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WO2024196698A2 - Composés et constructions utiles pour cibler protéine d'activation des fibroblastes - Google Patents

Composés et constructions utiles pour cibler protéine d'activation des fibroblastes Download PDF

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WO2024196698A2
WO2024196698A2 PCT/US2024/019912 US2024019912W WO2024196698A2 WO 2024196698 A2 WO2024196698 A2 WO 2024196698A2 US 2024019912 W US2024019912 W US 2024019912W WO 2024196698 A2 WO2024196698 A2 WO 2024196698A2
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compound
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cycloalkyl
alkyl
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WO2024196698A3 (fr
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Alison Ann Armour
Darin M. Taverna
Eric J. Miller
Sean D. CARLIN
Scott D. Larsen
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Curadh Mtr
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Curadh Mtr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/533—Production of labelled immunochemicals with fluorescent label
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • Fibroblast activation protein is a type 2 transmembrane serine proline peptidase that is only transiently expressed during normal development and rarely expressed in healthy adult tissues. It is highly upregulated in the stromal cells at sites of active tissue remodeling such as wound healing, fibrosis, arthritis, atherosclerosis, and in over 90% of human epithelial cancers, such as breast, colorectal, prostate, pancreatic, and skin tumors (Garin-Chesa et al., PNAS, 1990, 87.18:7235; Park et al., J Biol Chem, 1999, 274: 36505; Pure et al., Oncogene, 2018, 37: 4343; Rettig et al.
  • FAP Fibroblast activation protein
  • FAP is considered to be a suitable marker for radiopharmaceutical diagnostics and a suitable target for radiopharmaceutical therapy for various epithelial cancers (Siveke, J Nucl Med, 2018, 59: 1412; Christiansen et al., Neoplasia, 2013, 15: 348; Zi et al., Mol Med Rep, 2015, 11: 3203).
  • current agents targeting FAP do not have sufficient specificity when tested on homologous proteins, such as other dipeptidyl peptidases, and suffer from poor pharmacokinetic characteristics and cellular retention. Specificity of FAP targeting is sufficient for diagnostic use, however improved pharmacokinetic properties of FAP targeting agents for radiopharmaceutical therapy is desired.
  • FAP FAP-associated pulmonary fibrosis
  • idiopathic pulmonary fibrosis Crohn’s disease
  • liver fibrosis and atherosclerosis.
  • Bauer et al. Arthritis Res Ther, 2006, 8: R171; Milner et al., Arthritis Res Ther, 2006, 8:R23; Truffi et al., Inflamm Bowel Dis, 2018, 24: 332; Monslow et al., Circulation, 2013, 128: A17597; Fan et ai., J Biol Chem, 2016, 291 :8070; Santacroce et al., Cells, 2022 11 :429; Fitzgerald and Weiner, Cancer Metastasis Rev, 2020, 39:783).
  • the method includes some or all of the steps of: a) providing a small molecule library; b) performing an in silico rigid docking analysis for each member of the small molecule library to i) the surface of the protein of interest and to ii) the surface of a second protein that is similar in structure and/or function to the protein of interest (e.g., a homolog), to select a first subset of the small molecule library; c) performing an in silico flexible docking analysis for each member of the first subset to i) the surface of the protein of interest and to ii) the surface of the second protein, to select a second subset of the small molecule library; and d) performing an in vitro binding assay (e.g., a surface plasmon resonance (SPR) assay) for each member of the second subset to i) the surface of the protein of
  • SPR surface plasmon resonance
  • the in vitro binding assay is a surface plasmon resonance (SPR) assay.
  • the method further includes: e) correcting for non-specific binding in the in vitro binding assay; and optionally may further include f) generating a concentrationresponse curve for each member of the second subset from the concentration-dependent binding signal; and optionally g) calculating the binding dissociation constant (Kd) from the concentrationresponse curve.
  • selecting the first subset of the small molecule library in step b) comprises selecting small molecules that have a binding affinity for the protein of interest that is at least 100- fold more favorable than for the second protein.
  • selecting the second subset of the small molecule library in step c) further comprises selecting small molecules that have a high predicted binding affinity for the protein of interest and a low predicted binding affinity for the second protein.
