14–3.01(m,1H),2.97–2.83(m,1H),2.67(dt,J＝33.6,12.7Hz,2H),2.40(dt,J＝15.4,6.9Hz,4H),2.12–1.97(m,1H),1.84(dd,J＝14.3,7.5Hz,1H),1.68(s,1H),1.49(d,J＝19.0Hz,4H),1.36(s,1H),1.13(d,J＝7.4Hz,2H),0.93(s,2H),0.66(d,J＝12.2Hz,1H),0.54(s,1H).
实施例2
Figure PCTCN2022116453-appb-000099
(((S)-5-((S)-2-((((1R,4S)-4-(氨基甲基)环己基)甲基)氨基)-3-(2-萘基)丙酰胺基)-1-羧基戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000100
步骤1：
室温下，将反式-4-(Boc-氨甲基)环己烷甲醇化合物e-1(3g，12mmol)溶解于60mL DCM中，降温至-60℃，加入DMP/DCM溶液(7.95g，18mmol,DCM 60mL)，加毕，自然升至室温搅拌反应4小时。TLC监测反应完毕。反应液依次用100mL Na 2CO 3和Na 2S 2O 3水溶液、100mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系正庚烷/乙酯＝10:1～4:1洗脱纯化，化合物e-2(1.8g，产率：59.7％)。
MS m/z(ESI):242.3[M+1] +
步骤2：
室温下，将化合物e-3(1.56g，6.8mmol)、化合物e-2(1.48g，6.1mmol)、溶解于40mL DCM/THF(V1:V2＝1:1)溶液中，搅拌反应2h。缓慢加入氰基硼氢化钠(0.5g，7.9mmol)，冰醋酸(0.3mL)，搅拌反应3h。反应液用水洗涤、DCM萃取(40mL*3)，合并有机相，50mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系正庚烷/乙酯＝10:1～4:1洗脱纯化，化合物e-4(1.54g，产率：55.6％)。
MS m/z(ESI):455.3[M+1] +
步骤3：
室温下，将化合物e-4(1.5g，3.3mmol)溶解于12mL THF和5mL水中，加入氢氧化锂(0.24g，9.9mmol)，加毕于室温反应过夜。向反应液中加入10mL水，乙酸乙酯萃取(10mL×2)，合并水相，冰浴降至0℃，用0.5N的柠檬酸调节PH＝3～4，析出固体，补加H 2O 100mL、DCM50mL，搅拌反应0.5h复测pH不变，过滤，滤饼真空干燥(40℃，4h)至恒重，得到产物化 合物e-5(1.1g，产率：75.9％)。
MS m/z(ESI):441.3[M+1] +
步骤4：
室温下，将化合物e-5(0.13g，0.3mmol)、HATU(0.16g，0.42mmol)、DIEA(0.18g，1.41mmol)，DCM(1mL)加入反应瓶内，搅拌溶清，加入化合物e-6，搅拌反应过夜。反应液用水洗涤、EA萃取(30mL*3)，合并有机相，50mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系正庚烷/乙酯＝EA(0％～90％)洗脱纯化，得到产物化合物e-7(0.13g，产率：59.4％)。
MS m/z(ESI):784.4[M+1] +
步骤5：
室温下，将化合物e-7(0.13g，0.16mmol)溶解于2mL乙酸乙酯内，搅拌下加入2M的HCL/EA溶液(2mL，4mmol)，搅拌反应2h。TLC监测反应完毕。反应液减压浓缩至恒重，得到产物化合物e-8(0.11g，产率：92％)。
MS m/z(ESI):684.3[M+1] +
步骤6：
室温下，将化合物e-8(0.11g，0.16mmol)溶解于2mL THF和1mL水中，加入氢氧化锂(29mg，1.2mmol)，加毕于室温反应过夜。向反应液中加入TFA调节PH＝2～3，搅拌反应0.5h复测pH不变，高压制备液相色谱法纯化，得到标题产物化合物e(80mg，产率：78.4％)。
MS m/z(ESI):640.3[M-1] -
1H NMR(400MHz,Deuterium Oxide)δ7.94(t,J＝6.7Hz,3H),7.91–7.80(m,1H),7.54(p,J＝7.2Hz,1H),7.46(t,J＝7.8Hz,1H),7.38(d,J＝7.1Hz,1H),4.18(dt,J＝9.1,5.6Hz,2H),4.05(d,J＝7.6Hz,2H),3.69(dd,J＝13.3,4.9Hz,2H),3.53(t,J＝12.3Hz,2H),2.94–2.70(m,3H),2.42(s,1H),2.08(s,2H),1.80(s,1H),1.68(s,2H),1.58(s,2H),1.39(d,J＝9.7Hz,2H),1.27(s,3H),1.02(q,J＝10.5,9.9Hz,3H),0.63(s,2H),0.46(s,2H).
