WO2024014851A1 - Hif-1 단백질 억제제로서의 신규한 퓨린 유도체 화합물 - Google Patents
Hif-1 단백질 억제제로서의 신규한 퓨린 유도체 화합물 Download PDFInfo
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- WO2024014851A1 WO2024014851A1 PCT/KR2023/009896 KR2023009896W WO2024014851A1 WO 2024014851 A1 WO2024014851 A1 WO 2024014851A1 KR 2023009896 W KR2023009896 W KR 2023009896W WO 2024014851 A1 WO2024014851 A1 WO 2024014851A1
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- purin
- cyclopentyl
- fluoro
- acetamide
- phenyl
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Definitions
- the present invention relates to novel purine derivatives, and more specifically, to purine derivative compounds as HIF-1 protein inhibitors or angiogenesis-inducing factor VEGF inhibitors, and pharmaceutical compositions containing the same for the prevention or treatment of related diseases.
- Hypoxia refers to various disease states caused by insufficient oxygen supply at the cellular level.
- HIF hypoxia inducible factor
- HIF- ⁇ ⁇ -subunit
- HIF- ⁇ structurally expressed ⁇ -subunit
- HIF- ⁇ plays the role of an important sensor that recognizes hypoxia in the human body.
- HIF-PH Hydrophilia-inducible factor Prolyl Hydroxylase
- a hydroxyl group is introduced into HIF- ⁇ , VHL (Von Hippel Lindau) is attached to it, and it is immediately decomposed by the proteasome through the ubiquitination process. Therefore, HIF- ⁇ , which is continuously produced in the human body, undergoes the above process under normal oxygen conditions and disappears as soon as it is created with a fast half-life of about 5 minutes, allowing the oxygen concentration to be recognized.
- Angiogenesis is the process of forming new capillaries from existing microvessels. Angiogenesis normally occurs during embryonic development, tissue regeneration and wound healing, and during the development of the corpus luteum, which is a periodic change in the female reproductive system. Even in these cases, it proceeds in a strictly controlled manner. In adults, vascular endothelial cells grow very slowly and do not divide relatively well compared to other types of cells.
- angiogenesis occurs is generally the breakdown of the vascular basement membrane by protease, migration and proliferation of vascular endothelial cells, and the formation of a lumen by vascular endothelial cell differentiation through stimulation of angiogenesis-promoting factors, resulting in blood vessels being reorganized and new capillaries forming. It consists of being created.
- angiogenesis diseases caused by angiogenesis not being regulated autonomously and growing pathologically.
- Diseases related to angiogenesis that occur in pathological conditions include hemangioma, angiofibroma, vascular malformation, and cardiovascular diseases such as arteriosclerosis, vascular adhesion, and edematous sclerosis.
- Eye diseases caused by angiogenesis include macular degeneration, corneal transplant angiogenesis, and vascular disease. These include angiogenic glaucoma, diabetic retinopathy, corneal disease caused by new blood vessels, spot degeneration, pterygium, retinal degeneration, posterior lens fibroplasia, and granular conjunctivitis.
- Chronic inflammatory diseases such as arthritis, psoriasis, telangiectasia, pyogenic granuloma, seborrheic dermatitis, dermatological diseases such as acne, Alzheimer's disease, and obesity are also related to angiogenesis, and cancer growth and metastasis are essentially related to angiogenesis.
- angiogenesis inhibitors can be applied as treatments for various angiogenesis-related diseases, research has recently been actively conducted to treat the above diseases by inhibiting angiogenesis.
- macular degeneration is an eye disease that causes vision impairment due to degeneration of the macula.
- the cause is known to be related to increasing age, family history, race, and smoking.
- vision becomes blurred and near vision becomes distorted, but later it leads to blindness.
- Age-related macular degeneration causes severe, irreversible vision loss and is known to be a major cause of blindness in people over 50 years of age.
- non-neovascular age-related macular degeneration is the most common and accounts for 85% of all age-related macular degeneration cases. This dry type is characterized by oily patches and atrophic changes in the retinal pigment epithelium.
- neovascular age-related macular degeneration which is characterized by choroidal neovascularization. Choroidal neovascularization tends to leak blood and fluid into newly formed blood vessels. This leads to the formation of lesions in which fibrous tissue proliferates and photoreceptors are lost in the retinal tissue, and continues to progress, causing severe and irreversible vision loss.
- neovascular age-related macular degeneration treatments for neovascular age-related macular degeneration include photodynamic therapy and intraocular injection of drugs to block vascular endothelial growth factor.
- VEGF vascular endothelial growth factor
- various anti-vascular endothelial growth factor drugs have been developed to treat neovascular age-related macular degeneration, the representative drug among which is Ranibizumab (Lucentis ® ), which binds to extracellular vascular endothelial growth factor and inhibits its activity. I order it.
- Ranibizumab has been reported to be an effective and safe treatment for patients with neovascular age-related macular degeneration through various clinical studies and is widely used around the world.
- the problem to be solved by the present invention is to provide a purine derivative compound with a novel structure that exhibits excellent inhibitory activity against HIF-1 ⁇ protein or the angiogenesis inducer VEGF.
- the problem of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases related to HIF-1 ⁇ protein or angiogenesis inducer VEGF, comprising the purine derivative compound of the novel structure.
- the problem of the present invention is to provide a method for preventing or treating diseases related to HIF-1 ⁇ protein or angiogenesis inducer VEGF, comprising administering the purine derivative compound of the novel structure to a subject in need. It is done.
- the problem of the present invention is the use of the purine derivative compound with the novel structure to produce a medicament for use in the prevention or treatment of diseases related to HIF-1 ⁇ protein or the angiogenesis inducer VEGF. is to provide.
- a purine derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof is provided.
- X 1 and X 2 are independently CH or N,
- X 3 and X 4 are independently C, CH or N, X 3 is optionally substituted with R 3 , X 4 is optionally substituted with R 4 ,
- Y is -C(O)-, or C 1-3 alkylene
- n is an integer from 0 to 3
- R 1 is C 3-7 cycloalkyl, or a 5- to 7-membered saturated heterocycle having 1 to 2 N, and R 1 is substituted or unsubstituted by one or more independent R a ,
- R a is C 1-4 alkyl or halogen
- R 2 is H; C 4-7 saturated or unsaturated cycloalkyl; C 5-7 aryl; or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, and R 2 is substituted or unsubstituted with R b ,
- R b is C 1-6 straight or branched chain alkyl; C 1-4 alkoxy, benzyloxy; halogen; C 1-4 haloalkyl; hydroxy; or aryl substituted or unsubstituted by halogen,
- R 3 is halogen or C 1-4 haloalkyl
- R 4 is halogen; or 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, wherein the heteroaryl may or may not be substituted with C 5-7 aryl, and at this time, the C 5-7 aryl is halogen. is replaced or not substituted.
- a disease related to HIF-1 ⁇ protein or the angiogenesis inducer VEGF comprising the purine derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- a pharmaceutical composition for the prevention or treatment of is provided.
- a HIF- A method for preventing or treating diseases related to 1 ⁇ protein or the angiogenesis inducer VEGF is provided.
- a formulation comprising a purine derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive is provided.
- novel purine derivative compound of the present invention exhibits an excellent inhibitory effect on the expression of HIF-1 ⁇ , a transcription factor stabilized in hypoxia, and the angiogenesis inducer VEGF, a downstream gene, thereby inducing HIF-1 ⁇ protein and angiogenesis. It has been found that it can be usefully used for the prevention or treatment of diseases related to factor VEGF.
- the present invention provides a purine derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
- X 1 and X 2 are independently CH or N,
- X 3 and X 4 are independently C, CH or N, X 3 is optionally substituted with R 3 , X 4 is optionally substituted with R 4 ,
- Y is -C(O)-, or C 1-3 alkylene
- n is an integer from 0 to 3
- R 1 is C 3-7 cycloalkyl, or a 5- to 7-membered saturated heterocycle having 1 to 2 N, and R 1 is substituted or unsubstituted by one or more independent R a ,
- R a is C 1-4 alkyl or halogen
- R 2 is H; C 4-7 saturated or unsaturated cycloalkyl; C 5-7 aryl; or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from the group consisting of N, O and S, and R 2 is substituted or unsubstituted with R b ,
- R b is C 1-6 straight or branched chain alkyl; C 1-4 alkoxy, benzyloxy; halogen; C 1-4 haloalkyl; hydroxy; or aryl substituted or unsubstituted by halogen,
- R 3 is halogen or C 1-4 haloalkyl
- R 4 is halogen; or 5- or 6-membered heteroaryl having 1 to 3 heteroatoms, wherein the heteroaryl may or may not be substituted with C 5-7 aryl, and at this time, the C 5-7 aryl is halogen. is replaced or not substituted.
- alkyl refers to a straight-chain or branched-chain saturated hydrocarbon, preferably C 1-10 alkyl.
- the alkyl is methyl, ethyl, n -propyl, iso -propyl, n -butyl, iso -butyl, tert -butyl, n -pentyl, iso -pentyl, n -hexyl, 3-methylhexyl, 2, It includes, but is not limited to, 2-dimethylpentyl, 2,3-dimethylpentyl, n -heptyl, n -octyl, n -nonyl, and n -decyl.
- alkylene refers to a divalent functional group derived from an alkyl group, and preferably contains 1 to 10 carbon atoms, but is not limited thereto.
- alkylene include -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 - and -CH 2 CH 2 CH 2 CH 2 CH 2 -, etc. This includes, but is not limited to.
- cycloalkyl refers to a partially or fully saturated single or fused ring cyclic hydrocarbon, preferably C 3-10 cycloalkyl. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexinyl, etc.
- hydroxy or "hydroxy” is defined as -OH, and the term “alkoxy”, unless otherwise defined, is an alkyl radical in which the hydrogen atom of the hydroxy group is substituted with 1 to 10 alkyl atoms. It means Oxy.
- halogen or “halo” means fluorine/fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
- haloalkyl means alkyl substituted with one or more halogen atoms.
- heteroatom means N, O or S.
- aryl refers to an aromatic hydrocarbon and includes polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other rings.
- C 5 -C 12 aryl Preferably C 5 -C 10 aryl.
- the aryl includes phenyl, naphthyl, tetrahydronaphthyl, etc., but is not limited thereto.
- heteroaryl or “aromatic heterocycle” refers to a single or It refers to a 3- to 12-membered, more preferably 5- to 10-membered aromatic hydrocarbon forming a fused ring.
- the heteroaryl includes pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, and indole.
- Li indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thiophenyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl. It includes, but is not limited to, etc.
- X 1 may be CH or N
- X 2 may be N
- Y may be -C(O)- or -CH 2 -.
- n may be 0 or 1.
- R 1 may be cyclobutyl, cyclopentyl, cyclohexyl, or piperidinyl.
- R a may be methyl or F.
- R 2 is H, cyclopentyl, cyclopentenyl; phenyl; It may be pyrrolyl, thiophenyl, furanyl, pyrazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyridazinyl.
- R b may be methyl, propyl, isopropyl, methoxy, benzyloxy, F, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxy, or fluorophenyl.
- R 3 may be F, Br, or trifluoromethyl.
- R 4 may be F or fluorophenyl-pyrazole.
- purine derivative compounds according to the present invention are as follows:
- the compound represented by Formula I according to the present invention can be prepared and used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, so the above prodrug, Hydrates, solvates and pharmaceutically acceptable salts are also within the scope of the present invention.
- prodrug refers to a substance that is transformed in vivo into the parent drug. Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioactive by oral administration, whereas the parent drug may not be. A prodrug may also have improved solubility in a pharmaceutical composition than the parent drug. For example, prodrugs may be in vivo hydrolyzable esters of compounds according to the invention and pharmaceutically acceptable salts thereof. Another example of a prodrug may be a short peptide (polyamino acid) in which the peptide is linked to an acid group that is metabolically converted to reveal the active site.
- polyamino acid polyamino acid
- hydrate refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt.
- isomers refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different.
- isomers include both structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers and geometric isomers (trans, cis). All these isomers and mixtures thereof are also included within the scope of the present invention.
- pharmaceutically acceptable salt refers to a salt form of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.
- the pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, etc.
- Organic carboxylic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed by sulfonic acids and the like are included.
- carboxylic acid salts include metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N- Organic salts such as methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine are included.
- the compound of formula I according to the present invention can also be converted into its salt by conventional methods.
- Examples 1 to 42 are shown as examples of the method for producing the compound of Formula I of the present invention, and the synthesis methods of Examples 1 to 42 are the methods of producing the compound of Formula I according to the present invention. It is not limited. It is obvious that the synthesis methods of Examples 1 to 42 are merely examples and can be easily modified by those skilled in the art depending on the specific substituent.
- the present invention also provides a method for preventing or treating diseases related to HIF-1 ⁇ protein or the angiogenesis inducer VEGF, comprising the purine derivative compound represented by Formula I, its hydrate, solvate, or pharmaceutically acceptable salt thereof as an active ingredient.
- a pharmaceutical composition for therapeutic use is provided.
- the present invention also provides HIF-1 ⁇ protein or blood vessel comprising the step of administering a purine derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof to a subject in need.
- a method for preventing or treating diseases related to the angiogenic factor VEGF is provided.
- the present invention also provides a purine derivative compound represented by Formula I, a hydrate thereof, and a solvate thereof for producing a medicament for use in the prevention or treatment of diseases related to HIF-1 ⁇ protein or the angiogenesis inducer VEGF. Or the use of a pharmaceutically acceptable salt thereof is provided.
- the prevention or treatment of diseases related to the HIF-1 ⁇ protein or the angiogenesis inducer VEGF may be by inhibiting angiogenesis.
- the inhibition of angiogenesis may be due to inhibition of HIF-1 ⁇ expression or inhibition of VEGF expression.
- the disease related to the HIF-1 ⁇ protein or the angiogenesis inducer VEGF is stroke, brainstem glioma, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, liver cancer, stomach cancer, breast cancer, colon cancer, bone cancer, pancreatic cancer, head or Cervical cancer, ovarian cancer, rectal cancer, colon cancer, esophageal cancer, small intestine cancer, perianal cancer, colon cancer, skin cancer, fallopian tube carcinoma, endometrial carcinoma, uterine cancer, vaginal carcinoma, genital carcinoma, Hodgkin's disease, oral cancer, prostate cancer, testicular cancer, bladder cancer , kidney cancer, ureteral cancer, small cell carcinoma, renal pelvic carcinoma, medulloblastoma, neuroblastoma, brain tumor, central nervous system tumor, melanoma, non-small cell lung cancer, lymphoma, non-Hodgkin lymphoma, cancer, cervical cancer, thyroid cancer
- Dermatitis Alzheimer's disease, Parkinson's disease, Huntington's disease, thyroiditis, Graves' orbitopathy, leukomalacia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myeloid leukemia, multiple myeloma, inflammatory bowel disease, Crohn's disease , ulcerative colitis, and Behcet's enteritis.
- the disease related to the HIF-1 ⁇ protein or the angiogenesis inducer VEGF may be a neovascular eye disease, and the neovascular eye disease includes corneal neovascularization, retinal neovascularization, choroidal neovascularization, intraocular neovascularization, It may be one or more types selected from the group consisting of neovascular glaucoma, proliferative diabetic retinopathy, neovascular macular degeneration, and retinopathy of prematurity.
- the present invention also provides a formulation comprising a purine derivative compound represented by Formula I, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
- the additive may include a pharmaceutically acceptable carrier or diluent, and can be used in oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, eye drops, and suppositories according to conventional methods. and can be formulated in the form of a sterile injectable solution.
- a pharmaceutically acceptable carrier or diluent such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, topical preparations, eye drops, and suppositories according to conventional methods. and can be formulated in the form of a sterile injectable solution.
- the pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, and microcrystalline. Contains cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It also includes diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
- Oral solid preparations include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient, such as starch, calcium carbonate, sucrose, or lactose. ), gelatin, etc., and may include lubricants such as magnesium stearate and talc.
- Oral liquid preparations include suspensions, oral solutions, emulsions, syrups, etc., and may include diluents such as water and liquid paraffin, humectants, sweeteners, fragrances, and preservatives.
- Parenteral preparations include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, freeze-dried preparations, and suppositories.
- Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, and vegetable oils such as olive oil. Includes injectable esters such as oil and ethyl oleate.
- injectable esters such as oil and ethyl oleate.
- As a base for suppositories witepsol, macrogol, tween 61, cacao, laurel, glycerogelatin, etc. can be used.
- the dosage of the active ingredient contained in the pharmaceutical composition of the present invention varies depending on the patient's condition and weight, degree of disease, form of the active ingredient, route and period of administration, and can be appropriately adjusted depending on the patient.
- the active ingredient can be administered at a dose of 0.0001 to 1000 mg/kg per day, preferably 0.01 to 100 mg/kg, and the administration may be administered once a day or in divided doses.
- the pharmaceutical composition of the present invention may contain the active ingredient at a weight percentage of 0.001 to 90% based on the total weight of the composition.
- the pharmaceutical composition of the present invention is administered to mammals such as rats, mice, livestock, and humans by various routes, for example, orally, through the skin, in the abdominal cavity, in the rectum, or intravenously, in muscle, subcutaneously, intrauterine dura, or intracerebrovascularly (intracerebroventricular). ) can be administered by injection.
- Step 2 8-cyclopentyl-7H-purin-6-amine [8-cyclopentyl-7H-purin-6-amine]
- 6-Chloro-8-cyclopentyl-7H-purine (1.84 g, 6.26 mmol) was added to 7 N NH 3 methanol solution (in MeOH, 30 mL) and reacted at 80°C for 48 hours. After completion of the reaction, the reaction mixture was concentrated and aq. After basification with an aqueous K 2 CO 3 solution, the water layer was extracted with CH 2 Cl 2 and the organic layer was dried with Na 2 SO 4 and filtered under reduced pressure. After concentration, the obtained residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to obtain the target compound. (980 mg, 77%) was obtained as a white solid.
- Step 1 2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetic acid [2-(3-fluoro-5-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide]
- Step 1 2-(3-fluoro-5-(thiophen-3-yl)phenyl)acetic acid [2-(3-fluoro-5-(thiophen-3-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiophen-3-yl)phenyl)acetamide [N-(8- cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiophen-3-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (35 mg, 0.17 mmol), 2-(3-fluoro-5-(thiophen-3-yl)phenyl)
- the target compound (6.0 mg, 8%) was obtained using acetic acid (41 mg, 0.17 mmol) and T3P (50 wt.% solution (in EtOAc), 332 mg, 0.52 mmol).
- Step 1 2-(5-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)acetic acid [2-(5-fluoro-4'-methyl-[1,1' -biphenyl]-3-yl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(5-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)acetama id [N-(8-cyclopentyl-7H-purin-6-yl)-2-(5-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (35 mg, 0.17 mmol), 2-(5-fluoro-4'-methyl-[1,1'-bi)
- the target compound 13 mg, 18%) was obtained using phenyl]-3-yl)acetic acid (50 mg, 0.20 mmol) and T3P (50 wt.% solution (in EtOAc), 332 mg, 0.52 mmol).
- Step 1 4-chloro-2-cyclopentyl-3H-imidazo[4,5-c]pyridine [4-chloro-2-cyclopentyl-3H-imidazo[4,5-c]pyridine]
- Step 2 2-cyclopentyl-3H-imidazo[4,5-c]pyridin-4-amine [2-cyclopentyl-3H-imidazo[4,5-c]pyridin-4-amine]
- the water layer was separated, adjusted to pH 8 ⁇ 9 with 1N NaOH, and extracted with EtOAc.
