JP6697074B2 - ヒストン脱アセチル化酵素6阻害剤としてのオキサジアゾールアミン誘導体化合物及びこれを含有する薬剤学的組成物 - Google Patents
ヒストン脱アセチル化酵素6阻害剤としてのオキサジアゾールアミン誘導体化合物及びこれを含有する薬剤学的組成物 Download PDFInfo
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- JP6697074B2 JP6697074B2 JP2018518487A JP2018518487A JP6697074B2 JP 6697074 B2 JP6697074 B2 JP 6697074B2 JP 2018518487 A JP2018518487 A JP 2018518487A JP 2018518487 A JP2018518487 A JP 2018518487A JP 6697074 B2 JP6697074 B2 JP 6697074B2
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- amine
- oxadiazol
- pyrimidin
- cyclobutyl
- difluoromethyl
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 108010023925 Histone Deacetylase 6 Proteins 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- 201000010099 disease Diseases 0.000 claims description 27
- 230000003287 optical effect Effects 0.000 claims description 24
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 12
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- IRFXHUXQYBARTM-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-(1-phenylcyclopropyl)pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC=CC=C1)F IRFXHUXQYBARTM-UHFFFAOYSA-N 0.000 claims description 3
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- OMTYOKNFBKZRCX-UHFFFAOYSA-N 3-[1-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl]amino]cyclobutyl]phenol Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C=1C=C(C=CC=1)O)F OMTYOKNFBKZRCX-UHFFFAOYSA-N 0.000 claims description 2
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- ITTIVAGNYVVBML-UHFFFAOYSA-N 5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-(2-methylphenyl)cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=C(C=CC=C1)C)F ITTIVAGNYVVBML-UHFFFAOYSA-N 0.000 claims description 2
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- GARYREBVDMJCRV-UHFFFAOYSA-N 5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-[3-(trifluoromethyl)phenyl]cyclobutyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CCC1)C1=CC(=CC=C1)C(F)(F)F)(F)F GARYREBVDMJCRV-UHFFFAOYSA-N 0.000 claims description 2
- WDUXNNMYTUAJJQ-UHFFFAOYSA-N 5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]-N-[1-[3-(trifluoromethyl)phenyl]cyclopropyl]pyrimidin-2-amine Chemical compound FC(C1=NN=C(O1)C=1C=NC(=NC=1)NC1(CC1)C1=CC(=CC=C1)C(F)(F)F)(F)F WDUXNNMYTUAJJQ-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
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- DHBILDQTSYOIEV-UHFFFAOYSA-N N-[1-(3-chloro-4-fluorophenyl)cyclobutyl]-5-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC=1C=C(C=CC=1F)C1(CCC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)(F)F DHBILDQTSYOIEV-UHFFFAOYSA-N 0.000 claims 1
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- PHSJJZPJMHPELO-UHFFFAOYSA-N N-[1-(4-chloro-2-fluorophenyl)cyclopropyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC1=CC(=C(C=C1)C1(CC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F)F PHSJJZPJMHPELO-UHFFFAOYSA-N 0.000 claims 1
- PXYOOEUTEMLNID-UHFFFAOYSA-N N-[1-(4-chloro-3-fluorophenyl)cyclopropyl]-5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-amine Chemical compound ClC1=C(C=C(C=C1)C1(CC1)NC1=NC=C(C=N1)C=1OC(=NN=1)C(F)F)F PXYOOEUTEMLNID-UHFFFAOYSA-N 0.000 claims 1
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- WHLAXDUXKMECTM-UHFFFAOYSA-N oxadiazol-4-amine Chemical class NC1=CON=N1 WHLAXDUXKMECTM-UHFFFAOYSA-N 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FPOHNWQLNRZRFC-ZHACJKMWSA-N panobinostat Chemical compound CC=1NC2=CC=CC=C2C=1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FPOHNWQLNRZRFC-ZHACJKMWSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- GGZDLAOKPXEJCP-UHFFFAOYSA-N phenyl piperidine-1-carboxylate Chemical compound C1CCCCN1C(=O)OC1=CC=CC=C1 GGZDLAOKPXEJCP-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- CESUXLKAADQNTB-UHFFFAOYSA-N tert-butanesulfinamide Chemical compound CC(C)(C)S(N)=O CESUXLKAADQNTB-UHFFFAOYSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
