imaging and radiotherapeutic agents targeting fibroblast-activating alpha protein (fap-alpha)

专利摘要:
  Imaging and radiotherapeutic agents targeting the fibroblast-activating alpha protein (FAP-alpha) and its use in imaging and treatment of diseases and disorders related to FAP-alpha are revealed.
公开号:BR112020008011A2
申请号:R112020008011-0
申请日:2018-10-23
公开日:2020-10-27
发明作者:Xing Yang；Sridhar Nimmagadda；Steven Rowe；Stephanie Slania；Martin G. Pomper
申请人:The Johns Hopkins University；
IPC主号:

专利说明:

[001] [001] The present application claims the benefit of US provisional application number 62 / 575,607, filed on October 23, 2017, which is incorporated into the present invention by reference in its entirety. Federal Government sponsored research or development
[002] [002] The present invention was made with government support under NIH CA197470 granted by the National Cancer Institute of the National Institutes of Health (HIH). The government has certain rights to the invention. Background
[003] [003] Expression of fibroblast-activating  protein (FAP-) was detected on the surface of fibroblasts in the stroma surrounding> 90% of the examined epithelial cancers, including malignant breast, colorectal, skin, prostate and pancreatic cancers. (Garin-Chesa, et al., 1990; Rettig, et al., 1993; Tuxhorn, et al., 2002; Scanlan, et al., 1994). It is a characteristic marker for fibroblast associated with carcinoma (CAF), which plays a critical role in promoting angiogenesis, proliferation, invasion and inhibition of cell tumor death. (Allinen, et al., 2004; Franco, et al., 2010). In healthy adult tissues, FAP-α expression is only limited to areas of tissue remodeling or wound healing. (Scanlan, et al., 1994; Yu, et al., 2010; Bae, et al., 2008; Kraman, et al., 2010). In addition, FAP-α- positive cells are seen during embryogenesis in areas of chronic inflammation, arthritis and fibrosis, as well as in soft tissue from bone sarcomas. (Scanlan, et al., 1994; Yu, et al., 2010). These characteristics make FAP- a potential radiotherapeutic and imaging target for cancer and inflammatory diseases.
[004] [004] As FAP- is expressed in tumor stroma, anti-FAP antibodies have been investigated for radioimmuno-targeting malignancies, including murine F19, sibrotuzumab (a humanized version of the F19 antibody), ESC11, ESC14 and others (Welt, et al., 1994; Scott, et al., 2003; Fischer, et al., 2012). Antibodies have also demonstrated the feasibility of imaging inflammation, such as rheumatoid arthritis. (Laverman, et al., 2015). The use of antibodies as molecular imaging agents, however, has pharmacokinetic limitations, including slow clearance of non-target tissue and blood (usually 2-5 days or longer) and non-specific organ absorption. Low molecular weight agents (LMW) demonstrate faster pharmacokinetics and a higher specific signal at clinically convenient times after administration. They can also be synthesized in radio-labeled form more easily and can offer a shorter route for regulatory approval. (Coenen, et al., 2010; Coenen, et al., 2012; Reilly, et al., 2015). To date, no LMW ligand has been reported with ideal properties for nuclear FAP- imaging.
[005] [005] In some respects, the matter currently disclosed provides a compound of the formula (I): (I) where: A is a fraction of targeting for FAP-α; B is any optical or radio-labeled functional group suitable for optical imaging, PET imaging, SPECT imaging, or radiotherapy; and L is a linker having bi-functionalization adapted to form a chemical bond with B and A.
[006] [006] In specific aspects, A is a fraction of targeting FAP-α having the structure of:
[007] [007] In more specific aspects, A is a fraction of targeting the FAP- having the structure in which indicates a point of attachment of the linker of FAP-α to the linker, L, or the reporter fraction, B, in that the point of attachment can be through any of the carbon atoms 5, 6, 7, or 8 of the quinolinyl ring thereof; and stereoisomers and pharmaceutically acceptable salts thereof.
[008] [008] Still in more specific aspects, A is selected from the group consisting of.
[009] [009] In other respects, the subject matter presently disclosed provides a pharmaceutical composition comprising a compound of formula (I).
[010] [010] In some respects, the material presently disclosed provides a method for imaging a disease or disorder associated with fibroblast-activating protein-((FAP-), the method comprising administering a compound of formula (I), wherein the compound of the formula (I) comprises an optical or radio-labeled functional group suitable for optical imaging, PET imaging, or SPECT imaging and imaging.
[011] [011] In other respects, the subject matter disclosed herein provides a method for inhibiting fibroblast-activating protein-((FAP-), the method comprising administering to a subject in need of an effective amount of a compound of formula (I) .
[012] [012] In yet other respects, the subject matter disclosed herein provides a method for treating a fibroblast-activating protein- disorder or disease (FAP-), the method comprising administering to a subject in need of treatment of the same amount efficacy of a compound of formula (I), wherein the compound of formula (I) comprises a radiolabeled functional group suitable for radiotherapy.
[013] [013] In certain respects, the disorder or disease related to (FAP-) is selected from the group consisting of a proliferative disease, including, but not limited to, breast cancer, colorectal cancer, ovarian cancer, prostate cancer , pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, connective tissue and bone sarcomas, renal cell carcinoma giant cell carcinoma, squamous cell carcinoma, and adenocarcinoma; diseases characterized by tissue remodeling and / or chronic inflammation; disorders involving endocrinological dysfunction; and blood clotting disorders.
[014] [014] Certain aspects of the matter currently disclosed have been mentioned earlier, which are treated wholly or in part by the material currently disclosed, other aspects will become evident as the description proceeds when taken with respect to the Examples and associated figures as best described below. BRIEF DESCRIPTION OF THE FIGURES
[015] [015] The application or patent file contains at least one drawing executed in color. Copies of that patent or publication of the patent application with color drawings will be provided by the Department upon application and payment of the necessary fee.
[016] [016] Having thus described the matter currently revealed in general terms, reference will now be made to the attached figures, which are not necessarily drawn to scale, and in which:
[017] [017] Figure 1A, figure 1B and figure 1C show the synthetic pathway and representative FAP-directed agent structures, XY-FAP-01 and [111In] -XY-FAP-02. Figure 1A shows the multistep synthesis of the ligand precursor, tert-butyl (S) - (3 - ((4 - ((2- (2-cyanopyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin- 6- ila) oxy) propyl) carbamate. After each step, the reaction mixture was loaded into a C18 cartridge of 25-g C18 and purified with a MeCN / water / TFA gradient. The identity of the intermediate products was confirmed with 1H NMR. Figure 1B shows the total structure of the optical imaging agent, XY-FAP-01. XY- FAP-01 was produced with a one-step reaction between the precursor and IRDye800CW-NHS. The main product was obtained in a 95% yield after purification with HPLC. Figure 1C shows the total structure of the SPECT image forming agent, [111In] -XY-FAP-02. First, the precursor was functionalized with DOTA through a one-step reaction between the precursor and
[018] [018] Figure 2 shows the inhibitory activity of XY-FAP-01 in human recombinant FAP. The XY-FAP-01 inhibitory activity was determined using a fluorogenic FAP assay kit. The enzymatic activity of recombinant human FAP on a native substrate was inhibited in a concentration-dependent manner by XY-FAP-01. Semi-log inhibitory curves of XY-FAP-01 activity were generated and the determined Ki value of XY-FAP-01 was 1.26 nM;
[019] [019] Figure 3A, figure 3B and figure 3C show the evaluation of the in vitro binding activity and specificity of XY-FAP-01 and [111In] -XY-FAP-02. Figure 3A shows the concentration-dependent absorption of XY-FAP-01 in various cell lines. Cells incubated with various concentrations (range: 50 nM to 0.78 nM) of XY-FAP-01 were imaged with the Pearl Impulser LL-COR Imager to assess agent absorption in various FAP-negative and FAP-positive cell lines. (left). XY-FAP-01 absorption dose response curves in FAP positive cell lines (NCIH2228, U87, and SKMEL24) and FAP-negative cell lines (PC3, NCIH226, and HCT116) were generated (right). Figure 3B shows the inhibition of XY-FAP-01 absorption in FAP-positive cell lines. Cells incubated with 25-nM XY-FAP-01 were incubated with various concentrations of a DPPIV and FAP inhibitor, Talabostat, or a DPPIV-only inhibitor, Sitagliptin. The absorption of XY-FAP-01 was measured and semi-log inhibitor response curves were generated for both Talabostat and Sitagliptin. Figure 3C shows the absorption of [111 In] -XY-FAP-02 in FAP-negative and F87-positive PC87 U3 cell lines. The cells were incubated with 1 µCi [111 In] - XY-FAP-02 and washed with cold PBS. The radioactivity of the cell pellets was measured and normalized for the incubated dose;
[020] [020] Figure 4 is a table showing the ex vivo tissue biodistribution of [111In] -XY-FAP-01 in tumor mice. At 5 min., 0.5 h, 2 h, 6 h and 12 h after injection of 10 µCi [111In] -XY-FAP-01, NOD / SKID mice with U87 and PC3 tumor xenografts were sacrificed and tissues were collected for biodistribution analysis. In addition, mice co-injected with unlabeled XY-FAP-02 and 10 µCi [111In] -XY-FAP-01 were sacrificed 6 h after injection to study the blocking effect on the absorption of the radio-labeled compound. The data presented as mean ± standard deviation. Comparison of the aStudent's t test of the average% ID / g of PC3 tumor versus U87 tumor demonstrated a significant difference between the two groups at 5 min, 0.5 h, 2 h, and 6 h after injection (p <0.0001). No significant difference between the two groups was seen in the 6 h block study. The comparison of bStudent's t test of% ID / g average of PC3 tumor versus U87 tumor showed a significant difference between the two groups 12 h after injection (p = 0.0006). The cStudent's t test comparison of% ID / g between PC3 tumor and U87 tumors 6 h after injection showed significant difference between% ID / g tumors in the 6 h blocking study versus normal 6 h biodistribution results (p <0.0001 );
[021] [021] Figure 5A and Figure 5B show the activity-time relationship of the ex vivo biodistribution of [111In] -XY-FAP-02. FIG. 5A shows tissue activity curves (TACs) of [111 In] -XY-FAP-02 activity in U87 tumor, PC3 tumor, and blood. Figure 5B shows the% ID / g ratios between U87 tumor and PC3 tumor tumor, blood and muscle (mm) versus time;
[022] [022] Figure 6 shows the serial NIRF-image formation of XY-FAP-01 in tumor mice. NOD / SKID mice with FAP-positive U87 tumor xenografts (yellow circle) and FAP-negative PC3 (red circle) were injected with 10 nmol XY-FAP-01 through the tail vein followed by serial NIRF imaging in the Pearl Impulse LI-COR imager. Representative images at 0.5 h, 1 h, 2.5 h and 4 h after injection are shown;
[023] [023] Figure 7 shows SPECT-CT images of [111In] -XY-FAP-02 at 30 min, 2 h, 6 h and 24 h after injection in female NOD / SKID mice with U87 and PC3 tumor xenografts on the flanks superior; and
[024] [024] Figure 8 shows three-dimensional SPEC-CT images of [111In] -XY-FAP-02 at 30 min, 2 h, 6 h and 24 h after injection in female NOD / SKID mice with U87 and PC3 tumor xenografts in upper flanks. DETAILED DESCRIPTION
[025] [025] The material currently revealed will now be described more fully below with reference to the attached figures, in which some, but not all, of the modalities of the material currently disclosed are shown. Similar numbers refer to similar elements from start to finish. The material presently revealed can be incorporated in many different forms and should not be interpreted as limited to the modalities exposed here; instead, these arrangements are provided so that this disclosure meets applicable legal requirements. Indeed, many modifications and other modalities of the material presently disclosed exposed in the present invention will come to the mind of a person skilled in the technique to which the material presently disclosed belongs, having the benefit of the teachings presented in the above descriptions and in the associated figures. Therefore, it should be understood that the matter currently disclosed should not be limited to the specific modalities disclosed and that modifications and other modalities are intended to be included in the scope of the appended claims. Imaging and radiotherapeutic agents targeting fibroblast-activating Protein- (FAP-)
[026] [026] FAP- is a type II integral membrane serine protease from the prolyl oligopeptidase family, which is distinguished by its ability to cleave the Pro-AA peptide bond (where AA represents any amino acid). It has been shown to play a role in cancer by modifying bioactive signaling peptides through this enzymatic activity (Kelly, et al., 2005; Edrosada, et al., 2006). FAP- expression was detected on the surface of fibroblasts in the stroma surrounding more than 90% of epithelial cancers, including, but not limited to, malignant breast, colorectal, skin, prostate, pancreatic, and similar cancers, and inflammatory diseases , including, but not limited to arthritis, fibrosis and the like, with almost no expression in healthy tissues. Therefore, imaging and radiotherapeutic agents targeted specifically at FAP- are of clinical importance.