实施例3
Figure PCTCN2022116453-appb-000101
(((S)-5-((S)-2-(4-(氨基甲基)-1-吡唑基)-3-苯基丙酰胺基)-1-羧基戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000102
步骤1：
室温下，将Boc-L-酪氨酸甲酯化合物g-1(0.5g，2.78mmol)溶解于120mL DCM中，加入吡啶(1.2mL，14.61mmol)，降温至0℃，加入三氟甲磺酸酐(2.4mL，14.10mmol)，加毕，自然升至室温搅拌反应3小时。TLC监测反应完毕。反应液依次用100mL饱和碳酸氢钠溶液、100mL 1N HCL、100mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，蒸干得到化合物g-2(0.84g，产率：99.0％)。
步骤2：
室温下，将4-(Boc-氨甲基)吡唑(0.61g，3.01mmol)溶解于25mL DCM中，加入DIEA(0.49g，3.72mmol)，搅拌反应1h。滴入化合物2(0.84g，2.69mmol)/DCM溶液，搅拌反应过夜。反应液依次用30mL饱和碳酸氢钠溶液、30mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系正庚烷/乙酯＝10:1～3:1洗脱纯化，化合物g-3(0.51g，产率：48.4％)。
MS m/z(ESI):360.2[M+1] +
步骤3：
室温下，将化合物g-3(0.51g，1.4mmol)溶解于1.5mL THF和1mL水中，加入氢氧化锂，加毕于室温反应过夜。向反应液中加入10mL水，乙酸乙酯萃取(10mL×2)，合并水相，冰浴降至0℃，用0.5N的柠檬酸调节PH＝3～4，加入乙酯萃取(10mL×3)，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物化合物g-4(0.39g，产率：80.0％)。
MS m/z(ESI):344.5[M-1] -
步骤4：
室温下，将实施例1中制备得到的树脂化合物S-4(1.1g，0.38mmol)用DCM溶胀0.5h，抽干,DMF洗涤三次备用。
将化合物g-4(0.36g，1.04mmol)、HATU(0.4g，1.04mmol)、HOBt(0.14g，1.04mmol)、DIEA(0.27g,2.08mmol)、DMF(10mL)加入反应瓶内，振荡溶清，将提前溶胀好的树脂加至反应瓶内，振荡反应过夜，Kaiser test检测树脂无色。抽干反应液，用DMF洗涤树脂三次，再用甲醇收缩后干燥，备用。得到产物化合物g-5。
步骤5：
室温下，配制裂解液(裂解液TFA：H2O：Tis＝95：2.5：2.5)10mL，搅拌下加入肽树脂化合物g-5反应2h。之后抽滤，除掉树脂，滤液旋蒸浓缩，将浓缩液加入到40mL异丙醚中析出固体，抽滤得到固体减压烘干，得到粗肽0.15g，产率72.1％。高压制备液相色谱法纯化，得到标题产物化合物g(26mg，产率：17.3％)。
MS m/z(ESI):547.8[M+1] +
1H NMR(400MHz,Deuterium Oxide)δ7.77(s,1H),7.54(s,1H),7.26–7.13(m,3H),7.13–7.06(m,2H),5.07(t,J＝8.2Hz,1H),4.17–4.08(m,1H),3.95(s,3H),3.32(d,J＝8.2Hz,2H),3.06(dt,J＝12.8,6.2Hz,1H),2.92(dt,J＝13.4,6.5Hz,1H),2.37(t,J＝7.3Hz,2H),2.04(dq,J＝13.1,7.2Hz,1H),1.83(dq,J＝14.9,7.3Hz,1H),1.59(s,1H),1.47(dd,J＝9.4,4.7Hz,1H),1.25–1.17(m,2H),0.98(d,J＝6.7Hz,2H).
实施例4
Figure PCTCN2022116453-appb-000103
(((S)-5-((S)-2-氨基-3-(4-吡啶)丙酰氨基)-1-羧基戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000104
步骤1：
室温下，将树脂化合物S-4(1.7g，0.65mmol)用DCM溶胀0.5h，抽干DMF洗涤三次备用。
将Boc-3-(4-吡啶基)-L-丙氨酸(0.54g，2.01mmol)、HATU(0.76g，2.01mmol)、HOBt(0.27g，2.01mmol)、DIEA(0.52g,4.02mmol)、DMF(15mL)加入反应瓶内，振荡溶清，将提前溶胀好的树脂加至反应瓶内，振荡反应2h，Kaiser test检测树脂无色。抽干反应液，用DMF洗涤树脂三次，再用甲醇收缩后干燥，备用。得到标题产物化合物j-1。
步骤2：
室温下，配制裂解液(裂解液TFA：H 2O：Tis＝95：2.5：2.5)20mL，搅拌下加入肽树脂化合物2反应2h。之后抽滤，除掉树脂，滤液旋蒸浓缩，将浓缩液加入到50mL异丙醚中析出固体，抽滤得到固体减压烘干，得到粗肽0.20g，产率66.7％。高压制备液相色谱法纯化，得到标题产物化合物j(75mg，产率：37.5％)。
MS m/z(ESI):468.8[M+1] +
1H NMR(400MHz,Deuterium Oxide)δ8.73–8.66(m,2H),7.90(d,J＝6.3Hz,2H),4.17(ddd,J＝23.5,9.1,5.6Hz,2H),4.00(dd,J＝8.9,5.0Hz,1H),3.50–3.30(m,2H),3.08(dt,J＝13.6,6.8Hz,1H),2.95(dt,J＝13.5,6.8Hz,1H),2.40(t,J＝7.3Hz,2H),2.07(dq,J＝13.2,7.2Hz,1H),1.85(ddd,J＝16.1,14.1,7.1Hz,1H),1.59(dtd,J＝55.3,14.5,14.1,7.9Hz,2H),1.25(s,2H),1.08(d,J＝9.0Hz,2H).