  • performing the in vitro binding assay in step d) further comprises repeatedly performing the assay with increasing concentrations of each member in the second subset to generate a concentration-dependent binding signal.
  • a member of the second subset is identified as capable of binding to the protein of interest based on the Kd value.
  • R 1 is selected from the group consisting of H, alky, and cycloalkyl; n is 0, 1, or 2;
  • R 2 is selected from the group consisting of H, alky, and cycloalkyl
  • R 3 is selected from the group consisting of NR', OR', alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or wherein R 2 and R 3 join to form a heterocycle (e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone).
  • a heterocycle e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone.
  • the compound of Formula VIII is in a compound of Formula VIIIA:
  • R 1 is selected from the group consisting of H, alky, and cycloalkyl
  • W, X and Y are each independently selected from the group consisting of CR 4 , O, N, and
  • NR 5 ; R 4 and R 6 are each independently selected from the group consisting of H, NR', OR', carbonyl, carboxy, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; and
  • R 5 is selected from the group consisting of H, acyl, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; or two of R 4 , R 5 and R 6 join to form a carbocycle, heterocycle, aryl, or heteroaryl.
  • the compound of Formula VIIIA is a compound of Formula VIIIA(a):
  • R 1 is selected from the group consisting of H, alky, and cycloalkyl
  • A is selected from the group consisting of N and C;
  • B is selected from the group consisting of O, S, and N;
  • R 5 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • R 7 is alkyl, A is C, and B is S.
  • the compound of Formula VIII or Formula VIIIA is a compound of Formula VIIIA(b):
  • R 1 is selected from the group consisting of H, alky, and cycloalkyl
  • Y is selected from the group consisting of CR 4b , N, and NR 5 ; and R 4a , R 4b and R 6 are each independently selected from the group consisting of H, NR', OR', carbonyl, carboxy, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or two of R 4a , R 4b , R 5 and R 6 join to form a cycloalkyl, heterocycle, aryl, or heteroaryl.
  • the compound of Formula VIIIA(b) is a compound of Formula VIIIA(b)(i): or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein:
  • R 1 is selected from the group consisting of H, alky, and cycloalkyl
  • R 4a , R 4b , and R 7 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl.
  • R 7 is halo
  • the compound of Formula VIIIA(b) is a compound of Formula wherein R 1 is selected from the group consisting of H, alky, and cycloalkyl;
  • R 6 and R 7 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and
  • Z 1 and Z 2 are each independently selected from the group consisting of N and CR', wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • R 6 and R 8 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and
  • Z 1 and Z 2 are each independently selected from the group consisting of N and CR', wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • R 8 is halo
  • R 8 is alkyl
  • the compound of Formula VIII is a compound of Formula VIIIB: or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein:
  • R 1 is selected from the group consisting of H, alky, and cycloalkyl
  • R 2 is selected from the group consisting of H, alky, and cycloalkyl
  • R 3 is selected from the group consisting of NR', OR', alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or wherein R 2 and R 3 join to form a heterocycle (e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone).
  • a heterocycle e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone.
  • the compound of Formula VIIIB is a compound of Formula VIIIB(a): or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein:
  • R 1 is selected from the group consisting of H, alky, and cycloalkyl
  • R 2 is selected from the group consisting of H, alky, and cycloalkyl
  • R 4 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • the compound of Formula VIIIB is a compound of Formula VIIIB(b): or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein:
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 6 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • R 1 and R 2 are each independently selected from the group consisting of H, NR', OR', alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
  • R 3 is selected from the group consisting of H, alkyl, and cycloalkyl; or wherein two of R 1 , R 2 and R 3 join to form a cycloalkyl, heterocycle, aryl, or heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, and alkynyl;
  • R 6 is selected from the group consisting of H, NR', OR', carbonyl, carboxy, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; and
  • R 7 is selected from the group consisting of H, alkyl, and cycloalkyl; or wherein two of R 4 , R 5 , R 6 and R 7 join to form a cycloalkyl, heterocycle, aryl, or heteroaryl.
  • the compound of Formula IX is a compound of Formula IXA:
  • R 1 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl;
  • R 4 , R 5 , and R 6 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl; and n is 0, 1, 2, or 3.