[027] [027] FAP- exists as a homodimer to perform its enzymatic function. Selectively targeted inhibitors to FAP- have been reported (Lo, et al., 2009; Tsai, et al., 2010; Ryabtsova, et al., 2012; Poplawski, et al., 2013; Jansen, et al., 2013; Jansen, et al., 2014). The material currently disclosed provides, in part, a fraction of selective targeting to FAP- that can be modified with an optical dye, a radiometal chelation complex, and other radio-labeled prosthetic groups, thus providing a platform for targeting training imaging and radiotherapy to FAP-.
[028] [028] Radionuclide molecular imaging, including positron emission tomography (PET), is the most mature molecular imaging technique without limitations on tissue penetration. Due to its advantages of high sensitivity and quantification capacity, radionuclide molecular imaging plays an important role in clinical and preclinical research (Youn, et al., 2012; Chen, et al., 2014). Many radionuclides, mainly  and alpha emitters, have been researched for targeted radioimmunotherapy and include both radio halogens and radiometals (see Table 1 for representative therapeutic radionuclides).
[029] [029] The specific and highly potent binding fraction targeting FAP- allows its use in nuclear imaging and radiation therapy. The matter currently revealed provides the first synthesis of nuclear imaging agents and radiotherapy based on this fraction of dual targeting to FAP-.
[030] [030] Therefore, in some embodiments, the material currently disclosed provides selective and potent low molecular weight (LMW) binders of FAP-, that is, a selective inhibitor of FAP-, combined with a feasible targeting fraction for modification with optical dyes and radiorrotation groups, including means of metal chelation and metal complexes, which allow in vivo optical image formation, nuclear image formation (optics, PET and SPECT), and FAP- targeting radiotherapy. Importantly, the compounds currently disclosed can be modified, for example, conjugated to labeling groups without significantly losing their potency. The currently revealed approach allows for convenient labeling of the FAP-lig ligand allows for convenient labeling of the FAP-lig ligand with optical dyes and PET or SPECT isotopes, including, but not limited to 68Ga, 64Cu, 18F, 86Y, 90Y, 89Zr , 111In, 99mTc, 125I, 124I, For FAP-α related imaging applications. In addition, the currently disclosed approach allows for radiorrotation of the FAP-α ligand with radiotherapeutic isotopes, including but limited to 90Y, 177Lu, 125I, 131I, 211At, 111In, 153Sm, 186Re, 188Re, 67Cu, 212Pb, 225Ac, 213Bi, 212Bi, 212Pb, and 67Ga, for radiotherapy related to FAP-α.
[031] [031] In a specific embodiment, an optical agent conjugated to IRDye-800CW (XY-FAP-01) was synthesized and showed selective absorption in vitro in a U87 FAP- + cell line and in vivo in a U87 FAP- tumor  + and clearly detected the tumor. In another specific modality, a binder labeled 111In (XY-FAP-02- [111In]) was successfully obtained in high yield and purity from its precursor with a metal chelating medium. The in vivo study showed a clear tumor radiotracer in mice with FAP- positive U87 tumors with minimal non-specific organ absorption, which allows specific formation of tumors expressing FAP-. The fraction of targeting to FAP- currently disclosed can be adapted for use with optical dyes and radioisotopes known in the art for therapeutic imaging applications targeting FAP-.
[032] [032] More particularly, in some embodiments, the material currently disclosed provides a compound of the general structure of formula (I): (I) where: A is a fraction targeting FAP-; B is any optical or radio-labeled functional group suitable for forming an optical image, positron emission tomographic image (PET), single photon emission computed tomography (SPECT) or radiotherapy and L is a connector having bi-functionalization adapted for form a chemical bond with B and A.
[033] [033] Representative fractions targeting the FAP- are revealed in the publication of U.S. patent application no. US2014 / 0357650 for Novel FAP Inhibitors by Jansen et al., Published on December 4, 2014; U.S. Patent No.
[034] [034] More particularly, US patent number 9,346,814 to Jansen et al., Discloses FAP- inhibitors of formula (X), or a stereoisomer, tautomer, racemate, salt, hydrate, or solvate thereof, which are suitable for use with the material currently disclosed:
[035] [035] In specific modalities, it is selected from the group consisting of: where * indicates the point of attachment of the aromatic or non-aromatic mono- or bicyclic heterocycle containing N 5 to 10 members with - (CH2) v-.
[036] [036] Therefore, in some modalities, A is a fraction of targeting FAP- having the structure of:
[037] [037] In specific modalities, it is selected from the group consisting of:
[038] [038] In some modalities, A is a fraction targeting FAP- having the structure of: y (R1x) (R2x) y y (R3x ') N C N H The N
[039] [039] In specific modalities, A is selected from the group consisting of:
[040] [040] In more specific modalities, A is selected from the group consisting of: And stereoisomers thereof.
[041] [041] Still in more specific ways, A is selected from the group consisting of:
[042] [042] In some modalities, the combination of L and B can be represented by: Where the subunits associated with the elements p1, p2, p3 and p4 can be in any order, t is an integer selected from the group consisting of 1 , 2, 3, 4, 5, 6, 7, and 8; p1, p3, and p4 are each independently 0 or 1; p2 is an integer selected from the group consisting of 0, 1, 2, and 3, and when p2 is 2 or 3, each R1 is the same or different; m1 and m2 are each, an integer independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; W1 is selected from the group consisting of a bond, –S–, –C (= O) –NR–, and –NR– C (= O) -; W2 is selected from the group consisting of a bond -S-, -CH2-C (= O) - NR-, –C (O) -, –NRC (O) -, –NR'C (O) NR–, –NRC (S) NR'2–, –NRC (O) O–, –OC (O) NR–, –OC (O) -, –C (O) NR–, –NR – C (O) -, –C (O) O–, - (O – CH2 – CH2) q– and - (CH2-CH2-O) q–, where q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; each R or R 'is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and –OR4, where R4 is selected from the group consisting of H, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl, where q is defined as immediately above; Tz is a triazole group that may be present or absent and, if present, is selected from the group consisting of and; each R1 is independently H, C1-C6 alkyl, C3-C12 aryl, - (CH2) q-C3-C12 aryl, -C4-C16 alkyl aryl, or - (CH2) q-C4-C16 alkyl aryl; R2 and R3 are each independently H and -CO2R5, where R5 is selected from the group consisting of H, C1-C6 alkyl, C3-C12 aryl, and C4-C16 alkyl aryl, where when one of R2 or R3 is CO2R5 , then the other is H; V is selected from the group consisting of –C (O) -, -C (S) -, –NRC (O) -, –NRC (S) -, and –OC (O) -; B is any optical or radio-labeled functional group suitable for radiation therapy or optical imaging, PET, or SPECT; and stereoisomers and pharmaceutically acceptable therefor.
[043] [043] In some modalities, L has the following general structure:
[044] [044] In specific modalities, L is: - (CR6H) q- (CH2) q-C (= O) -NR- (CH2) q-O- or -NR- (CH2) q-O-; Where each q and R is defined above; and R6 is H or –COOR5.
[045] [045] Still in more specific ways, L is selected from the group consisting of:
[046] [046] Suitable linkers are revealed in the publication of US patent application number US2011 / 0064657 A1, for "Labeled Inhibitors of Prostate Specific Membrane Antigen (PSMA), Biological Evaluation, and Use as Imaging Agents," published on March 17, 2011 de Pomper et al., and publication of US patent application no. US2012 / 0009121 A1, for "PSMA-Targeting Compounds and Uses Thereof," published on January 12, 2012 by Pomper et al, each of which is incorporated by reference in its entirety.
[047] [047] In some embodiments, B is a radio-labeled prosthetic group comprising a radioisotope selected from the group consisting of 18F, 124I, 125I, 131I, and 211At. Representative radio-labeled prosthetic groups include, but are not limited to: where each X is independently a radioisotope selected from the group consisting of 18F, 124I, 125I, 131I, and 211At; each R and R 'is defined above; and each n is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, and 20.
[048] [048] In more specific modalities, the radio-labeled prosthetic group is selected from the group consisting of:
[049] [049] In other embodiments, B comprises a chelating agent. Representative chelation agents include, but are not limited to:
[050] [050] In some embodiments, B comprises an optical dye, for example, in specific embodiments, a fluorescent dye. In some embodiments, the fluorescent dye fraction comprises carbocyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine and merocyanine, polymethylene, coumarin, rhodamine, xanthene, fluorescein, boron-dipyrromethane (BODIPY) Cy5, Cy5.5, Cy7, VivoTag-680, VivoTag-680, S680, VivoTag-S750, AlexaFluor660, AlexaFluor680, AlexaFluor700, AlexaFluor750, AlexaFluor790, Dy677, Dy676, Dy682, Dy752, Dy780, DyLight547, Dylight647, HiLyte Fluor 647, HiLyte Fluor 647, HiLyte Fluor 647, HiLyte Fluor 647, HiLyte , ADS780WS, ADS830WS, and ADS832WS.
[051] [051] Representative optical dyes include, but are not limited to:;
[052] [052] In some embodiments, the material currently disclosed provides a compound selected from the group consisting of: and
[053] [053] In specific modalities, the compound is selected from the group consisting of:
[054] [054] In another aspect the present disclosure provides a pharmaceutical product comprising a compound of formula (I) in admixture with a pharmaceutically acceptable carrier, diluent, excipient or adjuvant. a person skilled in the art will recognize that the pharmaceutical compositions include the pharmaceutically acceptable salts or hydrates of the compounds described above.
[055] [055] Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art and include salts of active compounds that are prepared with relatively non-toxic bases or acids, depending on the specific substituent fractions found in the compounds described in the present invention. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent or by ion exchange, whereby a against basic ion 9base) in an ionic complex is replaced by another. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic or magnesium salt, or a similar salt.
