Novel 5H-pyrrolo[3,2-b:5,4-c']dipyridine derivatives and 6,7,8,9-tetrahydro-5H-pyrrolo[3,2-b:5,4-c']dipyridines useful in cancer treatment.

Abstract

The present invention relates to either a compound of formula (I) or a pharmaceutically acceptable salt thereof. [Formula 1] JPEG2026517912000095.jpg53170 Here, R1 represents a halogen atom, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C2-C6) alkenyl group, a (C1-C6) alkoxy group, or a (C3-C6) cycloalkoxy group; X and Y independently represent a -CH= group, a -CR3= group, or a -N= group; Z1 and Z2 independently represent a -CH2- group, a =CH- group, or a =N- group; and R3 and R4 independently represent a hydrogen atom or a halogen atom. The present invention relates to such compounds for use as pharmaceuticals, in particular to cancers, in particular cancers exhibiting the mobilization of MDM2 to chromatin, more particularly cancers selected from the group consisting of bone cancer, brain cancer, ovarian cancer, breast cancer, lung cancer, colorectal cancer, osteosarcoma, skin cancer, hematological cancers including acute myeloid leukemia, pancreatic cancer, prostate cancer, and liposarcoma, and even more particularly cancers selected from the group consisting of skin cancer and hematological cancers, for example, cancers including but not limited to acute myeloid leukemia, melanoma, and liposarcoma.

Description

[Technical Field]

[0001] The present invention relates to 5H-pyrrolo[3,2-b:5,4-c']dipyridine derivatives and 6,7,8,9-tetrahydro-5H-pyrrolo[3,2-b:5,4-c']dipyridine derivatives, which are effective for treating and / or preventing cancer, in particular cancer that expresses chromatin-bound MDM2 (C-MDM2 cancer), or cancer that exhibits recruitment of MDM2 to chromatin and becomes C-MDM2. [Background technology]

[0002] Cancer is a group of diseases characterized by the development of abnormal cells that divide uncontrollably and invade and destroy normal body tissues. Cancer is the second leading cause of death worldwide. Numerous treatments have been developed to address various cancerous diseases. However, sometimes cancer cells can overcome the effectiveness of anti-cancer therapies. Therefore, it is important to specifically investigate and target the mechanisms of cancer to provide novel and more effective treatments.

[0003] Several cancers are caused and / or enhanced by alterations in the properties of the mouse double minute 2 (MDM2) oncoprotein. MDM2 is recognized as an essential component of the tumor suppressor p53 pathway and is frequently overexpressed in the cytoplasm of several types of human cancer (Biderman et al., 2012, Wade et al., 2013). Recently, it has been demonstrated that MDM2 also possesses p53-independent activity, meaning it can be recruited to chromatin independently of p53 and modulate transcriptional programs involved in amino acid metabolism, more particularly serine and glycine metabolism (Riscal et al. Mol Cell. 2016 Jun 16;62(6):890~902). In other words, "chromatin-bound MDM2," or "C-MDM2," may be involved in significant changes in cancer cell metabolism and thus in many cancers. C-MDM2, independently of p53, regulates serine / glycine metabolism and maintains cancer growth. Serine / glycine metabolism supports cancer cell proliferation by contributing to the anabolic demands of cancer cells and by regulating their redox state (Locasale JW. Nat Rev Cancer. 2013 Aug;13(8):572~83) and nucleotide synthesis (Cisse et al., Sci Transl Med. 2020 Jun 10;12(547)). To date, cancer treatment has been primarily studied by specifically inhibiting the function of MDM2 as a negative regulator of p53 using inhibitors of the MDM2-p53 interaction in the cytoplasmic compartment of cancer cells. However, these p53-dependent therapies are not entirely effective and induce toxicity in treated patients. In particular, to date, most MDM2 inhibitors designed to inhibit MDM2-p53 binding have had little or no effect on advanced cancers with mutant or deficient p53.

[0004] Cancers that express MDM2 (C-MDM2), or that exhibit MDM2 recruitment to chromatin and become C-MDM2, such as breast cancer and liposarcoma (LPS), are complex types of cancer, and treating or preventing them remains extremely important.

[0005] International Publication WO2023 / 012343 describes interleukin-6 (IL-6) signaling inhibitors selected from IL-6 inhibitors, IL-6 receptor inhibitors, IL-6 / IL-6 receptor complex inhibitors, gp130 inhibitors, and STAT3 inhibitors for use in methods for treating and / or preventing cancers exhibiting MDM2 mobilization to chromatin in patients requiring treatment and / or prevention of such cancers.

[0006] International Publication No. WO2016 / 049453 describes a pyrido[b]indole derivative, namely compound SP-141, which has the following structural formula and is useful in the treatment of cancer, and more particularly in the suppression of cancer growth, as described in Wang et al. Gastroenterology. “Identification of a New Class of MDM2 Inhibitor That Inhibits Growth of Orthotopic Pancreatic Tumors in Mice” 2014 October;147(4):893~902. [ka] In previous literature, no other compound besides SP-141 has been identified that can exhibit anticancer activity in p53 wild-type, p53 mutant, and p53-deficient cancer cells. Compound SP-141 was not developed as a candidate drug in clinical trials. This is thought to be due to its unfavorable drug development profile. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] Therefore, there remains a need to identify novel compounds exhibiting C-MDM2 expression inhibitory activity for use in the treatment and / or prevention of cancer, particularly cancers that exhibit MDM2 recruitment to chromatin, and more particularly, but not limited to, liposarcoma, melanoma, and acute myeloid leukemia. There also remains a need to identify novel compounds exhibiting C-MDM2 expression inhibitory activity that is independent of p53 status and further minimizes host toxicity. There also remains a need to identify novel compounds exhibiting C-MDM2 expression inhibitory activity useful for suppressing cancer growth and / or treating metastatic cancer. Furthermore, there remains a need to identify novel compounds that selectively bind to the C-MDM2 protein, induce its autoubiquitination, and result in its proteasomal degradation. There remains a need to establish novel pharmaceutical compositions and methods for the treatment and / or prevention of cancers expressing C-MDM2, particularly, but not limited to, liposarcoma, melanoma, and acute myeloid leukemia. Furthermore, there is a need to provide novel treatment methods that demonstrate the ability to induce cancer cell death far more potently than known methods against cancer cells expressing C-MDM2, particularly, but not limited to, liposarcoma, melanoma, and acute myeloid leukemia.

[0008] The present invention aims to satisfy all or part of these needs. [Means for solving the problem]

[0009] Compounds defined by the following formula (I) have been found to be useful in the treatment and / or prevention of cancer, particularly cancers exhibiting chromatin-bound MDM2 (C-MDM2), or cancers exhibiting mobilization of MDM2 to chromatin and becoming C-MDM2, more particularly liposarcoma, melanoma, and acute myeloid leukemia.

[0010] Therefore, compounds of formula (I) as defined below are provided herein.

[0011] (i) A pharmaceutical composition comprising at least a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier is provided herein.

[0012] Compounds of formula (I) as defined below, or pharmaceutically acceptable salts thereof, are provided herein for use as pharmaceuticals.

[0013] The present invention further relates to compounds of formula (I) as defined below for use in the treatment and / or prevention of cancer, particularly cancers exhibiting chromatin-bound MDM2 (C-MDM2) or mobilization of MDM2 to chromatin, more particularly cancers selected from the group consisting of bone cancer, brain cancer, ovarian cancer, breast cancer, lung cancer, colorectal cancer, osteosarcoma, skin cancer, hematological cancers including acute myeloid leukemia, pancreatic cancer, prostate cancer and liposarcoma, and even more particularly cancers selected from the group consisting of skin cancer, liposarcoma and hematological cancer, for example, but not limited to liposarcoma, melanoma and acute myeloid leukemia.

[0014] The present invention further relates to a method for treating and / or preventing cancer, particularly cancer exhibiting chromatin-bound MDM2 (C-MDM2) or cancer exhibiting mobilization of MDM2 to chromatin, more particularly liposarcoma, melanoma and acute myeloid leukemia, comprising the step of administering to a patient in need of treatment and / or prevention of cancer, particularly cancer exhibiting chromatin-bound MDM2 (C-MDM2) or cancer exhibiting mobilization of MDM2 to chromatin, more particularly liposarcoma, melanoma and acute myeloid leukemia, a compound of formula (I) as defined below, or a pharmaceutical composition containing the same.

[0015] The present disclosure relates to a method of treating and / or preventing cancer in a patient who needs to treat and / or prevent cancer, wherein the patient has been pre-classified as suffering from a cancer that expresses chromatin-binding MDM2 or C-MDM2, or a cancer that exhibits mobilization of MDM2 to chromatin, and the method comprises at least administering to the patient a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0016] The present disclosure also relates to a method of treating and / or preventing cancer in a patient who needs to treat and / or prevent cancer, the method comprising a) determining the eligibility of the patient to receive the treatment and / or prevention by detecting mobilization of MDM2 to chromatin in a biological sample previously obtained from the patient, and b) administering to the patient a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof when mobilization of MDM2 to chromatin is detected in step a). The present disclosure relates to the above method comprising the steps.

[0017] The present disclosure relates to a method of treating and / or preventing cancer in a patient who needs to treat and / or prevent cancer, the method comprising a) determining the eligibility of the patient to receive the treatment and / or prevention by detecting mobilization of MDM2 to chromatin in a biological sample previously obtained from the patient, and b) administering to the patient at least a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof when the patient is classified as suffering from a cancer that exhibits mobilization of MDM2 to chromatin in step a). The present disclosure relates to the above method comprising the steps.

[0018] According to another embodiment, the disclosure also relates to a pharmaceutical composition for use in a method of treating and / or preventing cancer in a subject requiring a method of treating and / or preventing cancer that exhibits the recruitment of MDM2 to chromatin, comprising (i) at least a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier.

[0019] According to another embodiment, the Disclosure also relates to a pharmaceutical composition for use in a method of treating and / or preventing cancer in a patient who is in need of treating and / or preventing cancer, comprising (i) at least a compound of formula (I) as defined herein after or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, wherein the patient is pre-classified as having cancer having the mobilization of MDM2 to chromatin.

[0020] According to another embodiment, the disclosure also relates to an in vitro method for determining whether a subject has cancer that exhibits the recruitment of MDM2 to chromatin, To determine whether MDM2 is localized in the nuclei of cancer cells in biological samples obtained from the subject. Includes, If MDM2 is localized within the nuclei of cancer cells in the biological sample, it indicates that the subject is infected with cancer that shows the recruitment of MDM2 to chromatin. Regarding the in vitro method described above.