实施例5
Figure PCTCN2022116453-appb-000105
(((S)-5-(2-(4-((S)-2-(2-氨基乙酰胺)-2-羧乙基)苯氧基)乙酰胺)-1-羧戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000106
步骤1：
室温下，将Fmoc-L-酪氨酸叔丁酯(5.0g，10.9mmol)溶解于50mL DMF中，加入碳酸钾(1.81g，13.1mmol)，室温搅拌反应12h。加入Boc-甘氨酸(2.29g，13.1mmol)和HATU(4.98g，13.1mmol)，冰浴降至0℃，滴加DIEA，室温搅拌反应2h。向反应液中加入100mL水，用乙酸乙酯萃取(100mL×2)，合并有机相，用饱和碳酸氢钠溶液(100mL)、饱和氯化铵溶液(100mL×2)、饱和氯化钠溶液洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系PE/EA＝100:1～50:50洗脱纯化，得到产物化合物O-1(3.8g，产率：70％)。
MS m/z(ESI):395.4[M+1] +
步骤2：
室温下，将化合物O-1(3.8g，9.7mmol)溶解于40mL DMF中，加入碳酸钾(1.81g，13.1mmol)和溴乙酸甲酯(2.22g，14.5mmol)，升至80℃搅拌反应5-10h。向反应液中加入100mL水，用乙酸乙酯萃取(100mL×2)，合并有机相，用饱和氯化钠溶液洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到产物化合物O-2(4.2g，产率：110％)。
MS m/z(ESI):467.4[M+1] +
步骤3：
室温下，将化合物O-2(4.2g，9.0mmol)溶解于50mL THF和50ml水中，冰浴降至0℃，缓慢加入氢氧化锂的水溶液，加毕于室温反应2h。向反应液中加入乙酸乙酯萃取(100mL×2)，合并水相，冰浴降至0℃，用0.5N的稀盐酸调节pH＝3～4，加入乙酸乙酯萃取(100mL×2)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系DCM/MeOH＝100:1～20:1洗脱纯化，得到产物化合物O-3(3.5g，产率：80％)。
MS m/z(ESI):451.4[M-1] -
步骤4：
室温下，将化合物O-3(500mg，1.1mmol)溶解于30mL DCM中，加入HATU，冰浴降至0℃，滴加DIEA，室温搅拌反应0.5h。冰浴降至0℃，加入化合物O-4，室温搅拌反应2-5h。向反应液中加入100mL水，用DCM萃取(100mL×2)，合并有机相，用饱和碳酸氢钠溶液(100mL)、饱和氯化钠溶液洗涤(100mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系DCM/MeOH＝100:1～20:1洗脱纯化，得到产物化合物O-5(970mg，产率：80％)。
MS m/z(ESI):796.5[M+1] +
步骤5：
室温下，将化合物O-5(970mg，1.22mmol)溶解于5mL乙酸乙酯中，加入2N氯化氢乙酸乙酯溶液(15mL)，搅拌反应1-2h。减压浓缩反应液，得到产物化合物O-6(1.2g，产率：110％)。
MS m/z(ESI):696.5[M+1] +
步骤6：
室温下，将化合物O-6(200mg，0.29mmol)溶解于10mL THF和10mL水中，冰浴降至0℃，缓慢加入氢氧化锂(41.76mg，1.74mmol)，加毕于室温反应12h。向反应液中加入乙酸乙酯萃取(20mL×2)，合并水相，冰浴降至0℃，1N的稀盐酸调节PH＝2～3，高压制备液相色谱法纯化，得到标题产物化合物O(20mg，产率：20％)。
MS m/z(ESI):598.3[M+1] +
1H NMR(400MHz,D2O)δ7.15(d,J＝8.6Hz,2H),6.85(d,J＝8.7Hz,2H),4.52(s,2H),4.44(dd,J＝8.9,5.1Hz,1H),4.09(dd,J＝8.6,5.0Hz,1H),3.99(dd,J＝8.2,4.9Hz,1H),3.73–3.58(m,3H),3.18(t,J＝6.6Hz,2H),3.10–3.04(m,1H),2.84(dd,J＝14.6,9.1Hz,1H),2.37(t,J＝7.3Hz,2H),2.07–2.00(m,1H),1.88–1.79(m,1H),1.67(s,1H),1.55(d,J＝7.5Hz,1H),1.46–1.39(m,2H),1.20(d,J＝15.5Hz,3H).
实施例6
Figure PCTCN2022116453-appb-000107
(((S)-5-(6-(4-(氨基甲基)苯甲酰胺基)吡啶酰胺基)-1-羧戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000108
步骤1：
室温下，将化合物q-1(3g,11.94mmol)，溶解于60mL二氯甲烷中，加入EDCI(5.49g,28.66mmol)(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，购自麦克林公司)，DMAP(4.37g,35.82mmol)，在N 2氛围下搅拌20min，加入化合物q-2(2.17g,14.33mmol)，室温搅拌反应16-18h。向反应液中加入60mL水，用二氯甲烷萃取(100mL×3)，合并有机相，用饱和氯化钠溶液(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系(PE/EA＝100％-50％)纯化所得残余物，得到产物化合物q-3(2.0g，产率：43.5％)。
MS m/z(ESI):386.2[M+1] +
步骤2：
室温下，将化合物q-3(1g,2.59mmol)，溶解于6mL四氢呋喃中，加入LiOH(187mg,7.77mmol)的4mL水溶液，室温搅拌反应16-18h。向反应液中加入20mL水，用乙酸乙酯萃取(50mL×2)，水相用0.5mol/L的柠檬酸调节PH＝3-4,然后用乙酸乙酯萃取(50mL×4)，合并有机相，用饱和氯化钠溶液(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题产物化合物q-4(0.6g，产率：62.5％)。
MS m/z(ESI):372.2[M+1] +
步骤3：
室温下，将树脂化合物S-4(2.11g,0.68mmol)用DMF(20mL)溶胀30min。将化合物q-4(760mg,2.05mmol)，HATU(779mg,2.05mmol)，HOBt(277mg,2.05mmol)，DIEA(529mg,4.09 mmol)溶解于DMF(15mL)后加入至溶胀树脂中室温反应2.5h.取少量树脂抽滤后用DMF(2mL×3)洗，然后用茚三酮显色为无色.反应树脂抽滤后用DMF(50mL×3)，DCM(50mL×3),异丙醚(50mL×3)洗，得湿品树脂化合物q-5。
步骤4：
室温下，将上一步所得树脂化合物q-5加入至TFA:Tis:H 2O＝95:2.5:2.5(20mL)中室温反应2h.树脂抽滤后用TFA(5mL×3)，滤液减压浓缩至无明显馏分，所得油状液体滴入至异丙醚(20mL)中，过滤后滤饼制备纯化后得到化合物q共20mg。
MS m/z(ESI):573.2[M+1] +。
1H NMR(400MHz,D2O):δ8.04(d,1H),7.86(dd,3H),7.65(d,1H),7.49(d,2H),4.18(s,2H),4.18(s,2H),4.12-4.06(m,2H),3.29(s,1H),3.36-3.20(m,2H),2.32(t,2H),2.03-1.94(m,1H),1.87-1.72(m,2H),1.70-1.47(m,3H),1.37(d,2H).