[056] [056] When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent or by ion exchange, whereby an acidic (acidic) counter in an ionic complex is replaced by another. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulphuric, hydrophilic, and the like, phosphorous and similar of relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, subterranean, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic and the like. Also included are salts of amino acids such as arinate and the like, and salts of organic acids such as glucuronic or galactunoric acids and the like (see, for example, Berge et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19 ). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted to acid or base addition salts.
[057] [057] Accordingly, pharmaceutically acceptable salts suitable for use with the subject matter disclosed herein include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsilate, carbonate, citrate, edetate, edisylate, stolate, esilate,
[058] [058] In therapeutic and / or diagnostic applications, the disclosure compounds can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).
[059] [059] Depending on the specific conditions being treated, such agents can be formulated in liquid or solid dosage forms and administered systemically or locally. The agents can be supplied, for example, in a controlled or regulated slow release form as known to those skilled in the art. Techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, inhalation, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articular, intra-sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular or other modes of supply.
[060] [060] For injection, developing agents can be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, appropriate penetration means for the barrier to be permeated are used in the formulation. Such penetration means are generally known in the art.
[061] [061] The use of pharmaceutically acceptable inert vehicles to formulate the compounds of the present invention disclosed for the practice of disclosure in dosages suitable for systemic administration is included in the scope of the disclosure. With proper choice of vehicle and proper manufacturing practice, the compositions of the present disclosure, in particular those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be formulated easily using pharmaceutically acceptable carriers well known in the art at dosages suitable for oral administration. Such vehicles allow the disclosure compounds to be formulated as tablets, pills, capsules, liquids, gels, syrups, pastes, suspensions and the like, for oral ingestion by an individual (eg, patent) to be treated).
[062] [062] For inhalation or nasal delivery, disclosing agents may also be formulated by methods known to those skilled in the art and may include, for example, but not limited to, examples of solubilizing, diluting or dispersing substances, as a solution saline; Condoms, such as benzyl alcohol; absorption promoters and fluorocarbons.
[063] [063] Pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active ingredients are contained in an effective amount to achieve their intended purpose. The determination of effective amounts is comprised in the ability of those skilled in the art, especially in light of the detailed disclosure provided in the present invention. In general, the compounds according to the disclosure are effective over a wide dosage range. For example, in the treatment of adult humans, dosages of 0.01 to 1000 mg, 0.5 to 100 mg, 1 to 50 mg per day, and 5 to 40 mg per day are examples of dosages that can be used. A non-limiting dosage is 10 to 30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the individual to be treated, the body weight of the individual to be treated, the bioavailability of the compound (s), the toxicity of absorption, distribution , metabolism, and excretion (ADME) of the compound (s) and the preference and experience of the attending physician.
[064] [064] In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliary means that facilitate the processing of the active compounds into preparations that can be used pharmaceutically. Preparations formulated for oral administration can be in the form of tablets, pills, capsules or solutions.
[065] [065] Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliary means, if desired, to obtain tablets or pill cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxy propyl methyl cellulose, sodium carboxymethyl cellulose (CMC) and / or polyvinyl pyrrolidone ( PVP: povidone). If desired, disintegrating agents can be added, such as cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.
[066] [066] Drage cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or mixtures of solvents. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[067] [067] Pharmaceutical preparations that can be used include orally plug-in capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The plug-in capsules can contain the active ingredients mixed with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols (PEGs). In addition, stabilizers can be added. C. Imaging methods using compounds of formula (I) or pharmaceutical compositions of the same
[068] [068] In some embodiments, the material currently disclosed provides a method for imaging a disease or disorder associated with fibroblast-activating protein-((FAP-), the method comprising administering a compound of formula (I), wherein the compound of formula (I) comprises a radio-labeled or optical functional group suitable for optical imaging, PET imaging or SPECT imaging, and obtaining an image.
[069] [069] Therefore, in some embodiments, the material presently disclosed provides a method for imaging one or more cells, organs, or tissues, the method comprising exposing cells or administering to an individual an effective amount of a compound of the formula ( I) with an optical or radioisotopic label suitable for image formation. In some embodiments, one or more organs or tissues include prostate tissue, kidney tissue, brain tissue, vascular tissue or tumor tissue.
[070] [070] The imaging methods of the invention are suitable for imaging any physiological process or characteristic in which FAP-  is involved, for example, identifying areas of tissue or targets that present or express high concentrations of FAP- . Physiological processes in which FAP- is involved include, but are not limited to: (a) proliferative diseases (including, but not limited to, cancer); (b) tissue remodeling and / or chronic inflammation (including, but not limited to, fibrotic disease, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders involving cartilage degradation); and (c) endocrinological disorders (including, but not limited to, glucose metabolism disorders).
[071] [071] In certain embodiments, the radio-labeled compound is stable in vivo.
[072] [072] In certain modalities, the radio-labeled compound is detected by positron emission tomography (PET) or computed tomography by single photon emission (SPECT).
[073] [073] In certain embodiments, the optical reporter fraction is detected by fluorescence, such as fluorescence microscopy.
[074] [074] In certain embodiments, the compounds currently disclosed are excreted from the body's tissues quickly to avoid prolonged radiation exposure of the radio-labeled compound administered to the individual. Typically, the currently disclosed compounds are eliminated from the body in less than approximately 24 hours. More typically, the currently disclosed compounds are eliminated from the body in less than approximately 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 90 minutes, or 60 minutes. Exemplifying compounds are eliminated between approximately 60 minutes and approximately 120 minutes. In certain embodiments, the compounds currently disclosed are stable in vivo so that substantially all, for example, more than approximately 50%, 60%, 70%, 80%, or 90% of the injected compound is not metabolized by the body prior to excretion .
[075] [075] Additionally, for in vitro applications, such as in vitro research and diagnostic applications, body fluids and cell samples from the above individuals will be suitable for use as mammals, particularly primates such as humans, blood, urine or tissue samples, or urine blood or tissue samples from the animals mentioned for veterinary applications.
[076] [076] Other modalities provide kits comprising a compound of the formula (I). in certain embodiments, the kit provides packaged pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of formula (I). in certain embodiments, the packaged pharmaceutical composition will comprise the reaction precursors necessary to generate the compound of formula (I) after combining with a radio-labeled precursor. Other packaged pharmaceutical compositions further comprise signals comprising at least one of: instructions for preparing compounds of formula (I) from provided precursors, instructions for using the composition for imaging cells or tissues expressing FAP-.
[077] [077] In certain embodiments, a kit containing approximately 1 to approximately 30 mCi of the radionuclide-labeled imaging agent described above, in combination with a pharmaceutically acceptable carrier, is provided. The imaging agent and vehicle can be supplied in solution or in lyophilized form. When the imaging agent and vehicle of the kit are in lyophilized form, the kit can optionally contain a physiologically acceptable and sterile reconstitution medium such as water, saline, buffered saline and the like. The kit can provide a compound of the formula (I) in solution or in lyophilized form, and these kit components can optionally contain stabilizers such as NaCl, silicate, phosphate buffers, ascorbic acid, gentisic acid, and the like. Additional stabilization of the kit components can be provided in this embodiment, for example, by providing the reducing agent in an oxidation-resistant form. The determination and optimization of such stabilizers and stabilization methods are well understood at the level of skill in the technique.
[078] [078] In certain embodiments, a kit provides a non-radio-labeled precursor to be combined with a radio-labeled reagent on site.
[079] [079] Imaging agents can be used according to the methods currently revealed by a person skilled in the art. Images can be generated due to differences in SPECT and similar devices. The extent of accumulation of the imaging agent can be quantified using known methods to quantify radioactive emissions or fluorescence. A particularly useful imaging approach employs more than one imaging agent to perform simultaneous studies.
[080] [080] In general, a detectably effective amount of the imaging agent of the invention is administered to a subject. An "detectably effective amount" of the imaging agent is defined as an amount sufficient to provide an acceptable image using equipment that is available for clinical use. A detectably effective amount of the imaging agent can be administered in more than one injection. The detectably effective amount of the imaging agent of the invention can vary according to factors such as the individual's degree of susceptibility, the individual's age, sex and weight, the individual's idiosyncratic responses and dosimetry. Detectably effective amounts of the imaging agent may also vary depending on factors related to film and instrument. The optimization of such factors is well understood in the skill level in the technique. The amount of imaging agent used for diagnostic purposes and the duration of the imaging study will depend on the radionuclide used to label the agent, the patient's body mass, the nature and severity of the condition being treated, the nature of therapeutic treatments to which the patient was submitted, and the patient's idiosyncratic responses. Finally, the attending physician will decide the amount of imaging agent to be administered to each individual patient and the duration of the imaging study. D. Methods of treating a FAP-relacionada-related disorder or disease using the compounds of formula (I) or pharmaceutical compositions thereof
[081] [081] In other embodiments, the currently disclosed compounds of formula (I) can be used to treat an individual afflicted with one or more disorders or diseases related to FAP-doenças including, but not limited to: (a) proliferation (including, but not limited to cancer); (b) tissue remodeling and / or chronic inflammation (including, but not limited to, fibrotic disease, wound healing, keloid formation, osteoarthritis, rheumatoid arthritis and related disorders involving cartilage degradation); and (c) endocrinological disorders (including, but not limited to, glucose metabolism disorders).
[082] [082] Therefore, in some modalities, one or more FAP-relacionada-related disorder or disease is selected from the group consisting of a proliferative disease, including, but not limited to, breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, connective tissue and bone sarcomas, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma; diseases characterized by tissue remodeling and / or chronic inflammation, disorders involving endocrinological dysfunction; and blood clotting disorders.
[083] [083] In general, the "effective amount" of an active agent or drug delivery device refers to the amount needed to elicit the desired biological response. As will be recognized by those of ordinary skill in the art, the effective amount of an agent or device can vary depending on such factors as the desired biological end point, the agent to be supplied, the formation of the pharmaceutical composition, the target tissue and the like.
[084] [084] In other modalities, the method can be put into practice in vitro or ex vivo by introducing, and preferably mixing, the compound and cell (s) or tumor (s) in a controlled environment, such as a tube or culture dish . The method can be put into practice in vivo, in which case contacting means exposing the target in an individual to at least one compound of the material currently disclosed, such as administering the compound to an individual through any suitable route. According to the matter currently disclosed, contacting may comprise introducing, exposing and the like, the compound at a site distant from the cells to be contacted, and allowing the individual's bodily functions, or natural movements (eg diffusion) or induced by man (eg, agitation) of fluids result in contact of the compound with the target.
[085] [085] The individual treated by the methods currently disclosed in its many modalities is desirably a human individual, although it should be understood that the methods described in the present invention are effective with respect to all vertebrate species, which are intended to be included in the term "individual." Accordingly, an “individual” can include a human individual for medical purposes, such as for the treatment of an existing condition or disease or prophylactic treatment to prevent the onset of a condition or disease, or an animal (non-human) individual for medical purposes. medical, veterinary or developmental purposes. Suitable animal individuals include mammals that include, but are not limited to, primates, for example, humans, monkeys, simians and the like; cattle, for example, cattle, oxen and the like; sheep, for example, sheep and the like; goats, for example, goats and the like; pigs, for example, pigs, wild boars and the like; horses, for example, horses, donkeys, zebras and the like; felines, including domestic and wild cats; canines, including dogs; lagomorphs, including rabbits, hares and the like; and rodents, including mice, rats and the like. An animal can be a transgenic animal. In some modalities, the individual is a human being including, but not limited to, fetal, neonatal, children, juveniles and adults. In addition, an "individual" may include a patient afflicted with or suspected of being afflicted with a condition or disease. Accordingly, the terms "individual" and "patient" are used interchangeably in the present invention. In some modalities, the individual is human. In other modalities, the individual is non-human.