- the organic layer was separated, dried over MgSO 4 and concentrated, and the obtained residue was subjected to silica gel column (5% MeOH in CH 2 Cl 2 ) to obtain the target compound (3 mg, 0.8%).
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrrol-2-yl)phenyl)acetamide [ N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrrol-2-yl)phenyl)acetamide]
- Step 1 2-(3-fluoro-5-(pyrimidin-5-yl)phenyl)acetic acid [2-(3-fluoro-5-(pyrimidin-5-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyrimidin-5-yl)phenyl)acetamide [N-(8- cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyrimidin-5-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (20 mg, 0.099 mmol), 2-(3-fluoro-5-(pyrimidin-5-yl)phenyl)
- the target compound (7.6 mg, 19%) was obtained using acetic acid (23 mg, 0.099 mmol), T3P (50 wt.% solution (in EtOAc), 95 mg, 0.30 mmol), and DIPEA (34 ⁇ L, 0.20 mmol).
- Step 1 2-(3-fluoro-5-(1-methyl-1H-pyrrol-3-yl)phenyl)acetic acid [2-(3-fluoro-5-(1-methyl-1H-pyrrol-3) -yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrrol-3-yl)phenyl)acetamide [ N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrrol-3-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (29 mg, 0.14 mmol), 2-(3-fluoro-5-(1-methyl-1H-pyrrole-3) -1) Phenyl) acetic acid (40 mg, 0.17 mmol), T3P (50 wt.% solution (in EtOAc), 140 mg, 0.43 mmol), and DIPEA (37 ⁇ L, 0.29 mmol) were used to prepare the target compound (25 mg, 42 mg) %) was obtained.
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(furan-2-yl)phenyl)acetamide [N-(8-cyclopentyl) -7H-purin-6-yl)-2-(3-fluoro-5-(furan-2-yl)phenyl)acetamide]
- Step 1 2-(3-fluoro-5-(1-isopropyl-1H-pyrazol-4-yl)phenyl)acetic acid [2-(3-fluoro-5-(1-isopropyl-1H-pyrazol) -4-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-isopropyl-1H-pyrazol-4-yl)phenyl)acetama [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-isopropyl-1H-pyrazol-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (35 mg, 0.17 mmol), 2-(3-fluoro-5-(1-isopropyl-1H-pyrazole) -4-yl)phenyl)acetic acid (41 mg, 0.16 mmol) and T3P (50wt.% solution (in EtOAc), 332 mg, 0.52 mmol) were used to obtain the target compound. (6.9 mg, 9%) was obtained.
- Step 1 2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)acetic acid [2-(3-(1-(difluoromethyl)-1H -pyrazol-4-yl)-5-fluorophenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-fluoro Phenyl)acetamide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (48 mg, 0.26 mmol), 2-(3-(1-(difluoromethyl)-1H-pyrazole- 4-yl)-5-fluorophenyl)acetic acid (75 mg, 0.28 mmol) and T3P (50wt.% solution (in EtOAc), 455 mg, 0.71 mmol) were used to prepare the target compound. (13 mg, 11%) was obtained.
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1H-pyrrol-2-yl)phenyl)acetamide [N-(8 -cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1H-pyrrol-2-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (31 mg, 0.15 mmol), 2-(3-fluoro-5-(1H-pyrrol-2-yl)phenyl )
- the target compound (12 mg, 19%) was obtained using acetic acid (40 mg, 0.18 mmol), T3P (50 wt.% solution (in EtOAc), 150 mg, 0.24 mmol), and DIPEA (39 ⁇ L, 0.30 mmol).
- Step 1 2-(3-fluoro-5-(isothiazol-4-yl)phenyl)acetic acid [2-(3-fluoro-5-(isothiazol-4-yl)phenyl)acetic acid]
- Step 2 N-(8-Cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(isothiazol-4-yl)phenyl)acetamide [N-(8 -cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(isothiazol-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (35 mg, 0.17 mmol), 2-(3-fluoro-5-(isothiazol-4-yl)phenyl ) Acetic acid (49 mg, 0.21 mmol), T3P (50wt.% solution (in EtOAc), 160 mg, 0.26 mmol), DIPEA (45 ⁇ L , 0.34 mmol), and EtOAc (2 mL ) were used to prepare the target compound (25 mg, 42%) was obtained.
- Step 1 2-(3-fluoro-5-(thiazol-5-yl)phenyl)acetic acid [2-(3-fluoro-5-(thiazol-5-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiazol-5-yl)phenyl)acetamide [N-(8- cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiazol-5-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (35 mg, 0.17 mmol), 2-(3-fluoro-5-(thiazol-5-yl)phenyl)
- the target compound was prepared using acetic acid (50 mg, 0.21 mmol) and T3P (50wt.% solution (in EtOAc), 332 mg, 0.52 mmol). (3.5 mg, 5%) was obtained.
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyridin-4-yl)phenyl)acetamide [N-(8-cyclopentyl) -7H-purin-6-yl)-2-(3-fluoro-5-(pyridin-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (35 mg, 0.17 mmol), 2-(3-fluoro-5-(pyridin-4-yl)phenyl)acetic acid
- the target compound (20 mg) was obtained using (50 mg, 0.22 mmol) and T3P (50 wt.% solution (in EtOAc), 332 mg, 0.52 mmol).
- Step 1 2-(3-fluoro-5-(pyridin-3-yl)phenyl)acetic acid [2-(3-fluoro-5-(pyridin-3-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyridin-3-yl)phenyl)acetamide [N-(8-cyclopentyl) -7H-purin-6-yl)-2-(3-fluoro-5-(pyridin-3-yl)phenyl)acetamide] ⁇
- Step 1 2-(4'-(benzyloxy)-5-fluoro-[1,1'-biphenyl]-3-yl)acetic acid [2-(4'-(benzyloxy)-5-fluoro- [1,1'-biphenyl]-3-yl)acetic acid]
- Step 2 2-(4'-(benzyloxy)-5-fluoro-[1,1'-biphenyl]-3-yl)-N-(8-cyclopentyl-7H-purin-6-yl ) Acetamide [2-(4'-(benzyloxy)-5-fluoro-[1,1'-biphenyl]-3-yl)-N-(8-cyclopentyl-7H-purin-6-yl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (53 mg, 0.26 mmol), 2-(4'-(benzyloxy)-5-fluoro-[1,1 '-Biphenyl]-3-yl)acetic acid (88 mg, 0.26 mmol), T3P (50wt.% solution (in EtOAc), 470 ⁇ L, 0.78 mmol), and DIPEA (89 ⁇ L, 0.52 mmol) were used to obtain the target compound. (30 mg, 22%) was obtained.
- Step 1 2-(3-(cyclopent-1-en-1-yl)-5-fluorophenyl)acetic acid [2-(3-(cyclopent-1-en-1-yl)-5-fluorophenyl )acetic acid]
- Step 2 2-(3-(Cyclopent-1-en-1-yl)-5-fluorophenyl)-N-(8-cyclopentyl-7H-purin-6-yl)acetamide [2 -(3-(cyclopent-1-en-1-yl)-5-fluorophenyl)-N-(8-cyclopentyl-7H-purin-6-yl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (37 mg, 0.18 mmol), 2-(3-(cyclopent-1-en-1-yl)-5- Fluorophenyl)acetic acid (40 mg, 0.18 mmol), T3P (50wt.% solution (in EtOAc), 320 ⁇ L, 0.55 mmol), and DIPEA (62 ⁇ L, 0.36 mmol) were used to prepare the target compound (25 mg, 33%). ) was obtained.
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiophen-2-yl)phenyl)acetamide [N-(8- cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiophen-2-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (37 mg, 0.18 mmol), 2-(3-fluoro-5-(thiophen-2-yl)phenyl)
- the target compound 24 mg, 31%) was prepared using acetic acid (43 mg, 0.18 mmol), T3P (50 wt.% solution (in EtOAc), 320 ⁇ L , 0.55 mmol), and DIPEA (62 ⁇ L , 0.36 mmol). got it
- Step 1 2-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetic acid [2-(3-(1-methyl-1H-pyrazol- 4-yl)-5-(trifluoromethyl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl ) Acetamide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (28 mg, 0.14 mmol), 2-(3-(1-methyl-1H-pyrazol-4-yl)- Using 5-(trifluoromethyl)phenyl)acetic acid (45 mg, 0.16 mmol), 50% T3P (50wt.% solution (in EtOAc), 275 mg, 0.42 mmol), DIPEA (51 ⁇ L , 0.29 mmol) The target compound (13 mg, 20%) was obtained.
- Step 1 2-(3-fluoro-5-(1-methyl-1H-pyrazol-3-yl)phenyl)acetic acid [2-(3-fluoro-5-(1-methyl-1H-pyrazol- 3-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-3-yl)phenyl)acetamide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-3-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (58 mg, 0.28 mmol), 2-(3-fluoro-5-(1-methyl-1H-pyrazole- 3-yl) phenyl) acetic acid (73 mg, 0.31 mmol), T3P, 50wt.% solution (in EtOAc) (553 mg, 0.87 mmol), and DIPEA (121 ⁇ L , 0.21 mmol) were used to prepare the target compound (13 mg) , 11%) was obtained.
- Step 1 2-(3-fluoro-5-(pyridazin-4-yl)phenyl)acetic acid [2-(3-fluoro-5-(pyridazin-4-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyridazin-4-yl)phenyl)acetamide [N-(8- cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyridazin-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (18 mg, 0.086 mmol), 2-(3-fluoro-5-(pyridazin-4-yl)phenyl)
- the target compound 25 mg, 68%) was prepared using acetic acid (20 mg, 0.086 mmol), T3P, 50 wt.% solution (in EtOAc) (150 ⁇ L , 0.26 mmol), and DIPEA (29 ⁇ L , 0.17 mmol). synthesized.
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (35 mg, 0.17 mmol), 2-(4-fluoro-3-(1-methyl-1H-pyrazole- 4-yl) phenyl) acetic acid (42 mg, 0.18 mmol), T3P, 50wt.% solution (in EtOAc) (365 mg, 0.57 mmol), and DIPEA (79 ⁇ L , 0.14 mmol) were used to prepare the target compound (20 mg) , 28%) was obtained.
- Step 1 2-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)acetic acid [2-(3-fluoro-5-(1-( trifluoromethyl)-1H-pyrazol-4-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazole-4-yl) Phenyl)acetamide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (20 mg, 0.098 mmol), 2-(3-fluoro-5-(1-(trifluoromethyl)- 1H-pyrazol-4-yl) phenyl) acetic acid (27 mg, 0.093 mmol), T3P (50 wt.% solution (in EtOAc), 181 mg, 0.28 mmol), DIPEA (41 ⁇ L, 0.24 mmol) for the purpose. Compound (11 mg, 24%) was obtained.
- Step 1 2-(3-fluoro-5-(2-methoxypyridin-4-yl)phenyl)acetic acid [2-(3-fluoro-5-(2-methoxypyridin-4-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(2-methoxypyridin-4-yl)phenyl)acetamide [N- (8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(2-methoxypyridin-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (0.193 mmol), 2-(3-fluoro-5-(2-methoxypyridin-4-yl)phenyl)
- the target compound (20 mg, 31%) was obtained using acetic acid (39 mg, 0.19 mmol), T3P (50 wt.% solution (in EtOAc), 337 mg, 0.53 mmol), and DIPEA (81 u L, 0.47 mmol).
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)acetamide [ N-(8-cyclopentyl-7H-purin-6-yl)-2-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (20 mg, 0.1 mmol), 2-(5-(1-methyl-1H-pyrazol-4-yl)pyridine -3-day)
- the target compound (1.5 mg, 4%) was obtained using acetic acid (20 mg, 0.1 mmol), T3P (50 wt.% solution (in EtOAc), 181 mg), and DIPEA (41 uL).
- Step 1 2-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)acetic acid [2-(2-(1-methyl-1H-pyrazol-4-yl)pyridin -4-yl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)acetamide [ N-(8-cyclopentyl-7H-purin-6-yl)-2-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)acetamide]
- Step 2 8-cyclohexyl-7H-purin-6-amine [8-cyclohexyl-7H-purin-6-amine]
- step 2 of Example 1 8-cyclohexyl-7H-purin-6-amine (20mg, 0.092 mmol), 2-(3-(1-(difluoromethyl)-1H-pyrazole-4 -yl)-5-fluorophenyl)acetic acid (27 mg, 0.092 mmol), T3P (50wt.% solution (in EtOAc), 181 mg, 0.28 mmol), DIPEA (41 ⁇ L , 0.24 mmol), ethyl acetate ( 4 mL) to obtain the target compound (10 mg, 23%).
- Step 1 8-(piperidin-1-yl)-7H-purin-6-amine [8-(piperidin-1-yl)-7H-purin-6-amine]
- Step 2 2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(8-(piperidin-1-yl)-7H-purine- 6-yl)acetamide [2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(8-(piperidin-1-yl)-7H-purin- 6-yl)acetamide]
- Step 1 2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid [2-(3-fluoro-5-(1-) (4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid]
- Step 2 N-(8-Cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl )Phenyl)acetamide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl )acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (42 mg, 0.21 mmol), 2-(3-fluoro-5-(1-(4-fluorophenyl) -1H-pyrazol-4-yl)phenyl)acetic acid (65 mg, 0.21 mmol), T3P (50wt.% solution (in EtOAc), 428 mg, 0.66 mmol), DIPEA (93 ⁇ L , 0.54 mmol) The target compound (25 mg, 24%) was obtained as a brown solid.
- Step 1 2-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid [2-(3-fluoro-4-(1-) (4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-4- (1-(4-fluorophenyl)-1H-pyrazol-4-yl )Phenyl)acetamide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl )acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (30 mg, 0.15 mmol), 2-(3-fluoro-4-(1-(4-fluorophenyl) -1H-pyrazol-4-yl)phenyl)acetic acid (45 mg, 0.15 mmol), T3P (50wt.% solution (in EtOAc), 300 mg, 0.46 mmol), DIPEA (65 ⁇ L , 0.38 mmol) The target compound (18 mg, 24%) was obtained as a white solid.
- Step 1 2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid [2-(4-(1-(4-fluorophenyl)-1H-pyrazol -4-yl)phenyl)acetic acid]
- Step 2 N-(8-cyclopentyl-7H-purin-6-yl)-2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetama Ide [N-(8-cyclopentyl-7H-purin-6-yl)-2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-cyclopentyl-7H-purin-6-amine (42 mg, 0.21 mmol), 2-(4-(1-(4-fluorophenyl)-1H-pyrazole -4-yl)phenyl)acetic acid (65 mg, 0.22 mmol), T3P (50wt.% solution (in EtOAc), 428 mg, 0.66 mmol), and DIPEA (93 ⁇ L , 0.54 mmol) were used to prepare the target compound (25 mg, 25%) was obtained as a white solid.
- 6-Chloro-8-cyclopentyl-7H-purine 51 mg, 0.23 mmol
- 2-(3-bromophenyl)ethanamine 36 ⁇ L, 0.25 mmol
- DIPEA 117 ⁇ L, 0.69 mmol
- EtOH 4.6 mL
- the reaction mixture was quenched with H 2 O, extracted with EtOAc, and the organic layer was dried over MgSO 4 and filtered under reduced pressure.
- the concentrated residue was purified by silica gel column chromatography (0 ⁇ 100 % EtOAc in n-Hex) to obtain the target compound (62 mg, 70.3%) as a light yellow solid.
- Step 1 6-chloro-8-(3,3-difluorocyclopentyl)-7H-purine [6-chloro-8-(3,3-difluorocyclopentyl)-7H-purine]
- Step 2 8-(3,3-difluorocyclopentyl)-7H-purin-6-amine [8-(3,3-difluorocyclopentyl)-7H-purin-6-amine]
- Step 3 N-(8-(3,3-difluorocyclopentyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazole- 4-yl)phenyl)acetamide [N-(8-(3,3-difluorocyclopentyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetamide]
- step 2 of Example 1 8-(3,3-difluorocyclopentyl)-7H-purin-6-amine (30 mg, 0.15 mmol), 2-(3-fluoro-5-( 1-methyl-1H-pyrazol-4-yl)phenyl)acetic acid (73 mg, 0.31 mmol), T3P (50 wt.% solution (in EtOAc), 212 mg, 0.34 mmol), DIPEA (48 ⁇ L , 0.28 mmol) ) was used to obtain the target compound (6 mg, 11%) as a yellow solid.
- step 2 of Example 1 8-(3,3-difluorocyclopentyl)-7H-purin-6-amine (30 mg, 0.15 mmol), 2-(3-fluoro-5-( 1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid (97 mg, 0.31 mmol), T3P (50wt.% solution (in EtOAc), 212 mg, 0.34 mmol), DIPEA ( The target compound (33 mg, 49%) was obtained as a yellow solid using 48 ⁇ L , 0.28 mmol).
- Step 1 6-chloro-8-(3,3-difluorocyclobutyl)-7H-purine [6-chloro-8-(3,3-difluorocyclobutyl)-7H-purine]
- Step 2 8-(3,3-difluorocyclobutyl)-7H-purin-6-amine [8-(3,3-difluorocyclobutyl)-7H-purin-6-amine]
- Step 3 N-(8-(3,3-difluorocyclobutyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazole- 4-yl)phenyl)acetamide [N-(8-(3,3-difluorocyclobutyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol- 4-yl)phenyl)acetamide]
- step 2 of Example 1 8-(3,3-difluorocyclobutyl)-7H-purin-6-amine (20 mg, 0.089 mmol), 2-(3-fluoro-5-( 1-methyl-1H-pyrazol-4-yl)phenyl)acetic acid (52 mg, 0.22 mmol), T3P (50 wt.% solution (in EtOAc), 151 mg, 0.24 mmol), DIPEA (34 ⁇ L , 0.20 mmol) ) to obtain the target compound (1.8 mg, 4.5%) as a yellow solid.
- step 2 of Example 1 8-(3,3-difluorocyclobutyl)-7H-purin-6-amine (20 mg, 0.089 mmol), 2-(3-fluoro-5-( 1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid (69 mg, 0.22 mmol), T3P (50wt.% solution (in EtOAc), 151 mg, 0.24 mmol), DIPEA ( The target compound (9.6 mg, 21%) was obtained as a yellow solid using 34 ⁇ L , 0.20 mmol).
- Step 1 6-chloro-8-(3,3-dimethylcyclobutyl)-7H-purine [6-chloro-8-(3,3-dimethylcyclobutyl)-7H-purine]
- Step 2 8-(3,3-dimethylcyclobutyl)-7H-purin-6-amine [8-(3,3-dimethylcyclobutyl)-7H-purin-6-amine]
- Step 3 N-(8-(3,3-dimethylcyclobutyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-(4-fluorophenyl)- 1H-pyrazol-4-yl)phenyl)acetamide [N-(8-(3,3-dimethylcyclobutyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-( 4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
- step 2 of Example 1 8-(3,3-dimethylcyclobutyl)-7H-purin-6-amine (47 mg, 0.22 mmol), 2-(3-fluoro-5-(1) -(4-Fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid (102 mg, 0.32 mmol), T3P (50wt.% solution (in EtOAc), 412 mg, 0.65 mmol) was dissolved in DIPEA (92 ⁇ L, 0.54 mmol) and EtOAc (2 mL) to obtain the target compound (18 mg, 16%) as a light brown solid.