  • the compound of Formula IXA is a compound of Formula IXA(a):
  • X and Y are each independently selected from the group consisting of N and CR 8 , wherein R 8 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl; and
  • the compound of Formula IXA is a compound of Formula IXA(b):
  • X and Y are each independently selected from the group consisting of N and CR 8 , wherein R 8 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl; and
  • R 4 , R 5 , and R 6 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl.
  • X is CR 8 and R 8 is halo.
  • the compound of Formula IX is a compound of Formula IXB:
  • R 1 and R 2 are each independently selected from the group consisting of H, NR', OR', alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; or wherein R 1 and R 2 join to form a cycloalkyl, heterocycle, aryl, or heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, and alkynyl; or wherein R 4 and R 5 join to form a cycloalkyl, heterocycle, aryl, or heteroaryl; and
  • R 7 is independently selected from the group consisting of H, alkyl, and cycloalkyl.
  • the compound of Formula IXB is a compound of Formula IXB(a): or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof, wherein: X and Y are each independently selected from the group consisting of N and CR 8 , wherein R 8 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl;
  • R 2 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, and alkynyl.
  • the compound of Formula IXB is a compound of Formula IXB(b):
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, and alkynyl.
  • a construct comprising a compound as described herein coupled to a chelating agent.
  • the chelating agent is bound to a radionuclide, which may be suitable for optical imaging, PET imaging, SPECT imaging, or radiotherapy.
  • the chelating agent is coupled to the compound by a linker.
  • a method of treatment for cancer comprising administering a construct as described herein to a subject in need thereof, or the use of the construct in a method for treating cancer, or for preparing a medicament for use in treating cancer.
  • a compound as described herein coupled to an imaging agent.
  • the imaging agent is coupled to the compound by a linker.
  • a method of detecting a tumor in a subject in need thereof comprising administering a construct described herein to the subject and detecting the imaging agent, or the use of the construct in a method of detecting a tumor in a subject, or for preparing a medicament useful for detecting a tumor.
  • composition comprising a compound or construct as taught herein and a pharmaceutically acceptable carrier.
  • FIG. 1 is a flowchart showing an example method for identifying a small molecule capable of binding to a protein of interest.
  • H refers to a hydrogen atom.
  • C refers to a carbon atom.
  • N refers to a nitrogen atom.
  • O refers to an oxygen atom.
  • S refers to a sulfur atom.
  • Halo refers to F, Cl, Br or I.
  • the term “hydroxy,” as used herein, refers to an -OH moiety.
  • Br refers to a bromine atom.
  • Cl refers to a chlorine atom.
  • I refers to an iodine atom.
  • F refers to a fluorine atom.
  • cyano or “nitrile” refers to a -CN moiety (i.e., -ON).
  • acyl is intended to mean a group -C(O)-R, where R is a suitable substituent, such as alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • R is a suitable substituent, such as alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • acyl include, but are not limited to, an acetyl group, a propionyl group, a butyroyl group, a benzoyl group, etc.
  • Alkyl refers to a straight or branched chain hydrocarbon containing from 1 or 2 to 10 or 20 or more carbon atoms (e.g., C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cl l, C12, C13, C14, C15, etc.). In some embodiments the alkyl can be a lower alkyl. “Lower alkyl” refers to a straight or branched chain alkyl having from 1 to 3, or from 1 to 5, or from 1 to 8 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
  • alkyl groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Representative examples of halo substituted alkyls include, but are not limited to, fluoromethyl, difluoromethyl and trifluoromethyl.
  • saturated refers to the state in which all available valence bonds of an atom (e.g., carbon) are attached to other atoms.
  • unsaturation refers to the state in which not all the available valence bonds are attached to other atoms; in such compounds the extra bonds usually take the form of double or triple bonds (usually with carbon).
  • a carbon chain is “saturated” when there are no double or triple bonds present along the chain or directly connected to the chain (e.g., a carbonyl), and is “unsaturated” when at least one double or triple bond is present along the chain or directly connected to the chain (e.g., a carbonyl).
  • the presence or absence of a substituent depending upon chain saturation will be understood by those of ordinary skill in the art to depend upon the valence requirement of the atom or atoms to which the substituent binds (e.g., carbon).
  • substituted indicates that the specified group is either unsubstituted, or substituted by one or more suitable substituents.