实施例7
Figure PCTCN2022116453-appb-000109
(((S)-5-((S)-2-(3-(氨基甲基)二环[1.1.1]戊烷-1-碳杂草酰氨基<乙二酰氨基>)-3-(萘-2-基)丙酰氨基)-1-羧基戊基)氨基甲酰)-L-谷氨酸
Figure PCTCN2022116453-appb-000110
步骤1：
室温下，将r-1(106mg，0.44mmol)、HATU(166mg，0.44mmol)、DIEA(113mg，0.88mmol)，DCM(10mL)加入反应瓶内，搅拌溶清，加入r-2(200mg，0.29mmol)，搅拌反应过夜。TLC监测反应完毕，反应液用水洗涤、DCM萃取(30mL*3)，合并有机相，20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇＝甲醇(0％～7％)洗脱纯化，得到r-3(200mg，产率：75.4％)。
MS m/z(ESI):908.9[M+1] +
步骤2：
室温下，将r-3(200mg，0.42mmoL)溶解于TFA(5mL)，加毕于33℃反应过夜。反应液蒸干，高压制备液相色谱法纯化，得到标题产物r(71.5mg，产率：50.7％)。
MS m/z(ESI):640.4[M-1] -
实施例8
Figure PCTCN2022116453-appb-000111
(((1S)-1-羧基-5-((2S)-3-(萘-2-基)-2-(6-氮杂螺[2.5]辛烷-1-碳杂草酰氨基<乙二酰氨基>)丙酰氨基)戊基)氨基甲酰)-L-谷氨酸
Figure PCTCN2022116453-appb-000112
步骤1：
将N-Ε-苄氧羰基-L-赖氨酸叔丁酯盐酸盐(10g，0.03mol)、DIEA(3.84g，0.03mol)溶解于120mL DCM中，降温至-10℃～0℃，搅拌0.5h，加入三光气(4.4g，0.015mol)，加毕，-10℃～0℃下滴加DIEA(19.2g，0.149mol)，滴毕，保温反应3h，加入L-谷氨酸二叔丁酯盐酸盐(10g，0.039mol),自然升至室温搅拌反应过夜。TLC监测反应完毕。反应液依次用100mL饱和NaHCO 3溶液、100mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系正庚烷/乙酯＝10:1～1:1洗脱纯化，蒸干溶剂，得到油状物t-3(9.8g，产率：53.2％)。
MS m/z(ESI):622.3[M+1] +
步骤2：
室温下，将t-3(9.8g，15.8mmol)溶解于100mL甲醇溶液中，搅拌溶清，加入Pd/C(4.9g含水量58％)。将反应瓶用氮气置换3次，氢气置换3次，室温搅拌反应5h，TLC监测反应完毕。将反应液过滤，滤液减压浓缩蒸干，得到t-4(6.2g，产率：80.7％)。
MS m/z(ESI):488.3[M+1] +
步骤3：
室温下，将Fmoc-3-(2-萘基)-L-丙氨酸(2.3g，5.3mmol)HATU(2.0g，5.3mmol)、DIEA(2.1g，16.4mmol)，DCM(20mL)加入反应瓶内，搅拌溶清，加入t-4(2g，4.1mmol)，搅拌反应过夜。TLC监测反应完毕，反应液用水洗涤、EA萃取(30mL*3)，合并有机相，50mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇＝甲醇(0％～10％)洗脱纯化，得到t-5(2.8g，产率：76％)。
MS m/z(ESI):907.5[M+1] +
步骤4：
室温下，将t-5(2.8g，3mmol)、DCM(20mL)加入反应瓶内，搅拌溶清，加入二乙胺，搅拌反应过夜。反应液用水洗涤、EA萃取(30mL*3)，合并有机相，50mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系正庚烷/乙酯＝EA(0％～100％)洗脱纯化，得到标题产物t-6(1.4g，产率：66.7％)。
MS m/z(ESI):685.4[M+1] +
步骤5：
室温下，将6-Boc-6-氮杂螺[2.5]辛烷-1-甲酸(145mg，0.57mmol)、HATU(216mg，0.57mmoL)、DIEA(226mg，1.75mmoL)，DCM(4mL)加入反应瓶内，搅拌溶清，加入t-6(300mg，0.44mmol)，搅拌反应过夜。TLC监测反应完毕，反应液用水洗涤、EA萃取(30mL*3)，合并有机相，50mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇＝甲醇(0％～10％)洗脱纯化，得到标题产物t-8(300mg，产率：74.2％)。
MS m/z(ESI):922.8[M+1] +
步骤6：
室温下，将t-8(300mg，325mmol)溶解于2mL DCM中，加入TFA(3mL)，加毕于30℃反应过夜。反应液蒸干，高压制备液相色谱法纯化，得到标题产物t(70mg，产率：32.8％)。
MS m/z(ESI):654.3[M-1] -
实施例9
Figure PCTCN2022116453-appb-000113
(((S)-1-羧基-5-((S)-3-(2-萘基)-2-((6S,9r)-4-(2-(4,7,10-三(羧基甲基)-1,4,7,10-四氮杂环十二烷基)乙酰基)-1-氧杂-4-氮杂螺[5.5]十一烷-9-甲酰胺基)丙酰胺基)戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000114
步骤1：
室温下，将DOTA(1636mg，2.86mmol)、HATU(1087mg，2.86mmol)、DIEA(N,N-二异丙基乙胺，851mg，6.6mmol)，DCM(10mL)加入反应瓶内，搅拌溶清，加入v-1(500mg，2.20mmol)，搅拌反应过夜。TLC监测反应完毕，反应液用水洗涤、EA萃取(30mL*3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇洗脱纯化，得到标题产物v-2(1290mg，产率：75.1％)。