- ARPE-19 cells Human retinal pigment epithelial cells: ATCC CRL-2302
- DMEM/F12 LM002-08
- FBS Fetal Bovine Serum, 16000-044, Gibco
- Welgene fetal bovine serum
- hypoxia is a very important indicator, and the expression of downstream genes is regulated by HIF-1 ⁇ , a transcription factor that is stabilized under hypoxia.
- HIF-1 ⁇ a transcription factor that is stabilized under hypoxia.
- the mixed hypoxic condition was used in the HIF-1 ⁇ stability test as it induces hypoxia with 1% oxygen and increases the stability of HIF-1 ⁇ with cobalt chloride (CoCl 2 , Cobalt(II) Chloride).
- Each example compound was diluted in DMEM/F12 medium without fetal bovine serum, pretreated for 16 hours or 2 hours, and cultured in mixed hypoxia for 1 hour or 24 hours.
- the cell medium was discarded and quickly treated with protein lysis buffer (RIPA Lysis and Extraction buffer, Thermo Fisher Scientific) to obtain protein lysate.
- LDS (4X BoltTM LDS Sample buffer) and reducing agent (10X BoltTM Sample Reducing Agent) were added to the protein lysate and heated at 70°C for 10 minutes.
- the lysate was separated by electrophoresis on a 4-12% Bis-Tris gel, transferred to a PVDF membrane, and blocked with 3% BSA (Albumin, Bovine, Fraction V, MPbio).
- Anti-HIF-1 ⁇ (ab179483, abcam) and anti-b-actin (MA515739, Invitrogen TM ) antibodies were mixed at a ratio of 1:4000 and incubated at 4°C overnight. The next day, the target protein was expressed and quantified using ECL substrate solution (ECL substrate solution, Clarity TM Western ECL substrate, Bio-rad) after treatment with peroxidase-conjugated secondary antibody at room temperature for 1 hour. .
- ECL substrate solution ECL substrate solution, Clarity TM Western ECL substrate, Bio-rad
- VEGF angiogenesis inducer VEGF
- HIF-1 ⁇ a major transcription factor under hypoxic conditions.
- VEGF protein expression can be quantitatively confirmed through ELISA (Enzyme Linked Immunosorbent Assay, Human VEGF Quantikine ELISA Kit, R&D systems).
- Each example compound was diluted in DMEM/F12 medium containing 1% fetal bovine serum, pretreated for 2 hours, and cultured in hypoxia for 24 hours to obtain a cell supernatant. This supernatant was centrifuged at 1000 rpm for 3 minutes, and then a certain amount was treated with a VEGF ELISA assay kit to measure the absorbance value to quantitatively confirm the expression of VEGF.
- Example % inhibition @1uM Hif-1 ⁇ Hypoxia, 1 hour VEGF One 100 100 2 100 100 3 92 - 4 86.2 - 5 19.8 - 7 100 - 8 60.5 - 9 100 13.5 10 100 100 11 100 - 12 100 - 13 79.8 - 14 100 - 15 57.3 - 18 99.6 - 19 78.8 - 20 76.9 - 21 100 - 23 42 - 25 10.5 - 26 3.6 - 27 97.8 29.6 28 65.6 - 29 96 18.1 30 36 - 31 100 - 32 51.3 - 33 6.2 - 34 97.1 * 100 35 38.6 * - 36 11.7 * - 37 2.1 * - 38 100 * - 39 100 * - 40 80.2 * - 41 73.4 * - 42 71.8 * -
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Abstract
본 발명은 HIF-1 단백질 억제제 또는 혈관신생 유도인자 VEGF 억제제로서의 퓨린 유도체 화합물 및 이를 포함하는 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다. 본 발명의 신규한 퓨린 유도체 화합물은 저산소 상태에서 안정화되는 전사인자인 HIF-1α 및 하위 유전자인 혈관신생 유도인자 VEGF의 발현에 있어서 우수한 억제 효과를 나타내는 것이 확인되어, HIF-1α 단백질 및 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료 용도로 유용하게 사용될 수 있다.
Description
본 발명은 신규한 퓨린 유도체에 관한 것으로, 더욱 상세하게는 HIF-1 단백질 억제제 또는 혈관신생 유도인자 VEGF 억제제로서의 퓨린 유도체 화합물 및 이를 포함하는 관련 질환의 예방 또는 치료용 약학 조성물에 관한 것이다.
저산소증(hypoxia)이란 세포 수준에서 산소 공급이 부족하여 나타나는 여러 가지 질환 상태를 말한다. 저산소증의 치료에 핵심적인 역할을 하는 것이 HIF (hypoxia inducible factor, 저산소증 유도 인자)이다. HIF는 산소 농도에 따라 조절되는 α-subunit(HIF-α)와 구조적으로 발현되는 β-subunit(HIF-β)으로 나뉘며, 이종의 유전자 전사로써 결합한 후 세포핵 안으로 들어가 다양한 유전자를 발현시켜 다양한 유전자에 결합하여 저산소증에 대한 보상작용을 한다.
따라서, HIF-α는 인체에서 저산소증 상태를 인지하는 중요한 센서(sensor)의 역할을 하는데, 산소가 존재하는 정상상태(normoxia)에서는 HIF-PH(Hypoxia-inducible factor Prolyl Hydroxylase) 효소가 산소를 매개로 HIF-α에 수산화기를 도입시키고 여기에 VHL(Von Hippel Lindau)이 붙은 후 유비퀴틴화(ubiquitination) 과정을 거쳐 프로테아좀(proteasome)에 의해 즉시 분해가 일어나게 된다. 그러므로 인체 내에서 지속적으로 생성되는 HIF-α는 정상산소 상태에서 상기 과정을 거쳐 5분 정도의 빠른 반감기로 생성되자마자 소멸됨으로써 산소 농도를 인지하게 한다.
그러나, 산소 부족 상태가 오면 산소를 매개로 하는 HIF-PH 효소에 의한 HIF-α의 수산화 반응이 일어나지 못하여 HIF-α의 분해도 일어나지 않으므로 HIF-α는 안정화되어 HIF-β와 결합한 후, 세포핵 안으로 들어가 산소부족으로 인한 위급상황의 세포들을 살리기 위해, 부족한 산소나 에너지가 보충될 수 있는 여러 생리학적 과정에 관여하는 유전자(EPO, VEGF, GLUT-1, ITF, CD73, TGFb, DMT-1등)들이 발현된다.
혈관신생(angiogenesis)이란 기존의 미세혈관으로부터 새로운 모세혈관이 형성되는 과정이다. 혈관신생이 정상적으로 일어나는 경우는 배아 발생(embryonic development), 조직재생 및 상처치료, 주기적인 여성의 생식기 계통의 변화인 황체가 발달될 때이며 이러한 경우에도 엄격히 조절되어 진행된다. 성인의 경우 혈관내피세포는 매우 느리게 자라며, 다른 종류의 세포에 비하여 상대적으로 잘 분열하지 않는다.
혈관신생이 일어나는 과정은 일반적으로 혈관신생 촉진인자의 자극에 의하여 프로테아제로 인한 혈관 기저막의 분해, 혈관 내피세포의 이동, 증식 및 혈관 내피세포 분화에 의한 관강의 형성으로 혈관이 재구성되어 새로운 모세혈관이 생성되는 것으로 이루어진다.
그러나, 혈관신생이 자율적으로 조절되지 못하고 병적으로 성장함으로써 야기되는 질환들이 있다. 병리학적 상태에서 나타나는 혈관신생에 관련된 질환으로는 혈관종, 혈관섬유종, 혈관기형 및 심혈관 질환인 동맥경화, 혈관유착, 부종성 경화증이 있고, 혈관신생에 의한 안과 질환으로는 황반변성, 각막이식성 혈관신생, 혈관신생성 녹내장, 당뇨병성 망막증, 신생혈관에 의한 각막 질환, 반점의 변성, 익상편, 망막 변성, 후수정체 섬유 증식증, 과립성 결막염 등이 있다. 관절염과 같은 만성 염증성 질환, 건선, 모세관 확장증, 화농성 육아종, 지루성 피부염, 여드름과 같은 피부과 질환, 알츠하이머 및 비만도 혈관신생과 관련이 있으며, 암의 성장과 전이는 필수적으로 혈관신생과 관련되어 있다.
따라서, 혈관신생 억제제를 이러한 각종 혈관신생 관련 질환의 치료제로 적용할 수 있으므로, 최근에 혈관신생을 억제시켜서 상기 질환들을 치료하려는 연구가 활발히 진행되고 있다.
한편, 황반변성(macular degeneration)은 황반 부분에 변성이 일어나 시력장애를 일으키는 안구 질환으로, 발병원인은 연령증가, 가족력, 인종, 흡연과 관련이 있다고 알려져 있다. 발병 초기에는 시야가 흐려지고 가까운 곳의 시력이 뒤틀려서 보이다가 나중에는 실명에 이르게 된다. 노인성 황반변성(age-related macular degeneration, AMD)은 중증의 비가역적인 시력상실을 야기하며 50세 이상 인구에서 실명의 주요 원인으로 알려져 있다.
나이 관련 황반변성에는 두 가지 유형이 있다. 첫 번째는 비-신생혈관성 나이 관련 황반변성으로, 가장 흔하며 전체 나이 관련 황반변성 사례의 85%를 차지한다. 이러한 건성 유형은 망막 색소 상피의 기름찌꺼기와 위축성 변화를 특징으로 한다. 두 번째는 신생혈관성 나이 관련 황반변성으로, 맥락막 신생혈관을 특징으로 한다. 맥락막 신생혈관은 새롭게 형성된 혈관으로 혈액과 체액을 유출시키는 경향이 있다. 이는, 망막조직에 섬유조직이 증식하고 광수용체가 소실된 병변의 형성을 유도하며, 지속적으로 진행하여 중증이며 비가역적인 시력상실을 야기한다.
신생혈관성 나이 관련 황반변성 치료법에는 광역학요법과 혈관내피성장인자를 차단하기 위한 약물을 안구 안으로 주사하는 방법이 있다. 그러나, 여러 대규모 다기관 임상연구들을 통해 광역학요법보다 유리체강내 혈관내피성장인자(vascular endothelial growth factor, VEGF) 억제 주사술을 시행하는 것이 더 나은 결과를 보여주었다. 이에 따라 신생혈관성 나이 관련 황반변성의 치료로 다양한 항-혈관내피성장인자 약물들이 개발되었는데, 그 중 대표적인 약제가 라니비주맙(Ranibizumab, Lucentis®)으로, 세포 밖의 혈관내피성장인자와 결합하여 활성을 억제시킨다. 라니비주맙은 다양한 임상연구를 통해 신생혈관성 나이 관련 황반변성 환자에서 효과적이고 안전한 치료임이 보고되어 전세계적으로 널리 사용되고 있다.
본 발명이 해결하고자 하는 과제는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF에 대하여 우수한 억제 활성을 나타내는 신규한 구조의 퓨린 유도체 화합물을 제공하는 것이다.
또한, 본 발명의 해결 과제는 상기 신규한 구조의 퓨린 유도체 화합물을 포함하는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.
또한, 본 발명의 해결 과제는 상기 신규한 구조의 퓨린 유도체 화합물을 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료 방법을 제공하는 것이다.
또한, 본 발명의 해결 과제는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료에 사용하기 위한 약제(medicament)를 제조하기 위한, 상기 신규한 구조의 퓨린 유도체 화합물의 용도(use)를 제공하는 것이다.
본 발명이 해결하고자 하는 과제는 이상에서 언급한 해결 과제로 제한되지 않으며, 언급되지 않은 또 다른 기술적 과제들은 아래의 기재로부터 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에게 명확하게 이해될 수 있을 것이다.
상기 과제를 해결하기 위하여, 본 발명의 일 측면에 따라, 하기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염이 제공된다.
<화학식 Ⅰ>
상기 식에서,
X1 및 X2는 독립적으로 CH 또는 N이고,
X3 및 X4는 독립적으로 C, CH 또는 N이고, X3는 R3로 치환되거나 치환되지 않고, X4는 R4로 치환되거나 치환되지 않고,
Y는 -C(O)-, 또는 C1-3 알킬렌이고,
n은 0 내지 3의 정수이고,
R1은 C3-7 사이클로알킬, 또는 1 내지 2개의 N을 가지는 5 내지 7원의 포화 헤테로사이클이고, R1은 단수 또는 복수의 독립적인 Ra로 치환되거나 치환되지 않고,
상기 Ra는 C1-4 알킬 또는 할로겐이고,
R2는 H; C4-7의 포화 또는 불포화 사이클로알킬; C5-7 아릴; 또는 N, O 및 S로 구성되는 군으로부터 선택되는 1개 내지 3개의 헤테로원자를 가지는 5원 또는 6원의 헤테로아릴이고, R2는 Rb로 치환되거나 치환되지 않고,
상기 Rb는 C1-6 직쇄 또는 분지쇄 알킬; C1-4 알콕시, 벤질옥시; 할로겐; C1-4 할로알킬; 히드록시; 또는 할로겐으로 치환되거나 치환되지 않은 아릴이고,
R3는 할로겐 또는 C1-4 할로알킬이고,
R4는 할로겐; 또는 1개 내지 3개의 헤테로원자를 가지는 5원 또는 6원의 헤테로아릴이고, 이 때의 상기 헤테로아릴은 C5-7 아릴로 치환되거나 치환되지 않고, 이 때의 상기 C5-7 아릴은 할로겐으로 치환되거나 치환되지 않는다.
본 발명의 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료용 약학적 조성물이 제공된다.
본 발명의 또 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료 방법이 제공된다.
본 발명의 또 다른 측면에 따라, HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료에 사용하기 위한 약제 (medicament)를 제조하기 위한, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염의 용도(use)가 제공된다.
본 발명의 또 다른 측면에 따라, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염과, 약제학적으로 허용가능한 첨가제를 포함하는 제형이 제공된다.
본 발명의 신규한 퓨린 유도체 화합물은 저산소 상태에서 안정화되는 전사인자인 HIF-1α 및 하위 유전자인 혈관신생 유도인자 VEGF의 발현에 있어서 우수한 억제 효과를 나타내는 것이 확인되어, HIF-1α 단백질 및 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료 용도로 유용하게 사용될 수 있음이 밝혀졌다.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 설명 또는 특허청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.
본 발명은 하기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 제공한다.
<화학식 Ⅰ>
상기 식에서,
X1 및 X2는 독립적으로 CH 또는 N이고,
X3 및 X4는 독립적으로 C, CH 또는 N이고, X3는 R3로 치환되거나 치환되지 않고, X4는 R4로 치환되거나 치환되지 않고,
Y는 -C(O)-, 또는 C1-3 알킬렌이고,
n은 0 내지 3의 정수이고,
R1은 C3-7 사이클로알킬, 또는 1 내지 2개의 N을 가지는 5 내지 7원의 포화 헤테로사이클이고, R1은 단수 또는 복수의 독립적인 Ra로 치환되거나 치환되지 않고,
상기 Ra는 C1-4 알킬 또는 할로겐이고,
R2는 H; C4-7의 포화 또는 불포화 사이클로알킬; C5-7 아릴; 또는 N, O 및 S로 구성되는 군으로부터 선택되는 1개 내지 3개의 헤테로원자를 가지는 5원 또는 6원의 헤테로아릴이고, R2는 Rb로 치환되거나 치환되지 않고,
상기 Rb는 C1-6 직쇄 또는 분지쇄 알킬; C1-4 알콕시, 벤질옥시; 할로겐; C1-4 할로알킬; 히드록시; 또는 할로겐으로 치환되거나 치환되지 않은 아릴이고,
R3는 할로겐 또는 C1-4 할로알킬이고,
R4는 할로겐; 또는 1개 내지 3개의 헤테로원자를 가지는 5원 또는 6원의 헤테로아릴이고, 이 때의 상기 헤테로아릴은 C5-7 아릴로 치환되거나 치환되지 않고, 이 때의 상기 C5-7 아릴은 할로겐으로 치환되거나 치환되지 않는다.
본 명세서를 통하여 화학식 Ⅰ의 화합물을 정의함에 있어서는 달리 언급하지 않는 한 다음의 정의가 적용된다.
본 명세서에서 사용된 용어 "알킬"은 직쇄형 또는 분지쇄형 포화 탄화수소로서, C1-10 알킬이 바람직하다. 예를 들어, 상기 알킬은 메틸, 에틸, n-프로필, iso-프로필, n-부틸, iso-부틸, tert-부틸, n-펜틸, iso-펜틸, n-헥실, 3-메틸헥실, 2,2-디메틸펜틸, 2,3-디메틸펜틸, n-헵틸, n-옥틸, n-노닐 및 n-데실 등을 포함하지만, 이에 한정되는 것은 아니다.
본 명세서에서 사용된 용어 "알킬렌"은 알킬기로부터 유도된 2가의 작용기를 지칭하며, 바람직하게는 1 내지 10 개의 탄소 원자를 포함하지만, 이에 한정되는 것은 아니다. 알킬렌의 예로는 -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- 및 -CH2CH2CH2CH2CH2- 등이 포함되지만, 이에 한정되지 않는다.
본 명세서에서 사용된 용어 "사이클로알킬"은 부분적 또는 전체적으로 포화된 단일 또는 융합환 고리형 탄화수소이며, C3-10 사이클로알킬이 바람직하다. 예를 들어 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헥시닐 등을 포함하지만, 이에 한정되는 것은 아니다.
본 명세서에서 사용된 용어 "히드록시" 또는 "하이드록시"는 -OH로서 정의되고, 용어 "알콕시"는 달리 정의하지 않는 한, 하이드록시 기의 수소 원자가 1 내지 10개의 알킬로 치환된 라디칼인 알킬옥시를 의미한다.
본 명세서에서 사용된 용어 "할로겐" 또는 "할로"는 불소/플루오르(F), 염소(Cl), 브롬(Br) 또는 요오드(I)를 의미한다.
본 명세서에서 사용된 용어 "할로알킬"은 1 이상의 할로겐 원자로 치환된 알킬을 의미한다.
본 명세서에서 사용된 용어 "헤테로원자"는 N, O 또는 S를 의미한다.
본 명세서에서 사용된 용어 "아릴"은 방향족 탄화수소를 의미하며, 카보사이클 방향족 고리 또는 헤테로아릴 고리가 1 이상의 다른 고리와 융합된, 폴리사이클 방향족 고리계를 포함한다. 바람직하게는 C5-C12 아릴, 더 바람직하게는 C5-C10 아릴이다. 예를 들어, 상기 아릴은 페닐, 나프틸, 테트라하이드로나프틸 등을 포함하지만, 이에 한정되는 것은 아니다.
본 명세서에서 사용된 용어 "헤테로아릴" 또는 "방향족 헤테로사이클"은 N, O 및 S 중에서 선택된 하나 이상의 헤테로 원자를 환원자로서 포함하고, 벤조 또는 C3-8 사이클로알킬과 융합될 수 있는 단일 또는 융합고리환을 이루는 3 내지 12원, 더 바람직하게는 5 내지 10원 방향족 탄화수소를 의미한다. 예를 들어, 상기 헤테로아릴은 피롤릴, 이미다졸릴, 피라졸릴, 트리아졸릴, 피리딜, 피라지닐, 피리미딜, 피리다지닐, 트리아지닐, 옥사디아졸릴, 이속사디아졸릴, 테트라졸릴, 인돌릴, 인다졸릴, 이속사졸릴, 옥사졸릴, 티아졸릴, 아이소티아졸릴, 퓨라닐, 벤조퓨라닐, 티오페닐, 벤조티아졸릴, 벤조옥사졸릴, 벤즈이미다졸릴, 퀴놀리닐, 이소퀴놀리닐 등을 포함하지만, 이에 한정되는 것은 아니다.