  • a “substituent” that is “substituted” is an atom or group which takes the place of a hydrogen atom on the parent chain or cycle of an organic molecule, for example, H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Alkenyl refers to a straight or branched chain hydrocarbon containing from 1 or 2 to 10 or 20 or more carbons, and containing at least one carbon-carbon double bond, formed structurally, for example, by the replacement of two hydrogens.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l -heptenyl, 3-decenyl and the like.
  • alkenyl groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Alkynyl refers to a straight or branched chain hydrocarbon group containing from 1 or 2 to 10 or 20 or more carbon atoms, and containing at least one carbon-carbon triple bond.
  • Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
  • alkynyl groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • cycloalkyl refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons or more.
  • Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • cycloalkyl groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Heterocycle refers to a monocyclic, bicyclic or tricyclic ring system.
  • Monocyclic heterocycle ring systems are exemplified by any 4-, 5-, 6- or 7-member ring containing 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of: O, N, and S.
  • the 4-member ring has 0 to 1 double bond
  • the 5-member ring has from 0 to 2 double bonds
  • the 6 and 7 member rings have from 0 to 3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidine, azepine, diazepine, 1,3- dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazol
  • Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein.
  • Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadi azole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3 -benzodi oxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline,
  • heterocyclo groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Aryl refers to a ring system having one or more aromatic rings.
  • Representative examples of aryl include azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
  • aryl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, aryloxy, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, -NR’R” (wherein, R’ and R” are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and -C
  • aryl groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Heteroaryl means a cyclic, aromatic hydrocarbon in which one or more carbon atoms have been replaced with heteroatoms. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo[b]thienyl.
  • Preferred heteroaryl groups are five and six membered rings and contain from one to three heteroatoms independently selected from the group consisting of: O, N, and S.
  • the heteroaryl group, including each heteroatom can be unsubstituted or substituted with from 1 to 4 suitable substituents, as chemically feasible.
  • heteroaryl groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
  • alkoxy groups as described herein are optionally substituted (e.g., from 1 to 3 or 4 times) with independently selected H, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • amine or “amino” is intended to mean the group -NH2.
  • Optionally substituted amines refers to -NH2 groups wherein none, one or two of the hydrogens is replaced by a suitable substituent as described herein, such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, carbonyl, carboxy, etc.
  • one or two of the hydrogens are optionally substituted with independently selected, halo, hydroxy, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, alkoxy, amino, amide, thiol, sulfide, sulfone, sulfoxide, carbonyl, or carboxy.
  • Disubstituted amines may have substituents that are bridging, i.e., form a heterocyclic ring structure that includes the amine nitrogen.
  • a “thiol” or “mercapto” refers to an -SH group.
  • a “sulfide” or “thioether” as used herein refers to a group -S-R, where R is a suitable substituent, such as alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • a “sulfone” as used herein refers to a sulfonyl functional group, generally depicted as: wherein, R can be any covalently-linked atom or atoms, for example, H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • a “sulfoxide” as used herein refers to a sulfinyl functional group, generally depicted as: wherein, R can be any covalently-linked atom or atoms, for example, H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • a “pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness of the free acids and bases of a specified compound and that is not biologically or otherwise undesirable.
  • pharmaceutically acceptable salts include sulfates, pyrosulfates, bi sulfates, sulfites, bi sulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, mal onates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4- dioates, hexyne- 1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzo
  • a “pharmaceutically acceptable hydrate” or “pharmaceutically acceptable hydrated salt” is intended to mean a pharmaceutically acceptable salt of the definition herein that has one or more molecule of water included in its crystalline lattice.
  • a ring as used herein with respect to two substituents, e.g., R 7 and R 8 together forming a ring, refers to the two groups being linked together via one or more atoms (e.g., carbon) to form ring atoms making up a cycloalkyl, heterocyclo, aryl or heteroaryl as described herein. Rings may be part of a monocyclic, bicyclic or tricyclic moiety, each of such ring being a saturated or unsaturated member of the monocyclic, bicyclic or tricyclic moiety.
