JP2016523865A - Fshrの調節剤としてのピラゾール化合物及びその使用 - Google Patents
Fshrの調節剤としてのピラゾール化合物及びその使用 Download PDFInfo
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- JP2016523865A JP2016523865A JP2016521900A JP2016521900A JP2016523865A JP 2016523865 A JP2016523865 A JP 2016523865A JP 2016521900 A JP2016521900 A JP 2016521900A JP 2016521900 A JP2016521900 A JP 2016521900A JP 2016523865 A JP2016523865 A JP 2016523865A
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- methoxy
- nitrogen
- dihydro
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- 125000005842 heteroatom Chemical group 0.000 claims description 77
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- 230000001105 regulatory effect Effects 0.000 description 1
- 230000027272 reproductive process Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical class [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- RGCVGPRJRNTWCB-UHFFFAOYSA-M sodium;2-methylpropane-1-sulfinate Chemical compound [Na+].CC(C)CS([O-])=O RGCVGPRJRNTWCB-UHFFFAOYSA-M 0.000 description 1
- CQSFZPDGBPHCHV-UHFFFAOYSA-M sodium;cyclopropanesulfinate Chemical compound [Na+].[O-]S(=O)C1CC1 CQSFZPDGBPHCHV-UHFFFAOYSA-M 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 230000028016 temperature homeostasis Effects 0.000 description 1
- WDPWEXWMQDRXAL-UHFFFAOYSA-N tert-butyl 1,4-diazepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCNCC1 WDPWEXWMQDRXAL-UHFFFAOYSA-N 0.000 description 1
- IPISOFJLWYBCAV-UHFFFAOYSA-N tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate Chemical compound C1=NN(C(=O)OC(C)(C)C)C=C1B1OC(C)(C)C(C)(C)O1 IPISOFJLWYBCAV-UHFFFAOYSA-N 0.000 description 1
- AWVKCRPWXGHMDV-UHFFFAOYSA-N tert-butyl 4-[3-[tert-butyl(methyl)carbamoyl]-7-methoxy-1-thiophen-3-yl-4h-chromeno[4,3-c]pyrazol-8-yl]pyrazole-1-carboxylate Chemical compound C1=2C=3C=C(C4=CN(N=C4)C(=O)OC(C)(C)C)C(OC)=CC=3OCC=2C(C(=O)N(C)C(C)(C)C)=NN1C=1C=CSC=1 AWVKCRPWXGHMDV-UHFFFAOYSA-N 0.000 description 1
- BDMXLEPPQUSRDL-UHFFFAOYSA-N tert-butyl N-[3-[(7-methoxy-8-propan-2-yloxy-1-thiophen-3-yl-4H-chromeno[4,3-c]pyrazole-3-carbonyl)amino]propyl]carbamate Chemical compound COc1cc2OCc3c(nn(-c4ccsc4)c3-c2cc1OC(C)C)C(=O)NCCCNC(=O)OC(C)(C)C BDMXLEPPQUSRDL-UHFFFAOYSA-N 0.000 description 1
- GDPUYKCOMIFDPO-UHFFFAOYSA-N tert-butyl diazepane-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCCN1 GDPUYKCOMIFDPO-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 238000011820 transgenic animal model Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- 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
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Reproductive Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pregnancy & Childbirth (AREA)
- Endocrinology (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本発明は2013年6月24日に出願した米国仮出願第61/838,460号及び2013年11月1日に出願した米国仮出願第61/898,608号の利益を主張する。上記の出願の内容の全体をここに参照により取り入れる。
本発明は、卵胞刺激ホルモン受容体(FSHR)のアゴニストとして有用なピラゾール化合物に関する。本発明はまた、本発明の化合物を含む医薬上許容されうる組成物及び種々の疾患の治療における該組成物の使用方法をも提供する。
ゴナドトロピンは、代謝、体温調節及び生殖過程を含む、身体のさまざまな機能に重要な機能を果たす。ゴナドトロピンは、特定の生殖細胞型に対して作用し、卵巣及び精巣分化ならびにステロイド産生を開始する。ゴナドトロピンFSH(卵胞刺激ホルモン)はゴナドトロピン放出ホルモン及びエストロゲンの影響下に下垂体前葉から放出され、そして妊娠中に胎盤から放出される。FSHはまた、黄体形成ホルモン(LH)及び甲状腺刺激ホルモン(TSH)と構造的類似性を有するヘテロ二量体糖タンパク質ホルモンであり、その両方も脳下垂体で産生され、また、絨毛性ゴナドトロピン(CG)は胎盤で産生される。女性において、FSHは卵胞の発達及び成熟の刺激において重要な役割を果たし、さらに、LHは、排卵を誘発するのに対し、エストロゲンの主要なホルモン調節分泌である。男性では、FSHは、精細管の完全性に対する責務を果たし、そして配偶子形成を支持するようにセルトリ細胞に作用する。
今回、本発明の化合物及びその医薬上許容されうる塩はFSHRの有効な調節剤であることが発見された。このような化合物は一般式I:
1.本発明の化合物の一般記載
特定の実施形態において、本発明は卵胞刺激ホルモン受容体(FSHR)の調節剤を提供する。特定の実施形態において、本発明はFSHRのポジティブアロステリック調節剤を提供する。幾つかの実施形態において、このような化合物は本明細書中に記載の式の化合物又はその医薬上許容されうる塩を包含し、ここで、各変数は本明細書中に規定及び記載されるとおりである。
本発明の化合物は一般に上記されるものを含み、そして本明細書中に開示されるクラス、サブクラス及び化学種によりさらに例示される。本明細書中に使用されるときに、以下の定義は別段の断りがないかぎり、適用されるであろう。本発明の目的で、化学元素は周期律表CASバージョン, Handbook of Chemistry and Physics, 75th Ed.によって特定される。さらに、有機化学の一般原理は"Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999及び"March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B.及びMarch, J., John Wiley & Sons, New York: 2001に記載されており、その全内容をここに参照により取り込む。
-F, -Cl, -Br, -I, 重水素、
-OH, 保護ヒドロキシ、アルコキシ、オキソ、チオオキソ、
-NO2, -CN, CF3, N3,
-NH2, 保護アミノ、-NHアルキル、-NHアルケニル、-NHアルキニル、-NHシクロアルキル、-NH-アリール、-NH-ヘテロアリール、-NH-複素環、-ジアルキルアミノ、-ジアリールアミノ、-ジヘテロアリールアミノ、
-O-アルキル、-O-アルケニル、-O-アルキニル、-O-シクロアルキル、-O-アリール、-O-ヘテロアリール、-O-複素環、