[0021] definition

[0022] As used herein, the term “patient” means either an animal, for example, a valuable animal for breeding, mating or preservation purposes, or preferably a human or human child who is suffering from or is likely to suffer from one or more of the diseases and conditions described herein.

[0023] In particular, as used in this application, the term "patient" refers to mammals, such as rodents, cats, dogs, primates, or humans, and preferably the patient is a human, and also extends to birds.

[0024] Identifying patients who require treatment for the diseases and conditions described herein is within the scope of the skills and knowledge of those skilled in the art. Veterinarians or physicians skilled in the art can easily identify patients who require such treatment by using clinical examinations, physical examinations, medical / family history, or biological and diagnostic tests.

[0025] In the context of the present invention, as used herein, the words “to treat” or “treatment” mean to reverse, alleviate, inhibit the progression of, or prevent the medical condition of a patient suffering from a disease described herein, particularly the disease described in the “Pathological Conditions” paragraph.

[0026] As used herein, “effective amount” means the amount of the compound of the present invention that is effective in preventing, mitigating, eliminating, treating, or controlling the diseases and conditions described herein. The term “control” is intended to mean all processes that may slow, interrupt, stop, or halt the progression of the diseases and conditions described herein, but is not necessarily intended to mean the complete elimination of the symptoms of all diseases and conditions, and is intended to include preventive measures.

[0027] The term "effective dose" includes both "preventive effective dose" and "treatment effective dose."

[0028] As used herein, the terms “prevention” or “to prevent” relating to disease or illness are in relation to preventive measures for the disease described herein. Prevention may include, but is not limited to, preventing or delaying the onset or progression of the diseases described herein, and / or maintaining one or more symptoms of the diseases described herein below a desired level or pathological level. The term “prevention” does not require the 100% elimination of the possibility or probability of the event occurring. Rather, it indicates that the probability of the event occurring is reduced in the presence of the composition or method described herein. More specifically, “prevention” or “preventing” means a reduction in the risk of developing cancer or symptoms in a patient. As stated above, prevention may be complete, i.e., the symptoms or disease may not be detectable, or it may be partial, resulting in fewer symptoms and less severe disease than if no treatment were performed.

[0029] The term "preventive effective dose" refers to the concentration of the compound of the present invention that is effective in suppressing, preventing, or reducing the probability of occurrence of the diseases described herein.

[0030] Similarly, the term "effective treatment dose" refers to the concentration of a compound that is effective in treating the diseases described herein.

[0031] Where used herein, “pharmaceutically acceptable” or “pharmaceutically acceptable” means, as necessary, molecular entities and compositions that do not cause adverse reactions, allergic reactions or other undesirable reactions when administered to mammals, particularly humans. pharmaceutically acceptable carriers or additives mean any kind of non-toxic, solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or formulation aids. Examples of pharmaceutically acceptable carriers include sterile water, sugars, e.g., sucrose or saccharose, starch, sugar alcohols, e.g., sorbitol, polymers, e.g., PVP or PEG, lubricants, e.g., magnesium stearate, preservatives, colorants, or fragrances.

[0032] The term "MDM2" has its general meaning in the art and refers to mouse double minute 2 oncoprotein. The term "MDM2" also refers to the E3 ubiquitin-protein ligase with UniProtKB access number Q00987.

[0033] The term "C-MDM2 expression inhibitor" refers to a compound that selectively binds to the chromatin-binding MDM2 protein or the C-MDM2 protein and induces its autoubiquitination and proteasomal degradation. As used herein, "selectively binds to the C-MDM2 protein" refers to a compound that preferentially binds to the C-MDM2 protein over other ubiquitin-protein ligases, related enzymes, or related transporters. Compounds that inhibit or inactivate the chromatin function of MDM2 may also downregulate enzymes associated with other members of the PHGDH, PSAT, PSPH, or SLC1 family proteins, which are downstream regulated elements of C-MDM2, and are therefore the subject of this invention.

[0034] In the context of this disclosure, "cancer exhibiting recruitment of MDM2 to chromatin" means that MDM2 is localized within the cell nucleus.

[0035] In the following description, the terms "cancer expressing chromatin-bound MDM2" and "cancer exhibiting recruitment of MDM2 to chromatin" are considered equivalent terms.

[0036] Finally, the term "cancer becoming C-MDM2" refers to cancer that does not spontaneously express chromatin-bound MDM2 (C-MDM2) before any treatment, but expresses C-MDM2 after treatment, for example, after one or more treatment cycles of radiotherapy, chemotherapy, and / or immunotherapy. [Modes for carrying out the invention]

[0037] The inventors have discovered that the compound of formula (I) below has the activity to inhibit the expression and degradation of C-MDM2.

[0038] A compound of formula (I) below, or any pharmaceutically acceptable salt thereof, is provided herein: [ka] Here, R1 represents a halogen atom, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C2-C6) alkenyl group, a (C1-C6) alkoxy group, or a (C3-C6) cycloalkoxy group, where one or two -CH2- groups present in the group may be substituted with -O-, -S-, or -NH-, and where the group may be substituted with one or two hydroxyl groups or (C1-C6) alkoxy groups. X and Y independently represent -CH= group, -CR3= group, or -N= group. Z1 and Z2 independently represent a -CH2- group, an =CH- group, or an =N- group. R3 and R4 independently represent a hydrogen atom or a halogen atom. JPEG2026517912000004.jpg14170 independently represents single or double bonds, and also, R2 is If JPEG2026517912000005.jpg13170 is a double bond, it does not exist, and, If JPEG2026517912000006.jpg13170 is a double bond, it represents a hydrogen atom, and, Here, If JPEG2026517912000007.jpg14170 represents a single bond, then both Z1 and Z2 represent a -CH2- group.

[0039] As shown in the examples, the degradation of MDM2 was evaluated in cancer cells that showed or did not show mobilization of MDM2 to chromatin after treatment with the compounds of the present invention (in the presence of IB111,C-MDM2, or in the absence of hPac / ZR75.1,C-MDM2). Cell viability after treatment with the compounds of the present invention was also evaluated. Finally, the specific antitumor effect against liposarcoma was demonstrated through in vivo evaluation in mice transplanted with liposarcoma cells IB111.

[0040] Furthermore, it has been observed that the compound of formula (I) of the present invention exhibits very interesting development potential properties. In particular, the solubility of the compound of formula (I) of the present invention was evaluated and is considered to be suitable in accordance with pharmacopoeia standards.

[0041] In the context of this invention, the following terms are defined as follows: - "Halogen atom" means a chlorine atom, fluorine atom, bromine atom, or iodine atom, and more specifically, a chlorine atom, fluorine atom, or bromine atom, and more specifically, a fluorine atom or a chlorine atom. - "(C1-C6) alkyl" as used herein refers to a linear or branched saturated hydrocarbon aliphatic group comprising 1 to 6 carbon atoms, particularly (C1-C3) alkyl or (C1-C5) alkyl. Examples include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, butyl, and pentyl. - When used herein, "(C2~C6) alkene group" refers to a linear or branched unsaturated or partially unsaturated aliphatic group containing one or more conjugated or unconjugated double bonds and containing 2 to 6 carbon atoms. - "(C3~C6) cycloalkyl" as used herein refers to cyclic saturated hydrocarbons containing 3 to 6 carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. - "(C1~C6) alkoxy" as used herein refers to an O-(C1~C6) alkyl residue where the alkyl is as defined above. Examples include, but are not limited to, methoxy, ethoxy, 1-propoxy, 2-propoxy, and butoxy, and, - "(C3~C6) cycloalkoxy" as used herein refers to an O-(C3~C6) cycloalkyl residue. Examples include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0042] The compounds of the present invention may exist in the form of a free base or as an addition salt with a pharmaceutically acceptable acid.

[0043] As used herein, the term “pharmaceutically acceptable salt” means a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which are incorporated herein by reference. pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts include salts of amino groups formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; or salts of amino groups formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; or salts of amino groups formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptone, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxyethane. This includes sulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malons, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectins, persulfates, 3-phenylpropionates, pivaphosphates, propions, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valersates, etc.

[0044] Physiologically acceptable and suitable acid addition salts of the compound of formula (I) include hydrobromide, tartrate, citrate, trifluoroacetate, ascorbate, hydrochloride, triflate, maleate, mesylate, formate, acetate, and fumarate.

[0045] The compound of formula (I) and / or salt thereof may form solvates or hydrates, and the present invention encompasses all such solvates and hydrates.

[0046] The terms "hydrate" and "solvate" simply mean that compound (I) according to the present invention may be in the form of a hydrate or solvate, i.e., a form bonded or associated with one or more water molecules or solvent molecules. This is merely a chemical property of such compounds and can be applied to all organic compounds of this kind.

[0047] Compounds of formula (I) may contain one or more chiral carbon atoms. Therefore, they may exist in the form of enantiomers or diastereomers. These enantiomers, diastereomers, and mixtures thereof (including racemic mixtures) are included within the scope of the present invention.

[0048] The compound of formula (I) and any of the compounds (1) to (17) defined herein may be in amorphous or crystalline form, and they are also included within the scope of the present invention.

[0049] In one embodiment, R1 represents a halogen atom, a (C1-C4) alkyl group, a (C1-C4) alkoxy group, or a (C3-C5) cycloalkoxy group, where the group may be substituted with one or two hydroxyl groups or (C1-C2) alkoxy groups, and more particularly, R1 represents a halogen atom, a (C1-C4) alkoxy group, or a (C3-C5) cycloalkoxy group, and more particularly, R1 represents a chlorine atom, a methoxy group, or a cyclopropoxy group.

[0050] In one embodiment, (a) X, Y, Z1 and Z2 simultaneously represent a -CH= group, Both in JPEG2026517912000008.jpg14170 represent a double bond, and in particular, R4 is either a hydrogen atom or a fluorine atom. (b) X and Z2 simultaneously represent a -CH= group, and Y and Z1 represent an =N- group, Both JPEG2026517912000009.jpg14170 represent a double bond, and in particular, R4 is a hydrogen atom. (c) Y, Z1 and Z2 simultaneously represent an =N- group, and X represents a -CH= group. Both JPEG2026517912000010.jpg14170 represent a double bond, and in particular, R4 is a hydrogen atom. (d) X, Y and Z2 simultaneously represent a -CH= group, and Z1 represents an =N- group or a -CF= group. Both JPEG2026517912000011.jpg14170 represent double bonds, and in particular, R4 is a hydrogen atom. (e) X, Z1 and Z2 simultaneously represent a -CH= group, and Y represents an =N- group or a -CF= group, Both JPEG2026517912000012.jpg14170 represent a double bond, and in particular, R4 is a hydrogen atom. (f) Y, Z1 and Z2 simultaneously represent a -CH= group, and X represents an =N- group. Both JPEG2026517912000013.jpg14170 represent a double bond, and in particular, R4 is a hydrogen atom. (g) X, Y, and Z1 simultaneously represent a -CH= group, and Z2 represents an =N- group or a -CF= group. Both JPEG2026517912000014.jpg14170 represent a double bond, and in particular, R4 is a hydrogen atom, or (h)X and Y simultaneously represent a -CH= group, and Z1 and Z2 represent a -CH2- group, Both JPEG2026517912000015.jpg14170 represent single bonds, and in particular, R4 is a hydrogen atom.

