Heteroaryl-derivative compound and use thereof

Abstract

The present invention relates to a heteroaryl-derivative compound and medicinal use thereof. The heteroaryl-derivative compound of the present invention exhibits excellent inhibitory activity against CSF1R and thus can be effectively used as a therapeutic agent for CSF1R-mediated diseases.

Description

Heteroaryl derivative compounds and uses thereof

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to heteroaryl derivative compounds having CSF1R inhibitory activity.

[0002] CSF1R (colony stimulating factor 1 receptor, also known as M-CSF receptor or c-FMS) is a type III receptor tyrosine kinase (RTK class III) that is critically involved in the growth, proliferation, differentiation, survival, motility and function of myeloid lineage cells, including osteoclasts, monocytes / macrophages, microglia, Langerhans cells of the skin and Paneth cells of the intestine.

[0003] The CSF1R signaling pathway is activated when CSF1R, which exists in an inactive autoinhibited state, binds to a ligand, inducing dimerization of CSF1R and autophosphorylation of tyrosine residues. Currently, two CSF1R ligands are known: M-CSF (Macrophage colony-stimulating factor, also known as CSF1) and IL-34 (Interleukin-34). M-CSF is a stimulatory factor (growth factor) that regulates the survival, proliferation, and differentiation of hematopoietic lineage cells and is widely expressed in many cell types, including osteoblasts, stromal cells, fibroblasts, epithelial cells, and several metastatic tumor cells. IL-34 is a cytokine that binds to CSF1R and is synthesized as a secreted glycoprotein. Similar to M-CSF, IL-34 activates downstream signaling pathways and regulates major cellular functions, including growth, proliferation, differentiation, survival, metabolism, cell adhesion, migration, and cytokine / chemokine expression.

[0004] CSF1R is known to promote the infiltration and immune evasion of suppressive immune cells, such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), within the tumor microenvironment (TME). Furthermore, CSF1R-mediated signaling is crucial for the growth, proliferation, survival, differentiation, and function of myeloid cells, including macrophages and MDSCs, making CSF1R another key regulator of macrophage polarization. Persistent CSF1R activation within the tumor microenvironment, driven by CSF1R ligands, leads to polarization of the M2 TAM phenotype and promotes tumor progression, suppressing immune-stimulatory signals. CSF1R is a promising target for immunotherapy, potentially improving the efficacy of T cell checkpoint immunotherapy and inducing tumor regression. CSF1 / CSF1R inhibition supports antigen presentation and enhances T cell activity within the tumor microenvironment, thereby reducing the number of remaining TAMs and decreasing immunosuppression through reprogramming.

[0005] Expression of CSF1R through the above ligand binding promotes the development and progression of cancer. Therefore, efforts are being made to develop inhibitory monoclonal antibodies targeting CSF1R or small molecule inhibitors targeting CSF1R or its ligands as a therapeutic strategy for CSF1R-mediated diseases. Currently, monoclonal antibodies such as AFS98 (anti-mouse CSF1R) and M279 (anti-mouse CSF1R) are under clinical trials, and small molecule inhibitors such as pexidartinib (PLX3397), pazopanib (GW786034), imatinib, edicotinib (JNJ-40346527), PLX5622, BLZ945, GW2580, and Ki20227 are under clinical trials. Among them, pexidartinib (product name: Turalio) has been approved and is currently sold as a treatment for tenosynovial giant cell tumor (TGCT). However, pexidartinib has serious hepatotoxic side effects, and pazopanib (product name: Votrient), which is sold as a treatment for renal cell carcinoma and soft tissue sarcoma, has an inhibitory effect on CSF1R (IC 50 : 146 nM, MedChemExpress ® ) is low. Other than the above two, there are no CSF1R inhibitors approved for the treatment or prevention of CSF1R-mediated diseases.

[0006] Therefore, there is an urgent need to develop a CSF1R inhibitor with excellent CSF1R inhibition effect and low toxicity as a drug for treating or preventing CSF1R-mediated diseases, especially cancer.

[0007] An object of the present invention is to provide a novel structural heteroaryl derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.

[0009] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound, and specifically, to provide a pharmaceutical composition for treating or preventing a CSF1R-related disease comprising the heteroaryl derivative compound as an active ingredient, a use for treating or preventing a CSF1R-related disease using the compound, or a method for treating or preventing a CSF1R-related disease comprising a step of administering the compound.

[0010] In order to achieve the above purpose, the inventors of the present invention completed the present invention by confirming through research efforts that heteroaryl derivative compounds represented by the following chemical formula 1, chemical formula 2, or chemical formula 3 effectively inhibit CSF1R.

[0011] Heteroaryl derivative compounds

[0012] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0013] [Chemical Formula 1]

[0014]

[0015] In the above chemical formula 1,

[0016] X1 to X4 are each independently CR X or N;

[0017] R X is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo;

[0018] R N -H or -C 1-6 It is alkyl;

[0019] Ring U is a five-membered heteroaryl;

[0020] R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6Hydroxyalkyl, -C 1-6 Haloalkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl, or null {wherein said 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl comprises one or more N, O, or S atoms in the ring; and one or more H in said 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, or 5-6 membered heteroaryl ring is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, or -halo substituted};

[0021] Q1 to Q3 are each independently CH or N;

[0022] R Q1 and R Q2 are each independently -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6 Alkyl, or -halo.