-C(O)-アルキル、-C(O)-アルケニル、-C(O)-アルキニル、-C(O)-カルボサイクリル、-C(O)-アリール、-C(O)-ヘテロアリール、-C(O)-ヘテロサイクリル、
-CONH2, -CONH-アルキル、-CONH-アルケニル、-CONH-アルキニル、-CONH-カルボサイクリル、-CONH-アリール、-CONH-ヘテロアリール、-CONH-ヘテロサイクリル、
-OCO2-アルキル、-OCO2-アルケニル、-OCO2-アルキニル、-OCO2-カルボサイクリル、-OCO2-アリール、-OCO2-ヘテロアリール、-OCO2-ヘテロサイクリル、-OCONH2, -OCONH-アルキル、-OCONH-アルケニル、-OCONH-アルキニル、-OCONH-カルボサイクリル、-OCONH-アリール、-OCONH-ヘテロアリール、-OCONH-ヘテロサイクリル、
-NHC(O)-アルキル、-NHC(O)- アルケニル、-NHC(O)-アルキニル、-NHC(O)-カルボサイクリル、-NHC(O)-アリール、-NHC(O)-ヘテロアリール、-NHC(O)-ヘテロサイクリル、-NHCO2-アルキル、-NHCO2-アルケニル、-NHCO2-アルキニル、-NHCO2-カルボサイクリル、-NHCO2-アリール、-NHCO2-ヘテロアリール、-NHCO2-ヘテロサイクリル、-NHC(O)NH2, -NHC(O)NH-アルキル、-NHC(O)NH-アルケニル、-NHC(O)NH-アルケニル、-NHC(O)NH-カルボサイクリル、-NHC(O)NH-アリール、-NHC(O)NH-ヘテロアリール、-NHC(O)NH-ヘテロサイクリル、NHC(S)NH2, -NHC(S)NH-アルキル、-NHC(S)NH-アルケニル、-NHC(S)NH-アルキニル、-NHC(S)NH-カルボサイクリル、-NHC(S)NH-アリール、-NHC(S)NH-ヘテロアリール、-NHC(S)NH-ヘテロサイクリル、-NHC(NH)NH2, -NHC(NH)NH-アルキル、-NHC(NH)NH-アルケニル、-NHC(NH)NH-アルケニル、-NHC(NH)NH-カルボサイクリル、-NHC(NH)NH-アリール、-NHC(NH)NH-ヘテロアリール、-NHC(NH)NH-ヘテロサイクリル、-NHC(NH)-アルキル、-NHC(NH)-アルケニル、-NHC(NH)-アルケニル、-NHC(NH)-カルボサイクリル、-NHC(NH)-アリール、-NHC(NH)-ヘテロアリール、-NHC(NH)-ヘテロサイクリル、
-C(NH)NH-アルキル、-C(NH)NH-アルケニル、-C(NH)NH-アルキニル、-C(NH)NH-カルボサイクリル、-C(NH)NH-アリール、-C(NH)NH-ヘテロアリール、-C(NH)NH-ヘテロサイクリル、
-S(O)-アルキル、- S(O)-アルケニル、- S(O)-アルキニル、-S(O)-カルボサイクリル、-S(O)-アリール、-S(O)-ヘテロアリール、-S(O)-ヘテロサイクリル-SO2NH2, -SO2NH-アルキル、-SO2NH-アルケニル、-SO2NH-アルキニル、-SO2NH-カルボサイクリル、-SO2NH-アリール、-SO2NH-ヘテロアリール、-SO2NH-ヘテロサイクリル、
-NHSO2-アルキル、-NHSO2-アルケニル、-NHSO2-アルキニル、-NHSO2-カルボサイクリル、-NHSO2-アリール、-NHSO2-ヘテロアリール、-NHSO2-ヘテロサイクリル、
-CH2NH2, -CH2SO2CH3,
-モノ-、ジ-又はトリ-アルキルシリル、
-アルキル、-アルケニル、-アルキニル、-アリール、-アリールアルキル、-ヘテロアリール、-ヘテロアリールアルキル、ヘテロシクロアルキル、-シクロアルキル、-炭素環式、-複素環式、ポリアルコキシアルキル、ポリアルコキシ、-メトキシメトキシ、-メトキシエトキシ、-SH, -S-アルキル、-S-アルケニル、-S-アルキニル、-S-カルボサイクリル、-S-アリール、-S-ヘテロアリール、-S-ヘテロサイクリル又はメチルチオメチルが挙げられる。
1つの態様によると、本発明は式Iの化合物又はその医薬上許容されうる塩を提供する。
YはO, S又はNRであり、
ZはO, S, SO, SO2又はNであり、ZがO, S, SO又はSO2であるときには、pは0であり、
各Rは、独立して、水素、C1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、又は、
同一の原子上の2つのR基が該原子と一緒に結合して、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環を形成し、その各々は場合により置換されていてよく、
環Aは縮合C3-10アリール、縮合3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する縮合3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する縮合5〜6 員単環式ヘテロアリール環であり、
R1は-OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R又は-N(R)2であり、
R2は-R、ハロゲン、-ハロアルキル、-OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R又は-N(R)2であり、
R3は水素、C1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、
各R4は独立して、-R, ハロゲン、-ハロアルキル、-OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R又は-N(R)2であり、
R5はC1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、
R6は水素、C1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、
又は、R5及びR6は、その各々が結合している原子と一緒に、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜8員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜8 員ヘテロアリール環を形成し、その各々は場合により置換されていてよく、
nは0, 1又は2であり、そして
pは0又は1である)。
医薬上許容されうる塩
別の実施形態によれば、本発明は、本発明の化合物又はその医薬上許容されうる誘導体及び医薬上許容されうるキャリア、アジュバント又はビヒクルを含む組成物を提供する。本発明の組成物における化合物の量は、生物学的サンプル又は患者において、FSHR又は変異体を測定可能に調節するのに有効であるような量である。特定の実施形態において、本発明の組成物における化合物の量は、生物学的サンプル又は患者において、FSHR又は変異体を測定可能に調節するのに有効であるような量である。特定の実施形態において、本発明の組成物は、そのような組成物を必要とする患者に投与するように製剤される。
特定の実施形態において、本発明は、患者又は生物学的サンプルにおいてポジティブな様式でアロステリックにFSHR又はその変異種を刺激する方法であって、本発明に係る化合物を前記患者に投与し又は前記生物学的サンプルと接触させることを含む方法を提供する。
(a)上記のとおりの方法により哺乳動物を治療すること、
(b)前記哺乳動物から卵子を回収すること、
(c)前記卵子を受精させること、及び、
(d)前記受精卵を宿主哺乳動物中に移植すること、
の工程を含む方法を提供する。
以下の実施例に示されるように、特定の例示的な実施形態において、化合物は、以下の一般的手順に従って調製される。一般的な方法が、本発明の特定の化合物の合成を記載しているが、以下の一般的な方法及び当業者に知られている他の方法は、本明細書中に記載されるとおりの、これらの各化合物の全ての化合物及びサブクラス及び種に適用することができることは理解されるであろう。
方法: A: H2O 中0.1 % TFA、B:ACN中0.1 % TFA:
操作時間: 6.5分
流速: 1.0 mL/分
勾配: 4.5分で5から95% B、波長254及び215 nM
カラム: Waters Sunfire C18, 3.0x50mm, 3.5um, + veモード
マススキャン: 100〜900 Da
7-メトキシ-8-(1H-ピラゾール-4-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 tert-ブチル-メチル-アミド (1)
工程1:3-ブロモ-1-(2,4-ジヒドロキシフェニル)プロパン-1-オン
1H NMR (400 MHz, DMSO-d6) δ 12.2 (bs, 1H), 10.6 (bs, 1H), 7.77-7.75 (d, J = 8 Hz, 1H), 6.38-6.35 (dd, J= 2.0, 8.8 Hz, 1H), 6.26-6.26 (d, J= 4.0 Hz, 1H), 3.74 (t, J= 6.8 Hz, 2H), 3.61-3.57 (dd, J= 6.0, 1 1.2 Hz, 2H)。
1H NMR (400 MHz, DMSO- d6)δ 10.52 (bs, 1H), 7.61-7.59 (d, J= 8.0 Hz, 1H), 6.48-6.45 (dd, J= 4.0, 12.0 Hz, 1H), 6.29-6.20 (d, J= 4.0 Hz, 1H), 4.44 (t, J= 4.0 Hz, 2H), 2.65 (t, J= 4.0 Hz, 2H)。