  • Radioisotope refers to synthetic and/or naturally occurring atoms that have excess nuclear energy and where this excess energy is emitted as radiation. Examples of this type of radiation energy are alpha rays, beta rays, and gamma rays. Examples of radioisotopes include n C, 13 N, 15 0, 68 Ga, 18 F, " m Tc, 212 Pb, 133 Xe, 2O1 T1, n i In, 123 I, 131 I, 90 Y, 64 Cu, 67 Cu, 186 Re, 177 LU, 149 Tb , 152 Tb , 155 Tb, and 161 Tb. “Xe” refers to a xenon atom.
  • chelate intended to mean a molecule with two or more functional groups that are able to donate at least two electron pairs and so bind a metal ion. It is common for the chelating agent to be an organic molecule. One chelating agent will often use its electron pairs to form a coordinate bond with one metal ion, though it is possible for a chelating agent to bond more than one metal ion.
  • chelating compounds include, but are not limited to, dimercaptopropanol, ethylenediaminotetraacetic acid (EDTA), di ethylenetriaminepentaacetic acid (DTP A), octadentate macrocyclic bifunctional 1,4,7,10- tetraazacyclododacane- 1,4,7, 10 -tetraacetic acid (DOTA), hexadentate macrocyclic bifunctional l,4,7-triazacyclononane-l,4,7-triacetic acid (NOTA), hydroxy ethylidene diphosphonic acid (HEDP), ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid) (EDTMP) and 1,4,7, 10-tetraazacy clododecane- 1,4,7, 10-tetraaminomethylenephosphonic acid (DOTMP), mercaptoacetyltriglycine (MAGs), salicylic acid, triethanolamine, ferrio
  • cancer and cancer are intended to mean the physiological condition typically characterized by unregulated cell growth in a portion of a multicellular organism. Often it is intended to mean a disease where the unregulated cell growth has the potential to spread and invade into multiple regions or tissues of the host organism (e.g., metastasis).
  • a “tumor comprises one or more cancerous cells. Examples of cancer include carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • radioactive label or “radiotracer” are used herein to refer to a radioisotope that is used to generate an image that is detectable often using an appropriate instrument.
  • radiotracers include positron emission tomography (PET) and single photon emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • radiation emitted by radiotracers include gamma rays and X-rays.
  • radiotherapy refers to a method of treating cancer whereby one or more tumors are destroyed using the radiation emitted from a radioisotope.
  • the amount and delivery method of the radioisotope are often controlled in such a way as to produce as minimal harm as possible to the host organism.
  • Examples of radiation used in radiotherapy include alpha rays, beta rays, and Auger electrons.
  • Imaging agent refers to any moiety useful for the detection, tracing, or visualization of a compound of the invention when coupled thereto.
  • Imaging agents include, but are not limited to, an enzyme, a fluorescent dye (e.g., carbocyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, merocyanine, polymethine, coumarine, rhodamine, xanthene, fluorescein, boron-dipyrromethane, Cy5, Cy5.5, Cy7, VivoTag-680, VivoTag-S680, VivoTag- S750, AlexaFluor660, AlexaFluor680, AlexaFluor700, AlexaFluor750, AlexaFluor790, Dy677, Dy676, Dy682, Dy752, Dy780, DyLight547, Dylight647, HiLyte Fluor 647, HiLyte Fluor 647, HiL
  • An imaging agent can be coupled to a compound of the invention by, for example, a covalent bond, ionic bond, van der Waals interaction or a hydrophobic bond.
  • An imaging agent of the invention can be a radiolabel coupled to a compound of the invention, or a radioisotope incorporated into the chemical structure of a compound of the invention.
  • Methods of detecting such imaging agents include, but are not limited to, positron emission tomography (PET), X-ray computed tomography (CT), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT).
  • active compounds useful for FAP targeting/binding are set forth below.
  • active compounds include those of Formula VIII, or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof.
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl; n is 0, 1, or 2; R 2 is selected from the group consisting of H, alkyl, and cycloalkyl; and R 3 is selected from the group consisting of NR', OR', alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • R 2 and R 3 join to form a ring such as a heterocycle (e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone).
  • a heterocycle e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone.
  • One example compound of Formula VIII in which n is 0, and R 2 and R 3 join to form a heterocycle, is a compound of Formula VIIIA.