MS m/z(ESI):782.5[M+1] +
步骤2：
室温下，将v-2(800mg，1.01mmol)溶解于12mL THF和10mL水中，加入氢氧化锂(73mg，3.2mmol)，加毕，于室温反应过夜。向反应液中加入稀盐酸调节PH＝2～3，搅拌反应0.5h复测pH不变，反应液用乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩蒸干，得到标题产物v-3(675mg，产率：87.5％)。
MS m/z(ESI):754.4[M+1] +
步骤3：
室温下，将v-3(600mg，0.80mmol)、HATU(303mg，0.80mmol)、DIEA(316mg，2.45mmol)，DCM(8mL)加入反应瓶内，搅拌溶清，加入v-4(420mg，0.61mmol，制备方法见实施例8中t-6)，搅拌反应。TLC监测反应完毕，反应液用水洗涤、EA萃取(30mL*3)，合并有机相，饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇洗脱纯化，得到v-5(638mg，产率：73.3％)。
MS m/z(ESI):1421[M+1] +
步骤4：
室温下，将v-5(500mg，0.35mmol)溶解于4mL DCM中，加入TFA(5mL)，加毕于30℃反应过夜。反应液蒸干，高压制备液相色谱法纯化，得到标题产物v，(27mg，产率：7.1％)。
MS m/z(ESI):1084.5[M-1] -
1H NMR(400MHz,Deuterium Oxide)δ7.84(t,3H),7.65(s,1H),7.47-7.49(m,2H),7.38(d,1H),4.55(t,1H),4.18-4.19(m,1H),3.10-3.87(m,33H),2.42(t,2H),1.91(dt,1H),1.89(m,1H),1.87(m,3H),0.84-1.42(m,14H).
实施例10
Figure PCTCN2022116453-appb-000115
(((S)-1-羧基-5-((S)-3-(2-萘基)-2-(4-((2-(4,7,10-三(羧基甲基)-1,4,7,10-四氮杂环十二烷基)-1-乙酰基)甲基)哌啶-1-甲酰胺基)丙酰胺基)戊基)氨基甲酰基)-L-谷氨酸
Figure PCTCN2022116453-appb-000116
步骤1：
室温下，将w-2(3g，11.3mmol)、DIEA(1.45g，11.3mmol)溶解于120mL DCM中，降温至-10℃～0℃，搅拌0.5h，加入三光气(1.7g，5.7mmol)，加毕，-10℃～0℃下滴加DIEA(7.3g，56.6mmol)，滴毕，保温反应3h，加入w-1(3.2g，14.7mmol),自然升至室温搅拌反应过夜。TLC监测反应完毕。反应液依次用100mL饱和NaHCO 3溶液、100mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，用硅胶柱色谱法以洗脱剂体系正庚烷/乙酯＝10:1～1:1洗脱纯化，蒸干溶剂，得到白色固体w-3(4.0g，产率：75.5％)。
MS m/z(ESI):470.6[M+1] +
步骤2：
室温下，将w-3(4.0g，8.5mmol)溶解于20mL THF和10mL水中，加入氢氧化锂(0.62g，25.6mmol)，加毕于室温反应过夜。向反应液中加入10mL水，乙酸乙酯萃取(10mL×2)，合并水相，冰浴降至0℃，用0.5N的柠檬酸调节PH 3～4，析出固体，搅拌反应0.5h复测pH不变，过滤，滤饼真空干燥(40℃，4h)至恒重，得到标题产物w-4(3.4g，产率：87.6％)。
MS m/z(ESI):456.6[M+1] +
步骤3：
室温下，将w-4(1.0g，2.2mmol)、HATU(1.02g，2.7mmol)、DIEA(1.39g，10.8mmol)，DCM(20mL)加入反应瓶内，搅拌溶清，加入w-5(0.66g，1.8mmol)，搅拌反应过夜。反应液用水洗涤、DCM萃取(40mL*3)，合并有机相，50mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇＝甲醇(0％～10％)洗脱纯化，得到标题产物w-6(0.86g，产率：59.4％)。
MS m/z(ESI):799.4[M+1] +
步骤4：
室温下，将w-6(0.86g，1.1mmol)溶解于2mL乙酸乙酯内，搅拌下加入4M的HCl/EA溶液(8mL，32mmol)，搅拌反应2h。TLC监测反应完毕。反应液减压浓缩至恒重，得到标题产物w-7(0.82g，产率：95.3％)。
MS m/z(ESI):699.3[M+1] +
步骤5：
室温下，将DOTA-tris(t-Bu ester)(209mg，0.36mmol)、HATU(137mg，0.36mmol)、DIEA(464mg，3.6mmol)，DCM(3mL)加入反应瓶内，搅拌溶清，加入w-7(170mg，0.24mmol)，搅拌反应过夜，原料剩余，补加DOTA-tris(t-Bu ester)(139mg，0.24mmol)、HATU(91mg，0.24mmol)，继续反应2h，反应完毕，反应液用水洗涤、DCM萃取(20mL*3)，合并有机相，20mL饱和氯化钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩用硅胶柱色谱法以洗脱剂体系二氯甲烷/甲醇＝甲醇(0％～20％)洗脱纯化，得到w-8(110mg，产率：36.6％)。
MS m/z(ESI):1253.4[M+1] +
步骤6：
室温下，将w-8(110mg)溶解于2mL THF和1mL水中，加入氢氧化锂，加毕于室温反应2h。反应完毕，减压蒸干，得到w-9。
步骤7：
室温下，将w-9、TFA(2mL)加入反应瓶内，搅拌溶清，加毕于室温反应2h。反应完毕，减压蒸干，高压制备液相色谱法纯化，得到标题产物w(13mg)。
MS m/z(ESI):1043.6[M+1] +
实施例11.