[0051] In the above options (a) to (h), R4 can be a hydrogen atom or a fluorine atom, and in particular in options (b) to (h), it is a hydrogen atom. In one embodiment, X, Y, Z1 and Z2 are simultaneously -CH= groups, Both R1 and R1 in JPEG2026517912000016.jpg14170 represent a double bond, R4 is a hydrogen atom, and R1 represents a halogen atom, a (C1-C4) alkoxy group, or a (C3-C5) cycloalkoxy group, more particularly, a chlorine atom, a methoxy group, or a cyclopropoxy group. The compounds of formula (I) or pharmaceutically acceptable salts thereof, such as their hydrochloride salts, are provided herein.

[0052] In one embodiment, Both JPEG2026517912000017.jpg15170 represent a double bond, and R2 is absent, or Both elements in JPEG2026517912000018.jpg15170 represent a single bond, and R2 is a hydrogen atom.

[0053] In another embodiment, R1 represents a methoxy group.

[0054] In another embodiment, R1 represents a chlorine atom.

[0055] In another embodiment, R1 represents a cyclopropoxy group.

[0056] In another embodiment, the halogen atom is a chlorine atom or a fluorine atom.

[0057] In another embodiment, R3 represents a hydrogen atom.

[0058] In another embodiment, R3 represents a fluorine atom.

[0059] In another embodiment, R4 represents a hydrogen atom.

[0060] In another embodiment, R4 represents a fluorine atom.

[0061] In another embodiment, Both JPEG2026517912000019.jpg15170 represent a double bond, R2 is absent, X is a -CH= group, and also, (i) JPEG2026517912000020.jpg14170 represents a double bond, and Y, Z1 and Z2 are simultaneously -CH= groups, or simultaneously -N= groups, or (ii) JPEG2026517912000021.jpg14170 represents a single bond, and is a -CH= group, and Z1 and Z2 are simultaneously -CH2- groups.

[0062] In another embodiment, the pharmaceutically acceptable salts of the compound according to the present invention are selected from hydrochloride, phosphate, oxalate, and citrate salts.

[0063] According to a particular embodiment of the present invention, the compound of formula (I) is selected from the following: (1) 2-Methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (2) 2-Methoxy-6-(1,5-naphthyridine-4-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (3) 2-Methoxy-6-(pyrido[2,3-b]pyrazine-8-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (4) 2-Methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride, (5) 2-Methoxy-6-(quinoline-8-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (6) 2-Methoxy-6-(quinoline-4-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (7)6-(isoquinoline-1-yl)-2-methoxy-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (8) 2-Methoxy-6-(quinoline-5-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (9) 2-Methoxy-6-(naphthalene-1-yl)-6,7,8,9-tetrahydro-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (10) 2-Methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine fumarate, (11) 2-Methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine 2-hydroxypropane-1,2,3-tricarboxylate, (12) 2-Methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine phosphate, (13) 2-Methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine sulfate, (14) 2-Methoxy-6-(5,6,7,8-tetrahydronaphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (15)6-(4-fluoronaphthalene-1-yl)-2-methoxy-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (16) 2-Methoxy-6-(5,6,7,8-tetrahydronaphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride, (17) 6-(4-fluoronaphthalene-1-yl)-2-methoxy-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride, (18) 2-chloro-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (19) 2-chloro-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride, (20)6-(3-fluoronaphthalene-1-yl)-2-methoxy-5H-pyrrolo[3,2-b:5,4- c'] Dipyridine hydrochloride, (21)6-(5-fluoronaphthalene-1-yl)-2-methoxy-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (22) 6-(5-fluoronaphthalene-1-yl)-2-methoxy-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride, (23) 6-(8-fluoronaphthalene-1-yl)-2-methoxy-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride, (24) 2-Cyclopropoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine, (25) 2-Cyclopropoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride, and their pharmaceutically acceptable salts.

[0064] Another embodiment is a compound selected from the above list or a pharmaceutically acceptable salt thereof for use as a pharmaceutical, particularly as a C-MDM2 expression inhibitor.

[0065] Another embodiment is a compound selected from the above list, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, particularly cancers expressing C-MDM2, more particularly cancers selected from the group consisting of bone cancer, brain cancer, ovarian cancer, breast cancer, lung cancer, colorectal cancer, osteosarcoma, skin cancer, hematological cancers including acute myeloid leukemia, pancreatic cancer, prostate cancer, and liposarcoma, and even more particularly cancers selected from the group consisting of skin cancer, liposarcoma, and hematological cancers, for example, cancers including but not limited to liposarcoma, melanoma, and acute myeloid leukemia.

[0066] The compounds of the present invention can be prepared by conventional organic synthesis methods practiced by those skilled in the art. The general reaction sequences outlined below represent general methods useful for preparing the compounds of the present invention and do not imply any limitation of their scope or usefulness. [ka]

[0067] In schemes 1, 2, and 3, each compound of formula (Ia) and (Ib) is included in formula (I), and the compound of formula (Ia) (where, Both JPEG2026517912000023.jpg15170 represent single joins, while, JPEG2026517912000024.jpg14170 independently represents a single bond or a double bond), and the compound of formula (Ib) (where, Both in JPEG2026517912000025.jpg15170 represent a double bond, while, JPEG2026517912000026.jpg14170 independently corresponds to a single bond or a double bond.

[0068] According to Scheme 1, here R1, R4, Z1, Z2, X, Y, JPEG2026517912000027.jpg14170 is as defined above, and the compound of formula (IX) can be converted to the compound of formula (VIII) under acetylation conditions in step 1. Under an inert atmosphere, for example under an argon atmosphere, the compound of formula (IX) and a base (e.g., triethylamine or pyridine) can be cooled to a temperature of -10 to 10°C, particularly 0°C, in a polar solvent (e.g., DCM, ethyl acetate, diethyl ether, tetrahydrofuran or acetone). A reagent (e.g., Ac2O or acetyl chloride) can be added dropwise. After addition, the mixture is heated under reflux for several hours (preferably 2 hours) and then cooled to room temperature. A saturated salt solution (e.g., Na2CO3, NaHCO3, KOH or NaOH) is added to neutralize the mixture and then phase separation occurs.

[0069] The compound of formula (VII) can be converted to the compound of formula (VI) in step 2 under diazotization and reduction conditions. To a cold solution (e.g., 0°C) of the compound of formula (VII) in an acidic solution (e.g., aqueous solution of HCl, HBr, or H2SO4), a solution of a nitrite source (e.g., sodium nitrite or ammonium nitrite in water) may be slowly added. The mixture is then stirred for approximately 30 minutes, and a solution of stannous chloride dihydrate in hydrochloric acid or sodium sulfite in water may be gradually added. The mixture is then stirred at cold temperatures for a further 2 hours, and then alkalized to pH=12 using, for example, a solution of KOH or NaOH.

[0070] Compounds of formulas (VIII) and (VI) may be reacted under Fischer reaction conditions in step 3 to obtain compound (V). To a solution of compound (VIII) in an aqueous acid solution (e.g., in an aqueous solution of H2SO4, HCl, or acetic acid), 1.0 equivalent of compound (VI) may be added. This mixture may be heated under reflux for 2-3 hours, preferably 2.30 hours, and then cooled to room temperature. A saturated salt solution (e.g., Na2CO3, NaHCO3, KOH, or NaOH) may be added to neutralize the mixture, and the organic phase may be extracted and combined.

[0071] The compound of formula (V) may be converted to the compound of formula (III) under deprotection conditions in step 4. A solution of the compound of formula (V) in an aqueous acidic solution (e.g., in an aqueous solution of H2SO4 or HCl) may be refluxed for several hours, preferably 16 hours, and then cooled to room temperature. A salt solution (e.g., a salt solution of NaOH, Na2CO3, NaHCO3, or KOH) may be added to neutralize the mixture until the pH reaches 9-10, and the organic phase may be extracted and combined.

[0072] Depending on the radical portion of the compound of formula (IV), the final reaction can be carried out in one, two, or three steps, regardless of whether a microwave reactor is used.

[0073] The compound of formula (III) can be converted to the compound of formula (II) in step 5 by reacting the compound of formula (III) with the compound of formula (IV) under condensation conditions. Under an inert gas atmosphere, for example, an argon atmosphere, the compound of formula (III) can be dissolved together with an aldehyde (e.g., naphthaldehyde) in an organic solvent (preferably an aprotic polar solvent, such as DCM, tetrahydrofuran, or diethyl ether). A drying agent (e.g., anhydrous sodium sulfate, anhydrous magnesium sulfate, or molecular sieve) may be added to the mixture, and the mixture may then be stirred at room temperature for several hours (e.g., 16 hours), then filtered, and then concentrated under reduced pressure.

[0074] The compound of formula (II) is obtained in step 6 under Piquet-Spengler conditions, formula (Ia) (where, Both JPEG2026517912000028.jpg15170 represent single bonds, and R2 is a hydrogen atom. These Pictet-Spengler conditions may be those described in particular in Molecules 2020, 25(2), 414 (https: / / doi.org / 10.3390 / molecules25020414) or in Current Pharmaceutical Design, 2016, 22, 1808-1850 (https: / / doi.org / 10.2174 / 1381612822666151231100247).

[0075] A catalyst (e.g., AlCl3 or BF3Et2) was added to a solution of the compound of formula (II) in a dry organic solvent (e.g., THF (tetrahydrofuran), DCM (dichloromethane), or toluene) in a dry tube under an inert atmosphere (e.g., argon). The tube was sealed and may be heated at 40°C to 80°C (e.g., 68°C) for 14 to 18 hours (e.g., 16 hours), or subjected to microwave irradiation at 100°C to 200°C (e.g., 150°C) for 45 to 90 minutes (e.g., 60 minutes), and then cooled to room temperature. The mixture may then be treated with a saturated salt solution (e.g., a saturated solution of NaHCO3).