일 구현예에서, 상기 X1은 CH 또는 N이고, 상기 X2는 N일 수 있다.
일 구현예에서, 상기 Y는 -C(O)- 또는 -CH2-일 수 있다.
일 구현예에서, 상기 n은 0 또는 1일 수 있다.
일 구현예에서, 상기 R1은 사이클로부틸, 사이클로펜틸, 사이클로헥실, 또는 피페리디닐일 수 있다.
일 구현예에서, 상기 Ra는 메틸 또는 F일 수 있다.
일 구현예에서, 상기 R2는 H, 사이클로펜틸, 사이클로펜테닐; 페닐; 피롤릴, 티오페닐, 퓨라닐, 피라졸릴, 티아졸릴, 이소티아졸릴, 피리디닐, 피리미디닐, 또는 피리다지닐일 수 있다.
일 구현예에서, 상기 Rb는 메틸, 프로필, 이소프로필, 메톡시, 벤질옥시, F, 플루오로메틸, 다이플루오로메틸, 트리플루오로메틸, 히드록시 또는 플루오로페닐일 수 있다.
일 구현예에서, 상기 R3는 F, Br 또는 트리플루오로메틸일 수 있다.
일 구현예에서, 상기 R4는 F 또는 플루오로페닐-피라졸일 수 있다.
본 발명에 따른 퓨린 유도체 화합물의 구체적인 예는 다음과 같다:
[1] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,
[2] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티오펜-3-일)페닐)아세타마이드,
[3] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-플루오로-4'-메틸-[1,1'-바이페닐]-3-일)아세타마이드,
[4] N-(2-사이클로펜틸-3H-이미다조[4,5-c]피리딘-4-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,
[5] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피롤-2-일)페닐)아세타마이드,
[6] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리미딘-5-일)페닐)아세타마이드,
[7] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피롤-3-일)페닐)아세타마이드,
[8] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(퓨란-2-일)페닐)아세타마이드,
[9] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-이소프로필-1H-피라졸-4-일)페닐)아세타마이드,
[10] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-(1-(다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세타마이드,
[11] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1H-피롤-2-일)페닐)아세타마이드,
[12] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(이소티아졸-4-일)페닐)아세타마이드,
[13] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티아졸-5-일)페닐)아세타마이드,
[14] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리딘-4-일)페닐)아세타마이드,
[15] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리딘-3-일)페닐)아세타마이드,
[16] 2-(4'-(벤질옥시)-5-플루오로-[1,1'-바이페닐]-3-일)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드,
[17] 2-(3-(사이클로펜트-1-엔-1-일)-5-플루오로페닐)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드,
[18] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티오펜-2-일)페닐)아세타마이드,
[19] 8-사이클로펜틸-N-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)벤질)-7H-퓨린-6-아민,
[20] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-(1-메틸-1H-피라졸-4-일)-5-(트리플루오로메틸)페닐)아세타마이드,
[21] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-3-일)페닐)아세타마이드,
[22] N-(8-사이클로펜틸-7H-퓨린-6-일)-3-플루오로-5-(1-메틸-1H-피라졸-4-일)벤즈아미드,
[23] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리다진-4-일)페닐)아세타마이드,
[24] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-플루오로-4'-히드록시-[1,1'-바이페닐]-3-일)아세타마이드,
[25] 2-(3-사이클로펜틸-5-플루오로페닐)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드,
[26] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4-플루오로-3-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,
[27] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(트리플루오로메틸)-1H-피라졸-4-일)페닐)아세타마이드,
[28] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(2-메톡시피리딘-4-일)페닐)아세타마이드,
[29] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4',5-다이플루오로-[1,1'-바이페닐]-3-일)아세타마이드,
[30] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아세타마이드,
[31] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(2-(1-메틸-1H-피라졸-4-일)피리딘-4-일)아세타마이드,
[32] N-(8-사이클로헥실-7H-퓨린-6-일)-2-(3-(1-다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세타마이드,
[33] 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)-N-(8-(피페리딘-1-일)-7H-퓨린-6-일)아세타마이드,
[34] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,
[35] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-4- (1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,
[36] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4-(1-(4- 플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,
[37] N-(3-브로모펜에틸)-8-사이클로펜틸-7H-퓨린-6-아민,
[38] N-(8-(3,3- 다이플루오로사이클로펜틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,
[39] N-(8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,
[40] N-(8-(3,3- 다이플루오로사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,
[41] N-(8-(3,3-다이플루오로사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드, 및
[42] N-(8-(3,3-다이메틸사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드.
본 발명에 따른 상기 화학식 Ⅰ로 표시되는 화합물은 생체내 흡수를 증진시키거나 용해도를 증가시키기 위하여 프로드럭, 수화물, 용매화물 및 약제학적으로 허용되는 염의 형태로 만들어 사용할 수 있으므로, 상기의 프로드럭, 수화물, 용매화물 및 약제학적으로 허용되는 염 역시 본 발명의 범위에 속한다.
용어 "프로드럭(prodrug)"은 생체내에서 모 약제(parent drug)로 변형되는 물질을 의미한다. 프로드럭은, 몇몇 경우에 있어서, 모 약제보다 투여하기 쉽기 때문에 종종 사용된다. 예를 들어, 이들은 구강 투여에 의해 생활성을 얻을 수 있음에 반하여, 모 약제는 그렇지 못할 수 있다. 프로드럭은 또한 모 약제보다 제약 조성물에서 향상된 용해도를 가질 수도 있다. 예를 들어, 프로드럭은, 본 발명에 따른 화합물의 생체 내 가수분해 가능한 에스테르 및 이의 제약상 허용되는 염일 수 있다. 프로드럭의 또 다른 예는 펩티드가 활성 부위를 드러내도록 물질 대사에 의해 변환되는 산기에 결합되어 있는 짧은 펩티드(폴리아미노산)일 수 있다.
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다.
용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변 이성질체(tautomer) 등의 구조 이성질체와, 비대칭 탄소 중심을 가지는 R 또는 S 이성질체, 기하 이성질체(트랜스, 시스) 등의 입체 이성질체가 모두 포함된다. 이들 모든 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.
용어 "약학적으로 허용가능한 염"은, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 화합물의 염의 형태를 의미한다. 상기 약학적 염은, 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수소산, 요드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플로로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약제학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르기닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸)메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다. 본 발명에 따른 화학식 Ⅰ의 화합물은 통상적인 방법에 의해 그것의 염으로 전환시킬 수도 있다.
본 발명의 화학식 Ⅰ의 화합물의 제조방법으로 실시예 1 내지 실시예 42의 합성법을 예시로 나타내었으며, 이러한 실시예 1 내지 실시예 42의 합성법이 본 발명에 따른 화학식 Ⅰ의 화합물을 제조하는 방법을 한정하는 것은 아니다. 실시예 1 내지 실시예 42의 합성법은 예시일 뿐이며, 특정 치환체에 따라 통상의 기술자에 의해 용이하게 변형될 수 있음은 자명하다.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료 방법을 제공한다.
본 발명은 또한, HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료에 사용하기 위한 약제 (medicament)를 제조하기 위한, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염의 용도(use)를 제공한다.
일 구현예에서, 상기 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료는 신생혈관 억제에 의한 것일 수 있다.
일 구현예에서, 상기 신생혈관 억제는 HIF-1α 발현 억제 또는 VEGF 발현 억제에 의한 것일 수 있다.
일 구현예에서, 상기 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환은 뇌졸중, 뇌간신경교종, 소뇌성상세포종, 대뇌성상세포종, 뇌실막종, 간암, 위암, 유방암, 결장암, 골암, 췌장암, 두부 또는 경부암, 난소암, 직장암, 대장암, 식도암, 소장암, 항문부근암, 결장암, 피부암, 나팔관암종, 자궁내막암종, 자궁암, 질암종, 음부암종, 호지킨병, 구강암, 전립선암, 고환암, 방광암, 신장암, 수뇨관암, 세장세포암종, 신장골반암종, 수모세포종, 신경모세포종, 뇌종양, 중추신경계 종양, 흑색종, 비소세포폐암, 림프종, 비호지킨림프종, 암, 자궁경부암, 갑상선암, 혈액암, 신세포암, 간세포 암, 전이성 암, 혈관종, 화농성 육아종, 카포시 육종, 혈관내피종, 고형 종양, 여포낭종, 자궁내막증, 자궁 경화증, 난소 고혈압, 난소 과활성, 자궁 기능장애, 사마귀, 흉터 켈로이드, 알레르기성 부종, 죽상 동맥 경화증, 복막 경화증, 심장 기능장애, 근위축성 측삭 경화증, 비만, 류마티스 관절염, 활막염, 뼈와 연골 파괴, 뼈의 악성 섬유성 조직구종, 골수염, 판누스막 성장, 간 섬유증, 폐섬유증, 섬유화증, NASH (non-alcoholic steato hepatitis), 폐렴, 천식, 비염, 폐 고혈압, 허혈성 급성 신손상, 사구체신염, 당뇨성신장병증, 악성 신경화증, 혈전성 미소혈관장, 기관이식거부, 신사구체병증, 염증신경퇴행성 질환, 니코틴 중독관련 혈관질환, 만성 신장 질환, 미숙아 망막병증, 당뇨망막병증, 각막이식거부, 허혈성 망막병증, 홍색증, 증식성 망막증, 건선, 혈우병성 관절, 켈로이드, 상처과립화, 혈관접착, 자가면역질환, 혈관 섬유종, 후수정체 섬유증식증, 백내장, 녹내장, 황반변성, 노인황반변성, 각막 혈관 신생, 망막 혈관 신생, 맥락막 혈관 신생, 안구내 혈관 신생, 신생혈관성 녹내장, 신생혈관성 황반변성, 망막동맥폐색증, 망막정맥폐색증, 망막세포종, 시각 경로 및 시상하부 신경교종, 횡문근육종, 조직육종, 염증, 각막궤양, 증식성 유리체 망막병증, 간경변, 천식, 치근막 질환, 알레르기성 피부염, 알츠하이머병, 파킨슨병, 헌팅턴병, 갑상선염, 그레이브스 안와병증, 백혈구연화증, 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈성, 만성 골수성 백혈병, 급성 골수성 백혈병, 다발성 골수종, 염증성 장질환, 크론병, 궤양성 대장염, 및 베체트 장염으로 구성된 군으로부터 선택된 1종 이상일 수 있다.
일 구현예에서, 상기 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환은 신생혈관성 안질환일 수 있으며, 상기 신생혈관성 안질환은 각막 혈관 신생, 망막 혈관 신생, 맥락막 혈관 신생, 안구내 혈관 신생, 신생혈관성 녹내장, 증식성 당뇨병성 망막증, 신생혈관성 황반변성 및 미숙아 망막병증으로 구성된 군으로부터 선택된 1종 이상일 수 있다.
본 발명은 또한, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염과, 약제학적으로 허용가능한 첨가제를 포함하는 제형을 제공한다.
상기 첨가제는 약제학적으로 허용가능한 담체 또는 희석제를 포함할 수 있으며, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 점안제, 좌제 및 멸균 주사용액의 형태로 제제화될 수 있다.
상기 약제학적으로 허용가능한 담체는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 포함한다. 또한, 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함한다. 경구용 고형 제제는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 포함할 수 있으며, 마그네슘 스테아레이트, 탈크 같은 윤활제 등을 포함할 수 있다. 경구용 액상 제제는 현탁제, 내용액제, 유제, 시럽제 등을 포함하며, 물, 리퀴드 파라핀 등의 희석제, 습윤제, 감미제, 방향제, 보존제 등을 포함할 수 있다. 비경구용 제제는 멸균된 수용액, 비수성용제, 현탁제, 유제, 크림제, 동결건조 제제, 좌제를 포함하며, 비수성 용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르류 등을 포함한다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.
본 발명의 약학적 조성물에 함유되는 유효성분의 투여량은 환자의 상태 및 체중, 질병의 정도, 유효성분 형태, 투여 경로 및 기간에 따라 다르며, 환자에 따라 적절하게 조절될 수 있다. 예를 들면, 상기 유효성분은 1일 0.0001 내지 1000 mg/kg으로, 바람직하게는 0.01 내지 100 mg/kg의 용량으로 투여할 수 있으며, 상기 투여는 하루에 한번 또는 수회 나누어 투여할 수도 있다. 또한, 본 발명의 약학적 조성물은 조성물 총 중량에 대하여 상기 유효성분을 0.001 내지 90 % 중량백분율로 포함할 수 있다.
본 발명의 약학적 조성물은 랫트, 마우스, 가축, 인간 등의 포유동물에 다양한 경로로, 예를 들면, 경구, 피부, 복강, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내(intracerebroventricular) 주사에 의해 투여될 수 있다.
이하, 본 발명을 합성예, 실시예 및 실험예를 통하여 더욱 상세히 설명한다. 그러나, 하기 합성예, 실시예 및 실험예는 본 발명을 예시하기 위한 것으로, 본 발명의 범위가 이에 제한되는 것은 아니다.
합성예 1
(단계 1) 6-클로로-8-사이클로펜틸-7H-퓨린 [6-chloro-8-cyclopentyl-7H-purine]
사이클로펜탄 카보닐 클로라이드 (3.5 g)와 6-클로로피리미딘-4,5-다이아민 (3.0 mL)에 POCl3 (30 mL)을 넣고 110 ℃에서 반응하였다. 2시간 후 반응 혼합물을 농축하고, aq. NaHCO3 용액으로 중화하였다. 물층을 CH2Cl2로 2회 추출하고 유기층을 Na2SO4로 건조, 감압 여과 후 농축한 다음 톨루엔(toluene)으로 재결정하여 목적화합물(3.4 g, 63%)을 노란색 고체 형태로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 3.37 - 3.32 (m, 1H), 2.11 -1.66 (m, 8H).
(단계 2) 8-사이클로펜틸-7H-퓨린-6-아민[8-cyclopentyl-7H-purin-6-amine]
6-클로로-8-사이클로펜틸-7H-퓨린 (1.84 g, 6.26 mmol)을 7 N NH3 메탄올액(in MeOH, 30 mL)에 넣고 80 ℃에서 48 시간 동안 반응하였다. 반응완료 후 반응혼합물을 농축하고, aq. K2CO3 수용액으로 염기화(basify)한 다음, 물층을 CH2Cl2 로 추출하고 유기층을 Na2SO4로 건조, 감압 여과하였다. 농축 후 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (0-10 % MeOH in DCM)로 정제하여 목적화합물 (980 mg, 77% )을 흰색 고체 형태로 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 3.33 (m, 1H), 2.18 (m, 2H), 1.96 - 1.80 (m, 4H), 1.79 - 1.69 (m, 2H).
LCMS, m/z 204 [M+H]+
실시예 1
(단계 1) 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세트산 [2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetic acid]
2-(3-브로모-5-플루오로페닐)아세트산 (100 mg), 1-메틸-2-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피롤 (208 mg), PdCl2(dppf) (20 mg)를 1,4-다이옥산 (3.0 mL)에 넣고, 2M K2CO3 (aq.) (750 μL) 첨가 후 10분동안 N2로 탈기(degassing) 시켰다. 반응 혼합물을 80 ℃에서 3시간 반응시킨 후 상온으로 식히고, 1M HCl로 산성화(acidify)하였다. 이 반응 혼합물을 EtOAc로 추출하고, 유기층을 MgSO4로 건조 후 감압 여과하였다. 유기층을 농축한 후 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (0-5% MeOH in CH2Cl2)으로 정제하여 목적화합물(73 mg, 72%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.19 (s, 1H), 7.92 - 7.84 (m, 1H), 7.38 - 7.23 (m, 2H), 6.94 - 6.88 (m, 1H), 3.85 (s, 3H), 3.60 (s, 2H).
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide]
8-사이클로펜틸-7H-퓨린-6-아민 (280 mg), 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세트산 (294 mg), T3P, 50wt.% 에틸아세테이트액(in EtOAc, 2.35 g)을 에틸 아세테이트(30 mL)에 녹인 후 DIPEA (532μL)를 넣고 50 ℃에서 반응시켰다. 12시간 후 반응혼합물에 에틸 아세테이트와 H2O를 넣고 추출한 후 유기층을 Na2SO4로 건조하고 감압 여과하였다. 유기층을 농축한 후 실리카 겔 컬럼 크로마토그래피 (0-5 % MeOH in DCM )로 정제하여 목적화합물 (190 mg, 33%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 11.36 (s, 1H), 8.58 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.41 (s, 1H), 7.34 (d, J = 10.1 Hz, 1H), 7.04 (d, J = 9.4 Hz, 1H), 3.92 (s, 2H), 3.86 (s, 3H), 3.50 (m, 1H), 2.02 (m, 2H), 1.92 - 1.70 (m, 4H), 1.68 - 1.53 (m, 2H).
LCMS, m/z 420[M+H]+
실시예 2
(단계 1) 2-(3-플루오로-5-(티오펜-3-일)페닐)아세트산 [2-(3-fluoro-5-(thiophen-3-yl)phenyl)acetic acid]
실시예 1의 단계1과 같은 방법으로2-(3-브로모-5-플루오로페닐)아세트산 (200 mg, 0.86 mmol) 와 4,4,5,5-테트라메틸-2-(티오펜-3-일)-1,3,2-다이옥사보롤란(420 mg, 2.0 mmol)을 이용하여 목적화합물(150 mg, 76%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.98 (dd, J = 2.9, 1.2 Hz, 1H), 7.66 (dt, J = 11.0, 5.5 Hz, 1H), 7.59 (dd, J = 4.9, 1.2 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.04 (d, J = 9.6 Hz, 1H), 3.66 (s, 2H).
LCMS, m/z 235[M-H]-
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티오펜-3-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiophen-3-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 2-(3-플루오로-5-(티오펜-3-일)페닐)아세트산 (41 mg, 0.17 mmol), T3P (50wt.% 용액 (in EtOAc), 332 mg, 0.52 mmol)을 이용하여 목적화합물(6.0 mg, 8%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.69 (s, 1H), 7.52 (s, 1H), 7.49 -7.44 (m, 2H), 7.33 (d, J = 12 Hz, 1H), 7.10 (d, J = 8 Hz, 1H), 3.95 (s, 2H), 3.39 (m, 1H), 2.16 (m, 2H), 1.94 - 1.86 (m, 4H), 1.74 - 1.71 (m, 2H).
LCMS, m/z 422 [M+H]+
실시예 3
(단계 1) 2-(5-플루오로-4'-메틸-[1,1'-바이페닐]-3-일)아세트산 [2-(5-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (200 mg, 0.86 mmol), 4,4,5,5-테트라메틸-2-(p-톨릴)-1,3,2-다이옥사보롤란 (430 mg, 2.0 mmol), PdCl2(dppf) (31 mg, 0.043 mmol), 2M K2CO3 (aq.) (1.5 mL, 3.0 mmol)을 이용하여 목적화합물(157 mg, 75%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.58 (d, J = 7.7 Hz, 2H), 7.45 - 7.34 (m, 2H), 7.28 (d, J = 7.7 Hz, 2H), 7.09 (d, J = 9.3Hz, 1H), 3.70 (s, 2H), 2.35 (s, 3H).
