WO2020263058A1 - Dérivé d'aminocyanopyridine et son utilisation - Google Patents

Dérivé d'aminocyanopyridine et son utilisation Download PDF

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WO2020263058A1
WO2020263058A1 PCT/KR2020/008471 KR2020008471W WO2020263058A1 WO 2020263058 A1 WO2020263058 A1 WO 2020263058A1 KR 2020008471 W KR2020008471 W KR 2020008471W WO 2020263058 A1 WO2020263058 A1 WO 2020263058A1
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amino
nicotinonitrile
phenyl
methoxy
imidazol
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Korean (ko)
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장선영
이경익
전승아
변은영
이용택
안영길
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한미약품 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a novel compound having an aminocyanopyridine skeleton having antagonistic activity against adenosine receptors and a pharmaceutical composition comprising the same as an active ingredient.
  • Adenosine is a modulator of various physiological activities in the cardiovascular and nervous systems that regulate various physiological functions through interaction with specific cell surface receptors.
  • adenosine is an immunosuppressive metabolite produced at a high level in the tumor microenvironment. Hypoxia, high cell turnover, and expression of CD39 and CD73 are very important factors in the production of adenosine.
  • the tumor microenvironment is one of the important regulators of immune functions that influence cancer progression and metastasis.
  • High concentrations of adenosine in the tumor microenvironment inhibit the responses of anti-tumor cytotoxic lymphocytes.
  • T cells express the inhibitory adenosine A2A receptor (A2AR), which inhibits their action and blocks the removal of tumors by immune.
  • A2AR inhibitory adenosine A2A receptor
  • Adenosine produced by the breakdown of adenosine triphosphate (ATP) in cells, promotes the survival of tumors through various mechanisms. Adenosine regulates many physiological functions through binding to specific purinergic receptors in different cell membranes. Adenosine is a neuromodulator that promotes sleep and inhibits arousal. It also expands blood vessels to improve blood flow. It is used for malignant tachycardia that does not improve as a treatment for arrhythmia In addition, it accumulates in solid tumors, promotes tumor proliferation and angiogenesis, and plays an important role in mediating the immune system's tumor avoidance, conferring resistance to the immune system to the tumor.
  • ATP adenosine triphosphate
  • Adenosine action is mediated by interactions with different membrane specific receptors belonging to the family of receptors coupled with the G protein.
  • A1 and A3 receptors inhibit adenylyl cyclase by binding to the inhibitory G protein, thereby reducing cellular cAMP (3',5'-cyclic AMP) levels
  • A2A and A2B receptors are active G By binding to the protein, it activates adenylyl cyclase, increasing cellular cAMP levels.
  • the A1 and A2A receptors regulate myocardial oxygen consumption and coronary blood flow in the heart, and regulate the secretion of neurotransmitters in the brain.
  • Each of these four adenosine receptors on the cell surface is known to be upregulated in various tumor cells.
  • Adenosine receptors are overexpressed in inflammatory and cancer cells, but low-expressed in normal cells.
  • adenosine inhibits the proliferation of T-cells in the immune system and reduces the ability of T-cells to destroy cancer cells. Therefore, inhibition of A2A receptors can activate the anticancer response of T-cells within the microenvironment of tumor cells.
  • Adenosine receptors play an essential role in many physiological processes in the cardiovascular and central nervous system and regulate anti-inflammatory and immune suppression responses.
  • this group of receptors has attracted excellent interest as a drug target for cardiovascular diseases, neurodegenerative diseases, autoimmune diseases and cancer.
  • cardiovascular diseases cardiovascular diseases, neurodegenerative diseases, autoimmune diseases and cancer.
  • A2A receptors suitable for the prevention or treatment of cancer or inflammation-related diseases.
  • Patent Document 001 International Publication Patent WO 2009/156737, "TRIAZOLO [4, 5-D] PYRAMIDINE DERIVATIVES AND THEIR USE AS PURINE RECEPTOR ANTAGONISTS"
  • Patent Document 002 International Publication Patent WO 2017/112917, "Methods of treating cancer"
  • One aspect is to provide novel compounds with antagonistic activity against human adenosine A2A receptors.
  • Another aspect is to provide a pharmaceutical composition comprising the novel compound.
  • Another aspect is to provide a pharmaceutical use of the novel compound as an anticancer agent or an inflammatory agent.