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • W, X and Y are each independently selected from the group consisting of CR 4 , O, N, and NR 5
  • R 4 and R 6 are each independently selected from the group consisting of H, NR', OR', carbonyl, carboxy, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl
  • R 5 is selected from the group consisting of H, acyl, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • two of R 4 , R 5 and R 6 join to form a carbocycle, heterocycle, aryl, or heteroaryl.
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl; A is selected from the group consisting of N and C; B is selected from the group consisting of O, S, and N; and R 5 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • Example compounds of Formula VIIIA(a), in which R 1 is H, A is C, B is S, and R 5 is alkyl, are shown below.
  • Formula VIIIA(a)(i) Formula VIIIA(a)(ii) Formula VIIIA(a)(i)
  • W is N and X is CR 4a
  • Formula VIIIA(b) is a compound of Formula VIII A(b).
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • Y is selected from the group consisting of CR 4b , N, and NR 5
  • R 4a , R 4 and R 6 are each independently selected from the group consisting of H, NR', OR', carbonyl, carboxy, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • two of R 4a , R 4b , R 5 and R 6 join to form a ring such as a cycloalkyl, heterocycle, aryl, or heteroaryl.
  • One example compound of VIIIA(b), in which Y is CR 4b and R 6 is aryl, is a compound of Formula VIIIA(b)(i).
  • R 1 is selected from the group consisting of
  • R 4a , R 4b , and R 7 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl.
  • Example compounds of Formula VIIIA(b)(i), in which R 4a and R 4b are each H, and R 7 is halo, are shown below.
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 6 and R 7 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl
  • Z 1 and Z 2 are each independently selected from the group consisting of N and CR', wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • One example compound of Formula VIIIA(b)(ii), in which R 7 is aryl, is a compound of Formula VIIIA(b)(ii)(a).
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 6 and R 8 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl
  • Z 1 and Z 2 are each independently selected from the group consisting of N and CR', wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • Example compounds of Formula VIIIA(b)(ii)(a), in which R 1 and R 6 are each H, and R 8 is halo or alkyl, are shown below.
  • One example compound of Formula VIII is a compound of Formula VIIIB.
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 2 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 3 is selected from the group consisting of NR', OR', alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl.
  • R 2 and R 3 join to form a ring such as a heterocycle (e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone).
  • a heterocycle e.g., azetidinone, pyrrolidinone, imidazolidinone, oxazolidinone, piperidinone, piperazinone, morpholinone, azepanone, diazepanone, or oxazepanone.
  • One example compound of Formula VIIIB is a compound of Formula VIIIB(a).
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 2 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 4 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • Example compounds of Formula VIIIB(a), in which R 1 and R 2 are each H, and R 3 is aryl, are shown below.
  • One example compound of Formula VIIIB is a compound of Formula VIIIB(b).
  • R 1 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 6 is selected from the group consisting of H, alkyl, and cycloalkyl
  • R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, and heteroaryl.
  • Example compounds of Formula VIIIB(b), in which R 1 , R 4 and R 5 are each alkyl, and R 6 is H, are shown below.
  • Active compounds of the current invention include those of Formula IX, or a pharmaceutically acceptable salt, hydrate, or hydrated salt thereof.
  • R 1 and R 2 are each independently selected from the group consisting of H, NR', OR', alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl;
  • R 3 is selected from the group consisting of H, alkyl, and cycloalkyl;
  • R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, and alkynyl;
  • R 6 is selected from the group consisting of H, NR', OR', carbonyl, carboxy, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; and
  • R 7 is selected from the
  • two of R 1 , R 2 and R 3 join to form a cycloalkyl, heterocycle, aryl, or heteroaryl.
  • two of R 4 , R 5 , R 6 and R 7 join to form a cycloalkyl, heterocycle, aryl, or heteroaryl.
  • One example compound of Formula IX in which R2 and R3 join to form a heterocycle, and R7 is H, is a compound of Formula IXA.
  • R 1 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl;
  • R 4 , R 5 , and R 6 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl; and n is 0, 1, 2, or 3.
  • One example compound of Formula IXA in which R 1 is aryl or heteroaryl and n is 1, is a compound of Formula IXA(a).
  • X and Y are each independently selected from the group consisting of N and CR 8 , wherein R 8 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl; and R 4 , R 5 , and R 6 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl.