LCMS, m/z 243 [M-H]-
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-플루오로-4'-메틸-[1,1'-바이페닐]-3-일)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(5-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 2-(5-플루오로-4'-메틸-[1,1'-바이페닐]-3-일)아세트산 (50 mg, 0.20 mmol), T3P (50wt.% 용액 (in EtOAc), 332 mg, 0.52 mmol)을 이용하여 목적화합물(13 mg, 18%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.32 (s, 1H), 8.56 (s, 1H), 7.59 (d, J = 8 Hz, 2H), 7.69 (s, 1H), 7.51 (s, 1H), 7.40 (d, J = 12 Hz, 1H), 7.28 (d, J = 8 Hz, 2H), 7.40 (d, J = 12 Hz, 1H), 3.97 (s, 2H), 3.47 (m, 1H), 2.33 (s, 3H), 1.99 (m, 2H), 1.83 - 1.75 (m, 4H), 1.61 (m, 2H).
LCMS, m/z 430 [M+H]+
실시예 4
(단계 1) 4-클로로-2-사이클로펜틸-3H-이미다조[4,5-c]피리딘 [4-chloro-2-cyclopentyl-3H-imidazo[4,5-c]pyridine]
2-클로로피리딘-3,4-다이아민 (399 mg, 2.78 mmol), 사이클로펜탄 카르복실산(carboxylic acid, 380 mg, 3.334 mmol), 인산(phosphoric acid, 3.63 mL)을 밀봉된 관(sealed tube)에 넣고 섞어준 후 145 ℃로 가열 교반하였다. 12시간 반응 후 반응혼합물을 상온으로 식히고 아이스 배스(ice bath)에서 암모니아수로 염기성화(basify) 하였다. (pH 8~9) 반응 혼합물을 EtOAc로 추출한 후, 유기층을 MgSO4로 건조하고 농축하였다. 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (5% MeOH in CH2Cl2)으로 정제하여 목적화합물 (490 mg, 80%)를 갈색 고체 형태로 얻었다.
LCMS, m/z 222 [M+H]+
(단계 2) 2-사이클로펜틸-3H-이미다조[4,5-c]피리딘-4-아민 [2-cyclopentyl-3H-imidazo[4,5-c]pyridin-4-amine]
4-클로로-2-사이클로펜틸-3H-이미다조[4,5-c]피리딘 (100 mg, 0.45 mmol)을 t-BuOH (0.5 mL)에 녹이고 히드라진(hydrazine, 359 mg, 11.2 mmol)을 가해준 후 120 ℃에서 16시간동안 교반하였다. 반응 혼합물을 감압 농축 후 얻어진 잔사(98 mg, 0.45 mmol)와 레이니 니켈(Raney Nickel, 75.5 mg)을 H2O 5 ml과 같이 바이알(vial)에 넣고 1시간 동안 환류 교반을 진행하였다. 이후 반응혼합물을 셀라이트(Celite)에서 여과하고 여과액을 CH2Cl2 로 희석하여 H2O로 씻어주었다. 유기층을 MgSO4로 건조한 후, 농축하고 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (0-10 % MeOH in DCM)로 정제하여 목적화합물 (25 mg, 27% )을 흰색 고체 형태로 얻었다.
LCMS, m/z 203 [M+H]+
(단계 3) N-(2-사이클로펜틸-3H-이미다조[4,5-c]피리딘-4-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드 [N-(2-cyclopentyl-3H-imidazo[4,5-c]pyridin-4-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide]
2-사이클로펜틸-3H-이미다조[4,5-c]피리딘-4-아민 (172 mg, 0.85 mmol)과 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세트산 (199 mg, 0.85 mmol), 50% 프로필 포스폰산 무수물 용액 (1.65 g, 2.55 mmol), 다이이소프로필에틸아민 (362 μL, 2.12 mmol), EtOAc 10 ml를 넣고 50 ℃에서 교반하였다. 16시간 후 반응혼합물에 H2O를 첨가한 후 산성화(pH 3~4)하고 EtOAc로 씻어주었다. 물 층을 분리하여 1N NaOH로 pH 8~9로 맞춘 후 EtOAc로 추출하였다. 유기층을 분리하여 MgSO4로 건조 후 농축하여 얻어진 잔사를 실리카 겔 컬럼 (5% MeOH in CH2Cl2)하여 목적화합물 (3 mg, 0.8%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 4 Hz, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.42 (s, 1H), 7.38 (s, 1H), 7.22 (d, J = 8 Hz, 1H), 7.05 (d, J = 12 Hz, 1H), 3.92 (s, 3H), 3.89 (s, 2H), 3.37 (m, 1H), 2.19 (m, 2H), 1.97 - 1.90 (m, 4H), 1.77 (m, 2H).
LCMS, m/z 419 [M+H]+
실시예 5
(단계 1) 2-(3-플루오로-5-(1-메틸-1H-피롤-2-일)페닐)아세트산 [2-(3-fluoro-5-(1-methyl-1H-pyrrol-2-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (200 mg, 0.86 mmol), 1-메틸-2-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피롤 (410 mg, 2.0 mmol), PdCl2(dppf) (31 mg, 0.043 mmol), 2M K2CO3 (aq.) (1.5 mL, 3.0 mmol)를 이용하여 목적화합물 (153 mg,76%)을 얻었다.
LCMS m/z 234 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피롤-2-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrrol-2-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (25 mg, 0.13 mmol), 2-(3-플루오로-5-(1-메틸-1H-피롤-2-일)페닐)아세트산 (35 mg, 0.15 mmol), T3P (50wt.% 용액 (in EtOAc), 120 mg, 0.19 mmol), DIPEA (43 μL, 0.25 mmol)를 이용하여 목적화합물(6.9 mg, 14%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 11.35 (s, 1H), 8.58 (s, 1H), 7.32 (s, 1H), 7.18 (dd, J = 17.9, 9.9 Hz, 2H), 6.90 - 6.84 (m, 1H), 6.25 (dd, J = 3.5, 1.8 Hz, 1H), 6.09 - 6.05 (m, 1H), 3.96 (s, 2H), 3.68 (s, 3H), 3.49 (d, J = 8.0 Hz, 1H), 2.03 (d, J = 8.2 Hz, 2H), 1.87 - 1.76 (m, 4H), 1.63 (dd, J = 7.0, 4.3 Hz, 2H).
LCMS, m/z 419 [M+H]+
실시예 6
(단계 1) 2-(3-플루오로-5-(피리미딘-5-일)페닐)아세트산 [2-(3-fluoro-5-(pyrimidin-5-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (200 mg, 0.86 mmol), 5-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리미딘 (410 mg, 2.0 mmol), PdCl2(dppf) (31 mg, 0.043 mmol), 2M K2CO3 (aq.) (1.5 mL, 3.0 mmol)를 이용하여 목적화합물 (23 mg, 12%)을 얻었다.
LCMS, m/z 233 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리미딘-5-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyrimidin-5-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (20 mg, 0.099 mmol), 2-(3-플루오로-5-(피리미딘-5-일)페닐)아세트산 (23 mg, 0.099 mmol), T3P (50wt.% 용액 (in EtOAc), 95 mg, 0.30 mmol), DIPEA (34 μL, 0.20 mmol)를 이용하여 목적화합물(7.6 mg, 19%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.33 (s, 1H), 9.20 (s, 1H), 9.16 (s, 2H), 8.56 (s, 1H), 7.68 - 7.63 (m, 2H), 7.35 (d, J = 9.6 Hz, 1H), 4.01 (s, 2H), 3.47 (s, 1H), 2.00 (d, J = 8.1 Hz, 2H), 1.77 (d, J = 13.6 Hz, 4H), 1.61 (s, 2H).
LCMS, m/z 418 [M+H]+
실시예 7
(단계 1) 2-(3-플루오로-5-(1-메틸-1H-피롤-3-일)페닐)아세트산 [2-(3-fluoro-5-(1-methyl-1H-pyrrol-3-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol), 1-메틸-3-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피롤 (200 mg, 0.99 mmol), PdCl2(dppf) (17 mg, 0.022 mmol), 2M K2CO3 (aq.) (0.75 mL, 1.5 mmol)을 이용하여 목적화합물(56 mg, 56%)을 얻었다.
LCMS, m/z 234 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피롤-3-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrrol-3-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (29 mg, 0.14 mmol), 2-(3-플루오로-5-(1-메틸-1H-피롤-3-일)페닐)아세트산 (40 mg, 0.17 mmol), T3P (50wt.% 용액 (in EtOAc), 140 mg, 0.43 mmol), DIPEA (37 μL, 0.29 mmol)을 이용하여 목적화합물 (25 mg, 42%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.70 (s, 1H), 11.35 (s, 1H), 8.58 (s, 1H), 7.34 (s, 1H), 7.27 - 7.20 (m, 2H), 6.94 (d, J = 9.7 Hz, 1H), 6.76 (t, J = 2.4 Hz, 1H), 6.45 - 6.41 (m, 1H), 3.63 (s, 2H), 3.49 (d, J = 8.0 Hz, 1H), 2.02 (dd, J = 13.8, 5.7 Hz, 2H), 1.87 - 1.75 (m, 4H), 1.63 (td, J = 7.7, 3.3 Hz, 2H).
LCMS, m/z 419 [M+H]+
실시예 8
(단계 1) 2-(3-플루오로-5-(퓨란-2-일)페닐)아세트산 [2-(3-fluoro-5-(furan-2-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol) 와 2-(퓨란-2-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란 (194 mg, 1.0 mmol)을 이용하여 목적화합물 (55 mg, 66%)을 얻었다.
LCMS, m/z 221 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(퓨란-2-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(furan-2-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 2-(3-플루오로-5-(퓨란-2-일)페닐)아세트산 (45 mg, 0.20 mmol), T3P (50wt.% 용액 (in EtOAc), 332 mg, 0.52 mmol)을 이용하여 목적화합물 (12 mg, 17%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.30 (d, J = 9.7 Hz, 1H), 7.06 (d, J = 9.3 Hz, 1H), 6.81 (d, J = 3.3 Hz, 1H), 6.51 (dd, J = 3.3, 1.8 Hz, 1H), 3.93 (s, 2H), 3.34 (s, 1H), 2.13 (s, 2H), 1.87 (m, 4H), 1.71 (m, 2H).
LCMS, m/z 406 [M+H]+
실시예 9
(단계 1) 2-(3-플루오로-5-(1-이소프로필-1H-피라졸-4-일)페닐)아세트산 [2-(3-fluoro-5-(1-isopropyl-1H-pyrazol-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol)과 1-이소프로필-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피라졸 (236 mg, 1.0 mmol)을 이용하여 목적화합물 (88 mg, 78%)을 얻었다.
LCMS m/z 263 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-이소프로필-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-isopropyl-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 2-(3-플루오로-5-(1-이소프로필-1H-피라졸-4-일)페닐)아세트산 (41 mg, 0.16 mmol), T3P (50wt.% 용액 (in EtOAc), 332 mg, 0.52 mmol)을 이용하여 목적화합물 (6.9 mg, 9%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.06 (s, 1H), 7.84 (s, 1H), 7.41 (s, 1H), 7.21 (d, J = 9.9 Hz, 1H), 7.00 (d, J = 9.4 Hz, 1H), 4.55(m, 1H), 3.92 (s, 2H), 3.35 (s, 1H), 2.22 - 2.04 (m, 2H), 1.95 - 1.78 (m, 4H), 1.69 (m, 2H), 1.55 - 1.50 (d, 6H).
LCMS, m/z 448 [M+H]+
실시예 10
(단계 1) 2-(3-(1-(다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세트산 [2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)acetic acid]
2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol)과 1-(다이플루오로메틸)-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피라졸 (244 mg, 1.0 mmol)을 이용하여 목적화합물 (65 mg, 56%)을 얻었다.
LCMS, m/z 271 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-(1-(다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (48 mg, 0.26 mmol), 2-(3-(1-(다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세트산 (75 mg, 0.28 mmol), T3P (50wt.% 용액 (in EtOAc), 455 mg, 0.71 mmol)을 이용하여 목적화합물 (13 mg, 11%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.50 (s, 1H), 7.32 (dd, J = 8.0, 1.8 Hz, 1H), 7.10 (d, J = 9.4 Hz, 1H), 3.95 (s, 2H), 3.35 (m, 1H), 2.14 (m, 2H), 1.97 - 1.79 (m, 4H), 1.78 - 1.59 (m, 2H).
LCMS, m/z 456 [M+H]+
실시예 11
(단계 1) 2-(3-플루오로-5-(1H-피롤-2-일)페닐)아세트산 [2-(3-fluoro-5-(1H-pyrrol-2-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol), 2-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피롤 (190 mg, 0.99 mmol), PdCl2(dppf) (17 mg, 0.022 mmol), 2M K2CO3 (aq.) (0.75 mL, 1.5 mmol)을 이용하여 목적화합물 (62 mg, 66%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 11.37 (s, 1H), 7.34 (dd, J = 10.0, 1.7 Hz, 2H), 6.94 - 6.81 (m, 2H), 6.59 (d, J = 3.6 Hz, 1H), 6.12 (dd, J = 5.8, 2.4 Hz, 1H), 3.96 (s, 2H).
LCMS, m/z 220 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1H-피롤-2-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1H-pyrrol-2-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (31 mg, 0.15 mmol), 2-(3-플루오로-5-(1H-피롤-2-일)페닐)아세트산 (40 mg, 0.18 mmol), T3P (50wt.% 용액 (in EtOAc), 150 mg, 0.24 mmol), DIPEA (39 μL, 0.30 mmol)를 이용하여 목적화합물(12 mg, 19%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 11.37 (d, J = 12.0 Hz, 2H), 8.58 (s, 1H), 7.45 (s, 1H), 7.37 (d, J = 10.5 Hz, 1H), 7.00 (d, J = 9.4 Hz, 1H), 6.88 (d, J = 1.4 Hz, 1H), 6.59 (s, 1H), 6.13 (dd, J = 5.7, 2.5 Hz, 1H), 3.92 (s, 2H), 3.50 (s, 1H), 2.02 (d, J = 8.2 Hz, 2H), 1.82 (ddd, J = 26.8, 13.2, 7.2 Hz, 4H), 1.68 - 1.56 (m, 2H).
LCMS, m/z 405 [M+H]+
실시예 12
(단계 1) 2-(3-플루오로-5-(이소티아졸-4-일)페닐)아세트산 [2-(3-fluoro-5-(isothiazol-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (200 mg, 0.86 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)이소티아졸 (409 mg, 2.0 mmol), PdCl2(dppf) (31 mg, 0.043 mmol)를, 2M K2CO3 (aq.) (1.5 mL, 3.0 mmol)을 이용하여 목적화합물 (111 mg, 55%)을 얻었다.
LCMS, m/z 238 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(이소티아졸-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(isothiazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 2-(3-플루오로-5-(이소티아졸-4-일)페닐)아세트산 (49 mg, 0.21 mmol), T3P (50wt.% 용액 (in EtOAc), 160 mg, 0.26 mmol), DIPEA (45 μL, 0.34 mmol), EtOAc (2 mL)를 이용하여 목적화합물 (25 mg, 42%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.36 (s, 1H), 9.43 (s, 1H), 9.08 (s, 1H), 8.58 (s, 1H), 7.69 - 7.59 (m, 2H), 7.23 (d, J = 9.8 Hz, 1H), 3.99 (s, 2H), 3.49 (s, 1H), 1.99 (d, J = 7.5 Hz, 2H), 1.81 (d, J = 32.4 Hz, 4H), 1.62 (s, 2H).
LCMS, m/z 423 [M+H]+
실시예 13
(단계 1) 2-(3-플루오로-5-(티아졸-5-일)페닐)아세트산 [2-(3-fluoro-5-(thiazol-5-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol) 와 5-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)티아졸 (211 mg, 1.0 mmol)을 이용하여 목적화합물(50 mg, 49%)을 얻었다.
LCMS, m/z 238 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티아졸-5-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiazol-5-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 2-(3-플루오로-5-(티아졸-5-일)페닐)아세트산 (50 mg, 0.21 mmol), T3P (50wt.% 용액 (in EtOAc), 332 mg, 0.52 mmol)을 이용하여 목적화합물 (3.5 mg, 5%)을 얻었다
1H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 8.58 (s, 1H), 8.24 (s, 1H), 7.54 (s, 1H), 7.39 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 9.5 Hz, 1H), 3.98 (s, 2H), 3.39 (m, 1H), 2.15 (m, 2H), 1.89 (m, 4H), 1.74 (m, 2H).
LCMS, m/z 423 [M+H]+
실시예 14
(단계 1) 2-(3-플루오로-5-(피리딘-4-일)페닐)아세트산 [2-(3-fluoro-5-(pyridin-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol) 와 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리딘 (205 mg, 1.0 mmol)을 이용하여 목적화합물(70 mg, 70%)을 얻었다.
LCMS, m/z 232 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리딘-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyridin-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 2-(3-플루오로-5-(피리딘-4-일)페닐)아세트산 (50 mg, 0.22 mmol), T3P (50wt.% 용액 (in EtOAc), 332 mg, 0.52 mmol)을 이용하여 목적화합물 (20 mg)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.62 - 8.59 (m, 2H), 8.58 (s, 1H), 7.73 (dd, J = 4.7, 1.6 Hz, 2H), 7.64 (s, 1H), 7.46 (d, J = 9.7 Hz, 1H), 7.31 (d, J = 9.5 Hz, 1H), 4.03 (s, 2H), 3.38 (m, 1H), 2.15 (m, 2H), 1.98 - 1.80 (m, 4H), 1.73 (m, 2H).
LCMS, m/z 417 [M+H]+
실시예 15
(단계 1) 2-(3-플루오로-5-(피리딘-3-일)페닐)아세트산 [2-(3-fluoro-5-(pyridin-3-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol) 와 3-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리딘 (205 mg, 1.0 mmol)을 이용하여 목적화합물(50 mg, 50 %)을 얻었다.
LCMS, m/z 232 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리딘-3-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyridin-3-yl)phenyl)acetamide]ㅊ
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (48 mg, 0.23 mmol), 2-(3-플루오로-5-(피리딘-3-일)페닐)아세트산 (60 mg, 0.26 mmol), T3P (50wt.% 용액 (in EtOAc), 449 mg, 0.70 mmol)을 이용하여 목적화합물 (10 mg, 10%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 1.6 Hz, 1H), 8.52 (s, 1H), 8.49 (dd, J = 4.9, 1.5 Hz, 1H), 8.11 - 8.00 (m, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.47 (dd, J = 5.5, 3.2 Hz, 1H), 7.33 (d, J = 9.6 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H), 3.96 (s, 2H), 3.39 - 3.30 (m, 1H), 2.09 (m, 2H), 1.94 - 1.75 (m, 4H), 1.69 (m, 2H).
LCMS, m/z 417 [M+H]+
실시예 16
(단계 1) 2-(4'-(벤질옥시)-5-플루오로-[1,1'-바이페닐]-3-일)아세트산 [2-(4'-(benzyloxy)-5-fluoro-[1,1'-biphenyl]-3-yl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (200 mg, 0.86 mmol), (4-(벤질옥시)페닐)보론산 (450 mg, 2.0 mmol), PdCl2(dppf) (31 mg, 0.043 mmol), 2M K2CO3 (aq.) (1.5 mL, 3.0 mmol)을 이용하여 목적화합물(218 mg, 76%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 7.65 (s, 1H), 7.63 (s, 1H), 7.49 (d, J = 1.4 Hz, 1H), 7.47 (s, 1H), 7.43 - 7.34 (m, 7H), 7.12 (s, 1H), 7.10 (s, 1H), 7.05 (d, J = 9.6 Hz, 1H), 5.16 (s, 2H), 3.67 (s, 2H).