- C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Description
前記目的を解決するために、本発明では、下記化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩を提供する:
R1は、−CF2H又は−CF3であり;
L1又はL2は、それぞれ独立して、−(C1−C2アルキル)−又は何でもなく(null);
Z1〜Z4は、それぞれ独立して、N又はCRZであり(ここで、Z1〜Z4は、3つ以上が同時にNではない)、RZは、−H、−F、−Cl、−Br、−I、又は−O(C1−C4アルキル)であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、RCは、−H、−(C1−C6アルキル)、−(C1−C4アルキル)−OH、−(C1−C4アルキル)−O−(C1−C4アルキル)、−C(=O)−(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)−アリール、−(C1−C4アルキル)−C(=O)−O(C1−C4アルキル)、−(C1−C4アルキル)−NRARB、−S(=O)2−(C1−C4アルキル)、アリール、−(C1−C4アルキル)−アリール、−(C2−C4アルケニル)−アリール、ヘテロアリール、−(C1−C4アルキル)−ヘテロアリール、−C(=O)−(C3−C7シクロアルキル)、−(C2−C6ヘテロシクロアルキル)、又は−(C1−C4アルキル)−C(=O)−(C2−C6ヘテロシクロアルキル)であり、ここで、−(C1−C6アルキル)、−(C1−C4アルキル)−OH、−(C1−C4アルキル)−O−(C1−C4アルキル)、−C(=O)−(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)−アリール、−(C1−C4アルキル)−C(=O)−O(C1−C4アルキル)、−(C1−C4アルキル)−NRARB、−S(=O)2−(C1−C4アルキル)、アリール、−(C1−C4アルキル)−アリール、(C2−C4アルケニル)−アリール、ヘテロアリール、−(C1−C4アルキル)−ヘテロアリール、−C(=O)−(C3−C7シクロアルキル)、−C2−C6ヘテロシクロアルキル、又は−(C1−C4アルキル)−C(=O)−(C2−C6ヘテロシクロアルキル)の一つ以上のHは、−X(つまり、−F、Cl、Br又はI)で置換されていてもよく;
a及びbは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−SO2−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ヘテロシクロアルキル、ここで、ヘテロシクロアルキルは、置換されないか、C1−C4アルキル又はヘテロシクロアルキルで置換されていてもよく、
Y2は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、
Y3〜Y5は、それぞれ独立して、−CH−又は−N−であり,
c〜fは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、c及びeが共に0ではなく、d及びfが共に0ではない)、
RA及びRBは、それぞれ独立して、−H又は−(C1−C4アルキル)であり、ここで、−(C1−C4アルキル)の一つ以上のHは、−X(つまり、−F、Cl、Br又はI)又は−OHで置換されていてもよい。
R1は、−CF2H又は−CF3であり;
L1及びL2は、何でもなく(null);
Z1及びZ3は、Nであり;
Z2及びZ4は、CRZであり、RZは、−H、−F、−Cl、−Br、−I、又は−O(C1−C4アルキル)であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり、ここで、−C(=O)−O(C1−C4アルキル)−アリールの一つ以上のHは、−Xで置換されていてもよく;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ピペリジン、モルホリノ、ピペラジン、又はピロリジン、ここで、ピペリジン、モルホリノ、ピペラジン、又はピロリジンは置換されないか、C1−C4アルキルで置換されていてもよいく、又は
Y2は、−O−であり、
Y3及びY5は、−CH−であり、
Y4は、−N−であり、
c及びeは、それぞれ独立して、0、1、又は2であり(但し、c及びeが共に0ではない)、
d及びfは、それぞれ独立して、0、1、2、又は3の整数である(但し、d及びfが共に0ではない)。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない;好ましくは、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、好ましくは、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、ピペリジン(ここで、ピペリジンは、置換されないか、C1−C4アルキルで置換されていてもよい)、又は
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−CH2−、−CH2−SO2−、又は何でもなく(null);
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、
R7は、−H又は−(C1−C4アルキル)である。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−、−NH−、又は
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);及び
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、ピペリジン、(ここで、ピペリジンは、置換されないか、C1−C4アルキルで置換されていてもよい)、又は
R7は、−H又は−(C1−C4アルキル)である。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、a及びbによって形成される環は、3〜7員の飽和シクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);及び
X1及びX2は、それぞれ独立して、N又はCであり、ここで、X1及びX2は、同時にNではない。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、a及びbによって形成される環は、3〜7員の飽和シクロアルキルである);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもなく(null);及び
X3及びX4は、それぞれ独立して、S又はCであり、ここで、X3及びX4は、同時にS又は同時にCではない。
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、a及びbによって形成される環は、3〜7員の飽和シクロアルキルである);及び
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は何でもない(null)。
本発明は、化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩の製造方法を提供する。
本発明は、下記化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩を有効成分として含有する薬剤学的組成物を提供する。
化学式Iの化合物の具体的な製造方法は、下記の通りである。
[ステップ1]エチル2−((1−フェニルシクロプロピル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]2−((1−フェニルシクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]エチル2−((1−フェニルシクロブチル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]1−フェニルシクロペンタン−1−カルボニトリルの合成
[ステップ1]2−((1−フェニルシクロペンチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−フェニルシクロヘキサン−1−カルボニトリルの合成