Figure PCTCN2022116453-appb-000117
(((S)-1-羧基-5-((S)-3-(2-萘基)-2-((6R,9s)-4-(2-(4,7,10-三(羧基甲基)-1,4,7,10-四氮杂环十二烷基)乙酰基)-1-氧杂-4-氮杂螺[5.5]十一烷-9-甲酰胺基)丙酰胺基)戊基)氨基甲酰基)-L-谷氨酸
参考实施例9相同方法制备得到化合物x。
实施例12.化合物 177Lu-v的制备
反应总体积400μL，15nmol化合物v，15mCi  177Lu，在1.5mL离心管中加入321μL乙酸-乙酸钠缓冲液(0.1M，pH4.5)，再加入15μL化合物v溶液取核素7μL  177LuCl 3(活度：15.23mCi；放在恒温混匀仪上，振荡，反应温度95℃，反应时间15min，活度：15.15mCi，HPLC结果达到>99％。
实施例13.化合物 68Ga-v的制备
称取13.5mg化合物v，用超纯水溶解定容至25mL，称取136mg三水合乙酸钠、用1mL超纯水溶解，用移液枪量取20uL步骤1得到的溶液至反应西林瓶，依次加入4.5mL  68GaCl 3盐酸淋洗液、0.5mL步骤2缓冲液。轻微摇晃混合，置于95℃反应10分钟，自然冷却室温送检、使用。
测试例1.PSMA抑制活性测试
一、实验材料及仪器
1.多功能酶标仪(SPARK,TECAN)
2.rhPSMA(R&D,4234-ZN)
3.N-Acetyl-Asp-Glu(Sigma,A5930)
4.OPA(Sigma,P0657)
二、实验步骤
PSMA抑制剂可与PSMA酶结合来阻止PSMA酶分解底物N-Acetyl-Asp-Glu。本实验通过检测底物分解程度产生的紫外吸收变化来评价PSMA抑制剂与PSMA酶的结合能力，并根据IC 50大小评价化合物的活性。
使用缓冲液1(50mM HEPES,0.1M NaCl,pH 7.5)配置0.4μg/ml的rhPSMA溶液，以及40μM的底物N-Acetyl-Asp-Glu。将rhPSMA与待测小分子在96孔板中混合，保持rhPSMA的含量固定为50ng/孔，同时通过逐级稀释，使小分子终浓度为：1μM,100nM,33.3nM,11.1nM,3.7nM,1.2nM,0.41nM,0.137nM,0.045nM,0nM。并设置PSMA-617作为阳性对照。取40μL/孔的rhPSMA-小分子与40μL/孔40μM的底物N-Acetyl-Asp-Glu混合均匀，37℃避光孵育1小时，将反应在70℃下加热5分钟淬灭，冷却至室温。使用缓冲液2(0.2M NaOH,0.1％beta-Mercaptoethanol)配制15mM OPA溶液。将80μL/孔的OPA溶液加入反应体系，混合均匀后，在室温孵育10分钟。取100μL/孔混合液加入96孔Flat Black，设置激发波长330nm，发射波长465nm，读取信号强度，通过剂量-反应曲线求IC 50。
三、实验数据
本公开化合物与GCPII酶结合能力可通过以上试验进行测定，测得的IC 50值见表1。
表1.化合物IC 50值
Figure PCTCN2022116453-appb-000118
Figure PCTCN2022116453-appb-000119
测试例2.酶活法亲和性测定
使用缓冲液1(50mM HEPES,0.1M NaCl,pH 7.5)配置0.4μg/ml的rhPSMA溶液，以及40μM的底物N-Acetyl-Asp-Glu。将rhPSMA与待测小分子在96孔板中混合，保持rhPSMA的含量固定为50ng/孔，同时通过逐级稀释，使小分子终浓度为：1μM,100nM,33.3nM,11.1nM,3.7nM,1.2nM,0.41nM,0.137nM,0.045nM,0nM。并设置PSMA-617作为阳性对照。取40μL/孔的rhPSMA-小分子与40μL/孔40μM的底物N-Acetyl-Asp-Glu混合均匀，37℃避光孵育1小时，将反应在70℃下加热5分钟淬灭，冷却至室温。使用缓冲液2(0.2M NaOH,0.1％beta-Mercaptoethanol)配制15mM OPA溶液。将80μL/孔的OPA溶液加入反应体系，混合均匀后，在室温孵育10分钟。取100μL/孔混合液加入96孔Flat Black，设置激发波长330nm，发射波长465nm，读取信号强度，通过剂量-反应曲线求IC 50。
表2.