1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 6.73 (s, 1H), 4.53 (t, J= 8.0 Hz, 2H), 3.89 (s, 3H), 2.72 (t, J= 8.0 Hz, 2H)。
1H NMR (400 MHz, DMSO-d6) δ.8.04 (s, 1H), 6.43 (s, 1H), 5.32 (s, 2H), 4.40-4.32 (m, 2H), 3.95 (s, 3H), 1.42-1.37 (m, 3H)。
1H NMR (400 MHz, DMSO-d6) δ 10.08 (bs, 3H), 8.20 (bs, 1H), 7.48-7.46 (dd, J= 3.2, 5.2Hz, 1H), 6.87-6.85 (dd, J= 1.2, 4.8 Hz, 1H), 6.72-6.71 (dd, J= 1.6, 3.2 Hz, 1H)。
1H NMR (400 MHz, CDC13) δ 7.57-7.55 (dd, J= 4.0, 5.2 Hz, 1H), 7.52-7.50 (dd, J= 4.0, 5.2 Hz, 1H),7.22-7.21 (dd, J= 1.2, 5.2 Hz, 1H), 6.94 (s, 1H), 6.60 (s, 1H), 5.56 (s, 2H), 4.47-4.41 (dd, J= 8.0, 12 Hz. 2H), 3.88 (s, 3H), 1.42 (t, J= 8.0 Hz, 3H)。
1H NMR (400 MHz, DMSO-d6) δ 7.98-7.97 (dd, J= 1.4, 3.2 Hz, 1H), 7.80-7.85 (dd, J= 3.2 , 4.7 Hz, 1H), 7.33-7.32 (dd, J= 1.3, 5.1 Hz, 1H), 6.83 (s, 1H), 6.76 (s, 1H), 5.37 (s, 2H), 3.81 (s, 3H), 3.15 (s, 3H), 1.47 (s, 9H)。m/z: 476 [M+H]+。
1H NMR (400 MHz, DMSO-d6) δ 8.02-8.01 (dd, J= 1.4, 3.2 Hz, 1H), 7.89-7.87 (dd, J = 3.2 , 5.1 Hz, 1H), 7.54 (bs, 2H), 7.37-7.36 (dd, J= 1.4, 5.1 Hz, 1H), 6.85 (s, 1H), 6.74 (s, 1H), 5.35 (s, 2H), 3.83 (s, 3H), 3.16 (s, 3H), 1.42 (s, 9H)。m/z: 464 [M+H]+。
7-メトキシ-8-ピリジン-3-イル-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (2)
1H NMR (400 MHz, CDC13) δ 8.50-8.47 (m, 2H), 7.67-7.64 (m, 1H), 7.53-7.52 (dd, J= 1.2, 3.2 Hz, 1H), 7.49-7.47 (dd, J= 3.2, 5.2 Hz, 1H), 7.27-7.22 (m, 2H), 6.77 (s, 1H), 6.69 (s, 1H), 5.52 (s, 2H), 3.82 (s, 3H), 3.28 (s, 3H), 1.52 (s, 9H)。m/z: 475 [M+H]+。
(4-シクロブタンカルボニル-[1,4]ジアゼパン-1-イル)-(7-メトキシ-8-ピリジン-3-イル-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-メタノン (3)
工程1: (8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-(4-シクロブタンカルボニル-[1,4]ジアゼパン-1-イル)-メタノン
1H NMR (400 MHz, CDC13) δ 7.51-7.48 (m, 2H), 7.22-7.20 (m, 1H), 6.99 (t, J= 4.0 Hz, 1H), 6.60 (t , J= 2.4 Hz, 1H), 5.54-5.51 (dd, J= 4.0, 12.0 Hz, 2H), 4.18-4.17 (m, 2H), 3.86 (s, 3H), 3.81-3.79 (m, 3H), 3.71-3.60 (m, 3H), 3.57-3.54 (m, 1H), 2.36-2.34 (m, 2H), 1.99-1.95 (m, 2H), 1.94-1.90 (m, 4H)。m/z: 571 [M+H]+
1H NMR (400 MHz, CDC13) δ 8.49-8.47 (dd, J= 1.6, 4.8 Hz, 2H), 7.67 (t, J= 2.0 Hz, 1H), 7.52-7.47 (m, 2H), 7.27-7.24 (m, 2H), 6.83-6.80 (dd, J= 1.6, 4.8 Hz, 1H), 6.68 (t , J= 4.0, Hz, 1H), 5.59-5.56 (dd, J= 1.6, 10.4 Hz, 2H), 4.18-4.17 (m, 2H), 3.86 (s, 4H), 3.81-3.79 (m, 1H), 3.71-3.60 (m, 2H), 3.57-3.54 (m, 1H), 3.36-3.34 (m, 1H), 2.36-2.34 9m, 2H), 2.12-1.99 (m, 6H), 0.98-0.97 (m, 1H)。m/z: 570 [M+H]+
8-イソブチル7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (5)
工程1: 7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸エチルエステル
1H NMR (400 MHz, DMSO-d6) δ 8.00 (m, 1H), 7.83-7.82 (d, J= 3.2 Hz, 1H), 7.33-7.32 (dd, J= 1.6, 5.2 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.56 (s, 2H), 4.32-4.26 (m, 2H), 3.78 (s, 3H), 1.76 (s, 3H), 4.52 (s, 3H), 1.23-1.18 (m, 3H)。m/z: 411.5 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.97-7.96 (dd, J= 1.2, 3.2 Hz, 1H), 7.83-7.82 (dd, J= 3.2 , 5.2 Hz, 1H), 7.31-7.30 (dd, J= 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.43 (s, 2H), 4.32-4.27 (m, 2H), 3.75 (s, 3H), 2.12-2.10 (m, 2H), 1.62-1.55 (m, 1H), 1.31-1.22 (m, 3H), 0.85-0.83 (d, J= 4.0 Hz, 6H)。m/z: 413 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.02 (bs, 1H), 7.96-7.95 (dd, J= 1.6, 3.2 Hz, 1H), 7.83-7.81 (dd, J= 3.2 , 5.2 Hz, 1H), 7.31-7.29 (dd, J= 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.42 (s, 2H), 3.73 (s, 3H), 2.12-2.11 (m, 2H), 1.62-1.55 (m, 1H), 0.72-.711 (d, J= 4.0 Hz, 6H)。m/z: 385 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.91-7.90 (dd, J= 1.6, 3.2 Hz, 1H), 7.80-7.85 (dd, J= 3.2 , 5.2 Hz, 1H), 7.29-7.28 (dd, J= 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.40 (s, 1H), 5.29 (s, 2H), 3.73 (s, 3H), 3.14 (s, 3H), 2.13-2.11 (m, 2H), 1.63-1.55 (m, 1H), 1.41 (s, 9H), 0.72-.711 (d, J= 4.0 Hz, 6H)。m/z: 454 [M+H]+
7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 tert-ブチル-メチル-アミド (6)
工程1: 8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 tert-ブチル-メチル-アミド (4)
1H NMR (400 MHz, MeOD) δ 7.75 (dd, J= 3.2, 1.4 Hz, 1H), 7.69 (dd, J= 5.1, 3.2 Hz, 1H), 7.27 (dd, J= 5.1, 1.4 Hz, 1H), 6.70 (s, 1H), 6.63 (s, 1H), 6.07 (s, 1H), 5.33 (s, 2H), 3.80 (s, 3H), 3.20 (s, 3H), 1.80 (d, J= 1.3 Hz, 3H), 1.54 (s, 9H), 1.50 (d, J= 1.2 Hz, 3H)。m/z: 452 [M+H]+