[0023] According to a specific example of the present invention, the compound represented by the above chemical formula 1 may be in the following range:

[0024] X1 to X4 are each independently CR X or N;

[0025] R X is -H or -halo;

[0026] R N -H or -C 1-6 It is alkyl;

[0027] Ring U is a 5-membered heteroaryl {wherein said 5-membered heteroaryl contains two N atoms in the ring};

[0028] R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, phenyl, or benzyl, and {wherein, at least one H in the 3-6 membered cycloalkyl, phenyl, or benzyl ring is -C 1-6 Alkyl, -OC 1-6 alkyl, or -halo substituted};

[0029] Q1 to Q3 are each independently CH or N {wherein, at least one of Q1 and Q2 is N};

[0030] R Q1 and R Q2 are each independently -OC 1-6 It's alkyl.

[0031] In addition, the present invention provides a compound represented by the following chemical formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0032] [Chemical Formula 2]

[0033]

[0034] In the above chemical formula 2,

[0035] X1 and X2 are each independently CR X or N;

[0036] R X is -H, -C 1-6 Alkyl, -C1-6 Haloalkyl, or -halo;

[0037] R X1 and R X2 are each independently -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo;

[0038] R N -H or -C 1-6 It is alkyl;

[0039] Ring U is a five-membered heteroaryl;

[0040] R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl, or null {wherein said 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl comprises one or more N, O, or S atoms in the ring; and one or more H in said 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, or 5-6 membered heteroaryl ring is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, or -halo substituted};

[0041] Q1 and Q2 are each independently CH or N;

[0042] R Q1 and R Q2 are each independently -OC 1-6 It's alkyl.

[0043] According to a specific example of the present invention, the compound represented by the above chemical formula 2 may be in the following range:

[0044] X1 and X2 are each independently CR X or N;

[0045] R X is -H or -F;

[0046] R X1 and R X2 are each independently -H or -F.

[0047] According to a specific example of the present invention, the compound represented by the above chemical formula 2 may be in the following range:

[0048] The above ring U is , , , , , , or and;

[0049] R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, phenyl, or benzyl {wherein, at least one H in the 3-6 membered cycloalkyl, phenyl, or benzyl ring is -C 1-6 Alkyl, -OC 1-6}, which may be substituted with alkyl or -halo.

[0050] According to a specific example of the present invention, the compound represented by the above chemical formula 2 may be in the following range:

[0051] Q1 and Q2 are each independently CH or N {wherein, one of Q1 and Q2 is N};

[0052] R Q1 and R Q2 are each independently -OC 1-6 It's alkyl.

[0053] In addition, the present invention provides a compound represented by the following chemical formula 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0054] [Chemical Formula 3]

[0055]

[0056] In the above chemical formula 3,

[0057] X1 and X2 are each independently CR X or N;

[0058] R X is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo;

[0059] R X1 and R X2 are each independently -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo;

[0060] R N -H or -C 1-6 It is alkyl;

[0061] R U1 and R U2 are each independently -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -CN, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6Alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl comprises one or more N, O, or S atoms in the ring; and one or more H in the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, or -halo substituted};

[0062] n is 0, 1, 2, 3, or 4;

[0063] R W is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 alkyl)(C 1-6 alkyl), -OH, -OC 1-6 Alkyl, or -halo;

[0064] Q1 and Q2 are each independently CH or N;

[0065] R Q3 and R Q4 are each independently -C 1-6 It's alkyl.

[0066] According to a specific example of the present invention, the compound represented by the above chemical formula 3 may be in the following range:

[0067] X1 and X2 are each independently CR X or N;

[0068] R X is -H or -F;

[0069] R X1 and RX2 are each independently -H or -F;

[0070] R N -H or -C 1-6 It is alkyl;

[0071] R U1 and R U2 are each independently -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or 3-6 membered cycloalkyl, wherein at least one H in the 3-6 membered cycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, or may be substituted with -halo};

[0072] n is 0, 1, or 2;

[0073] R W is -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo;

[0074] Q1 and Q2 are each independently CH or N {wherein, one of Q1 and Q2 is N};

[0075] R Q3 and R Q4 are each independently -C 1-6 It's alkyl.

[0076] According to a specific example of the present invention, the compound represented by the chemical formula 1, 2, or 3 may be selected from the group consisting of compounds listed in Table 1 described below.

[0077] In the present invention, "alkyl" may mean a straight or branched chain acyclic, cyclic or saturated hydrocarbon with a combination thereof, unless otherwise specified. For example, "C 1-6"Alkyl" may mean alkyl having 1 to 6 carbon atoms. Acyclic alkyl may include, but is not limited to, methyl, ethyl, n-propyl, n-butyl, isopropyl, sec-butyl, isobutyl, or tert-butyl, as examples. Cyclic alkyl may be used interchangeably herein with "cycloalkyl" and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, as examples.

[0078] In the present invention, "alkenyl" and "alkynyl" may mean a straight or branched chain acyclic, cyclic or unsaturated hydrocarbon group combined therewith. For example, "C 1-6 "Alkenyl" may mean an unsaturated hydrocarbon having 1 to 6 carbon atoms with one or more double bonds, and "C 1-6 "Alkynyl" may mean an unsaturated hydrocarbon of 1 to 6 carbon atoms having one or more triple bonds.