[086] [086] As used herein, the term "treatment" may include reversing, alleviating, inhibiting the advance of, preventing or reducing the likelihood of the disease, or condition to which that term applies, or one or more symptoms or manifestations of that disease or condition.
[087] [087] “Prevention” refers to preventing a disease, condition, or symptom or manifestation from occurring, or worsening its severity. Therefore, the currently disclosed compounds can be administered prophylactically to prevent or reduce the incidence or recurrence of the disease or condition. II. Definitions
[088] [088] Although specific terms are used in the present invention, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by a person with common knowledge in the technique to which the subject currently described belongs.
[089] [089] Although it is believed that the following terms in relation to compounds of formula (I) are well understood by a person with common knowledge in the art, the following definitions are exposed to facilitate explanation of the matter currently disclosed. These definitions are intended to supplement and illustrate, not preclude, the definitions that would be evident to a person with common knowledge in the art after examining the present disclosure.
[090] [090] The terms substituted, whether preceded by the term "optionally" or not, and substituent, as used here, refer to the ability, as recognized by a person skilled in the art, to change a functional group by another functional group in a molecule , with the proviso that the valence of all atoms is maintained. When more than one position in any given structure can be replaced with more than one substituent selected from a specified group, the substituent can be the same or different in every position. The substituents may also be additionally substituted (for example, an aryl group substituent may have another substituent thereof, such as another aryl group, which is additionally substituted at one or more positions).
[091] [091] Where substituent groups or linking groups are specified by their conventional chemical formulas, written from left to right, they also cover the chemically identical substituent that would result from writing the structure from right to left, for example -CH2O - is equivalent to -OCH2-; -C (= O) O- is equivalent to -OC (= O) -; -OC (= O) NR- is equivalent to -NRC (= O) O-, and similar.
[092] [092] When the term “independently selected” is used, the substituents being mentioned (for example, groups R, such as groups R1, R2, and the like, or variables, such as “m” and “n”) can be identical or different . For example, both R1 and R2 can be substituted alkyls, or R1 can be hydrogen and R2 can be substituted alkyl and the like.
[093] [093] The terms "one", "one" or "one (one)", when used in reference to a group of substituents in the present invention, mean at least one. For example, where a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. In addition, when a fraction is replaced with an R substituent, the group can be referred to as "R-substituted". When a fraction is substituted-R, the fraction is replaced with at least one substituent R and each substituent R is optionally different.
[094] [094] A so-called "R" group will generally have the structure that is recognized in the art as corresponding to a group having the name, unless otherwise specified in the present invention. For purposes of illustration, certain representative "R" groups as set out above are defined below.
[095] [095] The descriptions of compounds in the present disclosure are limited by chemical bonding principles known to those skilled in the art. Therefore, where a group can be substituted by one or more of a number of substituents, such substitutions are selected to conform to chemical bonding principles and provide compounds that are not inherently unstable and / or would be known to a person. with common knowledge in the art as likely to be unstable in ambient conditions, such as aqueous, neutral and various known physiological conditions. For example, a heterocycloalkyl or heteroaryl is linked to the rest of the molecule via a ring heteroatom in accordance with chemical bonding principles known to those skilled in the art thereby avoiding inherently unstable compounds.
[096] [096] Unless otherwise explicitly defined, a “substituent group,” as used here, includes a functional group selected from one or more of the following fractions, which are defined here: The term hydrocarbon, as used here, if refers to any chemical group comprising hydrogen and carbon. The hydrocarbon can be substituted or unsubstituted. As would be known to a person skilled in this technique, all requirements must be met when making any substitutions. The hydrocarbon can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic or heterocyclic. Illustrative hydrocarbons are further defined below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, ally, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl and the like.
[097] [097] The term "alkyl", whether on its own or as part of another substituent, means, unless otherwise mentioned, a straight-chain (i.e., unbranched) or branched acyclic or cyclic hydrocarbon group, or combinations thereof, or combination thereof, which may be fully saturated, mono- or polyunsaturated and may include di- and multivalent groups, having the number of carbon atoms designated (ie, C1-C10 means one to ten carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons). In specific embodiments, the term "alkyl" refers to C1-20 inclusive, including, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18 19 and 20 carbons, linear (i.e. "straight chain") branched, or cyclic, saturated or at least partially and in some cases totally unsaturated (ie alkenyl and alkynyl) radicals derived from a hydrocarbon fraction containing between one and twenty carbon atoms by removing a single hydrogen atom.
[098] [098] Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
[099] [099] "Branched" refers to an alkyl group in which a lower alkyl group such as methyl, ethyl or propyl, is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having 1 to approximately 8 carbon atoms (i.e., C1-8 alkyl) for example, 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms . "Upper alkyl" refers to an alkyl group having approximately 10 to approximately 20 carbon atoms, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. In certain embodiments, "alkyl" refers, in particular, to C1-8 straight chain alkyls. In other embodiments, "alkyl" refers, in particular, to C3-8 branched chain alkyls.
[0100] [0100] Alkyl groups can be optionally substituted (a "substituted alkyl") with one or more alkyl group substituents, which can be the same or different. The term "alkyl group substituent" includes, but is not limited to, alkyl, substituted alkyl, halo, alkylamino, arylamino, acyl, hydroxyl, aryloxy, alkoxy, alkyl thio, aryl thio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo and cycloalkyl. One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms can be optionally inserted along the alkyl chain, where the nitrogen substituent is hydrogen, lower alkyl (also referred to here as "alkylamino alkyl") or aryl.
[0101] [0101] Thus, as used in the present invention, the term "substituted alkyl" includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including , for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxy, hydroxyl, nitro, amino, alkyl amino, dialkyl amino, sulfate and mercapto.
[0102] [0102] The term "heteroalkyl", alone or in combination with another term, means, unless otherwise mentioned, a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, consisting of at least at least one carbon atom and at least one hetero atom selected from the group consisting of O, N, P, Si and S, and in which the nitrogen, phosphorus, and sulfur atoms can be optionally oxidized and the nitrogen hetero atom can be optionally quaternized. The heteroatom (s) O, N, P and S and Si can be placed in any interior position of the heteroalkyl group or in the position in which the alkyl group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) -CH3, -CH2-S-CH2-CH3, - CH2-CH25-S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -CH = CH-O-CH3, -Si (CH3) 3, -CH2-CH = N-OCH3, - CH = CH-N (CH3) - CH3, O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms can be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si (CH3) 3.
[0103] [0103] As described above, heteroalkyl groups, as used in the present invention, include those groups that are linked to the rest of the molecule through a heteroatom, such as, -C (O) NR ', -NR'R ”, -OR ', -SR, -S (O) R, and / or - S (O2) R'. Where “heteroalkyl” is cited, followed by quotes from specific heteroalkyl groups, such as -NR’R or similar, it will be understood that the terms heteroalkyl and -NR’R ”are not redundant or mutually exclusive. Instead, specific heteroalkyl groups are cited to add clarity. Therefore, the term "heteroalkyl" should not be interpreted here as excluding specific heteroalkyl groups, such as -NR'R "or similar.
[0104] [0104] "Cyclic" and "cycloalkyl" refer to a non-aromatic mono- or multicyclic ring system of approximately 3 to approximately 10 carbon atoms, for example, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The cycloalkyl group can optionally be partially unsaturated. The cycloalkyl group can also be optionally substituted with an alkyl group substituent as defined in the present invention, oxo, and / or alkylene. One or more atoms of unsubstituted substituted oxygen, sulfur or nitrogen can be optionally inserted along the cyclic alkyl chain, where the nitrogen substituent is hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl, thereby providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Multicyclic cycloalkyl rings include adamantila, octahydronaftila, decalin, camphor, camphan and noradamantila and fused ring systems such as dihydro- and tetrahydronaphthalene and the like.
[0105] [0105] The term "cycloalkyl alkyl", as used in the present invention, refers to a cycloalkyl group as defined above, which is attached to the parent molecular moiety through an alkyl group, also as defined above. examples of cycloalkyl alkyl groups include cyclopropyl methyl and cyclopentyl ethyl.
[0106] [0106] The terms "cycloheteroalkyl" or "heterocycloalkyl" refer to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a substituted or unsubstituted cycloalkyl ring system with 3 to 10 members, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P) and silicon (Si), and optionally can include one or more bonds doubles.
[0107] [0107] The cycloheteroalkyl ring may optionally be fused with or otherwise bonded to other cycloetheroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocyclic rings include those having one to three hetero atoms independently selected from oxygen, sulfur and nitrogen, where the nitrogen and sulfur hetero atoms can optionally be oxidized and the nitrogen hetero atom can be optionally quaternized. In certain embodiments, the term heterocyclic refers to a 5-, 6- or 7-membered non-aromatic ring or a polycyclic group in which at least one ring atom is a heteroatom selected from O, S and N (where the nitrogen hetero atoms and sulfur can be optionally oxidized), including, but not limited to, a bi- or tricyclic group, comprising rings with six fused members having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, where (i) each ring with 5 members have 0 to 2 double bonds, each 6 member ring has 0 to 2 double bonds, and each 7 member ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms can be optionally oxidized, (iii ) the nitrogen heteroatom can optionally be quaternized, and (iv) any of the above heterocyclic rings can be fused with an aryl or heteroaryl ring. Representative cycloetheroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadetrazinuryl, thiadetrazinanil, thiadetrazinanilil, thiadetrazinanil, thiadetrazinanil, thiadetrazinanil, thiadetrazinanil, thiadetrazinanil, thiadetrazinanil, thiadetrazinanil, thiadetrazinanil,
[0108] [0108] The terms "cycloalkyl" and "heterocycloalkyl" by themselves or in combination with other terms, represent, unless otherwise mentioned, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position in which the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohepty, and the like. Examples of heterocycloalkyl include, but are not limited to 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl , tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms "cycloalkylene" and "heeterocycloalkylene" refer to divalent cycloalkyl and heterocycloalkyl derivatives, respectively.
[0109] [0109] An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), ethynyl , 1- and 3-propynyl, 3-butynyl and higher homologues and isomers. Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl."
[0110] [0110] More particularly, the term "alkenyl" as used in the present invention refers to a monovalent group derived from a C1-20 straight or branched hydrocarbon fraction including having at least one carbon-carbon double bond by removing a molecule single hydrogen. Alkenyl groups include, for example, ethylene (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, alenyl, and butadienyl.
[0111] [0111] The term "cycloalkenyl" as used here refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,3-cyclohexadienyl, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
[0112] [0112] The term "alkynyl" as used in the present invention refers to a monovalent group derived from a straight or branched C1-20 hydrocarbon of a designated number of carbon atoms containing at least one carbon-carbon triple bond. Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptinyl groups and the like.