7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸(2-アセチルアミノ-エチル)-アミド (7)
工程1:エチル7-メトキシ-8-(2-メチルプロプ-1-エン-1-イル)-1-(チオフェン-3-イル)-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボキシレート
1H NMR (400 MHz, DMSO-d6) δ 8.00 (m, 1H), 7.83-7.82 (d, J= 3.2 Hz, 1H), 7.33-7.32 (dd, J= 1.6, 5.2 Hz, 1H), 6.65 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.56 (s, 2H), 4.32-4.26 (m, 2H), 3.78 (s, 3H), 1.76 (s, 3H), 4.52 (s, 3H), 1.23-1.18 (m, 3H)。m/z: 411.5 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.02 (bs, 1H), 7.96-7.95 (dd, J= 1.6, 3.2 Hz, 1H), 7.83-7.81 (dd, J= 3.2 , 5.2 Hz, 1H), 7.31-7.29 (dd, J= 1.2, 5.2 Hz, 1H), 6.64 (s, 1H), 6.37 (s, 1H), 5.42 (s, 2H), 3.73 (s, 3H), 2.12-2.11 (m, 2H), 1.62-1.55 (m, 1H), 0.72-.711 (d, J= 4.0 Hz, 6H)。m/z: 383 [M+H]+
1H NMR (500 MHz, CD3OD) δ 7.74 (dd, J= 3.1, 1.2 Hz, 1H), 7.67 (dd, J= 5.0, 3.2 Hz, 1H), 7.26 (dd, J= 5.1, 1.1 Hz, 1H), 6.66 (s, 1H), 6.58 (s, 1H), 6.04 (s, 1H), 5.48 (s, 2H), 3.76 (s, 3H), 3.46 (t, J= 6.0 Hz, 2H), 3.41-3.33 (m, 2H), 1.94 (s, 3H), 1.78 (s, 3H), 1.48 (s, 3H)。m/z: 467 [M+H]+
8-イソプロポキシ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (19)
工程1: 3-クロロ-1-(2-ヒドロキシ-4,5-ジメトキシフェニル)プロパン-1-オン
1H NMR (400 MHz, DMSO-d6) δ 12.2 (bs, 1H), 7.27 (s, 1H), 6.55 (s, 1H), 4.12-4.10 (m, 2H), 3.79 (s, 3H), 3.71 (s, 3H), 2.48-2.43 (m, 2H)。
1H NMR (400 MHz, DMSO- d6) δ 7.12 (s, 1H), 6.59 (s, 1H), 4.47-4.44 (m, 2H), 3.80 (s, 3H), 3.72 (s, 3H), 2.69-2.65 (m, 2H)。
1H NMR (400 MHz, DMSO- d6) δ 9.72 (bs, 2H), 7.04 (s, 1H), 6.30 (s, 1H), 4.37-4.34 (m, 2H), 2.60-2.57 (m, 2H)。
1H NMR (400 MHz, DMSO-d6) δ 9.05 (bs, 1H), 7.05 (s, 1H), 6.53 (s, 1H), 4.43-4.40 (m, 2H), 3.80 (s, 3H), 2.64-2.61 (m, 2H)。
1H NMR (400 MHz, DMSO-d6) δ 7.13 (s, 1H), 6.59 (s, 1H), 4.48-4.40 (m, 3H), 3.80 (s, 3H), 2.68-2.65 (m, 2H), 1.21 (s, 3H), 1.20 (s, 3H)。
1H NMR (400 MHz, DMSO-d6) δ.7.17-7.13 (d, J= 16 Hz, 1H), 6.61-6.59 (d, J= 24 Hz, 1H), 5.16-5.12 (m, 1H), 4.47-4.24 (m, 1H), 4.21 (s, 3H), 2.97 (s, 3H), 2.54-5.53 (m, 1H), 1.21 (s, 6H)。
1H NMR (400 MHz, DMSO-d6) δ 8.02-8.01 (dd, J= 1.2, 2.4 Hz, 1H), 7.86-7.83 (dd, J= 4 , 16 Hz, 1H), 7.35-7.34 (dd, J= 1.2, 4 Hz, 1H), 6.68 (s, 1H), 6.19 (s, 1H), 5.40 (s, 2H), 4.31-4.26 (m, 2H), 3.94-3.88 (m, 1H), 3.72 (s, 3H), 1.31-1.287 (m, 3H), 1.07 (s, 6H)。
1H NMR (400 MHz, DMSO-d6) δ 13.16 (bs, 1H), 8.01-8.00 (dd, J= 1.2, 2.4 Hz, 1H), 7.85-7.83 (dd, J= 4 , 16 Hz, 1H), 7.35-7.33 (dd, J= 1.2, 4 Hz, 1H), 6.69 (s, 1H), 6.19 (s, 1H), 5.39 (s, 2H), 3.94-3.88 (m, 2H), 3.72 (s, 3H), 1.07 (s, 6H)。
1H NMR (400 MHz, DMSO-d6) δ 7.97-7.96 (dd, J= 1.2, 2.4 Hz, 1H), 7.82-7.80 (dd, 7 = 4 , 16 Hz, 1H), 7.34-7.32 (dd, J= 1.2, 4 Hz, 1H), 6.69 (s, 1H), 6.22 (s, 1H), 5.27 (s, 2H), 3.39-3.89 (m, 1H), 3.72 (s, 3H), 3.14 (s, 3H), 1.41 (s, 9H), 1.06 (s, 6H)。m/z: 456 [M+H]+
7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸メチル-[2-(2-オキソ-オキサゾリジン-3-イル)-エチル]-アミド(23)
1H NMR (400 MHz, CDC13) δ 7.56 - 7.42 (m, 2H), 7.24 (d, J= 4.9 Hz, 1H), 6.73 (d, J= 4.0 Hz, 1H), 6.57 (d, J= 2.8 Hz, 1H), 6.12 (s, 1H), 5.55 (s, 1H), 5.51 (s, 1H), 4.38 - 4.31 (m, 1H), 4.20 - 4.10 (m, 2H), 3.82 (s, 3H), 3.81 - 3.72 (m, 2H), 3.62 - 3.55 (m, 3H), 3.53 (s, 1H), 3.46 - 3.38 (m, 1H), 3.17 (s, 1H), 1.85 (s, 3H), 1.53 (d, J = 3.8 Hz, 3H)。m/z: 509 [M+H]+
(8-イソブチル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-[4-(テトラヒドロ-フラン-2-カルボニル)-[1,4]ジアゼパン-1-イル]-メタノン (21)
DCM (1.00 ml; 15.60 mmol; 85.68 eq.)中の8-イソブチル-7-メトキシ-1-(3-チエニル)-1,4-ジヒドロクロメノ[4,3-c]ピラゾール-3-カルボン酸 (70.00 mg; 0.18 mmol; 1.00 eq.)に、N,N-ジイソプロピルエチルアミン (0.04 ml; 0.22 mmol; 1.20 eq.)、1-boc-ヘキサヒドロ-1,4-ジアゼピン(0.04 ml; 0.22 mmol; 1.20 eq.)及び2,4,6-トリプロピル-1,3,5,2,4,6-トリオキサトリホスフィナン2,4,6-トリオキシド(0.08 ml; 0.27 mmol; 1.50 eq.)を添加した。室温で2時間の撹拌の後に、反応混合物を水で洗浄し、そして1N HClで洗浄した。有機層をNa2SO4で乾燥し、ろ過し、濃縮して4-(8-イソブチル7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル)-[1,4]ジアゼパン-1-カルボン酸 tert-ブチルエステル(103.00 mg; 0.18 mmol)を白色フォームとして提供した。メタノール (1.00 ml; 24.69 mmol; 135.58 eq.)中の4-(8-イソブチル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル)-[1,4]ジアゼパン-1-カルボン酸 tert-ブチルエステル(103.00 mg; 0.18 mmol)に塩化水素(0.46 ml; 1.82 mmol; 10.00 eq.) (ジオキサン中4M)を添加した。4時間の撹拌の後に、反応混合物を乾燥まで濃縮し、水で希釈した。混合物を凍結乾燥し、[1,4]ジアゼパン-1-イル-(8-イソブチル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-メタノンを白色固形分として提供した。
DCM (1.00 ml; 15.60 mmol; 242.64 eq.)中の[1,4] ジアゼパン-1-イル-(8-イソブチル7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-メタノン (30.00 mg; 0.06 mmol; 1.00 eq.)に、N,N-ジイソプロピルエチルアミン (0.01 ml; 0.08 mmol; 1.20 eq.)、テトラヒドロ-2-フロ酸(0.01 ml; 0.13 mmol; 2.00 eq.)及び2,4,6-トリプロピル-1,3,5,2,4,6-トリオキサトリホスフィナン-2,4,6-トリオキシド(0.03 ml; 0.10 mmol; 1.50 eq.)を添加した。室温にて30分間撹拌した後に、反応物を乾燥まで濃縮し、そしてフラッシュクロマトグラフィーにより精製し、所望の化合物(10.7mg, 30%)を白色固形分として提供した。
1H NMR (400 MHz, CDC13) δ 7.51 - 7.44 (m, 2H), 7.50 - 7.44 (m, 1H), 7.25 - 7.21 (m, 1H), 6.59 (d, J= 7.0 Hz, 1H), 6.56 (d, J= 2.7 Hz, 1H), 5.50 (dd, J= 4.9, 3.5 Hz, 2H), 4.70 - 4.58 (m, 1H), 4.53 - 4.41 (m, 1H), 4.41 - 4.22 (m, 1H), 4.19 - 4.09 (m, 1H), 4.08 - 3.82 (m, 4H), 3.79 (s, 3H), 3.71 - 3.59 (m, 2H), 3.58 - 3.42 (m, 1H), 2.36 - 2.26 (m, 1H), 2.26 - 2.20 (m, 2H), 2.19 -1.83 (m, 3H), 1.78 - 1.60 (m, 2H), 0.81 (d, J= 6.6 Hz, 6H)。m/z: 565 [M+H]+
7-メトキシ-8-(1H-ピラゾール-4-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸メチルアミド(22)
DCM (1.50 ml; 23.40 mmol; 95.64 eq.)中の8-(l-tert-ブトキシカルボニル-1H-ピラゾール-4-イル)-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (121.00 mg; 0.24 mmol; 1.00 eq.)に、DIPEA (0.09 ml; 0.49 mmol; 2.00 eq.)、o-(ベンゾトリアゾール-1-イル)-n,n,n',n'-テトラメチルウロニウムテトラフルオロボレート(157.13 mg; 0.49 mmol; 2.00 eq.)及びn-tert-ブチルメチルアミン (0.06 ml; 0.49 mmol; 2.00 eq.)を添加した。室温にて30分間撹拌した後に、混合物を乾燥まで濃縮し、フラッシュクロマトグラフィーにより精製し、4-[3-(tert-ブチル-メチル-カルバモイル)-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-8-イル]-ピラゾール-1-カルボン酸tert-ブチルエステルを白色固形分として提供した (99 mg, 72%)。
メタノール(3.00 ml; 74.06 mmol; 302.68 eq.)中の4-[3-(tert-ブチル-メチル-カルバモイル)-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-8-イル]-ピラゾール-1-カルボン酸tert-ブチルエステル(99.00 mg; 0.18 mmol)に塩酸(0.20 ml; 0.80 mmol; 3.27 eq.) (ジオキサン中4M)を添加した。室温にて1時間撹拌した後に、混合物を濃縮し、そしてフラッシュクロマトグラフィーにより精製し、所望の生成物(33.8 mg, 34%)を白色固形分として提供した。
1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 8.33 (dd, J= 9.4, 4.6 Hz, 1H), 8.07 (dd, J= 3.2, 1.4 Hz, 1H), 7.92 (dd, J= 5.1, 3.2 Hz, 1H), 7.77 (s, 1H), 7.41 (dd, J= 5.1, 1.4 Hz, 1H), 7.32 (s, 1H), 6.85 (s, 1H), 6.76 (s, 1H), 5.52 (s, 2H), 3.86 (s, 3H), 2.75 (d, J= 4.7 Hz, 3H)。m/z: 408[M+H]+
[4-(アゼチジン-1-カルボニル)-アゼパン-1-イル]-(8-イソプロポキシ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-メタノン (26)
1H NMR (400 MHz, CDC13) δ 7.54 - 7.45 (m, 2H), 7.24 (t, J= 5.0 Hz, 1H), 6.61 (s, 1H), 6.43 (d, J= 5.8 Hz, 1H), 5.55 - 5.41 (m, 2H), 4.59 (d, J= 14.3 Hz, 1H), 4.23 - 3.86 (m, 4H), 3.83 (s, 3H), 3.77 - 3.49 (m, 1H), 3.35 - 3.27 (m, 1H), 2.42 - 2.07 (m, 4H), 2.03 - 1.68 (m, 6H), 1.27 (t, J= 7.1 Hz, 1H), 1.21 (d, J= 6.1 Hz, 6H)。m/z: 551 [M+H]+
8-イソプロポキシ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (3-アミノ-プロピル)-アミド (27)
DCM (1.00 ml; 15.60 mmol; 50.24 eq.)中の8-イソプロポキシ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (120.00 mg; 0.31 mmol; 1.00 eq.)に、N,N-ジイソプロピルエチルアミン (0.07 ml; 0.37 mmol; 1.20 eq.)、n-boc-1,3-ジアミノプロパン (81.16 mg; 0.47 mmol; 1.50 eq.)及び2,4,6-トリプロピル-1,3,5,2,4,6-トリオキサトリホスフィナン2,4,6-トリオキシド(0.14 ml; 0.47 mmol; 1.50 eq.)を添加した。室温にて30分間撹拌した後に、反応混合物を乾燥まで濃縮し、そしてフラッシュクロマトグラフィーにより精製し、{3-[(8-イソプロポキシ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル)-アミノ]-プロピル}-カルバミン酸tert-ブチルエステル(170 mg, 100 %)を白色固形分として提供した。
メタノール(4.00 ml; 98.75 mmol; 317.98 eq.)中の{3-[(8-イソプロポキシ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル)-アミノ] -プロピル }-カルバミン酸tert-ブチルエステル (172.70 mg; 0.32 mmol)に、ジオキサン中の塩酸(0.31 ml; 1.24 mmol; 4.00 eq.)を添加した。室温にて18時間撹拌した後に、反応混合物を乾燥まで濃縮し、そしてフラッシュクロマトグラフィーにより精製し、所望の化合物(71.3 mg, 52%)を白色固形分として提供した。
1H NMR (400 MHz, CDC13) δ 8.77 - 8.64 (m, 2H), 7.55 (d, J= 7.2 Hz, 2H), 6.62 (s, 1H), 6.36 (s, 1H), 5.51 (s, 2H), 4.13 - 3.94 (m, 2H), 3.85 (s, 3H), 3.65 - 3.59 (m, 2H), 3.23 - 3.07 (m, 2H), 2.21 - 2.09 (m, 1H), 1.21 (d, J= 6.0 Hz, 6H)。m/z: 443 [M+H]+
8-イソプロポキシ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 [3-(シクロブタンカルボニル-アミノ)-プロピル]-アミド (28)
1H NMR (400 MHz, CDC13) δ 7.57 - 7.46 (m, 2H), 7.23 (d, J= 5.0 Hz, 1H), 7.16 (t, J= 6.3 Hz, 1H), 6.59 (s, 1H), 6.35 (m, 2H), 5.54 (s, 2H), 4.02 (dt, J= 12.1, 6.0 Hz, 1H), 3.82 (s, 3H), 3.46 (q, J= 6.2 Hz, 1H), 3.31 (q, J= 6.0 Hz, 2H), 3.03 (p, J= 8.6 Hz, 1H), 2.36 - 2.22 (m, 2H), 2.20 - 2.10 (m, 2H), 2.01 - 1.80 (m, 2H), 1.79 - 1.67 (m, 2H), 1.19 (d, J= 6.1 Hz, 6H)。m/z: 525[M+H]+
シクロブタンカルボン酸 {1-[7-メトキシ-8-(2-メチル-プロぺニル)-1- チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル]-アゼパン-4-イル}-アミド (37)