  • X is H or halogen
  • substituents are more than one, they are the same or different from each other, and two adjacent substituents may be optionally bonded to form a fused ring;
  • each independently a C 3-20 cycloalkyl or C 2-20 heterocycloalkyl a C 3-20 cycloalkyl or C 2-20 heterocycloalkyl optionally substituted by the substituents, may form a fused or spiro derivatives each other ;
  • the C 2-14 heteroaryl or C 2-20 heterocycloalkyl each independently includes 1 to 3 heteroatoms selected from the group consisting of N, O and S.
  • a pharmaceutical composition comprising the compound of Formula 1, its optical isomer, solvate, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition may be a pharmaceutical composition for preventing or treating cancer or inflammatory diseases.
  • the pharmaceutical use may be used for preventing or treating cancer or inflammatory diseases.
  • the cancer is lung cancer, stomach cancer, testicular cancer, bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, germ cell cancer, bone cancer, liver cancer, Thyroid cancer, skin cancer, neoplasms of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.
  • the inflammatory disease may be selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Crohns disease, ulcerative colitis, transplant versus host disease, systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, and insulin dependent diabetes.
  • the compound of Formula 1, an optical isomer, a solvate thereof, or a pharmaceutically acceptable salt thereof, according to an aspect, has an aminocyanopyridine skeleton, and is treated with various cancers or inflammatory diseases by antagonistic activity against adenosine receptors. And is effective in prevention, and in particular, it is promising for the development of a drug for the prevention or treatment of immuno-oncology.
  • halogen means fluorine, chlorine, bromine or iodine unless otherwise stated.
  • alkyl refers to a linear or branched saturated C1 to C6 hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and hexyl.
  • cycloalkyl refers to a C3 to C20 cyclic alkyl which may be substituted or unsubstituted unless otherwise stated, and may mean, for example, mono- or bicycloaliphatic.
  • heterocycloalkyl as used herein, unless otherwise stated, is a monocyclic or bicyclic or more polycyclic containing one or more, more specifically, 1 to 3 heteroatoms selected from O, N and S. Or, it represents a C2 to C20 cyclic hydrocarbon in the form of a spiro ring.
  • mono heterocycloalkyl include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl, and similar functional groups, but are limited thereto. no.
  • the heterocycloalkyl when in a bicyclic form, it may contain at least one aromatic compound.
  • Cycloalkyl or heterocycloalkyl is each independently substituted with cycloalkyl or heterocycloalkyl, so that "fusion" with each other means that two atoms are shared between two fused ring compounds, and "spiro derivative” Forming means that one atom is shared between the cyclic compounds forming the derivative.
  • the fused cyclic compound include, but are not limited to, tetrahydro-1H-furo[3,4-c]pyrrole, and hexahydropyrrolo[3,4-c]pyrrole.
  • spiro derivatives examples include azaspiro[2.4]heptane, 2-oxa-6-azaspiro[3.4]octane, 2-oxa-7-azaspiro[4.4]nonane, 2-oxa-7-azaspiro[3.5] Noan may be mentioned, but is not limited to these.
  • aryl refers to an aromatic compound of C6 to C30, more specifically C6 to C12, which may be substituted or unsubstituted unless otherwise stated, and only fused groups such as naphthyl, phenanthrenyl, etc. As well as monocyclic or bicyclic aromatic rings such as phenyl, substituted phenyl and the like.
  • the aryl group optionally has one or more substituents, i.e.
  • heteroaryl as used herein, unless otherwise stated, is a monocyclic or bicyclic containing one or more, for example, 1 to 4, or 1 to 3 heteroatoms selected from O, N and S. It means an aromatic group having more than a click C2 to C30, more specifically C2 to C14.
  • heteroaryl examples include furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, Pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazineyl, 1,2,3-triazineyl, 1,3,5-triazineyl, cinnolinyl, pteridineyl, purinyl , 6,7-dihydro-5H-[1]pyridinyl, or 5,6,7,8-tetrahydro-quinolin-3-yl,
  • the term “isomer” refers to different compounds having the same molecular formula
  • “optical isomer” refers to various stereoisomers and geometric isomers that may exist for the compounds according to the present invention.
  • Compounds of Formula 1 according to one aspect may have an asymmetric carbon center (free carbon), and thus may exist as optical isomers ( R or S isomers), racemates, diastereomers, or any mixture thereof, and all of these Isomers and mixtures are included within the scope of the present invention.
  • the optically active ( R )- and ( S )-isomers can be decomposed using conventional techniques, or can be prepared using chiral synthons or chiral reagents.
  • the substituent When the compound contains a double bond, the substituent may be in the E or Z form. When the compound contains a disubstituted cycloalkyl, it may be in cis- or trans form. Any tautomeric form may also be included in a compound according to one aspect.