化合物 IC 50(nM) 与PSMA-617比值
PSMA-617 1.654 1.00
实施例9 1.231 0.74
实施例11 13.01 7.85
具体结构如图1所示，通过酶活实验可以确定，对比实施例9的化合物v和实施例11的化合物x，其中，化合物v具有更佳的亲和性。
测试例3.化合物的荷瘤鼠的生物分布
通过小鼠的单次尾静脉注射给药，观察 68Ga标记的化合物v(实施例9)和x(实施例11)在阳性LnCaP荷瘤中的体内分布情况。
试验的时间点为2h，断颈处死动物，共3只动物，收集组织样本，包括血、心、肺、肝、脾、肾、胃、肠、骨、肉、脑、唾液腺、大肠、胰腺、肿瘤，先称取组织净重，再采用γ-计数仪对所取组织进行放射性计数。测定标记化合物在小鼠不同组织和脏器中的分布情况。同时，将受试样品准确稀释100倍，取0.1mL于计数管中，作为标准的1％ID(即给药剂量的百分之一)，于γ-计数器上同时测定1％ID标准和生物样品的放射性计数。生物分布的数据表达为每克组织或脏器的放射性计数占总给药剂量(放射性计数)的百分比(％ID/g)。
具体结果如图2所示，结果显示， 68Ga-v(实施例9)在LnCap肿瘤的摄取值最高，在～10Id％/g，其次是肾、肝、肺、脾，其余各组织摄取量都很低，对比证明 68Ga-v(实施例9)对LnCap肿瘤具有较好的靶向效果。 68Ga-v(实施例9)肿瘤摄取要优于 68Ga-x(实施例11)。
测试例4.药代及毒性
4.1  68Ga-v(实施例9)血液半衰期
通过小鼠的单次尾静脉注射给药，对 68Ga-v(实施例9)、PSMA-617进行血液药代动力学 研究。
每只小鼠给药50μCi/100μL，在给药后0.083、0.25、0.5、1、2、4h通过眼眶取血，每个时间点4只动物，收集于预先称重的样品管内，称重并记录血液样品重量，再采用γ-计数仪进行放射性计数。同时将受试样品准确稀释100倍，取0.1mL于计数管中，作为标准的1％ID(即给药剂量的百分之一)，于γ-计数器上同时测定1％ID标准和生物样品的放射性计数。血液的数据表达为每克血液的放射性计数占总给药剂量(放射性计数)的百分比(％ID/g)。根据血液药物浓度数据进行药代动力学参数计算。
正常小鼠血液中的摄取结果见下表3(n＝4).
表3.
Figure PCTCN2022116453-appb-000120
经计算药代动力学参数结果见下表4(0-4h)。
表4.
Figure PCTCN2022116453-appb-000121
以上实验结果显示， 68Ga-v(实施例9)、 68Ga-PSMA-617进入正常小鼠血液中放射性物质快速分布；血液中含量在注射后0.25h仅为1.25±0.22％ID/g、2.27±0.44％ID/g，并快速清除，血液半衰期仅为0.13h(7.8min)、0.22h(13.2min)。
68Ga-v(实施例9)在小鼠体内的血液半衰期0.13h(7.8min)，消除相半衰期分别为0.758h,一般按照5个半衰期估算完全代谢掉时间，应该药后3.9h基本能被代谢。另外成像数据观察， 4h后正常脏器基本没有信号。经计算，有效半衰期为Te＝0.45h,按照5个有效半衰期估算为2.27h。
4.2辐射吸收剂量
通过Bio-D生物分布的数据,算出药物代谢AUC，带入OLINDA软件，生成所有脏器的辐射吸收剂量。
表5.人体器官辐射剂量估算总结
Figure PCTCN2022116453-appb-000122
通过上表可知， 68Ga-v(实施例9)相对于 68Ga-PSMA-617辐射吸收剂量低一倍，具有更好的安全性， 177Lu-v(实施例9)辐射吸收剂量低于 177Lu-PSMA-617。

Claims (23)

  1. 一种式(IV)所示化合物或其药学上可接受的盐，
    Figure PCTCN2022116453-appb-100001
    其中：
    Q选自H或保护基团，优选H；
    R 1、R 2各自独立地选自H、C 1-4烷基，优选均为H，所述C 1-4烷基任选被一个或多个取代基团P取代或未取代；
    Q、R 1、R 2的每次出现可以是相同或不同的；
    Y 1是S或O，优选O；
    T选自-NR 4(CO)-、-NR 4(SO 2)-、-NR 4(CH 2)-；
    R 4选自H、C 1-6烷基、6-10元芳基、或5-12元杂芳基，所述C 1-6烷基、6-10元芳基、或5-12元杂芳基任选被一个或多个取代基团P取代或未取代；
    环A选自3-12元含氮杂环基，其中所述的3-12元含氮杂环基任选被一个或多个取代基团P取代或未取代；
    W选自6-10元芳基、5-12元的杂芳基，所述-10元芳基、5-12元的杂芳基任选地被一个或多个取代基团P取代或未取代；
    所述取代基团P选自C 1-C 6烷基、卤素、氘、羟基、巯基、-NR iR j、氧代、硫代、-C(O)R k、-C(O)OR k、-S(O)R k、-S(O)OR k、-S(O)(O)R k、-S(O)(O)OR k、-C(S)R k、硝基、氰基、C 1-C 6烷氧基、C 1-C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基、5至10元杂芳基、8至12元稠环芳基和5至12元稠杂芳基；
    R i、R j各自独立地选自氢原子、羟基、C 1～C 6烷基、C 1～C 6烷氧基；R k独立地选自氢原子、C 1～C 6烷基、C 1～C 6卤代烷基、C 1～C 6烷氧基、羟基、-NR iR j，其中所述的烷基、烷氧基、卤代烷基任选被选自C 1～C 6烷基、卤素、羟基、巯基、-NR iR j、氧代、硫代、羧基、硝基、氰基、C 1～C 6烷氧基、C 1～C 6烷硫醚基、C 2-C 6烯基、C 2-C 6炔基、3至10元环烷基、3至10元杂环基、6至10元芳基和5至10元杂芳基中的一个或多个取代基所取代；
    y、z、g、h各自独立地为0-6的整数；