[0113] [0113] The term "alkylene" alone or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having 1 to approximately 20 carbon atoms, for example, 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkyl group can also be optionally unsaturated and / or substituted with one or more "substituents on the alkyl group". One or more substituted or unsubstituted oxygen, sulfur or nitrogen atoms (also referred to herein as "alkylamino alkyl") may be optionally inserted along the alkylene group, where the nitrogen substituent is alkyl as previously described. Exemplifying alkylene groups include methylene (–CH2–); ethylene (–CH2 – CH2–); propylene (- (CH2) 3–); cyclohexylene (–C6H10–); –CH = CH – CH = CH–; –CH = CH – CH2–; - CH2CH2CH2CH2-, -CH2CH = CHCH2-, -CH2CsCCH2-, -CH2CH2CH (CH2CH2CH3) CH2-, - (CH2) qN (R) - (CH2) r–, where each q is independently an integer from 0 to approximately 20, for example, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylene dioxyl (- O – CH2 – O–); and ethylene dioxyl (-O- (CH2) 2 – O–). An alkylene group may have approximately 2 to approximately 3 carbon atoms and may also have 6-20 carbons. Typically, an alkyl (or alkylene) group will have 1 to 24 carbon atoms, with those groups having 10 or less carbon atoms being some embodiments of the present disclosure. A "lower alkyl" or "lower alkylene" is a group of lower alkyl or alkylene, generally having eight or less carbon atoms.
[0114] [0114] The term "heteroalkylene" alone or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited to -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2 -CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain terminals (for example, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). In addition, for alkylene and heteroalkylene bonding groups, no orientation of the bonding group is implied by the direction in which the bonding group formula is written. For example, the formula
[0115] [0115] The term "aryl" means, unless otherwise mentioned, an aromatic hydrocarbon substituent which can be a single ring or multiple rings (such as 1 to 3 rings) that are fused together or covalently bonded. The term "heteroaryl" refers to groups of aryl (or rings) that contain one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, where the nitrogen and sulfur atoms they are optionally oxidized, and the nitrogen atom (s) are optionally quaternized. A heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3- furyl, 2-thienil, 3-thienil, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the aforementioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.
[0116] [0116] For brevity, the term "aryl" when used in combination with other terms (for example, aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. therefore, the terms "arylalkyl" and heteroaryl alkyl "are intended to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (for example, benzyl, phenethyl, pyridyl methyl, furyl methyl, and the like) including those alkyl groups in which a carbon atom (for example, a methylene group) has been replaced, for example, with an oxygen atom (for example, phenoxymethyl, 2-pyridyloxy methyl, 3- (1-naphthyloxy) propyl and the like ). However, the term "haloaryl" as used here is intended to cover only aryls replaced with one or more halogens.
[0117] [0117] Where a heteroalkyl, heterocycloalkyl or heteroaryl includes a specific number of members (for example, "3 to 7 members"), the term "member" refers to a carbon or heteroatom.
[0118] [0118] In addition, a structure represented in general by the formula: (R) n or As used here refers to a ring structure, for example, but not limited to, a 3-carbon, a 4-carbon, a 5 -carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and / or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent group R , in which the R group can be present or absent, and when present, one or more R groups can be individually substituted on one or more available carbon atoms of the ring structure. The presence or absence of the R group and the number of R groups is determined by the value of the variable “n”, which is an integer in general having a value ranging from 0 to the number of carbon atoms in the ring available for substitution. Each group R, if more than one, is substituted on an available carbon of the ring structure rather than on another group R. for example, the above structure where n is 0 to 2 would comprise groups of compound including, but not limited to: And the like.
[0119] [0119] A dashed line representing a bond in a cyclic ring structure indicates that the bond may be present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure and an unsaturated ring structure.
[0120] [0120] The symbol () indicates the point of attachment of a fraction to the rest of the molecule.
[0121] [0121] When an atom named from an aromatic ring or a heterocyclic aromatic ring is defined as being "absent", the named atom is replaced by a direct bond.
[0122] [0122] Each of the above terms (for example, "alkyl," "heteroalkyl," "cycloalkyl" and "heterocycloalkyl", "aryl," "heteroaryl," "phosphonate," and "sulfonate" as well as their divalent derivatives) include both substituted and unsubstituted forms from the indicated group. Optional substitutes for each group type are provided below.
[0123] [0123] Substituents for monovalent and divalent derivative groups of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl (including those groups often mentioned as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl may be more or more heteroalkenyl) a variety of groups selected from, but not limited to -OR ', = O, = NR', = N-OR ', -NR'R ”, -SR', - halogen, -SiR'R” R '”, -OC (O) R ', -C (O) R', -CO2R ', - C (O) NR'R ”, -OC (O) NR'R”, - NR ”C (O) R', -NR'-C (O) NR ”R '”, -NR ”C (O) OR', -NR-C (NR'R”) = NR '”, -S (O) R', -S O) 2R ', -S (O) 2NR'R ”, -NRSO2R', -CN and -NO2 in a number ranging from zero to (2m '+ l), where m' is the total number of carbon atoms in such groups. R ', R ”, R'” and R ”” each can independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (for example: substituted aryl with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. As used here, an "alkoxy" group is an alkyl bonded to the rest of the molecule through divalent oxygen. When a compound of the disclosure includes more than one group R, for example, each of the groups R is independently selected as are each group R ', R ", R'" and R "" when more than one of these groups is present. When R 'and R ”are bonded to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR’R ”is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, a person skilled in the art will understand that the term "alkyl" is intended to include groups including carbon atoms attached to groups other than hydrogen groups, such as haloalkyl (for example, -CF3 and -CH2CF3) and acyl (for example, -C (O) CH3, -C (O) CF3, -C (O) CH2OCH3, and the like).
[0124] [0124] Similar to the substituents described for alkyl groups above, exemplary substituents for aryl and heteroaryl groups (as well as their divalent derivatives), are varied and are selected, for example, from: halogen,, -OR ', -NR' R ”, -SR ', -SiR'R” R' ”, -OC (O) R ', -C (O) R', -CO2R ', -C (O) NR'R”, - OC (O ) NR'R ”, -NR” C (O) R ', -NR'-C (O) NR ”R'”, -NR ”C (O) OR ', -NR-C (NR'R” R '”) = NR” ”, -NR-C (NR'R”) = NR' ”-S (O) R ', -S (O) 2R', -S (O) 2NR'R”, -NRSO2R ', -CN and -NO2, -R', -N3, -CH (Ph) 2, fluoro (C1-C4) alkoxy, and fluoro (C1-C4) alkyl, in a number ranging from zero to the total number of open valences in the aromatic ring system; and where R ', R ”, R'” and R ”” can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, unsubstituted substituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound of the disclosure includes more than one group R, each of the groups R is independently selected as are each group R ', R ", R'" and R "" when more than one of these groups is present.
[0125] [0125] Two of the substituents on adjacent atoms of aryl or heteroaryl ring can optionally form a ring of the formula -TC (O) - (CRR ') qU-, where T and U are independently -NR-, -O-, -CRR'- or a single bond eq is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of aryl or heteroaryl ring can be optionally substituted with a substituent of the formula -A- (CH2) rB-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S (O) -, -S (O) 2-, -S (O) 2NR'- or a bond single, er is an integer from 1 to 4.
[0126] [0126] One of the unique connections of the new ring thus formed can optionally be replaced with a double connection. Alternatively, two of the substituents on adjacent aryl or heteroaryl ring atoms can be optionally substituted with a substituent of the formula - (CRR ') s-X'- (C ”R'”) d-, where sed are independently integers of 0 a 3 and X 'is -O-, -NR'-, -S-, -S (O) -, - S (O) 2-, or -S (O) 2NR'-. The substituents R, R ', R "and R'" can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
[0127] [0127] As used here, the term "acyl" refers to an organic acid group in which the -OH of the carbonyl group has been replaced with another substituent and has the general formula RC (= 0) -, where R is a group alkyl, alkenyl, alkynyl, aryl, carbocyclic, heterocyclic or aromatic heterocyclic as defined in the present invention). As such, the term "acyl" specifically includes arylacyl groups, such as a 2- (furan-2-yl) acetyl group) - and a 2-phenylacetyl. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, -RC (= O) NR ', esters, -RC (= O) OR', ketones, -RC (= O) R ', and aldehydes -RC (= O) H.
[0128] [0128] The terms "alkoxy" or "alkoxy" are used interchangeably in the present invention and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O) group -) linked to the molecular fraction of origin through an oxygen atom, in which the terms "alkyl", "" alkenyl "and" alkynyl "are as previously described and may include linear, C1-20 oxohydrocarbon chains, branched, or cyclic, saturated or unsaturated, including, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and n-pentoxyl, neopentoxyl, n-hexoxy, and the like.
[0129] [0129] The term "alkoxoalkyl" as used herein refers to an alkyl-O-alkyl ether, for example, a methoxy ethyl group or an ethoxymethyl.
[0130] [0130] "Aryloxy" refers to an aryl-O- group in which the aryl group is as previously described, including a substituted aryl. The term "aryloxy" as used here can refer to phenyloxy or hexyloxy and alkyl, substituted alkyl, halo or substituted alkoxy, phenyloxy or hexyloxy.
[0131] [0131] "Aralkyl" refers to an aryl-alkyl group in which aryl and alkyl are as previously described and includes substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl and methyl naphthyl.
[0132] [0132] "Aralkyloxy" refers to an aralkyl-O- group in which the aralkyl group is as previously described. An exemplary aralkyloxy group is benzyloxy, i.e., C6H5-CH2-O-. An aralkyloxy group can be optionally substituted.
[0133] [0133] “Alkoxycarbonyl” refers to an alkyl group-O-C (= O) - Exemplifying alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,
[0134] [0134] "Aryloxycarbonyl" refers to a group of aryl-O-C (= 0) -. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
[0135] [0135] "Aralkoxycarbonyl" refers to an aralkyl group-O-C (= 0) -. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
[0136] [0136] "Carbamoyl" refers to an amide group of the formula -C (= 0) NH2. "Alkylcarbamoyl" refers to a group R'RN-C (= 0) - where one of R and R 'is hydrogen and the other of R and R' is alkyl and / or substituted alkyl as previously described. "Dialkylcarbamoyl" refers to a group R'RN-C (= 0) - where each of R and R 'is independently alkyl and / or substituted alkyl as previously described.
[0137] [0137] The term carbonyldioxyl, as used in the present invention, refers to a carbonate group of the formula -O-C (= O) -OR.
[0138] [0138] "Acyloxy" refers to an acyl-O- group in which acyl is as previously described.
[0139] [0139] The term "amino" refers to the group -NH2 also refers to a group containing nitrogen as known in the art derived from ammonia by replacing one or more hydrogen radicals with organic radicals. For example, the terms "acylamino" and "alkylamino" refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
[0140] [0140] An "aminoalkyl" as used in the present invention refers to an amino group covalently attached to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used in the present invention refer to one, two, or three, respectively, alkyl groups, as previously defined, linked to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR 'where R' is an alkyl group, as previously defined, while the term dialkylamino refers to a group having the structure -NR'R ”, where R 'and R ”are individually independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R "R" ", where R ', R' 'and R'" are individually independently selected from the group consisting of alkyl groups. Additionally, R ', R' 'and / or R' ”taken together can optionally be - (CH2) k- where k is an integer from 2 to 6. Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methyl ethylamino, isopropylamino, piperidine, trimethylamino and propylamino.
[0141] [0141] The amino group is -NR'R ”, where R 'and R” are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
[0142] [0142] The terms alkylthioether and thioalkoxy refer to a saturated (ie, S-alkyl) or unsaturated (ie, S-alkenyl and S-alkynyl) group attached to the parent molecular moiety through an atom of sulfur. Examples of thioalkoxy fractions include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio and the like.
[0143] [0143] "Acylamino" refers to an acyl-NH- group in which acyl is as previously described. "Aroílamino" refers to a group of aroíla-NH- in which aroíla is as previously described.