  • solvate may include a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules, for example ethanol or water.
  • a complex in which the solvent molecule is water is also referred to as a "hydrate”.
  • derivative refers to a compound obtained by substituting part of the structure of a compound with another atom or group of atoms.
  • treating refers to inhibiting a disease, for example, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, ie, Preventing the further occurrence of pathology and/or symptoms, or improving a disease, e.g., ameliorating a disease, condition or disorder in an individual experiencing or exhibiting a pathology or symptom of a disease, condition or disorder, i.e. It refers to reversing pathology and/or symptoms, such as reducing disease severity.
  • preventing means preventing a disease, for example, a disease in an individual who may have a tendency to a disease, condition or disorder but has not yet experienced or exhibited the pathology or signs of the disease, It refers to preventing a condition or disorder.
  • the term "individual” or “patient” refers to any animal including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates and humans. .
  • One aspect relates to a novel compound having antagonistic activity against the adenosine receptor, in particular, the A2A receptor, which is a compound of Formula 1, an optical isomer thereof, a solvate, or a pharmaceutically acceptable salt thereof:
  • X is H or halogen
  • substituents are more than one, they are the same or different from each other, and two adjacent substituents may be optionally bonded to form a fused ring;
  • each independently a C 3-20 cycloalkyl or C 2-20 heterocycloalkyl a C 3-20 cycloalkyl or C 2-20 heterocycloalkyl optionally substituted by the substituents, may form a fused or spiro derivatives each other ;
  • the C 2-14 heteroaryl or C 2-20 heterocycloalkyl each independently includes 1 to 3 heteroatoms selected from the group consisting of N, O and S.
  • the "pharmaceutically acceptable salt" of the compound of Formula 1 may be prepared by a person skilled in the art using known techniques, for example, hydrochloric acid, bromic acid, sulfuric acid, sodium hydrogen sulfate , Salts with inorganic acids such as phosphoric acid, nitric acid and carbonic acid; Such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gastisic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin).
  • Salts with organic acids Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, and the like; Salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.; metal salts obtained by reaction with alkali metals such as sodium and potassium; Or, it may include a salt with an ammonium ion.
  • amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, and the like
  • Salts with sulfonic acids such as methanesulfonic acid, ethane
  • the C 2-20 heterocycloalkyl may be one containing 1 to 3 N, O and S groups as heteroatoms.
  • the C 2-20 heterocycloalkyl may be pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl, but is not limited thereto.
  • A is C 6-12 aryl or C 2-14 heteroaryl, and may be substituted with C 2-20 heterocycloalkyl containing 1 or 2 heteroatoms selected from N and O, such
  • the C 2-20 heterocycloalkyl can be, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepanyl.
  • B is C 6-12 aryl or C 2-14 heteroaryl substituted with at least one substituent selected from the group consisting of halogen, -CN, C 1-6 alkyl, and C 1-6 alkoxy.
  • B may be selected from the group consisting of substituted or unsubstituted pyrazolyl, imidazolyl, triazolyl, furyl, thiophenyl, oxazolyl, and phenyl.
  • B is a C 6-12 aryl substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, -CF 3 , C 1-6 alkyl, and C 1-6 alkoxy
  • substituents selected from the group consisting of halogen, -OH, -CN, -CF 3 , C 1-6 alkyl, and C 1-6 alkoxy
  • B is a C 2-14 hetero substituted with at least one substituent selected from the group consisting of halogen, -OH, -CN, -CF 3 , C 1-6 alkyl, and C 1-6 alkoxy
  • Aryl for example pyrazolyl, imidazolyl, triazolyl, furyl, or thiophenyl.
  • A is C 6-12 aryl or C 2-14 heteroaryl, wherein C 6-12 aryl or C 2-14 heteroaryl are each independently C 3-20 cycloalkyl, C 2-20 heterocycloalkyl, -OR 1, -SR 1 and which is substituted by one substituent selected from (where R 1 is a C 3-20 cycloalkyl or C 2-20 heterocycloalkyl); Additionally -OCF 3 , -R 1 , -OR 1 , -SR 1 (wherein R 1 is C 1-6 alkyl or C 2-6 alkenyl) may be substituted with one substituent selected from the group consisting of;
  • B is C 6-12 aryl or C 2-14 heteroaryl, wherein C 6-12 aryl or C 2-14 heteroaryl are each independently H, halogen, -R 1 , -CHR 1 R 2 , -CN , -OH, -OCF 3 , C 1-6 alkyl, C 1-6 alkoxy, and -SR 1 may be substituted with one or more substituents selected from the group consisting of, where m is an integer from 0 to 3, and R 1 and R 2 may each independently be a compound that is H, halogen, -CF 3 , C 1-6 alkyl, or C 2-6 alkenyl.