LCMS, m/z 335 [M-H]-
(단계 2) 2-(4'-(벤질옥시)-5-플루오로-[1,1'-바이페닐]-3-일)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드 [2-(4'-(benzyloxy)-5-fluoro-[1,1'-biphenyl]-3-yl)-N-(8-cyclopentyl-7H-purin-6-yl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (53 mg, 0.26 mmol), 2-(4'-(벤질옥시)-5-플루오로-[1,1'-바이페닐]-3-일)아세트산 (88 mg, 0.26 mmol), T3P (50wt.% 용액 (in EtOAc), 470 μL, 0.78 mmol), DIPEA (89 μL, 0.52 mmol)를 이용하여 목적화합물 (30 mg, 22%)을 얻었다.
1H NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.49 (s, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.41 (d, J = 7.0 Hz, 2H), 7.37 - 7.34 (m, 1H), 7.30 (s, 1H), 7.23 (d, J = 10.8 Hz, 1H), 7.03 (t, J = 9.2 Hz, 3H), 5.11 (s, 2H), 3.95 (s, 2H), 3.34 (p, J = 8.2 Hz, 1H), 2.18 (d, J = 6.3 Hz, 2H), 1.98 (dd, J = 13.5, 6.6 Hz, 2H), 1.74 (d, J = 4.0 Hz, 3H).
LCMS, m/z 522 [M+H]+
실시예 17
(단계 1) 2-(3-(사이클로펜트-1-엔-1-일)-5-플루오로페닐)아세트산 [2-(3-(cyclopent-1-en-1-yl)-5-fluorophenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol), 2-(사이클로펜트-1-엔-1-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란 (190 mg, 0.99 mmol), PdCl2(dppf) (17 mg, 0.022 mmol), 2M K2CO3 (aq.) (0.75 mL, 1.5 mmol)을 이용하여 목적화합물 (50 mg, 53%)를 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 7.15 (d, J = 12.6 Hz, 2H), 6.95 (d, J = 9.4 Hz, 1H), 6.34 (s, 1H), 3.58 (s, 3H), 2.60 (d, J = 5.8 Hz, 2H), 2.47 - 2.45 (m, 2H), 1.95 - 1.91 (m, 2H).
LCMS, m/z 219 [M-H]-
(단계 2) 2-(3-(사이클로펜트-1-엔-1-일)-5-플루오로페닐)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드 [2-(3-(cyclopent-1-en-1-yl)-5-fluorophenyl)-N-(8-cyclopentyl-7H-purin-6-yl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (37 mg, 0.18 mmol), 2-(3-(사이클로펜트-1-엔-1-일)-5-플루오로페닐)아세트산 (40 mg, 0.18 mmol), T3P (50wt.% 용액 (in EtOAc), 320 μL, 0.55 mmol), DIPEA (62 μL, 0.36 mmol)를 이용하여 목적화합물(25 mg, 33%)을 얻었다.
1H NMR (400 MHz, CDCl3) δ 10.97 (s, 1H), 8.66 (s, 1H), 7.17 (s, 1H), 7.11 (d, J = 9.9 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.25 (s, 1H), 3.86 (s, 2H), 3.35 (t, J = 8.2 Hz, 1H), 2.67 (dd, J = 10.4, 4.7 Hz, 2H), 2.56 - 2.52 (m, 2H), 2.18 (s, 2H), 2.02 (d, J = 7.4 Hz, 2H), 1.88 (s, 2H), 1.72 (d, J = 2.7 Hz, 4H).
LCMS, m/z 406 [M+H]+
실시예 18
(단계 1) 2-(3-플루오로-5-(티오펜-2-일)페닐)아세트산 [2-(3-fluoro-5-(thiophen-2-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol), 2-(사이클로펜트-1-엔-1-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란(207 mg, 0.99 mmol), PdCl2(dppf) (17 mg, 0.022 mmol)를, 2M K2CO3 (aq.) (0.75 mL, 1.5 mmol)를 이용하여 목적화합물 (79 mg, 68%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.58 (dd, J = 4.3, 3.2 Hz, 2H), 7.46 - 7.33 (m, 2H), 7.14 (dd, J = 5.0, 3.7 Hz, 1H), 7.04 (d, J = 9.4 Hz, 1H), 3.65 (s, 2H).
LCMS, m/z 235 [M-H]-
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티오펜-2-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(thiophen-2-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (37 mg, 0.18 mmol), 2-(3-플루오로-5-(티오펜-2-일)페닐)아세트산 (43 mg, 0.18 mmol), T3P (50wt.% 용액 (in EtOAc), 320 μL, 0.55 mmol), DIPEA (62 μL, 0.36 mmol)를 이용하여 목적화합물 (24 mg, 31%)을 얻었다.
1H NMR (400 MHz, CDCl3) δ 10.97 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 7.36 (s, 1H), 7.35 (s, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.10 (dd, J = 5.0, 3.7 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H), 3.92 (s, 2H), 3.35 (t, J = 8.2 Hz, 1H), 2.23 - 2.16 (m, 2H), 1.93 (d, J = 25.3 Hz, 2H), 1.74 (dd, J = 7.3, 4.6 Hz, 4H).
LCMS, m/z 422 [M+H]+
실시예 19
8-사이클로펜틸-N-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)벤질)-7H-퓨린-6-아민 [8-cyclopentyl-N-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzyl)-7H-purin-6-amine]
8-사이클로펜틸-7H-퓨린-6-아민 (50 mg, 0.23 mmol), (3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)메탄아민 (55 mg, 0.27 mmol)을 DMA (3 mL)에 녹인 후 DIPEA (47 μL, 0.27 mmol)를 넣고 130 ℃에서 가열 교반 하였다. 3시간 후 반응혼합물을 상온으로 식힌 다음, CH2Cl2 로 희석하고 H2O로 씻어주었다. 유기층을 Na2SO4로 건조 후 농축하여 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (0-5 % MeOH in DCM)로 정제하여 목적화합물 (30 mg, 34%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 7.98 (s, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.81 (s, 3H), 3.92 (s, 2H), 3.31 (m, 1H), 2.16 - 1.75 (m, 8H).
LCMS, m/z 392 [M+H]+
실시예 20
(단계 1) 2-(3-(1-메틸-1H-피라졸-4-일)-5-(트리플루오로메틸)페닐)아세트산 [2-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-(트리플루오로메틸)페닐)아세트산 (283 mg, 1.0 mmol), 1-메틸-2-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피롤 (416 mg, 2.0 mmol), PdCl2(dppf) (46 mg), 2M K2CO3 (aq.) (1.74 mL)을 이용하여 목적화합물 (210 mg, 74%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.08 (s, 1H), 7.90 (s, 1H), 7.73 (s, 1H), 7.72 (s, 1H), 7.43 (s, 1H), 3.93 (s, 3H), 3.72 (s, 2H).
LCMS, m/z 285 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-(1-메틸-1H-피라졸-4-일)-5-(트리플루오로메틸)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (28 mg, 0.14 mmol), 2-(3-(1-메틸-1H-피라졸-4-일)-5-(트리플루오로메틸)페닐)아세트산 (45 mg, 0.16 mmol), 50% T3P (50wt.% 용액 (in EtOAc), 275 mg, 0.42 mmol), DIPEA (51 μL, 0.29 mmol)를 이용하여 목적화합물 (13 mg, 20%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 4.02 (s, 2H), 3.93 (s, 3H), 3.39 (m, 1H), 2.14 (m, 2H), 1.93 - 1.88 (m, 4H), 1.73 (m, 2H).
LCMS, m/z 470 [M+H]+
실시예 21
(단계 1) 2-(3-플루오로-5-(1-메틸-1H-피라졸-3-일)페닐)아세트산 [2-(3-fluoro-5-(1-methyl-1H-pyrazol-3-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol), 1-메틸-3-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피라졸 (208 mg, 1.0 mmol), PdCl2(dppf) (20 mg), 2M K2CO3 (aq.) (0.75 mL)를 이용하여 목적화합물 (80 mg, 79%)를 얻었다.
LCMS, m/z 235 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-3-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-3-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (58 mg, 0.28 mmol), 2-(3-플루오로-5-(1-메틸-1H-피라졸-3-일)페닐)아세트산 (73 mg, 0.31 mmol), T3P, 50wt.% 용액 (in EtOAc) (553 mg, 0.87 mmol), DIPEA (121 μL, 0.21 mmol)를 이용하여 목적화합물(13 mg, 11%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.63 (s, 1H), 3.94 (s, 2H), 3.93 (s, 3H), 3.36 (m, 1H), 2.13 (m, 2H), 1.92 - 1.87 (m, 4H), 1.74 (m, 2H).
LCMS m/z 420 [M+H]+
실시예 22
N-(8-사이클로펜틸-7H-퓨린-6-일)-3-플루오로-5-(1-메틸-1H-피라졸-4-일)벤즈아미드 [N-(8-cyclopentyl-7H-purin-6-yl)-3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)benzamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (35 mg, 0.17 mmol), 3-플루오로-5-(1-메틸-1H-피라졸-4-일)벤조산 (40 mg, 0.18 mmol), T3P, 50wt.% 용액 (in EtOAc) (365 mg, 0.57 mmol), DIPEA (79 μL, 0.14 mmol)를 이용하여 목적화합물 (21 mg, 30%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.66 (m, 2H), 3.95 (s, 3H), 3.46 (m, 1H), 2.23 (m, 2H), 1.99 - 1.94 (m, 4H), 1.78 (m, 2H).
LCMS, m/z 406 [M+H]+
실시예 23
(단계 1) 2-(3-플루오로-5-(피리다진-4-일)페닐)아세트산 [2-(3-fluoro-5-(pyridazin-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (200 mg, 0.86 mmol), 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리다진 (410 mg, 2.0 mmol), PdCl2(dppf) (31 mg, 0.043 mmol), 2M K2CO3 (aq.) (1.5 mL, 3.0 mmol)을 이용하여 목적화합물 (39 mg, 20%)를 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 9.67 (d, J = 1.3 Hz, 1H), 9.32 (d, J = 5.4 Hz, 1H), 8.05 (dd, J = 5.5, 2.5 Hz, 1H), 7.77 (d, J = 9.9 Hz, 1H), 7.73 (s, 1H), 7.32 (d, J = 9.5 Hz, 1H), 3.74 (s, 2H).
LCMS, m/z 233 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리다진-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(pyridazin-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (18 mg, 0.086 mmol), 2-(3-플루오로-5-(피리다진-4-일)페닐)아세트산 (20 mg, 0.086 mmol), T3P, 50wt.% 용액 (in EtOAc) (150 μL, 0.26 mmol), DIPEA (29 μL, 0.17 mmol)를 이용하여 목적화합물(25 mg, 68%)을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 11.08 - 11.07 (m, 1H), 9.50 (s, 1H), 9.28 (d, J = 5.5 Hz, 1H), 8.64 (s, 1H), 7.70 (s, 2H), 7.65 (s, 1H), 7.35 - 7.34 (m, 2H), 3.67 (s, 2H), 3.11 (s, 1H), 2.18 - 2.17 (m, 2H), 1.91 - 1.90 (m, 4H), 1.73 - 1.73 (m, 2H).
LCMS, m/z 418 [M+H]+
실시예 24
N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-플루오로-4'-히드록시-[1,1'-바이페닐]-3-일)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(5-fluoro-4'-hydroxy-[1,1'-biphenyl]-3-yl)acetamide]
2-(4'-(벤질옥시)-5-플루오로-[1,1'-바이페닐]-3-일)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드(실시예 16) (16 mg, 0.031 mmol)를 MeOH (3 mL)에 넣고, 10% 탄소 상 팔라듐 (Palladium on carbon, 6 mg, 0.031 mmol)를 첨가한 후, H2 기류하에 상온에서 반응시켰다. 2시간 후 반응혼합물을 셀라이트 패드(pad)에서 여과한 후 여과액을 농축하였다. 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (0-5% MeOH in CH2Cl2)으로 정제하여 목적화합물 (2 mg, 15%)을 얻었다.
1H NMR (400 MHz, CDCl3) δ 11.27 - 10.94 (m, 1H), 9.39 (s, 1H), 8.66 (d, J = 20.1 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 3.95 (d, J = 11.5 Hz, 2H), 3.33 (t, J = 8.2 Hz, 1H), 1.73 (d, J = 3.8 Hz, 8H).
LCMS, m/z 432 [M+H]+
실시예 25
2-(3-사이클로펜틸-5-플루오로페닐)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드 [2-(3-cyclopentyl-5-fluorophenyl)-N-(8-cyclopentyl-7H-purin-6-yl)acetamide]
실시예 24와 같은 방법으로2-(3-(사이클로펜트-1-엔-1-일)-5-플루오로페닐)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드 (실시예 17) (20 mg, 0.049 mmol)을 출발 물질로 이용하여 목적화합물(5 mg, 25%)를 얻었다.
1H NMR (400 MHz, CDCl3) δ 11.27 - 10.94 (m, 1H), 9.39 (s, 1H), 8.66 (d, J = 20.1 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 3.95 (d, J = 11.5 Hz, 2H), 3.33 (t, J = 8.2 Hz, 1H), 1.73 (d, J = 3.8 Hz, 8H).
LCMS, m/z 432 [M+H]+
실시예 26
N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4-플루오로-3-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민(35 mg, 0.17 mmol), 2-(4-플루오로-3-(1-메틸-1H-피라졸-4-일)페닐)아세트산 (42 mg, 0.18 mmol), T3P, 50wt.% 용액 (in EtOAc) (365 mg, 0.57 mmol), DIPEA (79 μL, 0.14 mmol)를 이용하여 목적화합물 (20 mg, 28%)을 얻었다.
1H NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 9.00 (s, 1H), 8.66 (s, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.51 (d, J = 4.0 Hz, 1H), 7.15 (d, J = 4.0 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 2H), 3.33 (m, 1H), 2.18 (m, 2H), 1.98 (m, 2H), 1.88 (m, 2H), 1.72 (m, 2H).
LC-MS, m/z 420 [M+H]+
실시예 27
(단계 1) 2-(3-플루오로-5-(1-(트리플루오로메틸)-1H-피라졸-4-일)페닐)아세트산 [2-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (86 mg, 0.80 mmol4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1-(트리플루오로메틸)-1H-피라졸 (262 mg, 1.0 mmol), PdCl2(dppf) (37 mg, 0.043 mmol), 2M K2CO3 (aq.) (1.4 mL, 3.0 mmol)를 이용하여 목적화합물 (70 mg, 30%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.62(s, 1H), 8.22 (s, 1H), 7.40 (s, 1H), 7.34 (d, J = 12 Hz, 1H), 7.02 (d, J = 12 Hz, 1H), 3.68 (s, 2H).
LCMS, m/z 289 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(트리플루오로메틸)-1H-피라졸-4-yl)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-(trifluoromethyl)-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (20 mg, 0.098 mmol), 2-(3-플루오로-5-(1-(트리플루오로메틸)-1H-피라졸-4-일)페닐)아세트산 (27 mg, 0.093 mmol), T3P (50wt.% 용액 (in EtOAc), 181 mg, 0.28 mmol), DIPEA (41 μL, 0.24 mmol)를 이용하여 목적화합물(11 mg, 24%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 7.52 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 3.96 (s, 2H), 3.42 (m, 1H), 2.15 (m, 2H), 1.93 (m, 4H), 1.75 (m, 2H).
LCMS, m/z 474 [M+H]+
실시예 28
(단계 1) 2-(3-플루오로-5-(2-메톡시피리딘-4-일)페닐)아세트산 [2-(3-fluoro-5-(2-methoxypyridin-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (149 mg, 0.64 mmol), 2-메톡시-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)피리딘 (181 mg, 0.77 mmol), PdCl2(dppf) (23 mg, 0.032 mmol), 2M K2CO3 (aq.) (1.1 mL)을 이용하여 목적화합물 (20 mg, 31%)을 얻었다.
LCMS, m/z 262 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(2-메톡시피리딘-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(2-methoxypyridin-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (0.193 mmol), 2-(3-플루오로-5-(2-메톡시피리딘-4-일)페닐)아세트산 (39 mg, 0.19 mmol), T3P (50wt.% 용액 (in EtOAc), 337 mg, 0.53 mmol), DIPEA (81 uL, 0.47 mmol)를 이용하여 목적화합물 (20 mg, 31%)을 얻었다.
1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.23 (d, J = 5.0 Hz, 1H), 7.39 - 7.38 (m, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 7.18 - 7.16 (m, 1H), 7.16 - 7.14 (m, 1H), 7.08 (d, J = 1.6 Hz, 1H), 7.07 (d, J = 1.5 Hz, 1H), 6.93 (dd, J = 1.5, 0.7 Hz, 12H), 3.98 (s, 3H), 3.93 (s, 2H), 3.40 - 3.26 (m, 1H), 2.27 - 2.13 (m, 3H), 2.04 - 1.96 (m, 3H), 1.94 - 1.83 (m, 3H).
LCMS, m/z 447 [M+H]+
실시예 29
N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4',5-다이플루오로-[1,1'-바이페닐]-3-일)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(4',5-difluoro-[1,1'-biphenyl]-3-yl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민(0.193 mmol), 2-(4',5-다이플루오로-[1,1'-바이페닐]-3-일)아세트산(39 mg, 0.19 mmol), T3P (50wt.% 용액 (in EtOAc), 337 mg, 0.53 mmol), DIPEA (81 uL, 0.47 mmol)를 이용하여 목적화합물 (4 mg, 5%)을 흰색 고체 형태로 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H),7.63 (m, 2H), 7.34 (s, 1H), 7.23 - 7.14 (m, 3H), 7.04 (d, J = 8.0 Hz, 1H), 3.53 (s, 2H), 3.34 (m, 1H), 2.18 (m, 2H), 1.93 - 1.84 (m, 4H), 1.75 (m, 2H).
LCMS, m/z 434 [M+H]+
실시예 30
(단계 1) 2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아세트산 [2-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)acetic acid]
2-(5-브로모피리딘-3-일)아세트산 (300 mg, 1.39 mmol), 1-메틸-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피라졸 (289 mg, 1.39 mmol), Pd(dppf)Cl2 (50.8 mg, 0.07 mmol) 및 Cs2CO3 (742 mg, 2.28 mmol)을 다이옥산/물 (10:1, 0.063 M)에 녹이고 15분간 탈기(degassing)하였다. 90 ℃에서 1.5시간 가열 교반한 후 농축하여 용매를 제거하였다. 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (0-22 % MeOH in DCM)로 정제하여 목적화합물 (150 mg, 50%))을 갈색 고체 형태로 얻었다.
LCMS m/z 218 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (20 mg, 0.1 mmol), 2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아세트산 (20 mg, 0.1 mmol), T3P (50wt.% 용액 (in EtOAc), 181 mg), DIPEA (41 uL)를 이용하여 목적화합물 (1.5 mg, 4%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 8.56 (s, 1H), 8.39 (d, J =4.0 Hz, 1H) ,8.04 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 3.99 (s, 2H), 3.92 (s, 3H), 3.35 (m, 1H), 2.10 (m, 2H), 1.93 - 1.81 (m, 4H), 1.70 (m, 2H).
LCMS, m/z 403 [M+H]+
실시예 31
(단계 1) 2-(2-(1-메틸-1H-피라졸-4-일)피리딘-4-일)아세트산 [2-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)acetic acid]
실시예 30의 단계 1과 같은 방법으로 2-(2-브로모피리딘-4-일)아세트산 (300 mg, 1.39 mmol), 1-메틸-4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보롤란-2-일)-1H-피라졸 (289 mg, 1.39 mmol), Pd(dppf)Cl2 (50.8 mg, 0.07 mmol), Cs2CO3 (742 mg, 2.28 mmol)을 이용하여 목적화합물(110 mg, 36%)을 얻었다.