[ステップ1]2−((1−フェニルシクロヘキシル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−メトキシフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(4−メトキシフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−メトキシフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(3−メトキシフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−フルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(3−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2−フルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−フルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(4−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2−クロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(3−クロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(4−クロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2−クロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(4−クロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(ピリジン−2−イル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(ピリジン−2−イル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(3−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(o−トリル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(o−トリル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(m−トリル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(m−トリル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(p−トリル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(p−トリル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]ベンジルビス(2−クロロエチル)カルバメートの合成
[ステップ1]化合物1678の合成
[ステップ1]2−(メチルチオ)ピリミジン−5−カルボン酸の合成
[ステップ1]N’−(2,2−ジフルオロアセチル)−2−((1−(4−フルオロフェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(4−フルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]N’−(2,2−ジフルオロアセチル)−2−((1−(3−フルオロフェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(3−フルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]エチル4−((1−(3−クロロ−4−フルオロフェニル)シクロプロピル)アミノ)ベンゾエートの合成
[ステップ1]2−((1−(3−クロロ−4−フルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−(トリフルオロメチル)フェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]エチル2−((1−(3−(トリフルオロメチル)フェニル)シクロプロピル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(3−(トリフルオロメチル)フェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(4−(トリフルオロメチル)フェニル)シクロプロピル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,4−ジフルオロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(3,4−ジフルオロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3−クロロ−4−フルオロフェニル)シクロブタン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(3−クロロ−4−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,5−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(ベンゾ[d][1,3]ジオキソール−5−イル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,5−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(4−(トリフルオロメトキシ)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,4,5−トリフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,3−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,6−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2,3−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2,3−ジクロロフェニル)シクロブチル)アミノ)−N’−(2,2−ジフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,4−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(3,4−ジクロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2,4−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−((1−(2,4−ジクロロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(2,6−ジクロロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(ピリジン−3−イル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−(2−クロロ−4−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(2−クロロ−4−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−(2−クロロ−5−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(2−クロロ−5−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−(5−クロロ−2−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(5−クロロ−2−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−(3−クロロ−2−フルオロフェニル)アセトニトリルの合成
[ステップ1]2−((1−(3−クロロ−2−フルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−ブロモフェニル)シクロブタン−1−カルボニトリル