  • the compound of Formula 1 may be selected from the group consisting of the following compounds, but is not limited thereto:
  • Another aspect relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula 1, an optical isomer, solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition may be a pharmaceutical composition for preventing or treating cancer or inflammatory diseases.
  • Another aspect provides a pharmaceutical use of the compound of Formula 1, an optical isomer, solvate, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical use may be used for preventing or treating cancer or inflammatory diseases.
  • Substances having antagonistic activity against A2A receptors are known to be effective in the treatment of various cancers and inflammatory diseases (WO 2017/112917, J. Immunol, 2012, 188(11), 5713-22), and the compound of Formula 1 Has been shown to have antagonistic activity against adenosine receptors, in particular, A2A receptors (see Experimental Example 1). Therefore, the compound of Formula 1 may act to increase immune recognition of cancer cells and destruction of cancer cells, and thus may be suitably used for the prevention and/or treatment of cancer, and for the prevention and/or treatment of inflammatory diseases. have.
  • the cancer is, for example, lung cancer, stomach cancer, testicular cancer, bladder cancer, breast cancer, uterine or cervical cancer, ovarian cancer, prostate cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, germ cell cancer, bone cancer. , Liver cancer, thyroid cancer, skin cancer, neoplasms of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, or virus-related cancer, but is not limited thereto.
  • the cancer may be metastatic cancer, refractory cancer, or recurrent cancer.
  • the inflammatory disease may be, for example, rheumatoid arthritis, multiple sclerosis, Crohns disease, ulcerative colitis, graft versus host disease, systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, insulin dependent diabetes, or inflammatory tumors, but is limited thereto. It is not.
  • composition of the present invention may be administered alone or in combination with one or more additional therapeutic agents.
  • Concurrent administration means administering a pharmaceutical composition according to an aspect and one or more additional therapeutic agents to an individual or patient to be treated at the same time or at different time points in any order. Accordingly, each component may be administered separately or may be administered in a sufficiently close time to provide the desired therapeutic effect.
  • therapeutic agents that can be administered together with the pharmaceutical composition according to one aspect are therapeutic agents that stimulate the immune system (e.g., PD-1 antagonist, PD-L1 antagonist, CTLA-4 antagonist, LAG-3 antagonist, GITR antagonist, anti -CD39 antibody, anti-CD73 antibody, anti-A2AR antibody) cell signal transduction inhibitors, mitosis inhibitors, alkylating agents, antimetabolites, antibiotics, Growth factor inhibitors, cell cycle inhibitors, topoisomerase inhibitors, immunoregulatory agents, biological reaction modifiers, antihormonal agents ), antiandrogens, cell differentiation/proliferation/survival inhibitors, apoptosis inhibitors, inflammation inhibitors and P-glycoprotein inhibitors ) May be selected from the group consisting of, but is not limited thereto.
  • the immune system e.g., PD-1 antagonist, PD-L1 antagonist, CTLA-4 antagonist, LAG-3 antagonist, GITR antagonist, anti -CD39 antibody, anti-CD73 antibody, anti-A2AR antibody
  • the dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of an individual or patient, and can be administered orally or parenterally as desired.
  • the active ingredient is 70 kg of active ingredient 1 kg of body weight per day based on an adult 0.01 to 1000 mg per day, more specifically 0.1 to 300 mg per day, based on the active ingredient when administered parenterally, 0.01 to 100 mg per 1 kg of body weight per day, more specifically 0.1 to 50 mg It can be administered in divided doses from 1 to several times so as to be administered in amounts.
  • the dosage to be administered for a specific individual or patient should be determined in the light of a number of related factors such as the patient's weight, age, sex, health status, diet, administration time, administration method, and disease severity, and can be appropriately adjusted by a specialist. It should be understood that there is, and the above dosage is not intended to limit the scope of the present invention in any way.
  • the pharmaceutical composition may include a conventional pharmaceutically acceptable carrier, excipient, or additive.
  • the pharmaceutical composition can be formulated according to a conventional method, and various oral dosage forms such as tablets, pills, trochees, powders, capsules, syrups, emulsions, microemulsions, suspensions, solutions, or intramuscular, intravenous or It can be prepared in parenteral dosage forms such as subcutaneous administration.
  • the carriers, excipients, or additives to be used include binders, disintegrants, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, antioxidants, preservatives, lubricants. , Fillers, fragrances, sweeteners, etc. may be included.