[0079] In the present invention, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C 1-6 "Alkoxy" is C 1-6 Alkoxy containing alkyl, i.e., -(OC 1-6 Alkoxy may mean, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, but is not limited thereto.

[0080] In the present invention, “halo” may be F, Cl, Br, or I.

[0081] In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more carbon atoms substituted with halo as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, each independently substituted with one or more halogens, such as F, Cl, Br, or I.

[0082] As used herein, "hydroxyalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with hydroxy (OH). Examples of such hydroxyalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, or n-butyl, each independently substituted with -OH.

[0083] In this specification, "aminoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino (NR'R"). Here, R' and R" are each independently hydrogen, C 1-6 alkyl, and N protecting groups (e.g., Boc), wherein the selected R' and R" may each be independently substituted or unsubstituted.

[0084] As used herein, “cyanoalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0085] In the present invention, "cycloalkyl" may mean a hydrocarbon ring that does not contain a heteroatom (such as N, O, P, P(=O), or S) within the ring, and may be saturated or partially unsaturated. Here, if unsaturated, it may be referred to as cycloalkenyl. Unless otherwise stated, a cycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring.

[0086] In the present invention, "heterocycloalkyl" may mean a ring containing one or more selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as heterocycloalkene. Unless otherwise stated, a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring. As an example, "heterocycloalkyl having 3 to 12 atoms" may mean a heterocycloalkyl having 3 to 12 ring-forming atoms, wherein the heterocycloalkyl is selected from the group consisting of pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, It may include, but is not limited to, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane.

[0087] In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaternary benzene, quincbenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. In the present specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl."

[0088] In the present invention, "heteroarene" may be a ring containing at least one of O, N, P, Si, and S as a heteroatom. The number of ring-forming carbon atoms of the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two-ring or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, Benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran, but are not limited thereto. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclo-arene comprising an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. As used herein, a residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as a "heteroaryl".

[0089] In the present invention, "stereoisomer" means a compound having the same chemical formula or molecular formula but being sterically different. In the present specification, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemates, and mixtures thereof are also included in the scope of the present invention. For example, since the chemical formula 1 of the present invention does not specify the stereochemical structure, it may include the stereoisomers of chemical formula 1. Unless otherwise stated, a solid bond ( ) is a wedge-shaped solid line combination representing the absolute arrangement of the stereocenter ( ) or wedge-shaped dotted line join ( ) may be included.

[0090] The compound represented by Chemical Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt." Accordingly, the category of the compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by Chemical Formula 1. The term "pharmaceutically acceptable salt" of the present invention means any organic or inorganic acid addition salt of the compound, which has a relatively non-toxic and harmless effective effect in a patient at a concentration, and wherein the side effects caused by the salt do not reduce the beneficial effects of the compound represented by Chemical Formula 1.

[0091] In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt can be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0092] Such pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.

[0093] The above acid addition salt can be prepared by a conventional method, for example, by dissolving the compound of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0094] In addition, the pharmaceutically acceptable salt may be a salt or metal salt obtained using a base. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. As an alkali metal salt, sodium, potassium, or calcium salts may be pharmaceutically suitable. In addition, a corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal with a suitable silver salt (e.g., silver nitrate), and can be prepared through a salt preparation method known in the art.

[0095] Uses of heteroaryl derivative compounds

[0096] The present invention provides a use of a compound represented by the following chemical formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0097] [Chemical Formula 1]

[0098]

[0099] [Chemical Formula 2]

[0100]

[0101] [Chemical Formula 3]

[0102]

[0103] The above chemical formula 1, 2, or 3 is as defined above.

[0104] According to one specific example of the present invention, the heteroaryl derivative represented by the chemical formula 1, 2, or 3 exhibits excellent inhibitory activity against CSF1R, and thus can be usefully used for the treatment or prevention of CSF1R-related diseases, particularly cancer.

[0105] In the present invention, the cancer includes all cancers that can exhibit therapeutic or preventive efficacy due to inhibition of CSF1R activity, and may be solid cancer or blood cancer. The type of cancer is not limited, but includes, for example, pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, It may be at least one selected from the group consisting of renal pelvis cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid tumor, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid tumor, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer. There is. In addition, the cancer includes not only primary cancer but also metastatic cancer.

[0106] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for treating or preventing a CSF1R-related disease, comprising a compound represented by Chemical Formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the CSF1R-related disease may be cancer. The type of cancer is as mentioned above.

[0107] The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by the chemical formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0108] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared so that it can be administered in various oral and parenteral dosage forms.

[0109] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above chemical formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a CSF1R-related disease. Specifically, the CSF1R-related disease may be cancer. The type of cancer is as mentioned above.

[0110] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above chemical formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing cancer. The type of cancer is as mentioned above.

[0111] In addition, according to one specific example of the present invention, a method for treating or preventing a CSF1R-related disease is provided, comprising administering a therapeutically effective amount of a compound represented by Chemical Formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal including a human. Specifically, the CSF1R-related disease may be cancer. The type of cancer is as mentioned above.

[0112] In addition, according to one specific embodiment of the present invention, the present invention provides a method for treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Chemical Formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The type of cancer is as mentioned above.