[0144] [0144] The term "carbonyl" refers to the group -COOH. Such groups are also mentioned in the present invention as a "carboxylic acid" fraction.
[0145] [0145] The terms "halo", "halide", or "halogen" as used in the present invention refer to groups of fluorine, chlorine, bromine and iodine. Additionally, terms like "haloalkyl" are intended to include monoaloalkyl and polyalkyl. For example, the term "halo (C1-C4) alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoromethyl, 4-chlorobutyl, 3-bromopropyl and the like.
[0146] [0146] The term "hydroxyl" refers to the -OH group.
[0147] [0147] The term "hydroxyalkyl" refers to an alkyl group substituted with an -OH group.
[0148] [0148] The term “mercapto” refers to the -SH group.
[0149] [0149] The term "oxo" as used in the present invention means an oxygen atom that is doubly bonded to a carbon atom or another element.
[0150] [0150] The term “nitro” refers to the group -NO2.
[0151] [0151] The term "uncle" refers to a compound described earlier in the present invention in which an oxygen or carbon atom is replaced by a sulfur atom.
[0152] [0152] The term "sulfate" refers to the group -SO4.
[0153] [0153] The term thiohydroxyl or thiol, as used in the present invention, refers to a group of the formula -SH.
[0154] [0154] More particularly, the term "sulfide" refers to the compound having a group of the formula -SR.
[0155] [0155] The term "sulfone" refers to the compound having a sulfonyl group - S (O2) R.
[0156] [0156] The term "sulfoxide" refers to a compound having a sulfinyl group - S (O) R.
[0157] [0157] The term ureido refers to a group of urea of the formula -NH-CO-NH2.
[0158] [0158] Throughout the specification and claims, a given name or chemical formula will cover all tautomers, congeners and optics and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.
[0159] [0159] Certain compounds of the present disclosure may have asymmetric carbon atoms (chiral or optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) - or (S) - or as D- or L- for amino acids, and individual isomers are covered within the scope of this disclosure. The compounds of the present disclosure do not include those that are known in the art to be too unstable to synthesize and / or isolate. The present disclosure intends to include compounds in racemic, scalemic and optically pure forms. (R) - and (S) -, or optically active D- and L-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described in the present invention contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.
[0160] [0160] Unless otherwise mentioned, structures shown in the present invention are also intended to include all stereochemical forms of the structure, that is, the R and S configurations for each asymmetric center. Therefore, unique stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are included in the scope of the disclosure.
[0161] [0161] It will be apparent to a person skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, all of these tautomeric forms of the compounds being included in the scope of the disclosure. The term "tautomer", as used in the present invention, refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another.
[0162] [0162] As used in the present invention the term "monomer" refers to a molecule that can be subjected to polymerization, thereby contributing constitutional units to the essential structure of a macromolecule or polymer.
[0163] [0163] A "polymer" is a molecule of high relative molecular mass, whose structure essentially comprises multiple unit repetition derived from low relative molecular mass molecules, that is, a monomer.
[0164] [0164] A "dendrimer" are highly branched star-shaped macromolecules with nanometer-scale dimensions.
[0165] [0165] As used here, an "oligomer" includes some monomer units, for example, in contrast to a polymer that can potentially comprise an unlimited number of monomers. Dimers, trimers and tetramers are non-limiting examples of oligomers.
[0166] [0166] The term “protection group” refers to chemical fractions that block some or all of the reactive fractions of a compound and prevent such fractions from participating in chemical reactions until the protection group is removed, for example, those fractions listed and described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protection groups are employed, that each (different) protection group is removable by a different means. Protection groups that are cleaved under totally different reaction conditions allow differential removal of such protection groups. For example, protecting groups can be removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyl dimethyl silyl are unstable in acid and can be used to protect reactive fractions of carboxy and hydroxy in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, that are unstable at base. Reactive fractions of hydroxy and carboxylic acid can be blocked with base unstable groups such as, without limitation, methyl, ethyl and acetyl in the presence of amines blocked with acid unstable groups such as tert-butyl carbamate or with carbamates that are both stable on base and acid but hydrolytically removable.
[0167] [0167] Reactive fractions of hydroxy and carboxylic acid can also be blocked with hydrolytically removable protecting groups like the benzyl group, while amine groups capable of hydrogen bonding with acids can be blocked with unstable groups on a base like Fmoc. Reactive carboxylic acid fractions can be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups can be blocked with fluoridelabile silyl carbamates.
[0168] [0168] Allyl blocking groups are useful in the presence of acid and base protecting groups since the former are stable and can subsequently be removed by pi-acid or metal catalysts. For example, an allyl blocked carboxylic acid can be deprotected with a palladium (O) catalyzed reaction in the presence of t-butyl carbamate protecting groups unstable in labile acid or amine acetate. Yet another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, this functional group is blocked and cannot react. After being released from the resin, the functional group is available to react.
[0169] [0169] Typical protection / blocking groups include, but are not limited to, the following fractions:
[0170] [0170] Following a long-standing patent law convention, the terms "one", "one" and "o, a" refer to "one or more" when used in this application, including in the claims. Thus, for example, reference to "an individual" includes a plurality of individuals, unless the context is clearly reversed (for example, a plurality of individuals) etc.
[0171] [0171] Throughout this specification and claims, the terms "understand", "understand" and "understanding" are used in a non-exclusive sense, except where the context requires otherwise. Similarly, the term "includes" and its grammatical variants are intended to be non-limiting, so that the citation of items in a list is not to the exclusion of other similar items that can be replaced or added to the listed items.
[0172] [0172] For the purposes of this specification and attached claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, proportions, formats, formulations, parameters,
[0173] [0173] In addition, the term “approximately” when used with respect to one or more numbers or numeric ranges, should be understood as referring to all of those numbers, including all numbers in a range and modifying that range by extending the limits above and below the numerical values exposed. The citation of numeric ranges by periods includes all numbers, for example, whole numbers, including fractions thereof, subsumed within this range (for example, the quotation from 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, for example 1.5, 2.25, 3.75, 4.1 and the like) and any range comprised in that range. EXAMPLES
[0174] [0174] The following Examples have been included to provide guidance for a person of ordinary skill in the art to put into practice modalities representative of the matter currently revealed. In light of the present disclosure and the general level of skill in the technique, those skilled in the art may recognize that the following Examples are intended to be exemplary only and that countless alterations, modifications and alterations can be employed without departing from the scope of the material currently disclosed. The following synthetic descriptions and specific examples are intended for illustrative purposes only, and should not be construed as limiting in any way making the compounds of the disclosure by other methods. Example 1 Experimental procedures 1.1 Synthesis of XY-FAP-01
[0175] [0175] Methyl glycinate (6-hydroxyquinoline-4-carbonyl) (3): 6- Hydroxyquinoline-4-carboxylic acid (1) 210 mg (1.1 mmol), methyl glycinate HCl salt (2) 143 mg (1.1 mmol), HBTU 420 mg (1.1 mmol) and HOBt 170 mg (1.1 mmol) were dissolved in 12 mL of dry DMF. To the solution, 0.77 mL of DIPEA (4.4 mmol) was added. The reaction was stirred at room temperature for 6 h. After the solvent was removed in vacuo, the mixture was loaded into a 25 g C18 cartridge (Silicycle, Canada) and the product was purified with a MeCN / water / TFA gradient (0/100 / 0.1 to 90/10 / 0.1 ). 290 mg of product 3 was obtained as a yellow powder in 76% yield. 1H-NMR (400 MHz, CD3OD): δ 8.69 (s, 1H), 7.94 (d, J
[0176] [0176] Methyl glycinate (6- (3 - ((tert-butoxycarbonyl) amino) propoxy) quinoline-4-carbonyl) (5): Methyl glycinate (6-hydroxyquinoline-4-carbonyl) (3) 360 mg ( 1.0 mmol), tert-butyl carbamate (3-bromopropyl) (4) 500 mg (2.1 mmol) were dissolved in 20 mL DMF. Cs2CO3 1 g (3.0 mmol) was added to the solution and the reaction was stirred at room temperature overnight. After filtration, the solvent was removed in vacuo and the remaining mixture was loaded into a 25 g C18 cartridge (Silicycle, Canada). The product was purified with a MeCN / water / TFA gradient (0/100 / 0.1 to 90/10 / 0.1). 270 mg of product 5 were obtained in a 54% yield. 1H-NMR (400 MHz, CDCl3): δ
[0177] [0177] Tert-butyl carbamate (S) - (3 - ((4 - ((2- (2-cyanopyrrolidin-1-yl) -2-
[0178] [0178] XY-FAP01. Compound 7 (1 mg, 1.7 µmol) was treated with 1 ml of TFA / methylene chloride solution (1/1) for 2 h. The solvent was removed in vacuo and the remaining material redissolved in 0.5 ml of DMSO. To the solution, LICOR800CW-NHS ester 0.5 mg (0.43 µmol) and Et3N 10 µL were added. After 1 h at room temperature, the solvent was removed and the product was purified by HPLC. 0.5 mg of product was obtained in 85% yield. HPLC condition: column
[0179] [0179] 2,2 ', 2 ”-10- (1-Carboxy-4 - ((3 - ((4 - ((2 - ((S) -2-cyanopyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) propyl) amino) -4-oxobutyl) -1,4,7,10- tetraazacyclododecane-1,4,7-triyl) triacetic acid (XY-FAP-02): The Compound 7 (15 mg, 31.3 µmol) was treated with a 1-mL solution of TFA / methylene chloride (1/1) for 1 h. The solvent was removed in vacuo and the remaining material redissolved in 0.5 ml of DMF. To the solution, DIPEA (27 µL, 156.5 µmol) was added, followed by the addition in drops of a solution of DOTA-GA (t-Bu) 4-NHS (25 mg, 31.3 µL) in 0.5 mL of DMF . The reaction mixture was stirred for 4 h at room temperature and then concentrated in vacuo. The t-Bu-protected intermediate was deprotected in situ without further purification using a mixture of 1 ml of TFA, H2O and triethylasilane (TES) (95: 2.5: 2.5). The reaction mixture was then concentrated and purified by semi-prepared HPLC, to provide the product as a white solid (8.5 mg, 33% yield). MS: calculated for [C39H54N9O12] +, 840.9 [M + H] +; found 840.5. HPLC (10 mm x 250 mm Phenomenex Luna C18 column, 10 µm, mobile phase 95/5 / 0.1% at 75/25 / 0.1% water / acetonitrile / TFA for 20 min, flow of 5 mL / min) XY-FAP-02 eluted at 11.8 min.
[0180] [0180] XY-XY-FAP-02- [In]. 113 / 115Indium (III) 2,2 ', 2' '- (10- (1-Carboxy-4 - ((3 - ((4 - ((2- ((S) -2-cyanopyrrolidin-1-yl)) -2-oxoethyl) carbamoyl) quinolin-6-yl) oxy) propyl) amino) -4-oxobutyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (XY-FAP-02 - [In]): At 2 mg (2.4 mol) of XY-FAP-02 in 1 ml of 0.2M AcONa, a solution of 1.4 mg (4.6 mol) of In (NO3) 3 at 0, 5 ml of water is added and heated in a bath at 60 ° C for 30 min. After cooling to room temperature, the mixture was purified by semi-prepared HPLC. The product was obtained as a white solid (1.8 mg, 79% yield). MS: calculated for [C39H51N9O12In] +, 951.7 [M + H] +; found 952.5. HPLC (10 mm x 250 mm Phenomenex Luna C18 column, 10 µm, mobile phase 95/5 / 0.1% at 75/25 / 0.1% water / acetonitrile / TFA for 20 min, flow 5 mL / min) XY-FAP-02- [In] eluted at 14.0 min.