1H NMR (400 MHz, CDC13) δ 7.53 - 7.44 (m, 2H), 7.23 (dd, J= 5.0, 1.3 Hz, 1H), 6.76 (s, 1H), 6.57 (s, 1H), 6.12 (s, 1H), 5.60 - 5.45 (m, 3H), 4.61 - 4.49 (m, 1H), 4.43 - 4.30 (m, 1H), 4.18 -3.99 (m, 2H), 3.82 (s, 3H), 3.60 - 3.48 (m, 1H), 3.45 - 3.34 (m, 1H), 3.26 (t, J= 10.3 Hz, 1H), 3.00 - 2.81 (m, 1H), 2.31 - 2.06 (m, 4H), 2.01 - 1.87 (m, 2H), 1.85 (s, 3H), 1.72 - 1.59 (m, 4H), 1.54 (s, 3H)。 m/z: 547 [M+H]+
8-(1,2-ジヒドロキシ-2-メチル-プロピル)-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (38)
1H NMR (400 MHz, CDC13) δ 7.51 (dd, J= 3.2, 1.3 Hz, 1H), 7.47 (dd, J= 5.1, 3.2 Hz, 1H), 7.21 (dd, J= 5.1, 1.3 Hz, 1H), 6.90 (s, 1H), 6.56 (s, 1H), 5.53 - 5.38 (m, 2H), 4.69 (s, 1H), 3.81 (s, 3H), 3.27 (s, 3H), 2.67 (s, 1H), 1.52 (s, 9H), 1.28 (dd, J= 6.0, 3.0 Hz, 1H), 1.15 (s, 3H), 0.97 (s, 3H)。m/z: 486 [M+H]+
1-[7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル]-アゼパン-4-カルボン酸ジメチルアミド(41)
1H NMR (500 MHz, cdcl3) δ 7.46 - 7.34 (m, 2H), 7.14 (ddd, J= 13.8, 4.9, 1.4 Hz, 1H), 6.67 (d, J= 12.0 Hz, 1H), 6.49 (d, J= 1.8 Hz, 1H), 6.03 (s, 1H), 5.52 - 5.41 (m, 2H), 4.61 - 4.55 (m, 1H), 4.22 - 4.10 (m, 1H), 3.98 - 3.85 (m, 1H), 3.73 (s, 3H), 3.55 - 3.48 (m, 1H), 3.45 - 3.37 (m, 1H), 3.22 - 3.14 (m, 1H), 2.96 (s, 1H), 2.88 (d, J= 8.1 Hz, 3H), 2.83 (s, 1H), 2.71 - 2.60 (m, 1H), 2.14 - 2.04 (m, 1H), 1.95 - 1.83 (m, 2H), 1.76 (s, 3H), 1.70 - 1.53 (m, 2H), 1.45 (d, 7 = 4.8 Hz, 3H)。m/z: 535 [M+H]+
1-[7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル]-アゼパン-4-カルボン酸メチルアミド (42)
1H NMR (500 MHz, cdcl3) δ 7.49 - 7.43 (m, 2H), 7.21 (d, J= 5.1 Hz, 1H), 6.74 (s, 1H), 6.56 (s, 1H), 6.10 (s, 1H), 5.55 (t, J= 4.9 Hz, 1H), 5.52 (t, J= 4.1 Hz, 2H), 4.49 - 4.43 (m, 1H), 4.18 (dt, J= 14.5, 5.4 Hz, 1H), 4.07 - 4.00 (m, 1H), 3.95 (dt, J= 9.5, 4.4 Hz, 1H), 3.85 - 3.82 (m, 1H), 3.80 (s, 3H), 3.72 - 3.63 (m, 1H), 3.49 - 3.42 (m, 1H), 2.78 (dd, J= 14.0, 4.8 Hz, 3H), 2.34 -2.12 (m, 1H), 2.05 - 1.91 (m, 1H), 1.84 (d, J= 1.2 Hz, 3H), 1.80 - 1.68 (m, 2H), 1.54 - 1.51 (s, 3H)。m/z: 521 [M+H]+
1-[7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル]-アゼパン-4-カルボン酸アミド (43)
1H NMR (500 MHz, cdcl3) δ 7.44 - 7.34 (m, 2H), 7.15 - 7.11 (m, 1H), 6.67 (s, 1H), 6.49 (s, 1H), 6.03 (s, 1H), 5.47 - 5.43 (m, 2H), 5.13 (s, 1H), 4.75 (s, 1H), 4.44 - 4.36 (m, 1H), 4.12 (dt, J= 14.7, 5.3 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.88 (d, J= 14.3 Hz, 1H), 3.83 - 3.74 (m, 1H), 3.73 (s, 3H), 3.66 - 3.56 (m, 1H), 3.43 - 3.37 (m, 1H), 2.36 - 2.25 (m, 1H), 2.23 - 2.11 (m, 1H), 2.03 -1.87 (m, 2H), 1.76 (d, J= 1.0 Hz, 3H), 1.45 (s, 3H)。m/z: 507 [M+H]+
7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3- カルボン酸 [3-(シクロブタンカルボニル-アミノ)-プロピル]-アミド (57)
例12の工程1と同様に、(3-{[7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル]-アミノ}-プロピル)-カルバミン酸tert-ブチルエステルを、7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (150mg, 0.39mmol)及びN-boc-1,3-ジアミノプロパン (102.5mg, 0.59mmol, 1.5 eq.)から得た。
例12の工程2と同様に、7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (3-アミノ-プロピル)-アミドを、(3-{ [7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボニル]-アミノ}-プロピル)-カルバミン酸tert-ブチル エステル及びHC1 (ジオキサン中4M)から得た。
例12の工程1と同様に、7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 [3-(シクロブタンカルボニル-アミノ)-プロピル]-アミドを、7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (3-アミノ-プロピル)-アミド (l00mg, 0.23 mmol)及びシクロブタンカルボン酸 (0.14 ml; 1.50 mmol; 6.58 eq.)から得た。所望の化合物は97%収率(115 mg)で白色固形分として得られた。
1H NMR (400 MHz, CDC13) δ 7.55 (s, 1H), 7.53 - 7.48 (m, 1H), 7.25 (d, J= 4.7 Hz, 1H), 7.11 (t, J= 7.1 Hz, 1H), 6.71 (s, 1H), 6.58 (s, 1H), 6.32 - 6.25 (m, 1H), 6.12 (s, 1H), 5.62 (s, 2H), 3.83 (s, 3H), 3.49 (dd, J= 12.3, 5.9 Hz, 2H), 3.34 (dd, J= 12.1, 6.0 Hz, 2H), 3.12 - 3.00 (m, 1H), 2.32 (dt, J= 19.0, 9.7 Hz, 2H), 2.19 (dd, J= 18.8, 9.9 Hz, 2H), 1.98 (dd, J= 18.7, 8.5 Hz, 2H), 1.85 (s, 3H), 1.79 - 1.71 (m, 2H), 1.52 (s, 3H)。m/z: 521 [M+H]+
7-メトキシ-8-(2-メチル-プロぺニル)-1-チアゾール-2-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (89)
工程1: 2-ヒドラジノ-1,3-チアゾールヒドロクロリド
1H NMR (400 MHz, DMSO-d6) δ 10.74 (bs, 1H), 7.27-7.26 (d, J= 4.0 Hz, 1H), 7.00-6.99 (d, J= 4.0 Hz, 1H), 3.45 (bs, 3H)。m/z: 116 [M+H]+
エチル8-ブロモ-7-メトキシ-1-(1,3-チアゾール-2-イル)-1,4-ジヒドロ-クロメノ [4,3-c]ピラゾール-3-カルボキシレート
1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.86-7.85 (d, J= 1.4 Hz, 2H), 6.86 (s, 1H), 5.45 (s, 2H), 4.37-4.32 (dd, J= 7.0, 14.2, 2H), 3.86 (s, 3H), 1.34-1.31 (t, J= 7.1, 14.2, 3H)。m/z: 438 [M+H]+