LCMS, m/z 218 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(2-(1-메틸-1H-피라졸-4-일)피리딘-4-일)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (30.0 mg, 0.15 mmol) 및 2-(2-(1-메틸-1H-피라졸-4-일)피리딘-4-일)아세트산 (30.0 mg, 0.14 mmol), T3P (50wt.% 용액 (in EtOAc), 0.25 mL), DIPEA (0.05 mL)를 이용하여 목적화합물(4.4 mg, 8%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 11.38 (s, 1H), 8.59 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.19 (d, J = 5.1 Hz, 1H), 3.95 (s, 2H), 3.88 (s, 3H), 3.53 - 3.44 (m, 1H), 2.11 - 1.96 (m, 2H), 1.93 - 1.72 (m, 4H), 1.70 - 1.57 (m, 2H)
LCMS, m/z 403 [M+H]+
실시예 32
(단계 1) 6-클로로-8-사이클로헥실-7H-퓨린 [6-chloro-8-cyclohexyl-7H-purine]
합성예 1의 단계1과 같은 방법으로 사이클로헥산카보닐 클로라이드 (cyclohexanecarbonyl chloride, 271 uL, 2.0 mmol), 6-클로로피리미딘-4,5-다이아민 (290 mg, 2.0 mmol), POCl3 (3 mL)를 이용하여 목적화합물(260 mg, 55%)을 얻었다.
1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 3.01 (m, 1H), 2.05 -1.36 (m, 10H)
LCMS, m/z 237[M+H]+
(단계 2) 8-사이클로헥실-7H-퓨린-6-아민 [8-cyclohexyl-7H-purin-6-amine]
합성예 1의 단계 2과 같은 방법으로 6-클로로-8-사이클로헥실-7H-퓨린 (250 mg, 1.06 mmol)과 7N NH3 메탄올액(in MeOH, 5 mL)을 이용하여 목적화합물(80mg, 35%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 2.91 (m, 1H), 2.11 (m, 2H), 1.91 (m, 2H), 1.80 (m, 1H), 1.65 (m, 2H), 1.46 (m, 3H).
LCMS, m/z 218 [M+H]+
(단계 3) N-(8-사이클로헥실-7H-퓨린-6-일)-2-(3-(1-다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세타마이드 [N-(8-cyclohexyl-7H-purin-6-yl)-2-(3-(1-difluoromethyl)-1H-pyrazol-4-yl)-5-fluorophenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로헥실-7H-퓨린-6-아민 (20mg, 0.092 mmol), 2-(3-(1-(다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세트산 (27 mg, 0.092 mmol), T3P (50wt.% 용액 (in EtOAc), 181 mg, 0.28 mmol), DIPEA (41 μL, 0.24 mmol), 에틸아세테이트(4 mL)를 이용하여 목적화합물(10 mg, 23%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.58 (s, 1H), 8.48 (s, 1H), 8.11 (s, 1H), 7.49 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 3.95 (s, 2H), 2.99 (m, 1H), 2.03 (m, 2H), 1.87 (m, 2H), 1.74 (m, 3H), 1.46 (m, 3H), 1.28(s, 1H)
LCMS, m/z 470 [M+H]+
실시예 33
(단계 1) 8-(피페리딘-1-일)-7H-퓨린-6-아민 [8-(piperidin-1-yl)-7H-purin-6-amine]
8-브로모-7H-퓨린-6-아민 (100 mg, 0.47 mmol)을 피페리딘 (2.0 mL, 27.2 mmol)에 녹인 후 150 ℃에서 가열 교반 하였다. 12시간 후 반응혼합물을 상온으로 식힌 다음, 반응혼합물을 감압 농축하였다. 얻어진 잔사에 CH2Cl2을 첨가한 후 녹지 않는 고체를 여과하고 여과액을 감압 농축하여 목적화합물(49 mg, 48%)을 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 3.45 (m, 4H),1.56 (m, 6H).
LCMS, m/z 219 [M+H]+
(단계 2) 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)-N-(8-(피페리딘-1-일)-7H-퓨린-6-일)아세타마이드 [2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-(8-(piperidin-1-yl)-7H-purin-6-yl)acetamide]
8-(피페리딘-1-일)-7H-퓨린-6-아민 (10 mg, 0.046 mmol), 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세트산 (11 mg, 0.047 mmol), T3P (50wt.% 용액 (in EtOAc), 99 mg)을 DMF (2 mL)에 녹인 후 DIPEA (21 μL)를 넣고 마이크로웨이브(microwave) 반응기를 이용하여 150 ℃에서 1시간 동안 반응시켰다. 반응혼합물에 포화 NaHCO3 수용액을 넣고 에틸아세테이트로 추출한 후 유기층을 Na2SO4로 건조하고 감압 여과하였다. 유기층을 농축한 후 실리카 겔 컬럼 크로마토그래피 (0-5 % MeOH in DCM)로 정제하여 목적화합물(14 mg, 70%)을 얻었다.
1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.36 (s, 1H), 7.20 (d, J = 12 Hz, 1H), 6.99 (d, J = 12 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 2H), 3.59 (m, 4H), 1.67 (m, 6H)
LCMS, m/z 435 [M+H]+
실시예 34
(단계 1) 2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 [2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(3-브로모-5-플루오로페닐)아세트산 (100 mg, 0.43 mmol) 와 (1-(4-플루오로페닐)-1H-피라졸-4-일)보론산 (119 mg, 0.51 mmol), PdCl2(dppf) (16 mg, 0.021 mmol), 2M K2CO3 (aq.) (0.75 mL, 1.5 mmol)을 이용하여 목적화합물(70 mg, 52%)을 갈색 고체로 얻었다.
LCMS, m/z 315 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (42 mg, 0.21 mmol), 2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 (65 mg, 0.21 mmol), T3P (50wt.% 용액 (in EtOAc), 428 mg, 0.66 mmol), DIPEA (93 μL, 0.54 mmol)를 이용하여 목적화합물(25 mg, 24%)을 갈색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 11.33(s, 1H), 9.04 (s, 1H), 8.57 (s, 1H), 8.24 (s, 1H), 7.91 - 7.86 (m, 2H), 7.54 (s, 1H), 7.50 - 7.46 (m, 1H), 7.37 (t, J = 8 Hz, 2H), 7.12 (d, J = 12 Hz, 1H), 3.95 (s, 2H), 3.50 - 3.46 (m, 1H), 2.05 - 1.95 (m, 2H), 1.90 - 1.70 (m, 4H), 1.69 - 1.57 (m, 2H).
LCMS, m/z 500 [M+H]+
실시예 35
(단계 1) 2-(3-플루오로-4-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 [2-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(4-브로모-3-플루오로페닐)아세트산 (100 mg, 0.43 mmol) 와 (1-(4-플루오로페닐)-1H-피라졸-4-일)보론산 (119 mg, 0.51 mmol), PdCl2(dppf) (16 mg, 0.021 mmol), 2M K2CO3 (aq.) (0.75 mL, 1.5 mmol)을 이용하여 목적화합물(50 mg, 37%)을 흰색 고체로 얻었다.
LCMS, m/z 315 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-4- (1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(3-fluoro-4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (30 mg, 0.15 mmol), 2-(3-플루오로-4-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 (45 mg, 0.15 mmol), T3P (50wt.% 용액 (in EtOAc), 300 mg, 0.46 mmol), DIPEA (65 μL, 0.38 mmol)를 이용하여 목적화합물(18 mg, 24%)을 흰색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 11.31(s, 1H), 8.88 (s, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 7.94 - 7.91 (m, 2H), 7.78 (t, J = 8 Hz, 1H), 7.41 - 7.25 (m, 4H), 3.93 (s, 2H), 3.50 - 3.46 (m, 1H), 2.07 - 1.96 (m, 2H), 1.92 - 1.71 (m, 4H), 1.68 - 1.58 (m, 2H).
LCMS, m/z 500 [M+H]+
실시예 36
(단계 1) 2-(4-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 [2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetic acid]
실시예 1의 단계 1과 같은 방법으로 2-(4-브로모페닐)아세트산 (93 mg, 0.43 mmol) 와 (1-(4-플루오로페닐)-1H-피라졸-4-일)보론산 (119 mg, 0.51 mmol), PdCl2(dppf) (16 mg, 0.021 mmol), 2M K2CO3 (aq.) (0.75 mL, 1.5 mmol)을 이용하여 목적화합물(70 mg, 55%)을 흰색 고체로 얻었다.
LCMS, m/z 297 [M+H]+
(단계 2) N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4-(1-(4- 플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-cyclopentyl-7H-purin-6-yl)-2-(4-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-사이클로펜틸-7H-퓨린-6-아민 (42 mg, 0.21 mmol), 2-(4-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 (65 mg, 0.22 mmol), T3P (50wt.% 용액 (in EtOAc), 428 mg, 0.66 mmol), DIPEA (93 μL, 0.54 mmol)를 이용하여 목적화합물(25 mg, 25%)을 흰색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 2H), 8.94 (s, 1H), 8.57 (s, 1H), 8.19 (s, 1H), 7.91 - 7.88 (m, 2H), 7.68 (d, J = 8 Hz, 2H), 7.41 - 7.31 (m, 4H), 3.89 (s, 2H), 3.50 - 3.46 (m, 1H), 2.10 - 1.97 (m, 2H), 1.92 - 1.70 (m, 4H), 1.68 - 1.59 (m, 2H).
LCMS, m/z 482 [M+H]+
실시예 37
N-(3-브로모펜에틸)-8-사이클로펜틸-7H-퓨린-6-아민
[N-(3-bromophenethyl)-8-cyclopentyl-7H-purin-6-amine]
6-클로로-8-사이클로펜틸-7H-퓨린 (51 mg, 0.23 mmol), 2-(3-브로모페닐)에탄아민 (36 μL, 0.25 mmol), DIPEA (117 μL, 0.69 mmol) 및 EtOH (4.6 mL)를 넣고 82 ℃에서 38시간 동안 교반하였다. 반응 혼합물을 H2O로 반응중단시키고 EtOAc로 추출한 후 유기층을 MgSO4로 건조하고 감압 여과하였다. 농축하여 얻어진 잔사를 실리카 겔 컬럼 크로마토그래피 (0→100 % EtOAc in n-Hex)로 정제하여 목적화합물 (62 mg, 70.3%)을 연한 노란색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.12 (s, 1H), 7.47 (broad, 2H), 7.38 (d, J = 6.8 Hz, 1H), 7.32 - 7.18 (m, 2H), 3.81 - 3.59 (broad, 2H), 3.27 - 3.13 (m, 1H), 2.91 (t, J = 7.3 Hz, 2H), 2.11 - 1.97 (m, 2H), 1.94 - 1.81 (m, 2H), 1.80 - 1.69 (m, 2H), 1.69 - 1.55 (m, 2H).
LCMS, m/z 386 [M+H]+
실시예 38
(단계 1) 6-클로로-8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린 [6-chloro-8-(3,3-difluorocyclopentyl)-7H-purine]
합성예 1의 단계 1과 같은 방법으로 3,3-다이플루오로사이클로펜탄카보닐 클로라이드 (1.12 g, 6.67 mmol), 6-클로로피리미딘-4,5-다이아민 (1.15 g, 8.0 mmol), POCl3(7.5ml)을 이용하여 목적화합물(1.0 g, 58%)을 노란색 고체로 얻었다.
LCMS, m/z 259 [M+H]+
(단계 2) 8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린-6-아민 [8-(3,3-difluorocyclopentyl)-7H-purin-6-amine]
합성예 1의 단계 2과 같은 방법으로 6-클로로-8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린 (1.0 g, 3.86 mmol)와 7 N NH3 메탄올액(in MeOH, 20 mL)을 이용하여 목적화합물(70 mg, 7.5%)을 흰색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.06 (s, 1H), 6.98 (s, 2H), 3.56 -3.52 (m, 1H), 2.62 - 2.55 (m, 2H), 2.30 - 2.23 (m, 2H), 2.13 - 2.06 (m, 2H).
LCMS, m/z 240 [M+H]+
(단계 3) N-(8-(3,3- 다이플루오로사이클로펜틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-(3,3-difluorocyclopentyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린-6-아민 (30 mg, 0.15 mmol), 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세트산 (73 mg, 0.31 mmol), T3P (50wt.% 용액 (in EtOAc), 212 mg, 0.34 mmol), DIPEA (48 μL, 0.28 mmol)를 이용하여 목적화합물(6 mg, 11%)을 노란색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 11.38 (s, 1H), 8.62 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.42 (s, 1H), 7.35 (d, J = 8 Hz, 1H), 7.06 (d, J = 8 Hz, 1H), 3.94 (s, 2H), 3.87 (s, 3H), 3.84 (m, 1H), 2.60 - 2.55 (m, 2H), 2.33 - 2.04 (m, 4H).
LCMS, m/z 456 [M+H]+
실시예 39
N-(8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-(3,3-difluorocyclopentyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린-6-아민 (30 mg, 0.15 mmol), 2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 (97 mg, 0.31 mmol), T3P (50wt.% 용액 (in EtOAc), 212 mg, 0.34 mmol), DIPEA (48 μL, 0.28 mmol)를 이용하여 목적화합물(33 mg, 49%)을 노란색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 11.41(s, 1H), 9.06 (s, 1H), 8.63 (s, 1H), 8.27 (s, 1H), 7.93 - 7.89 (m, 2H), 7.57 - 7.48 (m, 2H), 7.39 (t, J = 8 Hz, 2H), 7.14 (d, J = 8 Hz, 1H), 3.99 (s, 2H), 3.88 - 3.84 (m, 1H), 2.60 - 2.55 (m, 2H), 2.38 - 2.04 (m, 4H).
LCMS, m/z 536 [M+H]+
실시예 40
(단계 1) 6-클로로-8-(3,3-다이플루오로사이클로부틸)-7H-퓨린 [6-chloro-8-(3,3-difluorocyclobutyl)-7H-purine]
3,3-다이플루오로사이클로뷰테인카르복실산 (408 mg, 3.0 mmol), 6-클로로피리미딘-4,5-다이아민 (434 mg, 3.0 mmol)을 1,4-다이옥산 (8 mL)에 첨가한 후, T3P (50wt.%용액 (in EtOAc), 5.7 g, 9.0 mmol), DIPEA (1.3 mL, 7.5 mmol)을 넣고 마이크로웨이브 반응기를 이용하여 150 ℃에서 4시간 동안 반응시켰다. 반응혼합물에 H2O를 넣고 에틸아세테이트로 추출한 후 유기층을 MgSO4로 건조하고 감압 여과하였다. 유기층을 농축한 후 실리카 겔 컬럼 크로마토그래피 (0-3% MeOH in DCM)로 정제하여 목적화합물 (440 mg, 60%)을 연갈색의 고체형태로 얻었다.
1H NMR (400 MHz, DMSO-d6) 13.84 (s, 1H), 8.68 (s, 1H), 3.76 - 3.65 (m, 1H), 3.09 (dt, J = 15.6, 9.2 Hz, 4H).
LCMS, m/z 245 [M+H]+
(단계 2) 8-(3,3-다이플루오로사이클로부틸)-7H-퓨린-6-아민 [8-(3,3-difluorocyclobutyl)-7H-purin-6-amine]
합성예 1의 단계 2과 같은 방법으로 6-클로로-8-(3,3-다이플루오로사이클로부틸)-7H-퓨린 (440 mg, 1.80 mmol)와 0.4 N NH3 다이옥산액(in 다이옥산, 100 mL)을 이용하여 목적화합물(45 mg, 7.5%)을 흰색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.79 (s, 1H), 8.06 (s, 1H), 7.02 (s, 2H), 3.54 -3.51 (m, 1H), 3.06 - 2.98 (m, 4H).
LCMS, m/z 226 [M+H]+
(단계 3) N-(8-(3,3- 다이플루오로사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-(3,3-difluorocyclobutyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-(3,3-다이플루오로사이클로부틸)-7H-퓨린-6-아민 (20 mg, 0.089 mmol), 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세트산 (52 mg, 0.22 mmol), T3P (50wt.% 용액 (in EtOAc), 151 mg, 0.24 mmol), DIPEA (34 μL, 0.20 mmol)를 이용하여 목적화합물(1.8 mg, 4.5%)을 노란색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.19 (s, 1H), 7.90 (s, 1H), 7.41 (s, 1H), 7.34 (d, J = 8 Hz, 1H), 7.05 (d, J = 8 Hz, 1H), 3.94 (s, 2H), 3.87 (s, 3H), 3.84 (m, 1H), 3.08 -2.98 (m, 4H).
LCMS, m/z 442 [M+H]+
실시예 41
N-(8-(3,3-다이플루오로사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-(3,3-difluorocyclobutyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-(3,3-다이플루오로사이클로부틸)-7H-퓨린-6-아민 (20 mg, 0.089 mmol), 2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 (69 mg, 0.22 mmol), T3P (50wt.% 용액 (in EtOAc), 151 mg, 0.24 mmol), DIPEA (34 μL, 0.20 mmol)를 이용하여 목적화합물(9.6 mg, 21%)을 노란색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 11.43(s, 1H), 9.06 (s, 1H), 8.64 (s, 1H), 8.27 (s, 1H), 7.93 - 7.90 (m, 2H), 7.57 - 7.50 (m, 2H), 7.40 (t, J = 8 Hz, 2H), 7.14 (d, J = 12 Hz, 1H), 3.99 (s, 2H), 3.68 - 3.66 (m, 1H), 3.05 - 2.97 (m, 4H).
LCMS, m/z 522 [M+H]+
실시예 42
(단계 1) 6-클로로-8-(3,3-다이메틸사이클로부틸)-7H-퓨린 [6-chloro-8-(3,3-dimethylcyclobutyl)-7H-purine]
실시예 40의 단계1과 같은 방법으로 3,3-다이메틸사이클로뷰테인카르복실산 (385 mg, 3.0 mmol), 6-클로로피리미딘-4,5-다이아민 (434 mg, 3.0 mmol)을 1,4-다이옥산 (8 mL)에 첨가한 후, T3P (50wt.%용액 (in EtOAc), 5.7 g, 9.0 mmol), DIPEA (1.3 mL, 7.5 mmol)를 이용하여 목적화합물 (392 mg, 55%)을 연갈색의 고체형태로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 8.65 (s, 1H), 3.75 (p, J = 8.9 Hz, 1H), 2.21 (dtd, J = 35.8, 9.3, 2.2 Hz, 4H), 1.26 (s, 3H), 1.14 (s, 3H).
LCMS, m/z 237 [M+H]+
(단계 2) 8-(3,3-다이메틸사이클로부틸)-7H-퓨린-6-아민 [8-(3,3-dimethylcyclobutyl)-7H-purin-6-amine]
합성예 1의 단계2과 같은 방법으로 6-클로로-8-(3,3-다이메틸사이클로부틸)-7H-퓨린 (392 mg, 1.66 mmol)와 0.4 N NH3 다이옥산액(in Dioxane, 100 mL)을 이용하여 목적화합물(96 mg, 21%)을 연갈색 고체로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 7.95 (s, 1H), 3.49 - 3.46 (m, 1H), 2.19 (t, J = 10.3 Hz, 2H), 2.10 (t, J = 8.7 Hz, 2H), 1.24 (s, 3H), 1.12 (s, 3H).