[0076] The compound of formula (Ia) is converted in step 7 under aromatication conditions to the compound of formula (Ib) (where, Both R2 and R2 in JPEG2026517912000029.jpg15170 represent double bonds and may be added. A heterogeneous oxidizing agent (e.g., potassium permanganate or copper bromide) may be added to a solution of the compound of formula (Ia) in an organic solvent (e.g., acetone) in the presence of air. The mixture may be stirred at room temperature for at least 24 hours, preferably at least 48 hours, and then filtered, for example, with Celite. The filtrate may then be treated, for example, by extraction under classical conditions. [ka]

[0077] Scheme 2 shows an alternative route for obtaining the compound of formula (Ib) defined above.

[0078] The compound of formula (III) can be converted to the compound of formula (Ib) in two steps. To the compounds of formula (III) and formula (IV) defined above, an acid (e.g., TFA (trifluoroacetic acid), p-TSOH (p-toluenesulfonic acid), or DPP (diphenyl phosphate) may be added in a dry organic solvent (e.g., dry THF, DCM, or toluene) under an inert atmosphere (e.g., under argon). The reaction may be stirred at a low temperature for several hours (preferably 0°C for 1 hour) and then heated to room temperature. A saturated salt solution (e.g., a saturated solution of NaHCO3) may be added to the mixture, and then the organic layer may be extracted, dried, filtered, and concentrated under reduced pressure.

[0079] The residue may be secondarily diluted with a solvent (e.g., xylene, mesitylene, EtOH (ethanol), or octane). The mixture may be degassed, and a Pd / C catalyst may be added. The mixture may be heated under reflux for more than 8 hours (e.g., 16 hours), then cooled to room temperature, and filtered, for example, with Celite.

[0080] According to an alternative route, the compound of formula (III) can be directly converted to the compound of formula (Ib) in a single step by using a microwave reactor. The compound of formula (III) and the compound of formula (IV) can be placed in a dry microwave tube together with an aprotic polar solvent (e.g., 1,2-dichloroethane, DCM, or THF). A catalyst (e.g., a mixture of ytterbium triflate and trimethylsilyl chloride, ytterbium triflate, aluminum chloride, titanium chloride, or other Lewis acids, or Pd / C in the presence of lithium carbonate) can be added to this mixture. The tube is then sealed and heated to 100°C to 200°C (e.g., 150°C) under microwave irradiation for 30 minutes to 1 hour (e.g., 40 minutes), and then cooled to room temperature. The mixture may be treated with a saturated salt solution, for example, a saturated solution of NaHCO3, and then the organic phase is extracted, dried, filtered, and concentrated under reduced pressure.

[0081] Furthermore, a method for preparing one of the compounds of formula (I) defined above, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) below [ka] (Here, R1, R4, X, Y, Z1, Z2, JPEG2026517912000032.jpg14170 is as defined above. The mixture is reacted under Pictet-Spengler conditions, particularly in an organic solvent, under an inert atmosphere, and in the presence of a catalyst, such as AlCl3 or BF3OEt2, particularly at a temperature of 40-68°C for 14-18 hours, and then cooled to room temperature to obtain the compound of formula (Ia) (where, Both JPEG2026517912000033.jpg15170 represent a single join, and also, (JPEG2026517912000034.jpg14170 independently represents a single bond or a double bond.) The process includes at least the step of obtaining Here, the compound of formula (Ia) is optionally left under aromatization conditions, particularly in an organic solvent, in the presence of a heterogeneous oxidizing agent, such as potassium permanganate or copper bromide, particularly at room temperature for at least 24 hours, to form the compound of formula (Ib) (where, Both JPEG2026517912000035.jpg15170 represent a double bond, and also, (JPEG2026517912000036.jpg14170 independently represents a single bond or a double bond.) The above method, which may yield the above, is provided herein.

[0082] Also, the compound of formula (I) (where defined above) Both JPEG2026517912000037.jpg15170 represent double bonds, and R2 is absent,) or a method for preparing one of its pharmaceutically acceptable salts, Here, the method comprises at least the steps of sequentially reacting the compound of formula (III) below with the compound of formula (IV) below in the presence of an acid, such as trifluoroacetic acid, p-toluenesulfonic acid, or diphenyl phosphate, under an inert atmosphere, and in a second step, in a solvent, such as xylene, mesitylene, EtOH, or octane, in the presence of a catalyst, such as Pd / C, under heating under reflux, particularly for more than 8 hours, or alternatively, under microwave, in an aprotic polar solvent, in the presence of a catalyst, such as a mixture of ytterbium triflate and trimethylsilyl chloride, ytterbium triflate, aluminum chloride, titanium chloride, or other Lewis acid, or Pd / C in the presence of lithium carbonate, under heating, particularly at a temperature of 100°C to 200°C. [ka] (Here, R1 is as defined above.) [ka] (Here, R4, X, Y, Z1, Z2, JPEG2026517912000040.jpg14170 is as defined above. The above method is provided.

[0083] Some of the chemical structures and spectroscopic data of the compounds of formula (I) of the present invention are shown in Tables I and II below, respectively.

[0084] [Table 1] JPEG2026517912000042.jpg255142JPEG2026517912000043.jpg255139JPEG2026517912000044.jpg151170

[0085] [Table 2] JPEG2026517912000046.jpg255169JPEG2026517912000047.jpg22170

[0086] pathology

[0087] All compounds disclosed herein are of particular interest herein for the treatment and / or prevention of cancer, in particular cancers that express chromatin-bound MDM2 or C-MDM2, or cancers that exhibit the recruitment of MDM2 to chromatin.

[0088] As demonstrated in the examples, they inhibit C-MDM2 expression and promote C-MDM2 autoubiquitination and proteasomal degradation. They can be used to treat and / or prevent cancers expressing C-MDM2, whether p53-dependent or not, and regardless of the p53 state of the cancer cells. The present invention also relates to prophylactic treatment of cancer, for example, for individuals suspected of having cancer or at risk of developing cancer, particularly cancers expressing chromatin-bound MDM2 or C-MDM2, or cancers showing mobilization of MDM2 to chromatin.

[0089] While not intended to be constrained by any particular theory, it is identified that cancer exhibiting MDM2 recruitment to chromatin is not synonymous with cancer exhibiting intracellular MDM2 overexpression. Cancer exhibiting MDM2 recruitment to chromatin encompasses both (i) cancer exhibiting MDM2 overexpression and (ii) cancer not exhibiting MDM2 overexpression. Cancer exhibiting MDM2 recruitment to chromatin may be cancer in which the cancer cells exhibit cytoplasmic MDM2 overexpression and at least a portion of the intracellular MDM2 is localized in the cell nucleus. Cancer exhibiting MDM2 recruitment to chromatin may also be cancer in which MDM2 is not overexpressed in the cancer cells and at least a portion of the intracellular MDM2 is localized in the cell nucleus.

[0090] Therefore, in some embodiments, cancers that exhibit MDM2 recruitment to chromatin may not exhibit MDM2 overexpression in the cytoplasm.

[0091] Cancers exhibiting MDM2 mobilization to chromatin can be diagnosed using diagnostic methods disclosed, for example, in International Publication WO2019 / 106126 or in Cisse et al. (2020, Sci Trans Med, Vol.12;547).

[0092] In some embodiments, cancers exhibiting MDM2 recruitment to chromatin can be diagnosed in a subject using any method that allows observation of the localization of proteins, particularly MDM2, in cancer cell samples or cancer tissue samples.

[0093] In cancer subjects exhibiting MDM2 recruitment to chromatin, the determination can also be a classification method based on the type of cancer the subject has. In particular, subjects can be classified as having cancer that exhibits MDM2 recruitment to chromatin, or as having cancer that does not exhibit MDM2 recruitment to chromatin.

[0094] For example, methods to determine the localization of proteins, particularly MDM2, in cancer cell samples or cancer tissue samples are performed by immunofluorescence, particularly by microscopy, or by immunohistochemistry.

[0095] In some specific embodiments, in subjects where it is necessary to determine cancer exhibiting MDM2 recruitment to chromatin, a method for determining cancer exhibiting MDM2 recruitment to chromatin may include the steps of: a) preparing a cancer cell sample obtained from the subject; b) determining the localization of MDM2 in the cancer cells, particularly by immunofluorescence or immunohistochemistry; and c) concluding that the subject has cancer exhibiting MDM2 recruitment to chromatin if MDM2 is localized in the nucleus (and therefore on chromatin), or concluding that the subject does not have cancer exhibiting MDM2 recruitment to chromatin if MDM2 is not localized in the nucleus, particularly if MDM2 is localized only in the cytoplasm of the cancer cells.

[0096] Exemplary, the localization of MDM2 in target cancer cells can be determined by immunohistochemistry. Cancer cells or cancer tissue are collected from a tumor in the subject. The cancer cells are placed on a solid support. Next, an anti-MDM2 antibody is added to the cancer cell preparation. Subsequently, it is added to a secondary antibody bound to a detection system (an enzyme conjugated to the antibody, whose presence in the substrate causes a coloring (peroxidase) or fluorescence (rhodamine) reaction), producing a signal visible to the naked eye or visible by microscopy and spectrophotometric techniques. Subsequently, by observing the color of the signal, it can be determined whether MDM2 is localized in the nucleus (and therefore on chromatin) or in the cytoplasm.

[0097] In some other embodiments, in subjects where it is necessary to diagnose cancer showing MDM2 mobilization to chromatin, a method for diagnosing cancer showing MDM2 mobilization to chromatin is, i) Determining the level of nuclear-bound MDM2 in biological samples, particularly the level of chromatin-bound MDM2, ii) If the proportion of nuclear-bound MDM2 cells determined in step i) accounts for more than approximately 1% of the cancer cells in the sample, it is concluded that the subject is suffering from cancer that exhibits the recruitment of MDM2 to chromatin. This may include the following steps.

[0098] In some specific embodiments, in subjects where it is necessary to diagnose cancer showing MDM2 mobilization to chromatin, a method for diagnosing cancer showing MDM2 mobilization to chromatin is: i) To determine the level of nuclear-bound MDM2 in cancer cells of a biological sample, ii) If the proportion of nuclear-bound MDM2 cells determined in step i) accounts for more than approximately 1% of the cancer cells in the sample, it is concluded that the subject is suffering from cancer that exhibits the recruitment of MDM2 to chromatin. This may include the following steps.