    R 3选自H或螯合剂。
  2. 根据权利要求1所述的式(IV)所示化合物或其药学上可接受的盐，所述T为-NH(CO)-，环A为5-12元的含氮螺杂环基，优选5-12元的含氮单螺杂环基，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元、5元/6元、6元/6元含氮单螺杂环基，最优选
    Figure PCTCN2022116453-appb-100002
    Figure PCTCN2022116453-appb-100003
    Figure PCTCN2022116453-appb-100004
    特别优选
    Figure PCTCN2022116453-appb-100005
  3. 根据权利要求1至2任一项所述的式(IV)所示化合物或其药学上可接受的盐，其中，W选自6-10元芳基，优选萘基。
  4. 根据权利要求1至3任一项所述的式(IV)所示化合物或其药学上可接受的盐，其中，Y 1是O。
  5. 根据权利要求1至4任一项所述的(IV)所示化合物或其药学上可接受的盐，其中R 1和R 2各自独立地为H。
  6. 根据权利要求1至5任一项所述的(IV)所示化合物或其药学上可接受的盐，其中Q选自H或保护基团，优选H。
  7. 根据权利要求1至6任一项所述的(IV)所示化合物或其药学上可接受的盐，其中y和h各自独立地选自0、1或2，优选1。
  8. 根据权利要求1至6任一项所述的(IV)所示化合物或其药学上可接受的盐，其中g选自3或4，优选3。
  9. 根据权利要求1至6任一项所述的(IV)所示化合物或其药学上可接受的盐，其中z选自0或1，优选0。
  10. 根据权利要求1至9所述的化合物或其药学上可接受的盐，其特征在于，所述螯合剂选自：
    Figure PCTCN2022116453-appb-100006
    Figure PCTCN2022116453-appb-100007
    优选
    Figure PCTCN2022116453-appb-100008
  11. 根据权利要求1至10所述的化合物选自：
    Figure PCTCN2022116453-appb-100009
    Figure PCTCN2022116453-appb-100010
    Figure PCTCN2022116453-appb-100011
    其中R 3选自H或
    Figure PCTCN2022116453-appb-100012
  12. 根据权利要求1至11任一项所述的式(IV)所示化合物或其药学上可接受的盐，其为
    Figure PCTCN2022116453-appb-100013
    优选
    Figure PCTCN2022116453-appb-100014
    Figure PCTCN2022116453-appb-100015
    最优选
    Figure PCTCN2022116453-appb-100016
  13. 根据权利要求1至12任一项所述的化合物其特征在于，所述螯合剂包含放射性核素。
  14. 根据权利要求13所述的化合物或其药学上可接受的盐，其特征在于，所述放射性核素选自 18F、 11C、 68Ga、 124I、 89Zr、 64Cu、 86Y、 99mTc、 111In、 123I、 90Y、 125I、 131I、 177Lu、 211At、 153Sm、 186Re、 188Re、 67Cu、 212Pb、 225Ac、 213Bi、 212Bi、 212Pb或 67Ga中的至少一种，优选 68Ga或 177Lu。
  15. 一种式(IV)所示化合物或其药学上可接受的盐，其为
    Figure PCTCN2022116453-appb-100017
    所述螯合剂包含放射性核素，所述放射性核素为 68Ga。
  16. 一种式(IV)所示化合物或其药学上可接受的盐，其为
    Figure PCTCN2022116453-appb-100018
    所述螯合剂包含放射性核素，所述放射性核素为 177Lu。
  17. 一种组合物，包含根据权利要求1至16中任一项所述的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的赋形剂、稀释剂或载体。
  18. 根据权利要求1至16中任一项所述的化合物或其药学上可接受的盐，或根据权利要求17所述的组合物在制备用于在患者中成像的组合物中的用途。
  19. 根据权利要求1至16中任一项所述的化合物或其药学上可接受的盐，或根据权利要求17所述的组合物在制备用于诊断和/或治疗和/或预防PSMA介导的疾病或病症的药物中的用途。
  20. 根据权利要求1至16中任一项所述的化合物或其药学上可接受的盐，或根据权利要求17所述的组合物在制备用于诊断和/或治疗和/或预防肿瘤和癌症的药物中用途；优选地，所述肿瘤和癌症为前列腺癌。
  21. 一种式(IV)所示化合物或其药学上可接受的盐的制备方法，所示式(IV)所示化合物为式v所示化合物或其药学上可接受的盐，包括式v-5所示化合物脱叔丁基的步骤：
    Figure PCTCN2022116453-appb-100019
  22. 根据权利要求21所述的制备方法，进一步包括：式v-3所示化合物与式v-4所示化合物发生缩合反应得到式v-5所示化合物的步骤，
    Figure PCTCN2022116453-appb-100020
  23. 根据权利要求13至16任一项所述的化合物的制备方法，包括权利要求21或22任一项所述的制备式(IV)所示化合物或其药学上可接受的盐的步骤，进一步包括式(IV)所示化合物或其药学上可接受的盐中螯合剂与放射性核素络合的步骤。
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