エチル7-メトキシ-8-(2-メチル-プロプ-1-エン-1-イル)-1-(1,3-チアゾール-2-イル)-1,4-ジヒドロクロメノ[4,3-c]ピラゾール-3-カルボキシレート
1H NMR (400 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.87-7.86 (d, J= 3.5 Hz, 1H), 7.82-7.81 (d, J= 3.5 Hz, 1H), 6.69 (s, 1H), 6.01 (s, 1H), 5.42 (s, 2H), 4.35-4.33 (d, J= 7.1 Hz, 2H), 3.77 (s, 3H), 1.82 (s, 3H), 1.70 (s, 3H), 1.34-1.31 (t, J= 7.1, 14.2 Hz, 3H)。m/z: 412 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.57 (bs, 1H), 8.00 (s, 1H), 7.85-7.84 (d, J= 3.5 Hz, 1H), 7.80 (d, J= 3.5 Hz, 1H), 6.69 (s, 1H), 6.11 (s, 1H), 5.41 (s, 2H), 3.77 (s, 3H), 1.83 (s, 3H), 1.71 (s, 3H)。m/z: 384 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.79-7.76 (dd, J= 3.5, 6.3 Hz, 2H), 6.70 (s, 1H), 6.12 (s, 1H), 5.25 (s, 2H), 3.77 (s, 3H), 3.12 (s, 3H), 1.84 (s, 3H), 1.74 (s, 3H), 1.44 (s, 9H)。m/z: 453 [M+H]+
7-メトキシ-8-(2-メチル-プロぺニル)-1-チオフェン-2-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (90)
工程1:tert-ブチル1-(2-チエニル)ヒドラジンカルボキシレート
1H NMR (400 MHz, DMSO-d6) δ 6.89-6.87 (dd, J= 1.7, 5.4 Hz, 1H), 6.81-6.79 (dd, J= 3.4, 7.2 Hz, 2H), 5.38 (s, 2H), 1.49 (s, 9H)。m/z: 115 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 10.17 (bs, 3H), 8.41 (bs, 1H), 7.07-7.05 (dd, J= 1.4, 5.4 Hz, 1H), 6.85-6.83 (dd, J= 3.6, 5.4 Hz, 1H), 6.72-6.71 (dd, J= 1.4, 3.7 Hz, 1H)。m/z: 115 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.84-7.82 (dd, J= 1.2, 5.5 Hz, 1H), 7.49-7.47 (dd, J= 1.2, 3.6 Hz, 1H),7.24-7.22 (dd, J= 3.8, 5.4 Hz, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 5.51 (s, 2H), 4.33-4.28 (dd, J= 7.1, 14.2 Hz. 2H), 3.82 (s, 3H), 1.32- 1.28 (t, J= 7.1, 14.2 Hz, 3H)。m/z: 437 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.79-7.77 (dd, J= 1.4, 5.5 Hz, 1H), 7.46-7.45 (dd, J= 1.5, 3.7 Hz, 1H), 7.20-7.18 (dd, J= 3.7, 5.6 Hz, 1H), 6.66 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.47 (s, 2H), 4.33-4.27 (dd, J= 7.1,14.2 Hz, 2H), 3.74 (s, 3H), 1.73 (d, J= 1.1 Hz, 3H), 1.39 (d, J= 1.2 Hz,3H), 1.32-1.28 (t, J= 7.1,14.2 Hz, 3H)。m/z: 411 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 13.30 (bs, 1H), 7.78-7.76 (dd, J= 1.4, 5.6 Hz, 1H), 7.45-7.44 (dd, J= 1.4 , 3.7 Hz, 1H), 7.19-7.17 (dd, J= 3.7, 5.5 Hz, 1H), 6.66 (s, 1H), 6.56 (s, 1H), 6.00 (s, 1H), 5.46 (s, 2H), 3.73 (s, 3H), 1.73 (s, 3H), 1.39 (s, 3H)。m/z: 383 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.75-7.73 (dd, J= 1.4, 5.5 Hz, 1H), 7.42-7.41 (dd, J= 1.4, 3.6 Hz, 1H), 7.18-7.15 (dd, J= 3.8, 5.6 Hz, 1H), 6.66 (s, 1H), 6.59 (s, 1H), 6.01 (s, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.12 (s, 3H) 1.73 (s, 3H), 1.41 (s,12 H)。m/z: 452 [M+H]+
8-イソブチル-7-メトキシ-1-チオフェン-2-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (91)
工程1: 8-イソブチル-7-メトキシ-1-チオフェン-2-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸エチルエステル
1H NMR (400 MHz, DMSO-d6) δ 7.81-7.79 (dd, J= 1.4, 5.5 Hz, 1H), 7.43-7.41 (dd, J= 1.4, 3.7 Hz, 1H), 7.20-7.18 (dd, J= 3.7, 5.5 Hz, 1H), 6.65 (s, 1H), 6.36 (s, 1H), 5.44 (s, 2H), 4.33-4.27 (dd, J= 7.0,14.2 Hz, 2H), 3.74 (s, 3H), 2.12-2.10 (d, J= 6.9 Hz, 2H), 1.59-1.56 (m, 1H), 1.32-1.28 (t, J= 7.1,14.2 Hz, 3H), 0.86-0.85 (d, J= 6.6 Hz, 6H)。
1H NMR (400 MHz, DMSO-d6) δ 13.33 (bs, 1H), 7.79-7.78 (dd, J= 1.4, 5.5 Hz, 1H), 7.41-7.40 (dd, J= 1.4 , 3.7 Hz, 1H), 7.19-7.17 (dd, J= 3.8, 5.5 Hz, 1H), 6.65 (s, 1H), 6.36 (s, 1H), 5.43 (s, 2H), 3.73 (s, 3H),2.12-2.10 (d, J= 7.0 Hz, 2H), 1.59-1.56 (m, 1H), 0.71-0.70 (d, J= 6.6 Hz 6H)。 m/z: 385 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ 7.76-7.75 (dd, J= 1.4, 5.5 Hz, 1H), 7.38-7.37(dd, J= 1.4 , 3.7 Hz, 1H), 7.18-7.15 (dd, J= 3.7, 5.6 Hz, 1H), 6.64 (s, 1H), 6.39 (s, 1H), 5.30 (s, 2H), 3.73 (s, 3H), 3.12 (s, 3H),3.12 (s, 3H), 2.12-2.10 (d, J= 7.0 Hz, 2H), 1.60-1.56 (m, 1H), 1.41 (s, 9H) 0.71- 0.70 (d, J= 6.6 Hz 6H)。m/z: 454 [M+H]+
(3,3-ジメチル-モルホリン-4-イル)-(8-イソブチルスルファニル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-メタノン (97)
工程1:8-イソブチルスルファニル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3- c]ピラゾール-3-カルボン酸
1H-NMR (DMSO-d6): δ 8.02-7.98 (s, 1H), 7.88-7.83 (m, 1H), 7.35 (dd, 1H), 6.72 (s, 1H), 6.60 (s, 1H), 5.37 (s, 2H), 3.94 (m, 2H), 3.80 (s, 3H), 3.72 (t, 2H), 3.42 (s, 2H), 2.34 (d, 2H), 1.60 (七重項, 1H), 1.42 (s, 6H), 0.91 (d, 6H)。m/z = 514 [M+H]+
8-イソプロピルスルファニル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 tert-ブチル-メチル-アミド (52)
7-メトキシ-8-(プロパン-2-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (79)