[0099] The level of nuclear-bound MDM2, particularly chromatin-bound MDM2, in cancer cells of a biological sample can be readily determined by those skilled in the art.

[0100] The level of nuclear-bound MDM2 in the biological sample of interest can also be measured in patient-derived tumor samples by immunoblotting in cell fractions that separate chromatin.

[0101] In some embodiments, the biological sample may be a tissue sample.

[0102] In particular, the tissue sample may be a sample of the target cancer tissue. The techniques for collecting the target tissue sample are well known to those skilled in the art. For example, the collection of the tissue sample can be achieved by biopsy.

[0103] The diagnostic methods described herein may be implemented as biomarker tests to determine whether a subject has cancer that exhibits the recruitment of MDM2 to chromatin.

[0104] In some embodiments, the diagnostic methods described herein provide clinical information. Exemplarily, the diagnostic methods described herein can supplement information related to biopsy samples provided from subjects with cancer exhibiting MDM2 mobilization to chromatin.

[0105] Exemplary, the diagnostic methods described herein enable the determination of the presence of MDM2 in chromatin in a subject with cancer, where the detection of MDM2 in chromatin may enable a healthcare professional to determine whether to administer the C-MDM2 expression inhibitor of this disclosure to a subject with cancer.

[0106] According to this disclosure, in patients requiring the recruitment of MDM2 to chromatin in cancer cells, the recruitment of MDM2 to chromatin in cancer cells may occur only after a certain period following the onset of cancer, or conversely, immediately after the onset of cancer. In particular, the recruitment of MDM2 to chromatin may occur not only at the time of cancer onset, but also at various stages of cancer, including at least the administration of the initial treatment for the cancer to the target.

[0107] In some embodiments, the cancers expressing C-MDM2 disclosed herein may be selected from the group consisting of bone cancer, brain cancer, ovarian cancer, breast cancer, lung cancer, colorectal cancer, osteosarcoma, skin cancer, hematological cancers including acute myeloid leukemia, pancreatic cancer, prostate cancer, and liposarcoma, and more particularly from the group consisting of skin cancer, liposarcoma, and hematological cancer, for example, liposarcoma, melanoma, and acute myeloid leukemia. In some embodiments, the cancer expressing C-MDM2 disclosed herein may be liposarcoma.

[0108] The term "liposarcoma" or "LPS" has its general meaning in this art and refers to mesenchymal origin soft tissue sarcomas, as revised, for example, in the World Health Organization Classification (ICD10 C49.9). The term "liposarcoma" also refers to well-differentiated liposarcoma (WD-LPS) and de-differentiated liposarcoma (DD-LPS). The term "liposarcoma" is also related to malignant mesenchymal neoplasms, i.e., a type of soft tissue sarcoma, which comprises lipomatous tumors of varying severity, from slow-growing to invasive and metastatic. Liposarcoma most commonly occurs in the lower extremities or retroperitoneum, but can also occur in the upper extremities, neck, peritoneal cavity, spermatic cord, breast, vulva, and axilla. The term "liposarcoma" is also associated with undifferentiated liposarcoma and well-differentiated liposarcoma.

[0109] In some embodiments, the term "liposarcoma" refers to a liposarcoma that exhibits the recruitment of MDM2 to chromatin.

[0110] Compounds according to the present invention are also useful for reducing tumor growth and inhibiting metastasis.

[0111] The inventors have also demonstrated that the compounds of the present invention may be particularly useful as first-line treatment for melanoma, liposarcoma, and acute myeloid leukemia.

[0112] The inventors have further demonstrated that patients who have developed tumors and have been treated with first-line treatments such as radiotherapy, chemotherapy, and / or immunotherapy can be favorably treated with second-line treatment using the compounds of the present invention. In fact, the inventors have shown that the tumor cells were subsequently sensitive to C-MDM2 expression inhibitors, and more particularly to the compounds of the present invention.

[0113] Within the framework of this invention, first-line treatment for cancer refers to the recommended initial treatment or first treatment for the cancer. This may also be referred to as primary treatment, initial treatment, or induction therapy. First-line treatment for cancer is the treatment that is expected to provide the best possible outcome with minimal side effects in the majority of patients. Second-line cancer treatments, on the other hand, are used when the first-line treatment fails to improve the cancer or when it has shown temporary improvement and the cancer has progressed, and they generally tend to be less effective.

[0114] Accordingly, in one embodiment, compounds of formula (I) according to the present invention are provided herein for use in the treatment of cancers expressing chromatin-bound MDM2 or C-MDM2, or cancers exhibiting mobilization of MDM2 to chromatin, particularly cancers selected from melanoma, liposarcoma, and acute myeloid leukemia, in patients who have not been previously treated with another anticancer drug.

[0115] In another embodiment, compounds of formula (I) according to the present invention are provided herein for use in tumors that do not spontaneously express chromatin-bound MDM2 or C-MDM2 in patients previously treated with radiotherapy, chemotherapy and / or immunotherapy, or tumors that do not show mobilization of MDM2 to chromatin before any treatment but show mobilization of MDM2 to chromatin after treatment.

[0116] Pharmaceutical composition

[0117] In a further view, this disclosure relates to administering the compound of formula (I) described herein in the form of a pharmaceutical composition. In other words, this disclosure also relates to a pharmaceutical composition comprising the compound of formula (I) described herein.

[0118] Typically, the compounds of formula (I) described herein may be combined with pharmaceutically or physiologically acceptable additives or carriers and optionally with a sustained-release matrix, such as a biodegradable polymer, to form therapeutic compositions.

[0119] The pharmaceutical compositions provided herein contain an active agent, i.e., a compound of formula (I) as described herein, in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. As stated above, the actual effective amount for a particular use will depend, in particular, on the condition being treated, as well as various other factors well known in the art, such as the patient's age, weight, sex, presence of other potential aggravating factors, or diet. Determining the therapeutically effective amount of a compound of formula (I) as described herein is within the capabilities of those skilled in the art.

[0120] The pharmaceutical compositions described herein can be prepared in accordance with techniques known to those skilled in the art by using the compound of formula (I) described herein in combination with pharmaceutically acceptable additives or carriers.

[0121] These pharmaceutical compositions may contain one or more pharmaceutically acceptable excipients or carriers. Suitable carriers and additives, and their formulations, are, for example, Remington: The Science and Practice of Pharmacy, 21 st This is described in Edition, David B. Troy, ed., Lippicott Williams & Wilkins (2005). A pharmaceutically acceptable carrier means a substance that is not biologically or otherwise undesirable. That is, the substance is administered to a subject without causing undesirable biological effects or adverse interactions with other components of a pharmaceutical composition containing the substance.

[0122] The pharmaceutical composition may be in any form deemed suitable by those skilled in the art, such as a solid, semi-solid, liquid, granules, inhalant, or aerosol inhalant.

[0123] The liquid formulation may be suitable for oral or systemic administration.

[0124] Pharmaceutical compositions suitable for oral administration may be in the form of capsules, tablets, pills, powders, granules, solutions or suspensions in aqueous or non-aqueous liquids, foamy or stirred edible liquids, oil-in-water emulsions, or water-in-oil emulsions.

[0125] For example, in the case of oral administration in the form of capsules or tablets, the activators described herein may be combined with a pharmaceutically acceptable inert carrier, such as ethanol, glycerol, or water. Flavorings, preservatives, colorings, coatings, and / or dispersants may also be present.

[0126] Suitable pharmaceutical compositions for parenteral administration may include sterile aqueous or non-aqueous injection solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that maintain isotonicity with the blood of the recipient, as well as aqueous or non-aqueous sterile suspensions that may contain suspensions and thickeners. These compositions may be sterilized by conventional, well-known sterilization techniques.

[0127] Parenteral compositions may include a vehicle, such as sterile water or a parenterally acceptable oil, in which the compound may be contained in a solution or suspension. Alternatively, the solution may be lyophilized. The lyophilized parenteral pharmaceutical composition may be reconstituted with a suitable solvent immediately before administration.

[0128] The pharmaceutical composition may be filled into single-dose or multi-dose containers, such as sealed ampoules or vials, and may be stored in a lyophilized state, requiring only the addition of a sterile liquid solvent, such as water for injection, immediately before use. The injectable solutions and suspensions for compounding may be prepared from powders, granules, lyophilized products, and sterile compresses.

[0129] For parenteral administration, the composition containing the active ingredient may also be provided in individual containers that can be suitably mixed according to a desired dosage taking into account the weight, age, sex, and health condition of the patient requiring the composition containing the active ingredient.

[0130] In all cases, the pharmaceutical composition must be stable under the conditions of manufacture and storage, and must be protected against contamination by microorganisms, such as bacteria and fungi.

[0131] All or part of the specific features and embodiments relating to the pharmaceutical compositions pursuant to this disclosure also apply to the intended uses and methods of this disclosure.

[0132] In some embodiments, the present disclosure relates to the use of a compound of formula (I) according to the present disclosure for the manufacture of a pharmaceutical product for the prevention and / or treatment of the aforementioned cancers, particularly liposarcoma, in subjects requiring the prevention and / or treatment of the aforementioned cancers, particularly liposarcoma, wherein the subjects have been previously classified as having a cancer exhibiting the mobilization of MDM2 to chromatin.

[0133] The examples provided herein are intended to be illustrative only, and those skilled in the art will recognize, or verify using experiments within the usual range, numerous equivalents of certain compounds, materials, and procedures. All such equivalents are considered to be within the scope of the present invention and are encompassed by the appended claims.

[0134] Examples

[0135] In this embodiment, the following terms mean: MS: Molecular sieves DCM: Dichloromethane, THF: Tetrahydrofuran, TFA: Trifluoroacetic acid, RT: room temperature, DMEM: Dulbecco's Modified Eagle Medium.

[0136] Preparation of intermediates:

[0137] Synthesis of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethaneamine [ka]

[0138] Process 1 :N-(4,4-diethoxybutyl)acetamide [ka]

[0139] Under an argon atmosphere, 3.6 mL of 4,4-diethoxybutan-1-amine (20.8 mmol) and 7.2 mL of triethylamine (2.5 equivalents) were dissolved in 25 mL of dry DCM. The mixture was cooled to 0°C, and 11.8 mL of Ac₂O (6 equivalents) was added dropwise. After the addition was complete, the reaction was heated under reflux for 2 hours and then cooled to room temperature. It was neutralized with saturated Na₂CO₃ solution, and the layers were separated. The aqueous layer was extracted three times with DCM. The organic layer was collected, washed with saturated Na₂CO₃ solution and saline solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain N-(4,4-diethoxybutyl)acetamide, which was used without further purification.