[0113] In addition, according to one specific example of the present invention, the present invention provides a method for inhibiting CSF1R, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the chemical formula 1, 2, or 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0114] The term "therapeutically effective amount" as used herein refers to the amount of the compound represented by Chemical Formula 1, 2, or 3 that is effective in treating or preventing a CSF1R-related disease. Specifically, a "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used in amounts exceeding the determined dosage.

[0115] As used herein, “prevention” means any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering the compound, and “treatment” means any action that improves or beneficially changes the symptoms of the disease by administering the compound.

[0116] In addition, according to one specific embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formula 1, 2, or 3, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0117] Examples of additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, and the like. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavoring, and the like.

[0118] The above pharmaceutical composition may be formulated in various formulations for oral administration (e.g., tablets, pills, powders, capsules, syrups or emulsions) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).

[0119] For example, the pharmaceutical composition may be formulated as a preparation for oral administration, and the additives used in this case may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. In addition, liquid preparations for oral administration may include suspensions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.

[0120] Additionally, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include withepsol, macrogol, Tween 61, cacao butter, laurin, and glycerogelatin. Meanwhile, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0121] Additionally, it can be manufactured as a compound preparation with other active ingredients to have a synergistic effect of the active ingredients.

[0122] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they are contradictory.

[0123] Since the heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against CSF1R, it can be usefully used for the treatment or prevention of the CSF1R-related disease.

[0124] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0125] <Analysis and purification conditions>

[0126] The synthetic material was isolated using a Biotage Isolera UV spectra ACI System from Biotage. The material structure was analyzed using a 400 MHz NMR from Bruker, and the purity was confirmed by LC / MS using a Waters ACQUITY QDa with Alliance e2695 System.

[0127] Example 1. Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetamide (M1)

[0128]

[0129] Step 1: Preparation of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (2)

[0130] To a solution of phenylhydrazine (0.25 mL, 2.50 mmol) in EtOH (5 mL) were added ethyl (E)-2-((dimethylamino)methylene)-3-oxobutanoate (1) (0.694 g, 3.75 mmol) and K2CO3 (0.690 g, 4.99 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min and then at 65 °C for 6.5 h. The reaction was monitored by LC / MS and TLC. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4, concentrated, and purified by silica gel column chromatography (Biotage, Hex to 15% EtOAc / Hex) to give the title compound (0.523 g, 90.9%).

[0131] Step 2: Preparation of 5-methyl-1-phenyl-1H-pyrazole-4-carbonyl chloride (3)

[0132] To a solution of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (2) (0.52 g, 2.27 mmol) in THF / EtOH / H2O (1:2:2, 25 mL) was added LiOH·H2O (0.48 g, 11.4 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and then at 50 °C for 1 h. The solvent was evaporated, and the resulting suspension was adjusted to pH 4 by adding 1 M HCl. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to give 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (0.448 g, 97.5%). To a mixture of 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (0.56 g, 2.76 mmol) in toluene (20 mL) was added SOCl2 (10 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 5 h. After cooling to room temperature, the solvent was dried in vacuo to obtain the title compound (0.609 g, quant.).

[0133] Step 3: Preparation of 2-diazo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethan-1-one (4)

[0134] To a mixture of crude 5-methyl-1-phenyl-1H-pyrazole-4-carbonyl chloride (3) (0.609 g, 2.76 mmol) in THF / AcCN (1:1, 12 mL) was added a 2.0 M solution of TMSCHN2 in hexane (4 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 8 h and then warmed to room temperature overnight. After stirring at room temperature, Et2O was added, and the mixture was extracted with 10% citric acid, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 8% EtOAc / Hex to 50% EtOAc / Hex) to give the title compound (0.22 g, 35.2%).

[0135] Step 4: Preparation of methyl 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetate (5)

[0136] 2-Diazo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)ethan-1-one (4) (0.22 g, 0.97 mmol) was dissolved in anhydrous MeOH (10 mL). To the reaction solution was added a solution of AgOBz (70 mg, 0.29 mmol) in Et3N (0.5 mL, 3.89 mmol). The mixture was sonicated for 30 min at room temperature using an ultrasonic cleaner. The reaction was monitored by LC / MS. After the reaction was completed, the solvent was evaporated, and the residue was dissolved in EtOAc and extracted with saturated aqueous NaHCO3 solution, 1 M citric acid, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 8% EtOAc / Hex to 45% EtOAc / Hex) to obtain the title compound (0.17 g, 75.9%).

[0137] Step 5: Preparation of 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetyl chloride (6)

[0138] To a solution of methyl 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetate (5) (0.16 g, 0.69 mmol) in THF / MeOH / H2O (1:2:2, 15 mL) was added LiOH·H2O (0.14 g, 3.45 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated, and the pH of the resulting suspension was adjusted to 4 with 1 M HCl. The aqueous mixture was extracted with EtOAc, dried over MgSO4, filtered, and evaporated to give 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.129 g, 86.4%). To a mixture of 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (78 mg, 0.36 mmol) in CH2Cl2 (3.6 mL) was added SOCl2 (1.8 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 h. The solvent was dried in vacuo to obtain the title compound (85 mg, quant.).