  • One example compound of Formula IXA in which R 1 is aryl or heteroaryl and n is 2, is a compound of Formula IXA(b).
  • X and Y are each independently selected from the group consisting of N and CR 8 , wherein R 8 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl; and R 4 , R 5 , and R 6 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl.
  • Example compounds of Formula IXA(a), in which X is CR 8a wherein R 8a is halo, Y is CR 8b wherein R 8b is H, R 4 and R 6 are each alkyl, and R 5 is H, are shown below.
  • One example compound of Formula IX is a compound of Formula IXB.
  • R 1 and R 2 are each independently selected from the group consisting of H, NR', OR', alkyl, cycloalkyl, aminoalkyl, hydroxyalkyl, heterocycle, aryl, and heteroaryl, wherein R' is alkyl, cycloalkyl, heterocycle, aryl, or heteroaryl; R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, or alkynyl; and R 7 is selected from the group consisting of H, alkyl, and cycloalkyl.
  • R 1 and R 2 join to form a ring such as a cycloalkyl, heterocycle, aryl, or heteroaryl.
  • R 4 and R 5 join to form a ring such as a cycloalkyl, heterocycle, aryl, or heteroaryl.
  • X and Y are each independently selected from the group consisting of N and CR 8 , wherein R 8 is selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, alkyl, alkenyl, and alkynyl; R 2 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, and alkynyl.
  • Example compounds of Formula IXB(a), in which X is N, Y is CR 8 wherein R 8 is H, R 2 and R 5 are each alkyl and R 4 is H, are shown below.
  • One example compound of Formula IXB is a compound of Formula IXB(b).
  • R 8 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycle, aryl, and heteroaryl; and R 4 and R 5 are each independently selected from the group consisting of H, hydroxy, halo, alkoxy, cyano, acyl, alkyl, alkenyl, and alkynyl.
  • R 8 is substituted alkyl (haloarylalkyl such as halobenzyl), R 4 is H and R 5 is alkyl, are shown below.
  • the current invention is directed to a construct comprising a compound of the current invention that is coupled to a therapeutic, detectable group and/or a chelating agent.
  • the chelating agent coupled to the compound of the current invention is bound to a radionuclide that is suitable for use as an imaging agent (e.g., optical imaging, PET imaging, SPECT imaging). In some embodiments, the chelating agent coupled to the compound of the current invention is bound to a radionuclide that is suitable for use as a radiotherapeutic.
  • an imaging agent e.g., optical imaging, PET imaging, SPECT imaging.
  • the chelating agent coupled to the compound of the current invention is bound to a radionuclide that is suitable for use as a radiotherapeutic.
  • the chelating agent is coupled to the compound of the current invention by a linker, such as:
  • constructs include, but are not limited to: (with FAP Binder of Formula VIII), such as: , such as:
  • the current invention is directed to a construct comprising a compound of the current invention that is coupled to an imaging agent.
  • the current invention is directed to a method for treating cancer in a subject.
  • the method comprises administering a therapeutically effective amount of a construct of the current invention to a subject in need thereof, wherein the construct comprises a therapeutic, thereby treating a cancer.
  • the current invention is directed to a method of detecting a tumor in a subject.
  • the method comprises administering a construct of the current invention to a subject in need thereof and detecting an imaging agent.
  • FAP fibrinogen activation protein
  • a starting compound list was selected from the ZINC15 database (zincl5.docking.org/), which resulted in a virtual library of 2,444,661 molecules that were commercially available to purchase (zincl5.docking.org/catalogs/). Rigid docking analysis to FAP narrowed this list down to 145,000 compounds with an AutoDock Vina rigid binding affinity score ⁇ 10' 9 . Selectivity was determined by comparing predicted binding affinities to FAP and DPP4. Compounds with predicted binding affinities to FAP that were at least 100-fold more favorable than the predicted binding affinities to DPP4 were selected for further evaluation. These 594 compounds were then analyzed using flexible docking techniques, and 31 compounds were identified with high predicted FAP binding affinity and low predicted binding affinity to DPP4. Further chemical structure comparisons between these molecules were assessed using Tanimoto Similarity scores.