[0140] 1 ¹H NMR (250MHz, chloroform-d): δ 5.67 (s, 1H), 4.48 (t, J=5.3Hz, 1H), 3.65 (dq, J=9.5, 7.1Hz, 2H), 3.49 (dq, J=9.4, 7.1Hz, 2H), 3.35~3.18 (m, 2H), 1.96 (s, 3H), 1.73~1.50 (m, 4H), 1.20 (t, J=7.1Hz, 6H).

[0141] Process 2 :5-Hydradinyl-2-methoxypyridine [ka]

[0142] To a solution of 2.8 g of 6-methoxypyridine-3-amine (22.5 mmol) in 28 mL of 6 N aqueous HCl, a solution of 1.6 g of sodium nitrite (1 equivalent) in 14 mL of H2O was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then a solution of 12.7 g of tin chloride dihydrate in 28 mL of 6 N aqueous HCl was slowly added at 0°C. The reaction mixture was stirred at 0°C for a further 2 hours. Next, it was basicized with a 40% KOH solution until the pH was 12, and then extracted three times with siRNA. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 5-hydrazinyl-2-methoxypyridine, which was used without further purification.

[0143] 1 ¹H NMR (250MHz, chloroform-d): δ 7.76 (d, J=3.0Hz, 1H), 7.18 (dd, J=8.9, 3.0Hz, 1H), 6.64 (dd, J=8.8, 0.6Hz, 1H), 4.96 (brs, 1H), 3.86 (s, 3H), 3.60 (brs, 2H).

[0144] Process 3 :N-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethyl)acetamide [ka]

[0145] To a solution of 2.8 g of N-(4,4-diethoxybutyl)acetamide (13.9 mmol) in 40 mL of 5% aqueous H2SO4, 1.5 g of 5-hydrazinyl-2-methoxypyridine (1.0 equivalent) was added. The reaction mixture was heated under reflux for 2 hours and 30 minutes, and then cooled to room temperature. It was neutralized with saturated Na2CO3 solution and extracted four times with siRNA. The combined organic layers were washed with H2O, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0146] The crude product was purified by silica gel flash chromatography (100% siRNA to 90-10% siRNA / MeOH) to give pure N-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethyl)acetamide.

[0147] 1 ¹H NMR (250MHz, chloroform-d): δ 8.23 ​​(s, 1H), 7.59 (d, J=8.8Hz, 1H), 7.40~7.28 (m, 1H), 7.16 (d, J=2.7Hz, 1H), 6.74~6.52 (m, 1H), 4.03 (s, 3H), 3.67~3.49 (m, 2H), 3.07~2.90 (m, 2H), 1.94 (s, 3H).

[0148] Process 4 :2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethaneamine [ka]

[0149] 1.4 g of N-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethyl)acetamide (6.1 mmol) was dissolved in 80 mL of 2 M aqueous H2SO4. The reaction mixture was heated under reflux for 16 hours and then cooled to room temperature. It was neutralized with 1 M NaOH until the pH was 9-10 and then extracted four times with ELISA. The combined organic layers were washed with H2O, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain pure 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethaneamine.

[0150] 1 ¹H NMR (250MHz, chloroform-d): δ 8.32 (s, 1H), 7.52 (dd, J=8.8, 0.6Hz, 1H), 7.12 (s, 1H), 6.65~6.49 (m, 1H), 3.98 (s, 3H), 3.14~3.04 (m, 2H), 2.93 (t, J=6.3Hz, 2H).

[0151] Synthesis of 2-(5-cyclopropoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethaneamine [ka]

[0152] Process 1 :2-Cyclopropoxy-5-Hydradinylpyridine [ka]

[0153] To a solution of 2.8 g of 6-cyclopropoxypyridine-3-amine (4.9 mmol) in 6 mL of 6 N aqueous HCl, a solution of 335 mg of sodium nitrite (1 equivalent) in 4 mL of H2O was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then a solution of 2.7 g of tin chloride dihydrate in 6 mL of 6 N aqueous HCl was slowly added at 0°C. The reaction mixture was stirred at 0°C for more than 2 hours. Next, it was basicized with a 40% KOH solution until the pH was 12, and then extracted three times with siRNA. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 5-hydrazinyl-2-cyclopropoxypyridine, which was used without further purification.

[0154] 1 H NMR (250MHz, CDCl3) δ7.92~7.78(m,1H),7.21(ddd,J=8.8,3.0,0.4Hz,1H),6.70(dt,J=8.9,0.6 Hz, 1H), 5.00 (brs, 1H), 4.17~3.98 (m, 1H), 3.60 (s, 1H), 0.90~0.65 (m, 4H).

[0155] Process 2 :N-(2-(5-cyclopropoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethyl)acetamide [ka]

[0156] To a solution of 1.0 g of N-(4,4-diethoxybutyl)acetamide (4.9 mmol) in 15 mL of 5% aqueous H2SO4, 815 mg of 2-cyclopropoxy-5-hydrazinylpyridine (1.0 equivalent) was added. The reaction mixture was heated under reflux for 2 hours and 30 minutes and then cooled to room temperature. It was neutralized with saturated Na2CO3 solution and extracted four times with ELISA. The combined organic layers were washed with H2O, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0157] The crude product was purified by silica gel flash chromatography (DCM / MeOH, 99 / 1 to 95 / 5) to give pure N-(2-(5-cyclopropoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethyl)acetamide.

[0158] 1 H NMR (250MHz, CDCl3) δ8.23(brs,1H),7.60(d,J=8.7Hz,1H),7.43(brs,1H),7.16(d,J=2.6Hz,1H),6.70(d,J=8.8Hz ,2H),4.28~4.07(m,1H),3.79~3.34(m,2H),3.05~2.80(m,2H),1.91(s,3H),0.86~0.72(m,4H).

[0159] Process 3 :2-(5-cyclopropoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethaneamine [ka]

[0160] 450 mg of N-(2-(5-cyclopropoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)acetamide (1.7 mmol) was dissolved in 25 mL of 2 M aqueous H2SO4. The reaction mixture was heated to reflux for 16 h and then cooled to room temperature. It was neutralized with 1 M NaOH to pH = 9 - 10 and then extracted four times with EtOAc. The combined organic layers were washed with H2O, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give pure 2-(5-cyclopropoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine.

[0161] 1 1H NMR (250 MHz, CDCl3) δ 8.42 (s, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.15 (s, 1H), 6.67 (d, J = 8.7 Hz, 1H), 4.26 - 4.18 (m, 1H), 3.15 - 3.00 (m, 2H), 2.94 (t, J = 6.3 Hz, 2H), 0.95 - 0.38 (m, 4H).

[0162] Example 1 : 2-methoxy-6-(naphthalen-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (1)

Chemical Structure

[0163] Process 1 : Under an argon atmosphere, molecular sieves were added to a solution of 363 mg of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanamine (1.9 mmol) and 284 μL of naphthaldehyde (1.1 eq) in 12 mL of dry DCM. The reaction mixture was stirred at room temperature for 16 h, then filtered and concentrated under reduced pressure to give the crude imine, which was used without further purification.

[0164] 1¹H NMR (250MHz, chloroform-d): δ 8.80 (s, 1H), 8.57~8.44 (m, 1H), 8.30 (s, 1H), 7.91~7.80 (m, 3H), 7.55~7.37 (m, 4H), 7.05 (d, J=2.5Hz, 1H), 6.59 (d, J=8.8Hz, 1H), 4.25~4.13 (m, 2H), 4.04 (s, 3H), 3.30 (t, J=6.9Hz, 2H).

[0165] Process 2 In a dry tube, 127 mg of aluminum trichloride (0.5 equivalents) was added under argon to a solution of 600 mg of crude imine (1.9 mmol) in 20 mL of dry THF. The tube was sealed and heated at 68°C for 16 hours, and then cooled to room temperature. The reaction mixture was treated with a saturated NaHCO3 solution and extracted three times with siRNA. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 2-methoxy-6-(naphthalene-1-yl)-6,7,8,9-tetrahydro-5H-pyrrolo[3,2-b:5,4-c']dipyridine, which was used without further purification but can be purified by silica gel flash chromatography (99 / 1 DCM / MeOH ~ 90 / 10 DCM / MeOH).

[0166] 1 ¹H NMR (250MHz, chloroform-d): δ 8.31~8.14 (m,1H), 8.02~7.75 (m,2H), 7.61~7.44 (m,3H), 7.44~7.28 (m,3H), 6.51 (d,J=8.7Hz,1H), 5.86 (brs,1H), 4.02 (s,3H), 3.49~3.31 (m,1H), 3.26~3.09 (m,1H), 3.09~2.94 (m,2H).

[0167] Process 3To a solution of 600 mg of crude 2-methoxy-6-(naphthalene-1-yl)-6,7,8,9-tetrahydro-5H-pyrrolo[3,2-b:5,4-c']dipyridine (1.8 mmol) in 87 mL of acetone, 2.9 g of potassium permanganate (10.0 equivalents) was added under air. The reaction mixture was stirred at room temperature for 48 hours and then filtered through Celite. The filtrate was treated with a saturated Na2S2O3 solution and then basicized with 28% aqueous ammonia. The resulting solution was extracted three times with siRNA. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (70 / 30 siRNA / petroleum ether to 80 / 20 siRNA / petroleum ether) to give pure 2-methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine.

[0168] 1 ¹H NMR (250MHz, chloroform-d): δ 8.65 (d, J=5.3Hz, 1H), 8.19 (dd, J=5.3, 0.8Hz, 1H), 8.04~7.94 (m, 2H), 7.93 (s, 1H), 7.81~7.70 (m, 2H), 7.68~7.57 (m, 2H), 7.57~7.50 (m, 1H), 7.42 (ddd, J=8.5, 6.9, 1.4Hz, 1H), 6.93 (d, J=8.9Hz, 1H), 4.12 (s, 3H).

[0169] Example 2 :2-Methoxy-6-(1,5-naphthyridine-4-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (2) [ka]

[0170] In a dry microwave tube, 124 mg of 1,5-naphthyridine-4-carbaldehyde (1.0 equivalent), 194 mg of ytterbium triflate (0.4 equivalent), and 0.1 mL of trimethylsilyl chloride (1.0 equivalent) were added under argon to a solution of 150 mg of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl) in 3.6 mL of dry DCM. The tube was sealed and heated to 150°C under microwave irradiation for 40 minutes. After cooling to room temperature, the reaction mixture was treated with a saturated NaHCO3 solution and extracted four times with DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0171] The crude product was purified by silica gel chromatography (95 / 5 DCM / MeOH) to give pure 2-methoxy-6-(1,5-naphthyridine-4-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine.