[0139] Step 6: Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetamide (M1)

[0140] To a solution of 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetyl chloride (6) (84 mg, 0.36 mmol) in DMF (2 mL) were added 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (7) (75 mg, 0.24 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature for 6 h. The reaction was monitored by LC / MS and TLC. After evaporating the solvent to obtain the desired compound, the residue was dissolved in EtOAc / MeOH, extracted with 1 M HCl, dried over MgSO4, neutralized with NaHCO3 (powder), concentrated and purified by silica gel column chromatography (Biotage, 0.1% Et3N in EtOAc to 0.1% Et3N / 5% MeOH in EtOAc) to obtain the title compound (60 mg, 49.4%).

[0141] Example 5. Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluorophenyl)-2-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)acetamide (M5)

[0142]

[0143] Step 1: Preparation of ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (9)

[0144] To a solution of ethyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (8) (1.22 g, 5.09 mmol) and Et3N (2.13 mL, 15.26 mmol) in THF (6 mL) was added phenylhydrazine (0.50 mL, 5.09 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min and then at 50 °C for 4 h. The reaction was monitored by LC / MS and TLC. The mixture was concentrated, dissolved in EtOAc, and washed with water. The organic layer was dried over MgSO4, concentrated, and purified by silica gel column chromatography (Biotage, Hex to 30% EtOAc / Hex) to give the title compound (0.304 g, 21.0%).

[0145] Step 2: Preparation of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride (10)

[0146] To a solution of ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (9) (0.29 g, 1.02 mmol) in THF / EtOH / H2O (1:2:2, 15 mL) was added LiOH·H2O (0.21 g, 5.10 mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated, and the resulting suspension was adjusted to pH 4 by adding 1 M HCl. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to give 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.261 g, quant.). To a mixture of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid in toluene (8 mL) was added SOCl2 (4 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 5 hours. After cooling to room temperature, the solvent was dried under vacuum to obtain the title compound (0.279 g, quant.).

[0147] Step 3: Preparation of 2-diazo-1-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethan-1-one (11)

[0148] To a mixture of crude 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride (10) (0.279 g, 1.02 mmol) in THF / AcCN (1:1, 6 mL) was added a 2.0 M solution of TMSCHN2 in hexane (1.52 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 5 h and then warmed to room temperature overnight. After stirring at room temperature, Et2O was added, and the mixture was extracted with 10% citric acid, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 8% EtOAc / Hex to 50% EtOAc / Hex) to give the title compound (0.226 g, 79.4%).

[0149] Step 4: Preparation of methyl 2-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)acetate (12)

[0150] 2-Diazo-1-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)ethan-1-one (11) (0.22 g, 0.79 mmol) was dissolved in anhydrous MeOH (10 mL). To the reaction solution was added a solution of AgOBz (60 mg, 0.24 mmol) in Et3N (0.4 mL, 3.14 mmol). The mixture was sonicated for 30 min at room temperature using an ultrasonic cleaner. The reaction was monitored by LC / MS. After the reaction was completed, the solvent was evaporated, and the residue was dissolved in EtOAc and extracted with saturated aqueous NaHCO3 solution, 1 M citric acid, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 8% EtOAc / Hex to 45% EtOAc / Hex) to obtain the title compound (0.163 g, 73.0%).

[0151] Step 5. Preparation of 2-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)acetic acid (13)

[0152] To a solution of methyl 2-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)acetate (12) (0.17 g, 0.60 mmol) in THF / MeOH / H2O (1:2:2, 10 mL) was added LiOH·H2O (0.13 g, 2.99 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 5 h. The solvent was evaporated, and the pH of the resulting suspension was adjusted to 4 with 1 M HCl. The aqueous mixture was extracted with EtOAc, dried over MgSO4, filtered, and evaporated to give the title compound (0.161 g, quant.).

[0153] Step 6. Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluorophenyl)-2-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)acetamide (M5)

[0154] To a solution of 2-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)acetic acid (13) (54 mg, 0.20 mmol) in DMF (2 mL) were added HATU (0.12 g, 0.31 mmol) and Et3N (0.11 mL, 0.76 mmol), followed by 4-((6,7-dimethoxyquinolin-4-yl)oxy)-2-fluoroaniline (14) (48 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at 50 °C overnight. The reaction was monitored by LC / MS and TLC. The reaction mixture was diluted with EtOAc and washed sequentially with 1 M HCl, saturated aqueous NaHCO3 solution, and brine. The organic solvent layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 0.1% Et3N / 20% Hex in EtOAc to 0.1% Et3N in EtOAc to 0.1% Et3N / 5% MeOH in EtOAc) to obtain the title compound (69 mg, 79.8%).

[0155] Example 13. Preparation of N-(5-((6,7-dimethoxyquinolin-4-yl)-oxy)pyrimidin-2-yl)-2-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)acetamide (M13)

[0156]

[0157] Step 1: Preparation of ethyl 5-isopropyl-1-phenyl-1H-pyrazole-4-carboxylate (16)

[0158] To a solution of phenylhydrazine (0.14 mL, 1.39 mmol) in EtOH (5 mL) were added ethyl (E)-2-((dimethylamino)methylene)-4-methyl-3-oxopentanoate (15) (0.444 g, 2.08 mmol) and K2CO3 (0.383 g, 2.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min and then at 65 °C overnight. The reaction was monitored by LC / MS and TLC. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over MgSO4, concentrated, and purified by silica gel column chromatography (Biotage, Hex to 10% EtOAc / Hex) to give the title compound (0.318 g, 88.7%).