  • lactose for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, rubber tragacanth, alginic acid, sodium Alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.
  • the carrier, excipient, or additive may include water, saline, pseudo-glucose solution, alcohols, glycol ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, Glycerides, surfactants, suspending agents, emulsifying agents, and the like.
  • glycol ether e.g., polyethylene glycol 400
  • surfactants e.g., surfactants, suspending agents, emulsifying agents, and the like.
  • Another aspect is a method for preventing or treating cancer or inflammatory disease comprising administering to an individual or a patient the compound of Formula 1, an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof. to provide.
  • the dosage used in the method of preventing or treating is an amount effective for treating or preventing an individual or patient, and the description of the dosage of the pharmaceutical composition may be applied as it is.
  • the compound of Formula 1 according to the above aspect may be prepared according to the method shown in the following Examples, but is not limited thereto.
  • Those of ordinary skill in the field of organic compounds may prepare other synthetic methods by appropriately controlling specific reaction routes, reaction conditions, reaction amounts, and the like in a method different from the method specifically shown in the following Examples.
  • NAHMDS sodium bis(trimethylsilyl)amide
  • DIPEA N,N-diisopropylethylamine
  • BINAP 2,2'-bis(diphenylphosphino)-1,1'-binapthyl
  • Pd(PPh 3 )Cl 2 Bis(triphenylphosphine)palladium(II) dichloride
  • FRET Fluorescence resonance energy transfer
  • An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.
  • An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.
  • An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.
  • An intermediate was synthesized for use in making A2AR (A2A receptor) antagonists.
  • Example 38 Conducted in the same manner as in Example 37, but using (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate instead of bromocyclopentane in (Step 3) of Example 37, the implementation shown in Table 2 below.
  • the compound of Example 38 was obtained.
  • reaction solution was extracted with dichloromethane and water, and the separated organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure.
  • tert-butyl 3-(1-methylcyclopropane-1-carboxamido)azetidine-1-carboxylate (1.1 g, 4.32 mmol) synthesized in (Step 1) was dissolved in dichloromethane and trifluoro Acetic acid (TFA, 14 mL, 0.3 M) was added.
  • TFA trifluoro Acetic acid
  • reaction solution was stirred at room temperature for 12 hours, neutralized with aqueous ammonia, and distilled under reduced pressure. The next step was carried out with the obtained compound (666 mg, Quant.) without further purification steps.
  • Step 2 Tert-butyl (5-cyano-4-(3-methoxy-5-(3-methoxypyrrolidin-1-yl)phenyl)-6-(1-methyl-1H-pyrazole- Preparation of 4-yl)pyridin-2-yl)carbamate
  • Diisopropyl amine 22 mL, 157 mmol was added to 200 mL of tetrahydrofuran. After cooling to -78°C, n-butyllithium (2.5 M in Hex, 63 mL, 157 mmol) was added dropwise to the reaction solution while maintaining the temperature. The mixture was stirred at -30°C for 30 minutes.
  • Example 82 (R)-3-methoxy-1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro)
  • various borate derivatives were used instead of lan-2-yl)phenyl)pyrrolidine, and various amine/borate derivatives were used instead of imidazole in (Step 4), as shown in Table 9 below.
  • the compounds of Examples 83 to 87 were obtained.
  • the cultured cell lines were prepared in 2.5 ⁇ 10 3 cells/20 ⁇ l, placed in a 384 well plate, and cultured in EMEM containing 10% FBS for 24 hours. After removing the culture medium, HBSS was carried out in a solution of pH 7.4 containing 5 mM HEPES, 0.1% BSA, and 30 ⁇ M Rolipram.
  • the compound to be evaluated was subjected to stepwise dilution at a set concentration (eg, 5,000 to 0.32 nM, 1/5 dilution).
  • a solvent 1% DMSO
  • the 50% activity inhibition value (IC 50 ) for cAMP production of the compound was calculated using GraphPad Prism software. The results are shown in Table 10 below.

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Abstract

L'invention concerne : un composé, qui est un dérivé de 3-cyano-6-aminopyridine de formule chimique 1, un isomère optique ou un solvate de celui-ci, ou un sel pharmaceutiquement acceptable de celui-ci; et une utilisation du composé en tant que principe actif pour la prévention ou le traitement du cancer ou d'une maladie inflammatoire.
PCT/KR2020/008471 2019-06-28 2020-06-29 Dérivé d'aminocyanopyridine et son utilisation WO2020263058A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2

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