[0172] 1 ¹H NMR (400MHz, chloroform-d): δ 10.30 (brs, 1H), 9.19 (d, J=4.5Hz, 1H), 9.09 (dd, J=4.2, 1.8Hz, 1H), 8.72 (d, J=5.1Hz, 1H), 8.64 (dd, J=8.5, 1.8Hz, 1H), 8.42 (d, J=4.5Hz, 1H), 8.29 (d, J=5.1Hz, 1H), 7.81 (dd, J=8.6, 4.2Hz, 1H), 7.77 (d, J=8.8Hz, 1H), 6.99 (d, J=8.8Hz, 1H), 4.13 (s, 3H).

[0173] Example 3 :2-Methoxy-6-(pyrido[2,3-b]pyrazine-8-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (3) [ka]

[0174] To a solution of 90 mg of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethaneamine (0.5 mmol) and 90 mg of pyrido[2,3-b]pyrazine-8-carbaldehyde (0.6 mmol) in 10 mL of dry THF, 0.2 mL of TFA was added under argon at 0°C. The reaction mixture was stirred at 0°C for 1 hour and then warmed to room temperature. A saturated NaHCO3 solution was then added, and the reaction mixture was extracted three times with RINKAN. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0175] The residue was diluted with 10 mL of xylene, the solution was degassed, and 10% Pd / C of 100 mg was added. The reaction mixture was heated under reflux for 16 hours, then cooled to room temperature, and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (DCM / MeOH 90 / 10) to give pure 2-methoxy-6-(pyrido[2,3-b]pyrazine-8-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine.

[0176] 1 H NMR (400MHz,DMSO-d6) δ11.04(s,1H),9.38(d,J=4.3Hz,1H),9.23(d,J=1.6Hz,1H),8.97(d,J=1.6Hz,1H),8.54(d,J=5.3Hz,1H) ,8.18(d,J=5.3Hz,1H),8.10(d,J=4.3Hz,1H),7.80(d,J=8.9Hz,1H),7.02(d,J=8.8Hz,1H),4.02(s,3H).

[0177] Example 4 :2-Methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride (4) [ka]

[0178] To a solution of 180 mg of 2-methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (0.6 mmol) in dry DCM, 0.6 mL of 1 M HCl in Et2O (1.1 equivalents) was added. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness to give pure 2-methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride.

[0179] 1 H NMR (250MHz,DMSO-d6) δ12.49(s,1H),8.67(q,J=6.2Hz,2H),8.37(d,J=8.2Hz,1H),8.21(d,J=8.2Hz,1H),8.11~7.95(m,2H), 7.85(dd,J=8.2,7.1Hz,1H),7.74~7.62(m,1H),7.62~7.45(m,2H),7.28(d,J=9.1Hz,1H),4.08(s,3H).

[0180] Example 5 :2-Chloro-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (18) [ka]

[0181] To a solution of 100 mg of 2-methoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride (0.3 mmol) in a 3.3 mL mixture (3.2 / 0.1) of dry toluene and dry DMF, 0.1 mL of POCl3 (1.4 mmol) was slowly added under argon at 0°C. The reaction mixture was heated to 90°C overnight. After cooling to room temperature, the reaction mixture was treated with a saturated NaHCO3 solution and extracted three times with RINKAN. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

[0182] The crude product was purified by silica gel chromatography (100 / 0 DCM / MeOH to 98 / 2 DCM / MeOH) to give pure 2-chloro-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine.

[0183] 1 H NMR (400MHz,DMSO-d6) δ11.55(s,1H),8.63(d,J=5.3Hz,1H),8.23(d,J=5.3Hz,1H),8.15(d,J=7.0Hz,1H),8.09(d,J=8.4Hz,1H),7.95(d,J=8.6 Hz,1H),7.78(dd,J=7.0,1.5Hz,1H),7.73(t,J=7.5Hz,1H),7.67(d,J=8.6Hz,1H),7.62~7.54(m,2H),7.49~7.42(m,1H).

[0184] Example 6 :2-Chloro-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride (19) [ka]

[0185] To a solution of 20 mg of 2-chloro-6-(naphthalen-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (0.06 mmol) in dry DCM, 73 μL of 1 M HCl in Et2O (1.2 equivalents) was added. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated to dryness to give pure 2-chloro-6-(naphthalen-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride.

[0186] 1H NMR (400MHz,DMSO-d6) δ12.51(s,1H),8.83~8.66(m,2H),8.33(d,J=7.9Hz,1H),8.19(d,J=7.9Hz,1H),8.10(d,J=8.8Hz,1H),7.97(d ,J=7.0Hz,1H),7.86~7.81(m,1H),7.79(d,J=8.7Hz,2H),7.68(ddd,J=8.2,6.2,1.9Hz,1H),7.61~7.49(m,2H).

[0187] Example 7 :2-Cyclopropoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (24) [ka]

[0188] Process 1 Under an argon atmosphere, molecular sieves were added to a solution of 165 mg of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-yl)ethaneamine (0.8 mmol) and 100 μL of naphthaldehyde (1.0 equivalent) in 5 mL of dry DCM. The reaction mixture was stirred at room temperature for 16 hours, then filtered and concentrated under reduced pressure to obtain the crude imine, which was used without further purification.

[0189] 1 H NMR (250MHz, CDCl3) δ8.76(s,1H),8.62~8.41(m,1H),7.93~7.77(m,3H),7.73~7.37(m,4H),7.13(d,J=2.7Hz,1H),6. 69(d,J=8.7Hz,1H),4.33~4.22(m,1H),4.20~4.07(m,3H),3.39~3.17(m,3H),0.88~0.66(m,7H).

[0190] Process 2In a dry round-bottom flask fitted with a condenser, 80 mg of aluminum trichloride (0.8 equivalents) was added under argon to a solution of 270 mg of crude imine (0.8 mmol) in 8 mL of dry THF. The mixture was heated under reflux for 16 hours and then cooled to room temperature. The reaction mixture was treated with a saturated NaHCO3 solution and extracted three times with ethylacetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain crude 2-cyclopropoxy-6-(naphthalene-1-yl)-6,7,8,9-tetrahydro-5H-pyrrolo[3,2-b:5,4-c']dipyridine, which was used without further purification.

[0191] 1 H NMR (250MHz, CDCl3) δ9.31(s,1H),8.27~8.15(m,1H),8.03~7.71(m,2H),7.75~7.27(m,6H),6.64(d,J=8.7Hz,1H),5.84(s ,1H),4.29~4.16(m,1H),3.41~3.24(m,1H),3.24~3.10(m,1H),3.06~2.93(m,2H),0.67~0.54(m,4H).

[0192] Process 3To a solution of 270 mg of crude 2-cyclopropoxy-6-(naphthalene-1-yl)-6,7,8,9-tetrahydro-5H-pyrrolo[3,2-b:5,4-c']dipyridine (0.8 mmol) in 32 mL of acetone, 720 mg of potassium permanganate (6.0 equivalents) was added under air. The reaction mixture was stirred at room temperature for 64 hours. Celite was then added to the reaction mixture, and the residue was concentrated under reduced pressure. The dried residue was transferred to a Buchner funnel and rinsed with a sufficient amount of DCM. The filtrate was washed with saturated aqueous NaHCO3 solution and water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (90 / 10 petroleum ether / siRNA to 80 / 20 petroleum ether / siRNA) to give pure 2-cyclopropoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine.

[0193] 1 H NMR (250MHz,chloroform-d) δ8.68(d,J=5.1Hz,1H),8.24(d,J=5.3Hz,1H),8.01(t,J=8.7Hz,2H),7.92~7.82(m,1H),7. 82~7.72(m,2H),7.72~7.60(m,2H),7.59~7.50(m,1H),7.49~7.37(m,1H),7.00(dd,J=8.9, 0.3Hz, 1H), 4.53~4.35(m, 1H), 0.93~0.79(m, 4H).

[0194] Example 8 :2-Cyclopropoxy-6-(naphthalene-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride (25) [ka]

[0195] A solution of 25 mg of 2-cyclopropoxy-6-(naphthalen-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine (0.07 mmol) in dry DCM was treated with 85 μL of 1 M HCl in Et2O (1.2 eq). The reaction mixture was stirred at room temperature for 30 minutes and concentrated to dryness to give pure 2-cyclopropoxy-6-(naphthalen-1-yl)-5H-pyrrolo[3,2-b:5,4-c']dipyridine hydrochloride.

[0196] 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.82 - 8.64 (m, 2H), 8.35 (d, J = 8.3 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.00 (t, J = 7.5 Hz, 2H), 7.84 (t, J = 7.7 Hz, 1H), 7.74 - 7.61 (m, 1H), 7.59 - 7.45 (m, 2H), 7.25 (d, J = 8.9 Hz, 1H), 4.85 - 4.23 (m, 1H), 0.95 - 0.85 (m, 2H), 0.82 - 0.74 (m, 2H).

[0197] Pharmacological data

[0198] The compounds of the present invention are the subject of pharmacological tests demonstrating their utility as active substances in therapy, particularly for treating and / or preventing C-MDM2 cancer.

[0199] Example 9 : In vitro antitumor effects on cell line dependent (IB111) or independent (Hpac / ZR75.1) of C-MDM2

[0200] A. Materials and methods

[0201] Cancer cells that show or do not show the recruitment of MDM2 to chromatin (C-MDM2) were treated for 72 hours while increasing the concentration of the compound of formula (I) according to the present invention.

[0202] MDM2 degradation was measured by Western blotting and immunofluorescence.

[0203] Cells were seeded in 6-well plates (Sarsted) with complete DMEM medium, and three replicates (500,000 cells / well) were obtained for each condition. After 24 hours, compounds were added to the cells. Then, after 18 hours, cells were harvested for Western blotting or immunofluorescence. - Western blotting: Cells were harvested in Laemmli buffer, heated, and analyzed on an 8% acrylamide gel. - Immunofluorescence: Cancer cells were fixed with 4% paraformaldehyde (PFA) for 15 minutes, then permeabilized with 0.1% Triton-containing phosphate-buffered saline (PBS) for 15 minutes at room temperature (RT), and blocked with 0.3% phosphate-buffered saline-bovine serum albumin (PBS-BSA) for 1 hour at room temperature. Then, they were incubated overnight at 4°C with a mouse monoclonal antibody against MDM2 (MABE340 Millipore). Immunodetection was performed for 45 minutes at room temperature (RT) using an Alexa 488-conjugated anti-mouse IgG antibody (Thermos Fisher). Coverslips were mounted with Mowiol (Biovalley) and DAPI (Sigma), and then analyzed with a Zeiss apotome.