[0159] Step 2: Preparation of 5-isopropyl-1-phenyl-1H-pyrazole-4-carbonyl chloride (17)

[0160] To a solution of ethyl 5-isopropyl-1-phenyl-1H-pyrazole-4-carboxylate (16) (0.53 g, 2.17 mmol) in THF / EtOH / H2O (1:2:2, 25 mL) was added LiOH·H2O (0.27 g, 6.51 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and then at 50 °C for 7 h. The solvent was evaporated, and the pH of the resulting suspension was adjusted to 4 with 1 M HCl. The aqueous mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to give 5-isopropyl-1-phenyl-1H-pyrazole-4-carboxylic acid (0.386 g, 96.2%). To a mixture of 5-isopropyl-1-phenyl-1H-pyrazole-4-carboxylic acid (0.72 g, 3.13 mmol) in toluene (30 mL) was added SOCl2 (15 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 5 h. After cooling to room temperature, the solvent was dried under vacuum to obtain the title compound (0.778 g, quant.).

[0161] Step 3: Preparation of 2-diazo-1-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)ethan-1-one (18)

[0162] Curd 5-isopropyl-1-phenyl-1H-pyrazole-4-carbonyl chloride (17) (0.778 g, 3.13 mmol) was dissolved in a THF / AcCN (1:1, 14 mL) mixture, and a 2.0 M solution of TMSCHN2 in hexane (4 mL) was added to the mixture at 0 °C. The reaction mixture was stirred at 0 °C for 8 h and then warmed to room temperature overnight. After stirring at room temperature, Et2O was added, and the mixture was extracted with 10% citric acid, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 8% EtOAc / Hex to 50% EtOAc / Hex) to give the title compound (0.41 g, 51.5%).

[0163] Step 4: Preparation of methyl 2-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)acetate (19)

[0164] 2-Diazo-1-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)ethan-1-one (18) (0.27 g, 1.06 mmol) was dissolved in anhydrous MeOH (10 mL). To the reaction solution was added a solution of AgOBz (80 mg, 0.32 mmol) in Et3N (0.6 mL, 4.25 mmol). The mixture was sonicated for 30 min at room temperature using an ultrasonic cleaner. The reaction was monitored by LC / MS. After the reaction was completed, the solvent was evaporated, and the residue was dissolved in EtOAc and extracted with saturated aqueous NaHCO3 solution, 1 M citric acid, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 8% EtOAc / Hex to 45% EtOAc / Hex) to obtain the title compound (0.159 g, 58.0%).

[0165] Step 5: Preparation of 2-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)acetyl chloride (20)

[0166] To a solution of methyl 2-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)acetate (19) (0.16 g, 0.62 mmol) in THF / MeOH / H2O (1:2:2, 15 mL) was added LiOH·H2O (0.13 g, 3.08 mmol) at room temperature, and the reaction mixture was stirred at 50 °C for 2 h. The solvent was evaporated, and the pH of the resulting suspension was adjusted to 4 with 1 M HCl. The aqueous mixture was extracted with EtOAc, dried over MgSO4, filtered, and evaporated to give 2-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.15 g, 99.8%). To a mixture of 2-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (64 mg, 0.26 mmol) in CH2Cl2 (1 mL) was added SOCl2 (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 h. The solvent was dried in vacuo to obtain the title compound (69 mg, quant.).

[0167] Step 6: Preparation of N-(5-((6,7-dimethoxyquinolin-4-yl)-oxy)pyrimidin-2-yl)-2-(5-isopropyl-1-phenyl-1H-pyrazol-4-yl)acetamide (M13)

[0168] 2-(5-Isopropyl-1-phenyl-1H-pyrazol-4-yl)acetyl chloride (20) (66 mg, 0.25 mmol) was dissolved in pyridine (2 mL) at 0 °C, and 5-((6,7-dimethoxyquinolin-4-yl)oxy)pyrimidin-2-amine (21) (58 mg, 0.19 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by LC / MS and TLC. The reaction mixture was diluted with EtOAc and washed with 1 M HCl, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 0.1% Et3N in EtOAc to 0.1% Et3N / 10% MeOH in EtOAc) to obtain the title compound (7 mg, 6.9%).

[0169] Example 17. Preparation of 2-(1-benzyl-5-ethyl-1H-pyrazol-4-yl)-N-(4-((6,7-dimethoxyquinolin―4―yl)oxy)-3-fluorophenyl)acetamide (M17)

[0170]

[0171] Step 1: Preparation of ethyl 1-benzyl-5-ethyl-1H-pyrazole-4-carboxylate (23)

[0172] To a solution of benzylhydrazine dihydrochloride (0.40 g, 2.05 mmol) in EtOH (8 mL) was added ethyl (E)-2-((dimethylamino)methylene)-3-oxopentanoate (22) (0.613 g, 3.08 mmol) at room temperature. After 10 min at room temperature, the reaction mixture was stirred under reflux for 2 h. The reaction was monitored by LC / MS and TLC. The mixture was concentrated and purified by silica gel column chromatography (Biotage, Hex to 10% EtOAc / Hex) to give the title compound (0.419 g, 79.1%, compound / isomer = 1:0.2).