LCMS, m/z 218 [M+H]+
(단계 3) N-(8-(3,3-다이메틸사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드 [N-(8-(3,3-dimethylcyclobutyl)-7H-purin-6-yl)-2-(3-fluoro-5-(1-(4-fluorophenyl)-1H-pyrazol-4-yl)phenyl)acetamide]
실시예 1의 단계 2와 같은 방법으로 8-(3,3-다이메틸사이클로부틸)-7H-퓨린-6-아민 (47 mg, 0.22 mmol), 2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세트산 (102 mg, 0.32 mmol), T3P (50wt.% 용액 (in EtOAc), 412 mg, 0.65 mmol)을 DIPEA (92 μL, 0.54 mmol), EtOAc (2 mL)를 이용하여 목적화합물 (18 mg, 16%)을 연갈색 고체 형태로 얻었다.
1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 11.35 (s, 1H), 9.04 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 7.94 - 7.89 (m, 2H), 7.56 (s, 1H), 7.51 (d, J = 9.9 Hz, 1H), 7.39 (t, J = 8.7 Hz, 2H), 7.12 (d, J = 9.3 Hz, 1H), 3.97 (d, J = 6.1 Hz, 2H), 3.94 - 3.87 (m, 1H), 2.22 - 2.17 (m, 2H), 2.12 - 2.07 (m, 2H), 1.22 (s, 3H), 1.13 (s, 3H).
LCMS, m/z 514 [M+H]+
실험예 1. 세포배양
인간 망막 상피 세포인 ARPE-19 세포(Human retinal pigment epithelial cells :ATCC CRL-2302)는 10% 우태아 혈청 (FBS, Fetal Bovine Serum, 16000-044, Gibco)이 포함된 DMEM/F12 (LM002-08, Welgene) 배지에 함께 넣고, 5% 이산화탄소가 있는 37℃ 배양기에서 배양하였다. 세포가 충분히 자라면 단백질 분리, 배지 상층액을 얻기 위해 실험용 배양접시에서 배양하였다.
실험을 위해 세포를 분주할 경우, 트라이플(TrypLETM Express, Gibco)을 이용하여 배양용기에서 떼어낸 후 1000 rpm에서 3분 동안 원심분리를 한 뒤 세포계수를 하여 세포를 분주하였다. 정상 상태(Normoxic condition)를 유지할 때에는 일반적인 5% 이산화탄소가 있는 37℃ 항온기에서 배양하고, 저산소 상태를 유지할 때에는 저산소 배양기에 1% 산소, 5% 이산화탄소, 94% 질소 가스를 주입하여 배양하였다.
실험예 2. HIF-1α 단백질 발현 분석 (Western blot)
황반변성 질환에서 저산소는 매우 중요한 지표로서, 저산소 상태에서 안정화되는 전사인자인 HIF-1α에 의해 하위 유전자의 발현 조절이 이루어지고 있다. 혼합 저산소 상태(Mixed Hypoxic condition)는 1% 산소로 저산소를 유도하고, 코발트 클로라이드 (CoCl2, Cobalt(Ⅱ) Chloride)로 HIF-1α의 안정성을 높인 상태로써, HIF-1α 안정성 실험에 사용되었다.
우태아 혈청이 포함되지 않은 DMEM/F12 배지에 각각의 실시예 화합물을 희석하여 16시간 또는 2시간 동안 전처리 하고, 혼합 저산소 상태에서 1시간 또는 24시간 배양하였다. 세포의 배지를 버리고 빠르게 단백질 용해 버퍼 (RIPA Lysis and Extraction buffer, Thermo Fisher Scientific)를 처리하여 단백질 용해물 (Lysate)을 얻었다. 단백질 용해물에 LDS(4X Bolt™ LDS Sample buffer)와 환원제(10X Bolt™ Sample Reducing Agent)를 함께 넣고 70℃에서 10분간 가열하였다. 용해물을 4-12% Bis-Tris 겔에서 전기영동으로 분리하고, PVDF 막(PVDF membrane)으로 옮겨준 뒤 3% BSA(Albumin, Bovine, Fraction V, MPbio)으로 블록킹(blocking)하였다. 상기 막에 anti-HIF-1α(ab179483, abcam), anti-b-actin (MA515739, InvitrogenTM) 항체를 1:4000의 비율로 혼합해 넣어준 뒤 4℃에서 하룻밤 동안 배양하였다. 다음날 퍼옥시다제(peroxidase)가 결합된 2차 항체로 상온에서 1시간 동안 처리한 후 ECL 기질액 (ECL substrate solution, ClarityTM Western ECL substrate, Bio-rad)을 이용해 타겟 단백질을 발현시킨 후 정량하였다.
실험예 3. VEGF 분비 실험
저산소 상태에서의 주요 전사인자인 HIF-1α에 의해 하위 유전자인 혈관신생 유도인자 VEGF의 발현 조절이 이루어진다. VEGF 단백질 발현은 ELISA(Enzyme Linked Immunosorbent Assay, Human VEGF Quantikine ELISA Kit, R&D systems)를 통해 정량적으로 확인할 수 있다.
1% 우태아 혈청이 포함된 DMEM/F12 배지에 각각의 실시예 화합물을 희석하여 2시간 전처리 하고, 저산소 상태에서 24시간 배양하여 세포의 배지 상층액을 얻었다. 이 상층액을 1000 rpm에서 3분간 원심분리 한 후 일정양을 VEGF ELISA assay kit에 처리하여 흡광값을 측정함으로써 VEGF의 발현을 정량적으로 확인하였다.
실시예 | % inhibition @1uM | |
Hif-1α
Hypoxia, 1시간 |
VEGF | |
1 | 100 | 100 |
2 | 100 | 100 |
3 | 92 | - |
4 | 86.2 | - |
5 | 19.8 | - |
7 | 100 | - |
8 | 60.5 | - |
9 | 100 | 13.5 |
10 | 100 | 100 |
11 | 100 | - |
12 | 100 | - |
13 | 79.8 | - |
14 | 100 | - |
15 | 57.3 | - |
18 | 99.6 | - |
19 | 78.8 | - |
20 | 76.9 | - |
21 | 100 | - |
23 | 42 | - |
25 | 10.5 | - |
26 | 3.6 | - |
27 | 97.8 | 29.6 |
28 | 65.6 | - |
29 | 96 | 18.1 |
30 | 36 | - |
31 | 100 | - |
32 | 51.3 | - |
33 | 6.2 | - |
34 | 97.1* | 100 |
35 | 38.6* | - |
36 | 11.7* | - |
37 | 2.1* | - |
38 | 100* | - |
39 | 100* | - |
40 | 80.2* | - |
41 | 73.4* | - |
42 | 71.8* | - |
* % inhibition @10uM (hypoxia, 24시간)
Claims (18)
- 하기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염:<화학식 Ⅰ>상기 식에서,X1 및 X2는 독립적으로 CH 또는 N이고,X3 및 X4는 독립적으로 C, CH 또는 N이고, X3는 R3로 치환되거나 치환되지 않고, X4는 R4로 치환되거나 치환되지 않고,Y는 -C(O)-, 또는 C1-3 알킬렌이고,n은 0 내지 3의 정수이고,R1은 C3-7 사이클로알킬, 또는 1 내지 2개의 N을 가지는 5 내지 7원의 포화 헤테로사이클이고, R1은 단수 또는 복수의 독립적인 Ra로 치환되거나 치환되지 않고,상기 Ra는 C1-4 알킬 또는 할로겐이고,R2는 H; C4-7의 포화 또는 불포화 사이클로알킬; C5-7 아릴; 또는 N, O 및 S로 구성되는 군으로부터 선택되는 1개 내지 3개의 헤테로원자를 가지는 5원 또는 6원의 헤테로아릴이고, R2는 Rb로 치환되거나 치환되지 않고,상기 Rb는 C1-6 직쇄 또는 분지쇄 알킬; C1-4 알콕시, 벤질옥시; 할로겐; C1-4 할로알킬; 히드록시; 또는 할로겐으로 치환되거나 치환되지 않은 아릴이고,R3는 할로겐 또는 C1-4 할로알킬이고,R4는 할로겐; 또는 1개 내지 3개의 헤테로원자를 가지는 5원 또는 6원의 헤테로아릴이고, 이 때의 상기 헤테로아릴은 C5-7 아릴로 치환되거나 치환되지 않고, 이 때의 상기 C5-7 아릴은 할로겐으로 치환되거나 치환되지 않는다.
- 제1항에 있어서, 상기 X1이 CH 또는 N이고, 상기 X2가 N인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 Y가 -C(O)- 또는 -CH2-인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 n이 0 또는 1인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R1이 사이클로부틸, 사이클로펜틸, 사이클로헥실, 또는 피페리디닐인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 Ra가 메틸 또는 F인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R2가 사이클로펜틸, 사이클로펜테닐; 페닐; 피롤릴, 티오페닐, 퓨라닐, 피라졸릴, 티아졸릴, 이소티아졸릴, 피리디닐, 피리미디닐, 또는 피리다지닐인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 Rb가 메틸, 프로필, 이소프로필, 메톡시, 벤질옥시, F, 플루오로메틸, 다이플루오로메틸, 트리플루오로메틸, 히드록시 또는 플루오로페닐인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R3가 F, Br 또는 트리플루오로메틸인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 R4가 F 또는 플루오로페닐-피라졸릴인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 상기 화학식 Ⅰ로 표시되는 퓨린 유도체 화합물이 하기 화합물로 구성되는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염:[1] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,[2] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티오펜-3-일)페닐)아세타마이드,[3] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-플루오로-4'-메틸-[1,1'-바이페닐]-3-일)아세타마이드,[4] N-(2-사이클로펜틸-3H-이미다조[4,5-c]피리딘-4-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,[5] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피롤-2-일)페닐)아세타마이드,[6] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리미딘-5-일)페닐)아세타마이드,[7] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피롤-3-일)페닐)아세타마이드,[8] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(퓨란-2-일)페닐)아세타마이드,[9] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-이소프로필-1H-피라졸-4-일)페닐)아세타마이드,[10] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-(1-(다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세타마이드,[11] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1H-피롤-2-일)페닐)아세타마이드,[12] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(이소티아졸-4-일)페닐)아세타마이드,[13] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티아졸-5-일)페닐)아세타마이드,[14] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리딘-4-일)페닐)아세타마이드,[15] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리딘-3-일)페닐)아세타마이드,[16] 2-(4'-(벤질옥시)-5-플루오로-[1,1'-바이페닐]-3-일)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드,[17] 2-(3-(사이클로펜트-1-엔-1-일)-5-플루오로페닐)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드,[18] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(티오펜-2-일)페닐)아세타마이드,[19] 8-사이클로펜틸-N-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)벤질)-7H-퓨린-6-아민,[20] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-(1-메틸-1H-피라졸-4-일)-5-(트리플루오로메틸)페닐)아세타마이드,[21] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-3-일)페닐)아세타마이드,[22] N-(8-사이클로펜틸-7H-퓨린-6-일)-3-플루오로-5-(1-메틸-1H-피라졸-4-일)벤즈아미드,[23] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(피리다진-4-일)페닐)아세타마이드,[24] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-플루오로-4'-히드록시-[1,1'-바이페닐]-3-일)아세타마이드,[25] 2-(3-사이클로펜틸-5-플루오로페닐)-N-(8-사이클로펜틸-7H-퓨린-6-일)아세타마이드,[26] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4-플루오로-3-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,[27] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(트리플루오로메틸)-1H-피라졸-4-일)페닐)아세타마이드,[28] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(2-메톡시피리딘-4-일)페닐)아세타마이드,[29] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4',5-다이플루오로-[1,1'-바이페닐]-3-일)아세타마이드,[30] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)아세타마이드,[31] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(2-(1-메틸-1H-피라졸-4-일)피리딘-4-일)아세타마이드,[32] N-(8-사이클로헥실-7H-퓨린-6-일)-2-(3-(1-다이플루오로메틸)-1H-피라졸-4-일)-5-플루오로페닐)아세타마이드,[33] 2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)-N-(8-(피페리딘-1-일)-7H-퓨린-6-일)아세타마이드,[34] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,[35] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(3-플루오로-4- (1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,[36] N-(8-사이클로펜틸-7H-퓨린-6-일)-2-(4-(1-(4- 플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,[37] N-(3-브로모펜에틸)-8-사이클로펜틸-7H-퓨린-6-아민,[38] N-(8-(3,3- 다이플루오로사이클로펜틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,[39] N-(8-(3,3-다이플루오로사이클로펜틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드,[40] N-(8-(3,3- 다이플루오로사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-메틸-1H-피라졸-4-일)페닐)아세타마이드,[41] N-(8-(3,3-다이플루오로사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드, 및[42] N-(8-(3,3-다이메틸사이클로부틸)-7H-퓨린-6-일)-2-(3-플루오로-5-(1-(4-플루오로페닐)-1H-피라졸-4-일)페닐)아세타마이드.
- 제1항 내지 제11항 중 어느 한 항의 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료용 약학적 조성물.
- 제12항에 있어서, 상기 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환의 예방 또는 치료가 신생혈관 억제에 의한 것을 특징으로 하는 약학적 조성물.
- 제13항에 있어서, 상기 신생혈관 억제가 HIF-1α 발현 억제 또는 VEGF 발현 억제에 의한 것을 특징으로 하는 약학적 조성물.
- 제12항에 있어서, 상기 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환이 뇌졸중, 뇌간신경교종, 소뇌성상세포종, 대뇌성상세포종, 뇌실막종, 간암, 위암, 유방암, 결장암, 골암, 췌장암, 두부 또는 경부암, 난소암, 직장암, 대장암, 식도암, 소장암, 항문부근암, 결장암, 피부암, 나팔관암종, 자궁내막암종, 자궁암, 질암종, 음부암종, 호지킨병, 구강암, 전립선암, 고환암, 방광암, 신장암, 수뇨관암, 세장세포암종, 신장골반암종, 수모세포종, 신경모세포종, 뇌종양, 중추신경계 종양, 흑색종, 비소세포폐암, 림프종, 비호지킨림프종, 암, 자궁경부암, 갑상선암, 혈액암, 신세포암, 간세포 암, 전이성 암, 혈관종, 화농성 육아종, 카포시 육종, 혈관내피종, 고형 종양, 여포낭종, 자궁내막증, 자궁 경화증, 난소 고혈압, 난소 과활성, 자궁 기능장애, 사마귀, 흉터 켈로이드, 알레르기성 부종, 죽상 동맥 경화증, 복막 경화증, 심장 기능장애, 근위축성 측삭 경화증, 비만, 류마티스 관절염, 활막염, 뼈와 연골 파괴, 뼈의 악성 섬유성 조직구종, 골수염, 판누스막 성장, 간 섬유증, 폐섬유증, 섬유화증, NASH (non-alcoholic steato hepatitis), 폐렴, 천식, 비염, 폐 고혈압, 허혈성 급성 신손상, 사구체신염, 당뇨성신장병증, 악성 신경화증, 혈전성 미소혈관장, 기관이식거부, 신사구체병증, 염증신경퇴행성 질환, 니코틴 중독관련 혈관질환, 만성 신장 질환, 미숙아 망막병증, 당뇨망막병증, 각막이식거부, 허혈성 망막병증, 홍색증, 증식성 망막증, 건선, 혈우병성 관절, 켈로이드, 상처과립화, 혈관접착, 자가면역질환, 혈관 섬유종, 후수정체 섬유증식증, 백내장, 녹내장, 황반변성, 노인황반변성, 각막 혈관 신생, 망막 혈관 신생, 맥락막 혈관 신생, 안구내 혈관 신생, 신생혈관성 녹내장, 신생혈관성 황반변성, 망막동맥폐색증, 망막정맥폐색증, 망막세포종, 시각 경로 및 시상하부 신경교종, 횡문근육종, 조직육종, 염증, 각막궤양, 증식성 유리체 망막병증, 간경변, 천식, 치근막 질환, 알레르기성 피부염, 알츠하이머병, 파킨슨병, 헌팅턴병, 갑상선염, 그레이브스 안와병증, 백혈구연화증, 백혈병, 급성 림프구성 백혈병, 만성 림프구성 백혈성, 만성 골수성 백혈병, 급성 골수성 백혈병, 다발성 골수종, 염증성 장질환, 크론병, 궤양성 대장염, 및 베체트 장염으로 구성된 군으로부터 선택된 1종 이상인 것을 특징으로 하는 약학적 조성물.
- 제12항에 있어서, 상기 HIF-1α 단백질 또는 혈관신생 유도인자 VEGF 관련 질환이 신생혈관성 안질환인 것을 특징으로 하는 약학적 조성물.
- 제16항에 있어서, 상기 신생혈관성 안질환이 각막 혈관 신생, 망막 혈관 신생, 맥락막 혈관 신생, 안구내 혈관 신생, 신생혈관성 녹내장, 증식성 당뇨병성 망막증, 신생혈관성 황반변성 및 미숙아 망막병증으로 구성된 군으로부터 선택된 1종 이상인 것을 특징으로 하는 약학적 조성물.
- 제1항 내지 제11항 중 어느 한 항의 퓨린 유도체 화합물, 이의 수화물, 이의 용매화물, 또는 이의 약학적으로 허용가능한 염과, 약제학적으로 허용가능한 첨가제를 포함하는 것을 특징으로 하는 제형.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20080099855A (ko) * | 2006-01-26 | 2008-11-13 | 유니버시타이트 라이덴 | A3 아데노신 수용체 알로스테릭 조절제 |
KR20110040958A (ko) * | 2008-07-30 | 2011-04-20 | 온코세라피 사이언스 가부시키가이샤 | 벤조이미다졸 유도체 및 이를 유효성분으로 함유하는 글라이코겐 합성 카이네이즈-3 베타 저해제 |
WO2014120748A1 (en) * | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
WO2014207260A1 (en) * | 2013-06-27 | 2014-12-31 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Pyrrolo[3,2-c]pyridine compounds as g-protein-coupled receptor kinase 5 (grk5) modulators |
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WO2005026164A1 (en) | 2003-09-18 | 2005-03-24 | Altana Pharma Ag | Pharmacologically active imidazo[4,5-c]pyridines |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20080099855A (ko) * | 2006-01-26 | 2008-11-13 | 유니버시타이트 라이덴 | A3 아데노신 수용체 알로스테릭 조절제 |
KR20110040958A (ko) * | 2008-07-30 | 2011-04-20 | 온코세라피 사이언스 가부시키가이샤 | 벤조이미다졸 유도체 및 이를 유효성분으로 함유하는 글라이코겐 합성 카이네이즈-3 베타 저해제 |
WO2014120748A1 (en) * | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
WO2014207260A1 (en) * | 2013-06-27 | 2014-12-31 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Pyrrolo[3,2-c]pyridine compounds as g-protein-coupled receptor kinase 5 (grk5) modulators |
Non-Patent Citations (1)
Title |
---|
LAMBERTUCCI C., BUCCIONI M., DAL BEN D., KACHLER S., MARUCCI G., SPINACI A., THOMAS A., KLOTZ K.-N., VOLPINI R.: "New substituted 9-propyladenine derivatives as A 2A adenosine receptor antagonists", MEDCHEMCOMM, ROYAL SOCIETY OF CHEMISTRY, UNITED KINGDOM, vol. 6, no. 5, 13 May 2015 (2015-05-13), United Kingdom , pages 963 - 970, XP093128209, ISSN: 2040-2503, DOI: 10.1039/C5MD00034C * |
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