[0204] B. result

[0205] Deterioration was evaluated using the protocol described above, and the results were summarized in Table III below.

[0206] [Table 3]

[0207] C. conclusion

[0208] Therefore, experiments have shown that the compound of formula (I) according to the present invention is a C-MDM2 expression inhibitor.

[0209] Example 10 :Cell viability after administration of MDM2 inhibitors (IC 50 )

[0210] A. Materials and methods

[0211] Cell viability after MDM2 inhibitor treatment (IC) 50 This was determined using the sulforhodomamine B assay (SRB assay).

[0212] Cancer cells showing or not showing MDM2 recruitment to chromatin were treated with compounds at progressively increasing concentrations for 72 hours.

[0213] Cells were seeded in complete DMEM medium in 96-well plates (Sarsted) to obtain three sets (5,000 cells / well) for each condition. After 24 hours, serial dilutions of the specified compounds were added to the cells. Next, after 48 hours, the cells were fixed by adding a 10% trichloroacetic acid solution and then stained with a 0.4% SRB solution in 1% acetic acid. The immobilized SRB was finally dissolved in a 10 mM Tris-HCl solution, and the absorbance at 560 nm was read using a PHERAstar FSX plate reader.

[0214] B. result

[0215] Compounds (1), (4), (10), (11), (12), (13), (14), (15), (16), (19), (20), (24), and (25) showed IC25112 in cancer cells (IB111) that exhibited MDM2 mobilization to chromatin. 50 It was observed to have a <500 nM concentration. Furthermore, the compound was ineffective against cancer cells (Hpac / ZR75.1) that did not exhibit MDM2 recruitment to chromatin.

[0216] C. conclusion

[0217] Thus, experimental evidence (i) indicates that the compounds according to the invention may be useful for treating and / or preventing cancer, and (ii) shows their selectivity with respect to cancers that show mobilization of MDM2 to chromatin, particularly liposarcoma.

[0218] Example 11 : In vivo evaluation of anti-tumor efficacy

[0219] To confirm the in vitro results, an in vivo evaluation of the anti-tumor efficacy was performed on compound (4) according to the invention, which showed anti-tumor activity in Examples 9 and 10 above.

[0220] A. Materials and methods

[0221] IB111 liposarcoma cells were transplanted into 10 mice per group. The mice were housed in a sterile barrier facility in accordance with the regulations of the regional ethics committee for animal warfare (n°CEEA-LR-12067). When the tumors reached 100 mm 3 the compounds of formula (I) were administered by intraperitoneal (i.p.) injection daily at a dose of 20 mg / kg for 3 weeks.

[0222] B. result

[0223] In vivo efficacy was evaluated using nude mice. Tumor shrinkage of more than 75% was observed.

[0224] C. conclusion

[0225] Therefore, the results of tests performed on the compounds disclosed in this invention indicate that the compounds may be useful for treating and / or preventing cancer, cancers exhibiting MDM2 mobilization to chromatin, and, more particularly, liposarcoma.

Claims

1. Compounds of formula (I) or pharmaceutically acceptable salts thereof: 【Chemistry 1】 Here, R 1 represents a halogen atom, a (C 1 to C 6 ) alkyl group, a (C 3 to C 6 ) cycloalkyl group, a (C 2 to C 6 ) alkenyl group, a (C 1 to C 6 ) alkoxy group or a (C 3 to C 6 ) cycloalkoxy group, wherein one or two -CH 2 - groups present in the above groups may be substituted by -O-, -S- or -NH-, and wherein the above groups may be substituted by one or two hydroxy groups or (C 1 to C 6 ) alkoxy groups. X and Y are independent of -CH=base and -CR 3 = represents a base or -N= represents a base. Z 1 and Z 2 -CH 2 - represents a group, =CH- group, or =N- group. R 3 and R 4 This independently represents a hydrogen atom or a halogen atom. 【change】 These independently represent a single bond or a double bond, and also, R 2 teeth, 【change】 It does not exist when it is a double bond, and, 【change】 When it is a double bond, it represents a hydrogen atom, and, Here, 【change】 If both represent a single bond, then Z 1 and Z 2 Both are -CH 2 - Represents the base.

2. R 1 (C) is a halogen atom. 1 ~C 4 ) alkyl group, (C 1 ~C 4 )alkoxy group or (C 3 ~C 6 ) represents a cycloalkoxy group, where the group is one or two hydroxyl groups or (C 1 ~C 2 ) may be substituted with an alkoxy group, and in particular, R 1 (C) is a halogen atom. 1 ~C 4 )alkoxy group or (C 3 ~C 5 ) represents a cycloalkoxy group, and more specifically, R 1 The compound of formula (I) according to claim 1, wherein is a chlorine atom, a methoxy group, or a cyclopropoxy group.

3. (a) X, Y, Z 1 and Z 2 It simultaneously represents a -CH= group, Both represent a double bond, and in particular, R 4 is a hydrogen atom or a fluorine atom, (b) X and Z 2 It simultaneously represents the -CH= group, as well as Y and Z 1 represents an N-group, Both represent a double bond, and in particular, R 4 It is a hydrogen atom, (c) Y, Z 1 and Z 2 X simultaneously represents an N-group, and X represents a CH-group. Both represent a double bond, and in particular, R 4 It is a hydrogen atom, (d) X, Y and Z 2 This simultaneously represents a -CH= group, and also Z 1 represents an N- group or a CF- group, Both represent a double bond, and in particular, R 4 It is a hydrogen atom, (e) X, Z 1 and Z 2 represents a -CH= group, and Y represents an =N- group or a -CF= group. Both represent a double bond, and in particular, R 4 It is a hydrogen atom, (f) Y, Z 1 and Z 2 X simultaneously represents a -CH= group, and X represents an =N- group. Both represent a double bond, and in particular, R 4 It is a hydrogen atom, (g) X, Y and Z 1 This simultaneously represents a -CH= group, and also Z 2 represents an N- group or a CF- group, Both represent a double bond, and in particular, R 4 is a hydrogen atom, or, (h) X and Y simultaneously represent the -CH= group, and Z 1 and Z 2 ha-CH 2 - Represents the base, Both represent single bonds, and in particular, R 4 It is a hydrogen atom. A compound of formula (I) according to claim 1 or 2. Claim 4: Both of the following represent a double bond, and R 2 It does not exist, or, Both represent a single bond, and also, R 2 It is a hydrogen atom. A compound of formula (I) according to any one of claims 1 to 3. 【Request Item 5】 【Chemistry 2】 【change】 【change】 【change】 A compound of formula (I) according to any one of claims 1 to 4, selected from, or a pharmaceutically acceptable salt thereof.

6. (i) a compound of formula (I) as described in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier, comprising a pharmaceutical composition.

7. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

8. A compound of formula (I) according to any one of claims 1 to 5 for use in the treatment and / or prevention of cancer, in particular cancers exhibiting the recruitment of MDM2 to chromatin, more particularly cancers selected from the group consisting of bone cancer, brain cancer, ovarian cancer, breast cancer, lung cancer, colorectal cancer, osteosarcoma, skin cancer, hematological cancers including acute myeloid leukemia, pancreatic cancer, prostate cancer and liposarcoma, and even more particularly cancers selected from the group consisting of skin cancer, liposarcoma and hematological cancers, for example, cancers including but not limited to liposarcoma, melanoma and acute myeloid leukemia.

9. A compound of formula (I) according to any one of claims 1 to 5 for use in the treatment of cancers exhibiting MDM2 mobilization to chromatin in patients who have not been previously treated with another anticancer drug, particularly cancers selected from melanoma, liposarcoma and acute myeloid leukemia.

10. A compound of formula (I) according to any one of claims 1 to 5, for use in tumors that do not spontaneously express chromatin-bound MDM2 or C-MDM2 in patients previously treated with radiotherapy, chemotherapy and / or immunotherapy, or tumors that do not show mobilization of MDM2 to chromatin before any treatment but show mobilization of MDM2 to chromatin after treatment.

11. A synthesis method for producing one of the compounds of formula (I) described in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) is as follows: 【Transformation 3】 (Here, R 1 , R 4 X, Y, Z 1 , Z 2 , 【change】 (This is as defined in any one of claims 1 to 4.) This is done under Pictet-Spengler conditions, particularly in an organic solvent, under an inert atmosphere, and with a catalyst such as AlCl 3 or BF 3 OEt 2 The reaction is carried out in the presence of, in particular, at a temperature of 40–68°C for 14–18 hours, and then cooled to room temperature to obtain the compound of formula (Ia) (where, 【change】 Both represent a single bond, and also, 【change】 (Each represents either a single bond or a double bond.) The process includes at least the step of obtaining Here, the compound of formula (Ia) is optionally left under aromatization conditions, particularly in an organic solvent, in the presence of a heterogeneous oxidizing agent, such as potassium permanganate or copper bromide, particularly at room temperature for at least 24 hours, to obtain the compound of formula (I) (where, 【change】 Both represent a double bond, and also, 【change】 (Each represents either a single bond or a double bond.) The method described above may yield the following result.

12. Compound of formula (I) (wherein described in any one of claims 1 to 4) 【change】 Both represent a double bond, and R 2 A synthesis method for producing any one of the pharmaceutically acceptable salts thereof (which does not exist), Herein, the method comprises at least the steps of sequentially reacting the compound of formula (III) below with the compound of formula (IV) below in the presence of an acid, such as trifluoroacetic acid, p-toluenesulfonic acid, or diphenyl phosphate, under an inert atmosphere, and in a second step, in a solvent, such as xylene, mesitylene, EtOH, or octane, in the presence of a catalyst, such as Pd / C, under heating under reflux, particularly for more than 8 hours, or alternatively, under microwave, in an aprotic polar solvent, in the presence of a catalyst, such as a mixture of ytterbium triflate and trimethylsilyl chloride, ytterbium triflate, aluminum chloride, titanium chloride, or other Lewis acid, or Pd / C in the presence of lithium carbonate, under heating, particularly at a temperature of 100°C to 200°C. 【Chemistry 4】 (Here, R 1 (This is as described in claim 1 or 2.) 【Transformation 5】 (IV) (Here, R 4 X, Y, Z 1 , Z 2 , 【change】 (as defined in claim 1 or 3) The aforementioned synthesis method.

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