[0173] Step 2: Preparation of (1-benzyl-5-ethyl-1H-pyrazol-4-yl)methanol (24)

[0174] To a solution of ethyl 1-benzyl-5-ethyl-1H-pyrazole-4-carboxylate (23) (0.54 g, 2.09 mmol) in anhydrous THF (4 mL) was added LiAlH4 (1.0 M in THF, 4.18 mL, 4.18 mmol) under Ar gas at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 30 min. The reaction was monitored by LC / MS and TLC. The mixture was diluted with EtOAc and quenched by the addition of saturated aqueous Na2SO4 solution at 0 °C. The resulting solid was filtered through a pad of Celite. The organic layer was dried over Na2SO4 and concentrated to give the title compound (0.452 g, crude).

[0175] Step 3: Preparation of (1-benzyl-5-ethyl-1H-pyrazol-4-yl)methyl methanesulfonate (25)

[0176] To a solution of (1-benzyl-5-ethyl-1H-pyrazol-4-yl)methanol (24) (0.444 g, 2.05 mmol) and TEA (0.57 mL, 4.11 mmol) in DCM (20 mL) was added MsCl (0.21 mL, 2.67 mmol) dropwise at 0 °C for 20 min. After addition, the reaction mixture was stirred under reflux for 2 h. After cooling to room temperature, the reaction mixture was observed by LC / MS and TLC. The mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, and concentrated to give the title compound (0.604 g, crude).

[0177] Step 4: Preparation of 2-(1-benzyl-5-ethyl-1H-pyrazol-4-yl)acetonitrile (26)

[0178] To a solution of (1-benzyl-5-ethyl-1H-pyrazol-4-yl)methyl methanesulfonate (25) (0.60 g, 2.04 mmol) in DMF (7 mL) were added 18-crown-6 (0.11 mL, 0.408 mmol) and NaCN (0.20 g, 4.08 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, then warmed to room temperature and stirred for 1 day. The reaction was monitored by LC / MS and TLC. The mixture was quenched with water, extracted with EtOAc, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, 100% Hex to 30% EtOAc in Hex) to give the title compound (0.15 g, 3 steps, 32.7%).

[0179] Step 5. Preparation of 2-(1-benzyl-5-ethyl-1H-pyrazol-4-yl)acetic acid (27)

[0180] To a solution of 2-(1-benzyl-5-ethyl-1H-pyrazol-4-yl)acetonitrile (26) (0.15 g, 0.67 mmol) in EtOH (5 mL) was added KOH (70 mg, 1.33 mmol). The reaction mixture was stirred under reflux overnight, concentrated, and diluted with water. The mixture was acidified to pH 4 with 1 M HCl, extracted with EtOAc, dried over MgSO4, and concentrated to give the title compound (60 mg, 37.0%).

[0181] Step 6: Preparation of 2-(1-benzyl-5-ethyl-1H-pyrazol-4-yl)-N-(4-((6,7-dimethoxyquinolin―4―yl)oxy)-3-fluorophenyl)acetamide (M17)

[0182] To a solution of 2-(1-Benzyl-5-ethyl-1H-pyrazol-4-yl)acetic acid (27) (40 mg, 0.17 mmol) in DMF (2 mL) were added HATU (0.10 g, 0.25 mmol) and Et3N (0.09 mL, 0.636 mmol), followed by 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluoroaniline (7) (40 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 3.5 days. The reaction was monitored by LC / MS and TLC. The reaction mixture was diluted with EtOAc and washed with 1 M citric acid, saturated aqueous NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (Biotage, EtOAc to 5% MeOH in EtOAc) to obtain the title compound (25 mg, 36.3%).

[0183] <Example 1> to <Example 20>

[0184] All other example compounds of the present invention were prepared in a similar manner to the above examples 1, 5, 13 or 17, and the compound name, chemical structure, properties, NMR, and MS analysis results of each example compound are summarized and shown in Table 1 below.

[0185] [Table 1]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191] Experimental Example 1. Evaluation of CSF1R kinase inhibitory activity

[0192] We commissioned Eurofins DiscoverX to perform a Kinase Dimerization Assay for CSF1R.50 Results were obtained (assay target: CSF1R, ligand: M-CSF, assay format: agonist). The results are shown in Table 2 below.

[0193] (1) Cell treatment

[0194] PathHunter cell lines were expanded from frozen stocks according to standard procedures. Cells were seeded in a total volume of 20 μL in white-walled 384-well microplates and cultured for the appropriate time before use.

[0195] (2) Agent format

[0196] To determine the agonist, cells were incubated with the sample to induce a response. An intermediate dilution of the sample stock was performed to generate a 5X sample in assay buffer. 5 μL of the 5X sample was added to the cells and incubated at room temperature for 3 hours. The vehicle concentration was 1%.

[0197] (3) Signal detection

[0198] For the agonist assay, 12.5 or 15 μL (50% v / v) of PathHunter detection reagent cocktail was added once and incubated at room temperature for 1 hour to generate an analytical signal. For chemiluminescent signal detection, a PerKinElmer Envision TM After signal generation using the device, the microplate was read.

[0199] (4) Data analysis

[0200] Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). For agonist mode analysis, % activity was calculated using the following formula:

[0201] % Activity = 100% x (Average RLU of test samples - Average RLU of control vehicle) / (Average maximum RLU of control ligand - Average RLU of control vehicle)

[0202] [Table 2]

[0203]

[0204] (A = IC 50 < 0.5; B = 0.5 < IC 50 < 2; C = IC 50 > 2)

[0205] Through the results of the above experimental examples, it was confirmed that the exemplary compounds of the present invention exhibited high inhibitory activity against CSF1R.