[ステップ1]N−シクロブチリデン−2−メチルプロパン−2−スルフィンアミドの合成
[ステップ1]1−(2,4−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2−(トリフルオロメトキシ)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−ベンジルシクロブタン−1−アミンヒドロクロリドの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(2−(トリフルオロメトキシ)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(2,4−ジフルオロフェニル)シクロブチル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]2−((1−(4−ブロモフェニル)シクロブチル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]エチル2−((1−(4−(1−エチルピペリジン−4−イル)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]エチル2−((1−(4−(1−イソプロピルピペリジン−4−イル)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボキシレートの合成
[ステップ1]2−メチル−N−(1−(チオフェン−3−イル)シクロブチル)プロパン−2−スルフィンアミドの合成
[ステップ1]1−(チオフェン−2−イル)シクロプロパン−1−アミンの合成
[ステップ1]1−(4−(ピペリジン−1−イル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(2−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]1−(4−(トリフルオロメチル)フェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]N’−(2,2,2−トリフルオロアセチル)−2−((1−(4−(トリフルオロメチル)フェニル)シクロブチル)アミノ)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(3,4−ジフルオロフェニル)シクロブタン−1−カルボニトリルの合成
[ステップ1]2−(3−ブロモ−4−フルオロフェニル)アセトニトリルの合成
[ステップ1]1−(2−メトキシフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(3−メトキシフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(4−メトキシフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(3−クロロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(3−クロロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−クロロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]2−((1−(4−クロロフェニル)シクロプロピル)アミノ)−N’−(2,2,2−トリフルオロアセチル)ピリミジン−5−カルボヒドラジドの合成
[ステップ1]1−(4−クロロ−3−フルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(o−トリル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]1−(4−クロロ−2−フルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(3,5−ジフルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(3,4−ジフルオロフェニル)シクロプロパン−1−アミンの合成
[ステップ1]1−(3−ブロモフェニル)シクロブタン−1−カルボキサミドの合成
[ステップ1]1−(2,4−ジフルオロフェニル)シクロプロパン−1−アミンヒドロクロリドの合成
[ステップ1]t−ブチル(1−(4−モルホリノフェニル)シクロブチル)カルバメートの合成
<実験例1>HDAC酵素活性の阻害の検索(in vitro)
HDAC1及びHDAC6酵素活性の阻害実験により、本発明の化学式Iで表される化合物のHDAC6の選択性を確認すべく、既存の開発物質を対照群とし、比較実験を行った。
Claims (11)
- 下記化学式Iで表されるオキサジアゾールアミン誘導体化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
R1は、−CF2H又は−CF3であり;
L1又はL2は、単結合であり;
Z1及びZ3は、Nであり;
Z2及びZ4は、それぞれ独立して、CRZであり、RZは、−H、−F、−Cl、−Br、−I、又は−O(C1−C4アルキル)であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、RCは、−H、−(C1−C6アルキル)、−(C1−C4アルキル)−OH、−(C1−C4アルキル)−O−(C1−C4アルキル)、−C(=O)−(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)、−C(=O)−O(C1−C4アルキル)−アリール、−(C1−C4アルキル)−C(=O)−O(C1−C4アルキル)、−(C1−C4アルキル)−NRARB、−S(=O)2−(C1−C4アルキル)、アリール、−(C1−C4アルキル)−アリール、−(C2−C4アルケニル)−アリール、ヘテロアリール、−(C1−C4アルキル)−ヘテロアリール、−C(=O)−(C3−C7シクロアルキル)、−(C2−C6ヘテロシクロアルキル)、又は−(C1−C4アルキル)−C(=O)−(C2−C6ヘテロシクロアルキル)であり;
a及びbは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−SO2−、−(C1−C2アルキル)−SO2−、又は単結合であり;
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ヘテロシクロアルキル(ここで、ヘテロシクロアルキルは、置換されないか、C1−C4アルキル又はヘテロシクロアルキルで置換されていてもよい)、
Y2は、−CH2−、−NRc−、−O−、−C(=O)−、又は−S(=O)2−であり、
Y3〜Y5は、それぞれ独立して、−CH−又は−N−であり,
c〜fは、それぞれ独立して、0、1、2、3、又は4の整数であり(但し、c及びeが共に0ではなく、d及びfが共に0ではない)、
RA及びRBは、それぞれ独立して、−H又は−(C1−C4アルキル)である(ここで、−(C1−C4アルキル)の一つ以上のHは、−X又は−OHで置換されていてもよく、Xは、−F、Cl、Br又はIである) - 前記化学式Iで表される化合物は、
R1は、−CF2H又は−CF3であり;
R2は、−H又は−(C1−C4アルキル)であり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は単結合であり;
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、ピペリジン、モルホリノ、ピペラジン、又はピロリジン(ここで、ピペリジン、モルホリノ、ピペラジン、又はピロリジンは置換されないか、C1−C4アルキルで置換されていてもよい)、又は
Y2は、−O−であり、
Y3及びY5は、−CH−であり、
Y4は、−N−であり、
c及びeは、それぞれ独立して、0、1、又は2であり(但し、c及びeが共に0ではない)、
d及びfは、それぞれ独立して、0、1、2、又は3の整数である(但し、d及びfが共に0ではない)、
請求項1に記載の化学式 I で表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩。 - 前記化学式Iで表される化合物は、下記化学式IIで表される化合物である、請求項1に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は−C(=O)−O(C1−C4アルキル)−アリールであり;
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではない);