[0181] [0181] 1.3 Radiorrotation methods. Briefly, 20 mg of XY-FAP-02 solution in 20 mL of 0.2 M NaOAc was added to a 10 mL 4.6 mCi 111InCl3 solution (Nordion, Ottawa, Canada) and adjusted to a final pH of 5.5-
[0182] [0182] 1.4 FAP inhibition assay. XY-FAP-01 inhibitory activity was determined using a fluorogenic FAP Assay Kit (BPS Bioscience, San Diego, CA). Briefly, XY-FAP-01, DPP substrate and recombinant FAP were loaded onto a 96-well plate to initiate the enzyme reaction. The reaction was left for 10 minutes at room temperature before fluorescence was measured with a VICTOR3 V multi-label plate reader (PerkinElmer Inc., Waltham, MA). The data were normalized and semi-log inhibition curves were generated to determine the IC50 value (XY-FAP-01 concentration where the enzyme activity is 50% inhibited) for XY-FAP-01 and subsequent enzyme inhibition constant ( Ki) using the Cheng-Prusoff conversion. The generation of semi-log inhibition curves and IC50 values were performed using GraphPad Prism (San Diego, CA).
[0183] [0183] 1.5 Cell lines. Six human cancer cell lines were used to assess the binding of a FAP: glioblastoma (U-87-MG), melanoma (SK-MEL-24), prostate (PC-3), non-small cell lung cancer ( NCI-H2228), colorectal carcinoma (HCT 116), and squamous cell carcinoma of the lung (NCI-H226). From the literature, cell lines U-87-MG, SK-MEL-24, and NCI-H2228 have been identified as having high levels of FAP expression [FAP-positive (+)] whereas PC-3 cells, NCI-H226, and HCT 116 expressed very low levels of FAP [FAP-negative (-)]. These expression profiles were further confirmed by flow cytometry with an anti-FAP antibody conjugated to APC (R&D Systems, Minneapolis, MN) and quantitative real-time PCR. All cell lines were purchased from the American Type Culture Collection (ATCC, Manassas, VA).
[0184] [0184] U-87-MG cells were maintained in MEM (Corning Cellgro,
[0185] [0185] 1.6 Cell absorption studies. All studies of specific binding and cell absorption were performed in triplicate to ensure reproducibility. The cells were detached using 0.05% trypsin (Corning), resuspended in 1 million aliquots of cells in binding buffer and incubated with various concentrations (range, 50 nM to 0.78 nM) of XY-FAP-01 by 1 hour at 37 ° C and 5% CO2. To assess the specific absorption of XY-FAP-02, cells were pre-blocked with a FAP and specific inhibitor of DPP-IV (ValboroPro, MilliporeSigma, Burlington, MA) or a specific inhibitor of DPP-IV (Sitagliptin, Santa Cruz Biotechnology, Inc., Dallas, TX) in various concentrations (range, 10-10 M to 10-4 M) before incubation with 25 nM XY-FAP-02 solution in binding buffer for 1 hour at 37 ° C ° C and 5% CO2. Cell absorption ended by washing the cells with ice-cold PBS (1x) three times. The cells were resuspended in binding buffer and transferred to a 96-well plate for imaging. The images were captured on the LI-COR Pearl Impulse Imager (Lincoln, NE) using an excitation wavelength of 785 nm and detection of the emission wavelength at 800 nm. The images were analyzed using the LI-COR Pearl Impulse Software (Version 2.0) and the fluorescence intensity was run for the background signal and normalized for the well area.
[0186] [0186] Cellular absorption of 111In-XY-FAP-02 has also been evaluated in cells. Aliquots of cells (1 million) were incubated with 1 µCi 111In-XY-FAP-02 in saline solution for 30 minutes at 37 ° C and 5% CO2. The cells were washed three times with cold PBS (1x) and cell pellet activity was measured with the 1282 gamma well counter CompuGamma CS (Pharmacia / LKB Nuclear, Inc., Gaithersburg, MD). The percentage of absorption of the administered activity was calculated by comparison with samples of a standard dose.
[0187] [0187] 1.7 Formation of near-infrared fluorescence of small animal (NIFR). NIRF images were captured on the LI-COR Pearl Impulse Imager using an excitation wavelength of 785 nm and a detection wavelength of 800 nm. Mice used for imaging studies were anesthetized with 3% isofluorane (v / v) and kept in 1.5% isofluorane during the imaging procedure. NOD / SKID mice with tumor xenografts FAP + U-87-MG and FAP-PC-3 were injected with 10 nmol of XY-FAP-01 through injection into the tail vein and images were captured at 30 min, 1 h, 2 h, 2.5 h, and 4 h after tracer injection. The data were displayed and analyzed using the LI-COR Pearl Impulse Software (Version 2.0).
[0188] [0188] 1.8 Small animal SPECT-CT image formation. SPECT-CT studies were performed in NOD / SKID mice with tumor xenografts FAP + U-87-MG and FAP-PC-3. For imaging studies, the mice were anesthetized with 3% isoflurane before being placed in the scanner bed and kept warm with an external light source. Isoflurane levels were decreased to 1.5% for the rest of the imaging procedure. After the mice were injected with 300 µCi 111In-XY-FAP-02 in 200 µL of saline, SPECT-CT imaging was performed using a SPECT Gamma Medica-Ideas scanner equipped with CT (Northridge, CA) at the indicated time (30 min, 2 h, 6 h, and 24 h) after radiotracer injection. A CT scan was performed at the end of each SPECT scan for joint anatomical recording. Data sets obtained were reconstructed using the supplied Gamma Medica-Ideas software and final data visualization and imaging were prepared using Amira® software (FEI, Hillsboro, OR).
[0189] [0189] 1.9 Ex-vivo biodistribution. NOD / SKID mice with tumor xenografts FAP + U-87-MG and FAP-PC-3 were injected with 10 µCi 111In-XY-FAP-02 in 200 µL saline through the tail vein. At 5 min, 30 min, 2 h, 6 h, and 12 h after injection, mice (n = 4) were sacrificed by CO2 asphyxiation and the blood was immediately collected by cardiac puncture. In addition, the heart, lungs, liver, stomach, pancreas, spleen, fat, kidney, small intestine, large intestine, bladder, muscle, femur, FAP + U-87-MG xenograft, and FAP-PC-3 xenograft were collected for biodistribution analysis. Each tissue was weighed and radioactivity was measured using a 2480 Wizard2 automated gamma counter (PerkinElmer, Waltham, MA). Radioactivity measurements were corrected for the decrease and compared with samples from a standard dilution of the initial dose to calculated percentage of injected dose per gram (% ID / g).
[0190] [0190] For blocking studies, mice (n = 5 per group) were injected together with unlabeled XY-FAP-02 (50 µg per mouse) and 10 µCi 111In-XY-FAP-02 in 200 µL of saline . Mice (n = 5) injected with 10 µCi 111In-XY-FAP-02 in 200 µL of saline solution served as a control. At 6 h after injection, mice were sacrificed, tissues were collected and radioactivity was measured with the gamma well counter.
[0191] [0191] 1.10 Data analysis. Data are expressed as mean ± standard deviation (SD). Prism software (GraphPAD, San Diego, CA) was used for analysis and statistical significance was calculated using a two-tailed Student’s t test. A P-value <0.05 was considered significant.
[0192] [0192] 1.11 Xenograft tumor model. Female 6-week-old NOD / SCID mice were injected subcutaneously into the upper left and right flanks with 1 million U87 cells (FAP +) and PC3 cells (FAP-) in RPMI 1640 media supplemented with 1% FBS. The mice were monitored for tumor size and used for optical imaging or SPECT / CT when the tumor size reached around 100 mm3. Example 2 Representative results
[0193] [0193] 2.1 FAP inhibition assay. XY-FAP-01 demonstrated high binding affinity with recombinant human FAP. The enzyme inhibition constant (Ki) for the compound was determined to be 1.26 nM.
[0194] [0194] 2.2 Cell absorption studies. FAP-positive cell lines showed concentration-dependent absorption of XY-FAP-01 whereas FAP-negative cell lines did not show significant XY-FAP-01 binding at all concentrations (see, for example, FIG. 3A) . Saturated binding of XY-FAP-01 was observed at a concentration of 25 nM, which was subsequently used as the base concentration for all binding inhibition studies. When pre-blocked with a specific DPP-IV and FAP inhibitor, XY-FAP-01 binding was significantly inhibited in FAP-positive cells (FIG. 3B). Interestingly, this phenomenon has not been observed in FAP-positive cell lines pre-blocked with a specific DPP-IV inhibitor. These results additionally justify the specificity of XY-FAP-01 for FAP in relation to DPPIV, since the DPPIV block did not result in a change in the binding capacity of XY-FAP-01.
[0195] [0195] Similar specificity was observed, with the radioactive analogue, 111In-XY-FAP-02. Positive FAP cell line, U-87-MG, demonstrated more than 30% absorption of administered radioactive dose after incubation whereas the FAP negative cell line, PC-3, had absorption of 0.01% of administered dose ( FIG 3C). Taken together, these results support the specificity of XY-FAP-01 and 111In-XY-FAP-02 in the involvement of FAP in vitro.
[0196] [0196] 2.3 Ex-vivo biodistribution. Ex-vivo biodistribution of 111In-XY-FAP-02 results correlated with the observed imaging results (figure 4). Initially, blood pool activity is very high, with more than 10%% ID / g in 30 minutes after injection. With clearance of the compound, we see blood pool activity drop significantly after 2 hours of distribution and remained less than 5%% ID / g 2 hours after injection (FIG. 5A). High activity was also observed in the pancreas, small intestines and bladder up to 2 hours after injection. Positive tumor absorption peaked 30 minutes after injection and remained between 13-11%% ID / g up to 6 hours. Tumor elimination was observed 12 hours after injection, with% ID / g falling below 5%. The PC-3, FAP negative xenograft had less than 3.5%% ID / g for all time points.
[0197] [0197] Co-injection of cold compound with 111In-XY-FAP-02 resulted in significant blocking of tracer absorption in U-87 xenografts, with% ID / g falling from 11.20% without blocking versus 0.27% with lock (p <0.0001). In addition, cold compost resulted in% ID / g of all tissues falling significantly, with most values being less than 0.1%. This decrease in absorption is more likely due to the blocking of non-specific tracer binding to non-target tissues and the blocking of specific FAP binding in U-87 xenografts.
[0198] [0198] 2.4 Formation of near-infrared fluorescence of small animal (NIRF). NIRF imaging of XY-FAP-01 demonstrated specific tracer absorption in the U-87-MG xenograft as early as 30 minutes after injection 9 (figure 6). After one hour of distribution, clearance of the tracer through the bladder was observed with retained absorption of the tracer in the positive xenograft FAP. Tracer absorption was retained in the positive xenograft after four hours of distribution. In contrast, no significant absorption of tracer was observed in the FAP negative tumor at all imaging time points. References
[0199] [0199] All publications, patent applications and other references mentioned in the specification are indicative of the level of those skilled in the technique to which the material currently disclosed belongs. All publications, patent applications, patents and other references (eg websites, databases, etc.) mentioned in the specification are hereby incorporated by reference in full to the same extent as if each individual publication, patent application , patent and other reference were specifically and individually indicated to be incorporated by reference. It will be understood that, although a number of patent applications, patents and other references are mentioned here, such reference does not constitute an admission that any such documents are part of the general common knowledge in the art. In the event of a conflict between the specification and any of the incorporated references, the specification (including any amendments thereto, which may be based on an incorporated reference). Meanings of terms accepted in the standard technique are used here unless otherwise indicated. Standard abbreviations for various terms are used in the present invention.