[0206] While the present invention has been described in detail through preferred embodiments and experimental examples, the scope of the present invention is not limited to the specific examples and should be interpreted in accordance with the appended claims. Furthermore, those skilled in the art will appreciate that numerous modifications and variations are possible without departing from the scope of the present invention.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X 1 Inland X 4 are each independently CR X or N; R X is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo; R N Silver -H or -C 1-6 It is alkyl; Ring U is a five-membered heteroaryl; R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C 1-6 alkynyl, -CN, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl, or null {wherein said 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl comprises one or more N, O or S atoms in the ring; and one or more H in said 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, or 5-6 membered heteroaryl ring is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 {which may be substituted with alkyl or -halo}; Q 1 Inland Q 3 are each independently CH or N; R Q1 and R Q2 are each independently -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -CN, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 Alkyl, or -halo.

2. In paragraph 1, X 1 Inland X 4 are each independently CR X or N; R X is -H or -halo; R N Silver -H or -C 1-6 It is alkyl; Ring U is a 5-membered heteroaryl {wherein said 5-membered heteroaryl contains two N atoms in the ring}; R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, phenyl, or benzyl, and {wherein, at least one H in the 3-6 membered cycloalkyl, phenyl, or benzyl ring is -C 1-6 Alkyl, -OC 1-6 {which may be substituted with alkyl or -halo}; Q 1 Inland Q 3 are each independently CH or N, {where, Q 1 and Q 2 {At least one of them is N}; R Q1 and R Q2 are each independently -OC 1-6 alkyl; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

3. A compound represented by the following chemical formula 2, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical formula 2] In the above chemical formula 2, X 1 and X 2 are each independently CR X or N; R X is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo; R X1 and R X2 are each independently -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo; R N Silver -H or -C 1-6 It is alkyl; Ring U is a five-membered heteroaryl; R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C 1-6 alkynyl, -CN, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, 5-6 membered heteroaryl, or null {wherein said 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl comprises one or more N, O or S atoms in the ring; and one or more H in said 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, benzyl, or 5-6 membered heteroaryl ring is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 {which may be substituted with alkyl or -halo}; Q 1 and Q 2 are each independently CH or N; R Q1 and R Q2 are each independently -OC 1-6 It's alkyl.

4. In paragraph 3, X 1 and X 2 are each independently CR X or N; R X is -H or -F; R X1 and R X2 are each independently -H or -F; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

5. In paragraph 3, The above ring U is , , , , , , or and; R U1 Inland R U3 are each independently -H, -C 1-6 Alkyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, phenyl, or benzyl {wherein, at least one H in the 3-6 membered cycloalkyl, phenyl, or benzyl ring is -C 1-6 Alkyl, -OC 1-6 {which may be substituted with alkyl or -halo}; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

6. In paragraph 3, Q 1 and Q 2 are each independently CH or N, {where, Q 1 and Q 2 {one of which is N}; R Q1 and R Q2 are each independently -OC 1-6 alkyl; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

7. A compound represented by the following chemical formula 3, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 3] In the above chemical formula 3, X 1 and X 2 are each independently CR X or N; R X is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo; R X1 and R X2 are each independently -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo; R N Silver -H or -C 1-6 It is alkyl; R U1 and R U2 are each independently -H, -C 1-6 Alkyl, -C 1-6 Aminoalkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Haloalkyl, -C 1-6 Alkenyl, -C 1-6 alkynyl, -CN, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 alkyl, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, and {wherein said 3-6 membered heterocycloalkyl comprises one or more N, O or S atoms in the ring; and one or more H in said 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl ring is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 {which may be substituted with alkyl or -halo}; n is 0, 1, 2, 3, or 4; R W is -C 1-6 Alkyl, -C 1-6 Hydroxyalkyl, -C 1-6 Aminoalkyl, -C 1-6 Haloalkyl, -NH 2 , -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -OH, -OC 1-6 Alkyl, or -halo; Q 1 and Q 2 are each independently CH or N; R Q3 and R Q4 are each independently -C 1-6 It's alkyl.

8. In paragraph 7, X 1 and X 2 are each independently CR X or N; R X is -H or -F; R X1 and R X2 are each independently -H or -F; R N Silver -H or -C 1-6 It is alkyl; R U1 and R U2 are each independently -H, -C 1-6 Alkyl, -C 1-6 haloalkyl, or a 3-6 membered cycloalkyl, wherein at least one H in the 3-6 membered cycloalkyl ring is -C 1-6 Alkyl, -C 1-6 {haloalkyl, or -halo, which may be substituted}; n is 0, 1, or 2; R W is -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -halo; Q 1 and Q 2 are each independently CH or N, {where, Q 1 and Q 2 {one of which is N}; R Q3 and R Q4 are each independently -C 1-6 alkyl; A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

9. A compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for treating or preventing cancer, comprising a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

12. In paragraph 11, A pharmaceutical composition wherein the compound treats or prevents cancer by inhibiting CSF1R.

13. In paragraph 11, The above cancers are pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, paranasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, A pharmaceutical composition comprising at least one selected from the group consisting of duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, pulmonary adenocarcinoma, lung cancer, pulmonary squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.

14. Use of a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment or prevention of a disease associated with CSF1R.

15. A method for treating or preventing a CSF1R-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 9, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

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