L3は、−(C1−C2アルキル)−、−(C1−C2アルキル)−SO2−、又は単結合であり;
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、ピペリジン(ここで、ピペリジンは、置換されないか、C1−C4アルキルで置換されていてもよい)、又は
- 前記化学式IIで表される化合物は、
R1は、−CF2H又は−CF3であり;
R2は、−Hであり;
Y1は、−CH2−又は−NRc−であり、RCは、−H又は
a及びbは、それぞれ独立して、0、1、2、又は3の整数であり(但し、a及びbが共に0ではなく、Y1が−CH2−であるとき、Y1、a、及びbによって形成される環は、3〜7員の飽和シクロアルキルであり、Y1が−NRc−であるとき、Y1、a、及びbによって形成される環は、一つのNを含む3〜7員の飽和ヘテロシクロアルキルである);
L3は、−CH2−、−CH2−SO2−、又は単結合であり;
R4〜R6は、それぞれ独立して、−H、−F、−Cl、−Br、−I、−OH、−O(C1−C4アルキル)、−(C1−C4アルキル)、−CF3、−OCF3、モルホリノ、
R7は、−H又は−(C1−C4アルキル)である、
請求項3に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩。 - 前記化学式Iで表される化合物は、下記に記載の化合物のうちから選択されるいずれか一つである、請求項1に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロプロピル)ピリミジン−2−アミン;
N−(1−フェニルシクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロペンチル)ピリミジン−2−アミン;
N−(1−フェニルシクロペンチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロヘキシル)ピリミジン−2−アミン;
N−(1−フェニルシクロヘキシル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(4−メトキシフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(3−メトキシフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(3−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(4−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−2−イル)シクロブチル)ピリミジン−2−アミン;
N−(1−(ピリジン−2−イル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(o−トリル)シクロブチル)ピリミジン−2−アミン;
N−(1−(o−トリル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(m−トリル)シクロブチル)ピリミジン−2−アミン;
N−(1−(m−トリル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(p−トリル)シクロブチル)ピリミジン−2−アミン;
N−(1−(p−トリル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
ベンジル4−((5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−イル)アミノ)−4−フェニルピペリジン−1−カルボキシレート;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(4−フェニルピペリジン−4−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(4−フルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(3−フルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロプロピル)ピリミジン−2−アミン;
3−(1−((5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−イル)アミノ)シクロブチル)フェノール;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,4−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(3,4−ジフルオロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,5−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(ベンゾ[d][1,3]ジオキソール−5−イル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,5−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメトキシ)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,4,5−トリフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,3−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,6−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2,3−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,3−ジクロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3,4−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3,4−ジクロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,4−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,4−ジクロロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,6−ジクロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−3−イル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロ−4−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロ−5−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−クロロ−5−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(5−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(5−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロ−2−フルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−(オキセタン−3−イル)ピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(トシルメチル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,4−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−(トリフルオロメトキシ)フェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−ベンジルシクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2−(トリフルオロメトキシ)フェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(2,4−ジフルオロフェニル)シクロブチル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−メチルピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−エチルピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(1−イソプロピルピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(チオフェン−3−イル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(チオフェン−2−イル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(ピペリジン−1−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−(トリフルオロメチル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,4−ジフルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロ−3−モルホリノフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−メトキシフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−メトキシフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−メトキシフェニル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロプロピル)−5−(5−(トリフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロ−3−フルオロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(o−トリル)シクロプロピル)ピリミジン−2−アミン;
N−(1−(4−クロロ−2−フルオロフェニル)シクロプロピル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,5−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3,4−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−(1−(オキセタン−3−イル)ピペリジン−4−イル)フェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2,4−ジフルオロフェニル)シクロプロピル)ピリミジン−2−アミン;及び
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−モルホリノフェニル)シクロブチル)ピリミジン−2−アミン。 - 前記化学式Iで表される化合物は、下記に記載の化合物のうちから選択されるいずれか一つである、請求項5に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロプロピル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロペンチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−メトキシフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(4−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(4−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;及び
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−2−イル)シクロブチル)ピリミジン−2−アミン。 - 前記化学式Iで表される化合物は、下記に記載の化合物のうちから選択されるいずれか一つである、請求項6に記載の化学式Iで表される化合物、その光学異性体、又はその薬剤学的に許容可能な塩:
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−フェニルシクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(3−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(2−フルオロフェニル)シクロブチル)ピリミジン−2−アミン;
N−(1−(2−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;
N−(1−(3−クロロフェニル)シクロブチル)−5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)ピリミジン−2−アミン;及び
5−(5−(ジフルオロメチル)−1,3,4−オキサジアゾール−2−イル)−N−(1−(ピリジン−2−イル)シクロブチル)ピリミジン−2−アミン。 - 請求項1乃至請求項7のいずれか1項に記載の化合物、その光学異性体、又はその薬剤学的に許容可能な塩を有効成分として含有する薬剤学的組成物。
- 請求項1乃至請求項7のいずれか1項に記載の化合物、その光学異性体、又はその薬剤学的に許容可能な塩を有効成分として含有するヒストン脱アセチル化酵素6(Histone deacetylase 6、HDAC6)の阻害と関連する疾患の予防又は治療のための薬剤学的組成物。
- ヒストン脱アセチル化酵素6の阻害と関連する疾患は、感染性疾患;新生物(neoplasm);内分泌;栄養及び代謝疾患;精神及び行動障害;神経疾患;眼及び付属器疾患;循環器疾患;呼吸器疾患;消化器疾患;皮膚及び皮下組織の疾患;筋骨格系及び結合組織の疾患;及び先天奇形、変形及び染色体異常より選択されるいずれか一つ以上である、請求項9に記載のヒストン脱アセチル化酵素6の阻害と関連する疾患の予防又は治療のための薬剤学的組成物。
- ヒストン脱アセチル化酵素6の阻害剤の製造における、請求項1乃至請求項7のいずれか1項に記載の化学式Iで表される化合物、又はその光学異性体、又は薬剤学的に許容可能なその塩の使用。
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EP3362445A1 (en) | 2018-08-22 |
TWI694073B (zh) | 2020-05-21 |
AU2016338118A1 (en) | 2018-04-12 |
CA3001666C (en) | 2021-03-30 |
DK3362445T3 (da) | 2023-02-27 |
NZ740809A (en) | 2019-04-26 |
US10494355B2 (en) | 2019-12-03 |
MX2018004447A (es) | 2018-08-01 |
ES2940413T3 (es) | 2023-05-08 |
PT3362445T (pt) | 2023-03-20 |
EP3362445A4 (en) | 2019-05-22 |
CN108699048B (zh) | 2021-12-28 |
JP2018530571A (ja) | 2018-10-18 |
PH12018500773B1 (en) | 2018-10-29 |
KR20170043091A (ko) | 2017-04-20 |
KR101839137B1 (ko) | 2018-03-26 |
MY196174A (en) | 2023-03-20 |
WO2017065473A1 (en) | 2017-04-20 |
HRP20230201T1 (hr) | 2023-03-31 |
US20180273495A1 (en) | 2018-09-27 |
FI3362445T3 (fi) | 2023-03-21 |
PH12018500773A1 (en) | 2018-10-29 |
EP3362445B1 (en) | 2023-01-25 |
TW201716397A (zh) | 2017-05-16 |
CN108699048A (zh) | 2018-10-23 |
BR112018007289A2 (pt) | 2018-10-23 |
CA3001666A1 (en) | 2017-04-20 |
RU2695133C1 (ru) | 2019-07-22 |
PL3362445T3 (pl) | 2023-08-07 |
HUE061967T2 (hu) | 2023-09-28 |
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