[0200] [0200] Although the above matter has been described in some detail by way of illustration and example for the sake of clarity and understanding, it will be understood by those skilled in the art that certain changes and modifications can be put into practice within the scope of the attached claims.

权利要求:
Claims (27)
[1]
1. Compound CHARACTERIZED by the fact that it presents the formula (I): (I) where: A is a fraction targeting FAP-α; B is any optical or radio-labeled functional group suitable for optical imaging, PET imaging, SPECT imaging, or radiotherapy; and L is a linker having bi-functionalization adapted to form a chemical bond with B and A.
[2]
2. Compound, according to claim 1, CHARACTERIZED by the fact that A is a fraction targeting FAP-α having the structure of: (X '); where each y is independently an integer selected from the group consisting of 0, 1, and 2; R1x, R2x, and R3xʹ, are each independently selected from the group consisting of H, OH, halogen, C1-6alkyl, -O-C1-6alkyl, and -S-C1-6alkyl; R3x is selected from the group consisting of H, -CN, -B (OH) 2, - C (O) alkyl, -C (O) aryl-, -C = CC (O) aryl, -C = CS (O) 2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, and 5-tetrazolyl; R4x is H;
R5x, R6x, and R7x are each independently selected from the group consisting of H, -OH, oxo, halogen, -C1-6alkyl, -O-C1-6alkyl, -S-C1-
6alkyl, -NR8xR9x, -OR12x, -Het2 and -Ar2; each of C1-6alkyl being optionally substituted with 1 to 3 substituents selected from -OH and halogen; R8x, R9x, and R12x are each independently selected from the group consisting of H, -OH, halo, -C1-6alkyl, -O-C1-6alkyl, -S-C1-6alkyl, and -Ar3; R10x, R11x, R13x and R14x are each independently selected from the group consisting of H, -OH, halogen, -C1-6alkyl, -O-C1-6alkyl, and -S-C1-
6alkyl; Ar1, Ar2 and Ar3 are each independently a 5- or 6-membered aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of Ar1, Ar2 and Ar3 being optionally and independently substituted with 1 to 3 substituents selected from - NR10xR11x, -C1-6alkyl, -O-C1-6alkyl, and -S-C1-6alkyl; Het2 is a 5- or 6-membered non-aromatic monocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; Het2 being optionally substituted with 1 to 3 substituents selected from -NR13xR14x, -C1-6alkyl, -O-C1-6alkyl, and -S-C1-6alkyl; v is 0, 1, 2, or 3; and represents an aromatic or non-aromatic mono- or bicyclic heterocycle containing 5-10 N members, the heterocycle optionally further comprising 1, 2 or 3 heteroatoms selected from O, N and S; where it indicates a point of attachment of the FAP-α linker to the linker, L, or the reporter fraction, B, where the point of attachment can be through any of the carbon atoms of the aromatic mono- or bicyclic heterocycle or non-aromatic containing 5 to 10 N members thereof; and stereoisomers and pharmaceutically acceptable salts thereof.
[3]
3. Compound, according to claim 2, CHARACTERIZED by the fact that it is selected from the group consisting of: e; where * indicates the point of attachment of the aromatic or non-aromatic mono- or bicyclic heterocycle containing 5 to 10 N members for - (CH2) v–.
[4]
4. Compound, according to claim 2, CHARACTERIZED by the fact that A is a fraction of targeting to FAP-α having the structure of:
; where it indicates a point of attachment of the FAP-α linker to the linker, L, or the reporter fraction, B, where the point of attachment can be through any of the carbon atoms 5, 6, 7, or 8 the quinolinyl ring thereof; and stereoisomers and pharmaceutically acceptable salts thereof.
[5]
5. Compound according to claim 4, CHARACTERIZED by the fact that A is selected from the group consisting of:; e.
[6]
6. Compound according to claim 5, CHARACTERIZED by the fact that A is selected from the group consisting of:; and; and stereoisomers of it.
[7]
7. Compound according to claim 5, CHARACTERIZED by the fact that A is selected from the group consisting of:
;and .
[8]
8. A compound according to any one of claims 1 to 7, CHARACTERIZED by the fact that L and B are selected from the group consisting of (a), (b), (c), or (d): (a); where: p1, p2, p3 and p4 can be in any order; t is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; p1, p3, and p4 are each independently 0 or 1; p2 is an integer selected from the group consisting of 0, 1, 2, and 3, and when p2 is 2 or 3, each R1 is the same or different; m1 and m2 are each an integer independently selected from the group consisting of 0, 1, 2, 3, 4, 5, and 6; W1 is selected from the group consisting of a bond, –S–, - C (= O) –NR–, and –NR – C (= O) -; W2 is selected from the group consisting of a bond, -S-, -CH2- C (= O) -NR-, –C (O) -, –NRC (O) -, –NR'C (O) NR–, –NRC (S) NR'2–, –NRC (O) O–, –OC (O) NR–, –OC (O) -, –C (O) NR–, –NR – C (O) -, –C (O) O–, - (O – CH2 – CH2) q– and - (CH2-CH2-O) q, where q is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
each R or R 'is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and –OR4, where R4 is selected from the group consisting of H, alkyl , substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl, where q is defined as immediately above; Tz is a triazole group that may be present or absent, and, if present, is selected from the group consisting of and; each R1 is independently H, C1-C6 alkyl, C3-C12 aryl, - (CH2) q-C3-C12 aryl, -C4-C16 alkyl aryl, or - (CH2) q-C4-C16 alkyl aryl; R2 and R3 are each independently H and -CO2R5, where R5 is selected from the group consisting of H, C1-C6 alkyl, C3-C12 aryl, and C4-C16 alkyl aryl, where when one of R2 or R3 is CO2R5, then the other is H; V is selected from the group consisting of –C (O) -, -C (S) -, –NRC (O) -, –NRC (S) -, and –OC (O) -;
(b) where p1, p2, p3, m1, m2, Tz, W2, R, R1, R2, R3, and V are defined as above; (c) -L1-, -L2-L3-, or -L1-L2-L3-, where: L1 is -NR- (CH2) q- [O-CH2-CH2-O] q- (CH2) qC (= O) -; L2 is -NR- (CH2) q-C (COOR5) -NR-; and L3 is - (O =) C- (CH2) q-C (= O) -;
where each q is independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; and R and R5 are as defined above; (d) B- (CR6H) q- (CH2) q-C (= O) -NR- (CH2) q-O- or B-NR- (CH2) q-O-; where each q and R is defined above; and R6 is H or –COOR5; and B is any optical or radio-labeled functional group suitable for optical imaging, PET imaging, SPECT imaging, or radiotherapy; and stereoisomers and pharmaceutically acceptable salts thereof.
[9]
9. Composed according to any one of claims 1-8, CHARACTERIZED by the fact that L is selected from the group consisting of:; and where u is an integer selected from 1, 2, 3, 4, 5, 6, 7, and 8; and R and R5 are as defined above.
[10]
A compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that B is a radio-labeled prosthetic group comprising a radioisotope selected from the group consisting of 18F, 124I, 125I, 131I, and 211At.
[11]
11. Compound according to claim 10, CHARACTERIZED by the fact that the radio-labeled prosthetic group is selected from the group consisting of:; and each X is independently a radioisotope selected from the group consisting of 18F, 124I, 125I, 131I, and 211At; each R and R 'is defined above; and each n is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, and 20.
[12]
12. Compound according to claim 11, CHARACTERIZED by the fact that the radio-labeled prosthetic group is selected from the group consisting of:
;and .
[13]
13. A compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that B comprises a chelating agent.
[14]
14. Compound. according to claim 13, CHARACTERIZED by the fact that the chelating agent is selected from the group consisting of:; ; ; ; ; ; ; ; ;
; ; ;
; ; ;
; ; ;
; ;
; ;
; ;
; ; ; ; ; ; , ,and .
[15]
A compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that B comprises an optical dye.
[16]
16. A compound according to claim 15, CHARACTERIZED by the fact that the optical dye comprises a fluorescent dye.
[17]
17. Compound according to claim 16, CHARACTERIZED by the fact that the fluorescent dye is selected from the group consisting of carbocyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine and merocyanine, polymethin, coumarin, rhodamine, xanthene, fluorescein, boro-dipyrromethane (BODIPYromromethane) ), Cy5, Cy5.5, Cy7, VivoTag-680, VivoTag-S680,
VivoTag-S750, AlexaFluor660, AlexaFluor680, AlexaFluor700, AlexaFluor750, AlexaFluor790, Dy677, Dy676, Dy682, Dy752, Dy780, DyLight547, Dylight647, IRLyte Fluor 647, IRLYte, 800, HiLyte Fluor 647, HiLyte Fluor , ADS830WS, and ADS832WS.
[18]
18. A compound according to claim 15, CHARACTERIZED by the fact that the optical dye is selected from the group consisting of:; ; ; ;
; ;
; ;
;
; ; and
.
[19]
19. The compound according to any one of claims 1 to 9, CHARACTERIZED by the fact that the compound is selected from the group consisting of: e.
[20]
20. Compound according to claim 19, CHARACTERIZED by the fact that the compound is selected from the group consisting of: e.
[21]
21. Pharmaceutical composition CHARACTERIZED by the fact that it comprises the compound as defined in any of claims 1 to 20.
[22]
22. Composition according to claim 21, CHARACTERIZED by the fact that it further comprises one or more pharmaceutically acceptable vehicles, diluents, excipients or adjuvants.
[23]
23. Method for imaging a disorder or disease associated with fibroblast activating α-protein (FAP-α), the method being CHARACTERIZED by the fact that it comprises administering a compound as defined in any of claims 1 to 20 or a pharmaceutical composition as defined in claim 21 to an individual, wherein the compound of formula (I) comprises an optical or radio-labeled functional group suitable for optical imaging, PET imaging, or SPECT imaging; and obtaining an image.
[24]
24. Method for inhibiting fibroblast activation α-protein (FAP-α), the method being CHARACTERIZED in that it comprises administering to an individual needing an effective amount of a compound as defined in any one of claims 1 to 20 or a pharmaceutical composition as defined in claim 21.
[25]
25.Method to treat a disorder or disease related to fibroblast-activating protein-α (FAP-α), the method being CHARACTERIZED in that it comprises administering to an individual in need of treatment an effective amount of a compound as defined in any one of claims 1 to 20 or a pharmaceutical composition as defined in claim 21, wherein the compound of formula (I) comprises a radiolabeled functional group suitable for radiotherapy.
[26]
26.Method, according to claim 25, CHARACTERIZED by the fact that the disorder or disease related to (FAP-α) is selected from the group consisting of a proliferative disease; diseases characterized by tissue remodeling and / or chronic inflammation, disorders involving endocrinological dysfunction; and blood clotting disorders.
[27]
27. Method, according to claim 26, CHARACTERIZED by the fact that the proliferative disease is selected from the group consisting of breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer , melanoma, fibrosarcoma, connective tissue and bone sarcomas, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma and adenocarcinoma.

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