  • Example 2 Surface plasmon resonance binding assays
  • SPR Surface plasmon resonance
  • SPR binding assays are better suited to detect binders to the protein of interest than the majority of functional assays, which are often designed to measure only stimulation or inhibition of protein function. Accordingly, SPR-based binding assays were used for the evaluation of top virtual screening hits and ultimate identification of novel FAP binders with high FAP affinity and selectivity over DPP-IV.
  • FIG. 1 A flow chart of the screening process as described in Examples 1 and 2 above is presented in FIG. 1.
  • a target system human FAP alpha
  • DPP4 a second protein
  • the fold Rmax is the experimental Rmax divided by the theoretical Rmax calculated from the protein immobilization levels and molecular weights of protein and test compound. Fold Rmax values that are either 0 or very high may be indicative of invalid results, as Fold Rmax 0 indicates very little extent of binding whereas high Fold Rmax values (e.g., >20) indicate significant nonspecific binding.
  • Target cell lines may include both epithelial cancer cells (e.g., breast tumors, colorectal tumors, pancreatic tumors, melanoma, etc.) and non-cancerous cells, both epithelial (e.g., primary cell lines) and non-epithelial (e.g., 293T) cells. These cell lines are cultured in 24-, 96-, or 384- well plates with the appropriate medium and then incubated for up to 48 hours with varying concentrations of test constructs as described herein, with a compound as described herein coupled to a chelating agent that is bound to a therapeutic radionuclide.
  • epithelial cancer cells e.g., breast tumors, colorectal tumors, pancreatic tumors, melanoma, etc.
  • non-cancerous cells both epithelial (e.g., primary cell lines) and non-epithelial (e.g., 293T) cells.
  • epithelial e.g.
  • Live cells are counted using either colorimetric staining (e.g., with crystal violet), ATP quantitation (e.g., CellTiter-Glo® Luminescent Cell Viability Assay), and/or tetrazolium reduction assays (e.g., 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assays). Percent of cell viability is calculated by comparing the total cell count to the live cell count.
  • colorimetric staining e.g., with crystal violet
  • ATP quantitation e.g., CellTiter-Glo® Luminescent Cell Viability Assay
  • tetrazolium reduction assays e.g., 3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide [MTT] assays.
  • Percent of cell viability is calculated by comparing the total cell count to the live

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Abstract

L'invention concerne des méthoes d'identification de petites molécules pouvant se lier à une protéine d'intérêt en utilisant une analyse d'amarrage rigide et flexible in silico, qui peut être suivie par des immunodétections in vitro.<i /> <i /> L'invention concerne également des constructions comprenant un composé qui peut être couplé à un agent chélatant, qui peut à son tour être lié à un radionucléide. L'invention concerne en outre des méthodes de traitement du cancer et/ou des méthodes de détection d'une tumeur, comprenant l'administration d'une construction telle que décrite dans la description à un sujet en ayant besoin.
PCT/US2024/019912 2023-03-17 2024-03-14 Composés et constructions utiles pour cibler protéine d'activation des fibroblastes Pending WO2024196698A2 (fr)

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Publication number Priority date Publication date Assignee Title
DE69911980T2 (de) * 1998-08-21 2004-09-09 Smithkline Beecham P.L.C., Brentford Pyrimidinonderivate zur behandlung von atheroscleros
EP1242066B1 (fr) * 1999-10-27 2006-06-28 Teva Pharmaceutical Industries Ltd. Utilisation de derives de 1-aminoindan pour le traitement de la manie liee a la psychose maniacod pressive
EP1461308B1 (fr) * 2001-12-04 2006-12-20 De Novo Pharmaceuticals Ltd. Inhibiteurs d'enzymes bacteriennes
US20090023718A1 (en) * 2003-11-26 2009-01-22 Aton Pharma, Inc. Diamine and Iminodiacetic Acid Hydroxamic Acid Derivatives
AU2008275891B2 (en) * 2007-07-19 2013-10-10 H.Lundbeck A/S 5-membered heterocyclic amides and related compounds
CA2699631A1 (fr) * 2007-10-31 2009-05-07 Nissan Chemical Industries, Ltd. Derives de pyridazinone et leur utilisation comme inhibiteurs du recepteur p2x7

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