(8-シクロプロパンスルホニル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-(3,3-ジメチル-モルホリン-4-イル)-メタノン (106)
例23の工程2と同様にして、(8-シクロプロパンスルホニル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-(3,3-ジメチル-モルホリン-4-イル)-メタノンを8-(シクロプロピルスルホニル)-7-メトキシ-1-(チオフェン-3-イル)-1 ,4ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (30.00 mg; 0.07 mmol; 1.00 eq.)及び3,3-ジメチル-モルホリン (0.05 ml; 0.10 mmol; 1.50 eq.)から得た。所望の化合物は12 mg (33 %)の収量で青色固形分として得られた。
LCMS: m/z = 530 [M+H]+HPLC 保持時間= 3.24分
(3,3-ジメチル-モルホリン-4-イル)-[7-メトキシ-8-(プロパン-2-スルホニル)-1-チオフェン-3-イル-1,4- ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル]-メタノン (112)
例26(工程1)と同様にして、7-メトキシ-8-(プロパン-2-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸を8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (100.00 mg; 0.25 mmol; 1.00 eq.)及びプロパン-2-スルフィン酸ナトリウム(47.94 mg; 0.37 mmol; 1.50 eq.)から粗製青色固形分として得た。
例26(工程2)と同様にして、(3,3-ジメチル-モルホリン-4-イル)-[7-メトキシ-8-(プロパン-2-スルホニル)-1-チオフェン-3-イル-1 ,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル]-メタノンを7-メトキシ-8-(プロパン-2-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (100.00 mg; 0.23 mmol; 1.00 eq.)及び3,3-ジメチル-モルホリン (0.17 ml; 0.35 mmol; 1.50 eq.)から8.2%収率(10 mg)で青色固形分として得た。LCMS: m/z = 532 [M+H]+, HPLC 保持時間= 3.25分
(3,3-ジメチル-モルホリン-4-イル)-[7-メトキシ-8-(2-メチル-プロパン-1-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル]-メタノン (127)
例26(工程1)と同様にして、7-メトキシ-8-(2-メチル-プロパン-1-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸を8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (100.00 mg; 0.25 mmol; 1.00 eq.)及び2-メチル-プロパン-1-スルフィン酸ナトリウム(53.10 mg; 0.37 mmol; 1.50 eq.)から青色固形分として得た。
例26(工程2)と同様にして、(3,3-ジメチル-モルホリン-4-イル)-[7-メトキシ-8-(2-メチル-プロパン-1-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル]-メタノンを7-メトキシ-8-(2-メチル-プロパン-1-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (30.00 mg; 0.07 mmol; 1.00 eq.)及び3,3-ジメチル-モルホリン (46.22 mg; 0.40 mmol; 6.00 eq.)から白色固形分として13.7 %収率(5 mg)で得た。LCMS: m/z = 546 [M+H]+, HPLC 保持時間= 3.56分。
7-メトキシ-8-(プロパン-2-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3c]ピラゾール-3-カルボン酸(3-ヒドロキシメチル-オキセタン-3-イル)-アミド (187)
1H-NMR (DMSO-d6): δ 8.77 (s, 1H), 8.02 (dd, 1H), 7.86 (dd, 1H), 7.34 (dd, 1H), 7.19 (s, 1H), 6.93 (s, 1H), 5.64 (s, 2H), 5.14 (s, 1H), 4.67 (d, 2H), 4.51 (d, 2H), 3.90 (s, 3H), 3.68 (d, 2H), 3.45 (七重項, 1H), 1.08 (d, 6H)。m/z = 520 [M+H]+
7-メトキシ-8-(プロパン-2-スルホニル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸(3-メチル-オキセタン-3-イル)-アミド (188)
1H-NMR (DMSO-d6): δ 8.95 (s, 1H), 8.03 (dd, 1H), 7.85 (dd, 1H), 7.34 (dd, 1H), 7.18 (s, 1H), 6.93 (s, 1H), 5.64 (s, 2H), 4.71 (d, 2H), 4.31 (d, 2H), 3.90 (s, 3H), 3.45 (七重項, 1H), 1.59 (s, 3H), 1.07 (d, 6H)。m/z = 504 [M+H]+
(3,3-ジメチル-モルホリン-4-イル)-[8-(l-ヒドロキシ-2-メチル-プロピル)-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル]-メタノン (131)
1H-NMR (DMSO-d6): δ 7.86 (dd, 1H), 7.78 (dd, 1H), 7.28 (dd, 1H), 6.92 (s, 1H), 6.65 (s, 1H), 5.39 (d, 1H), 5.26 (d, 1H), 4.56 (d, 1H), 4.50 (t, 1H), 4.03-3.96 (m, 1H), 3.93-3.85 (m, 1H), 3.77 - 3.70 (m, 5H), 3.42 (s, 2H), 1.61 (七重項, 1H), 1.42 (d, 6H), 0.74 (d, 3H), 0.68 (d, 3H)。m/z = 498 [M+H]+
(3,3-ジメチル-モルホリン-4-イル)-[7-メトキシ-1-チオフェン-3-イル-8-(5-トリメチルシラニル-5H-[1,2,4]トリアゾール-3-イル)-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル]-メタノン (139)
1H-NMR (DMSO-d6): δ 7.92 (dd, 1H), 7.72 (dd, 1H), 7.28 (dd, 1H), 6.79 (s, 1H), 6.73 (s, 1H), 5.43 (s, 2H), 3.96 - 3.92 (m, 2H), 3.74 - 3.68 (m, 5H), 3.42 (s, 2H), 3.18 (s, 1H), 1.43 (s, 6H), 0.06 (s, 9H)。m/z = 565 [M+H]+
(3,3-ジメチル-モルホリン-4-イル)-[7-メトキシ-1-チオフェン-3-イル-8-(5H-[1,2,4]トリアゾール-3-イル)-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル]-メタノン(161)
1H-NMR (DMSO-d6) (テトラブチルアンモニウム塩): δ 7.89 (dd, 1H), 7.79 (dd, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.31 (dd, 1H), 6.70 (s, 1H), 5.31 (s, 2H), 3.96 (t, 2H), 3.83 (s, 3H), 3.73 (t, 2H), 3.43 (s, 2H), 3.20 - 3.13 (m, 9H), 1.64-1.52 (m, 9H), 1.43 (s, 6H), 1.33 (七重項, 9H), 0.94 (t, 12H)。 m/z = 493 [M+H]+
(8-アミノメチル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-(3,3-ジメチル-モルホリン-4-イル)-メタノン (166)
1H NMR (400 MHz, DMSO) δ 8.05-8.04 (dd, J= 1.4, 3.1 Hz, 1H), 7.90-7.88 (dd, J= 3.2, 5.1 Hz, 1H), 7.37-7.35 (dd, J= 1.4, 5.1 Hz, 1H), 5.63 (s, 1H), 4.33-4.28 (m, 2H), 3.89 (s, 1H), 1.32-1.28 (t, J= 12.9 Hz, 3H)。m/z = 382 [M+H]+
メタノール(6.00 ml; 177.52 mmol; 225.69 eq.)中に溶解した8-シアノ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸エチルエステル(300.00 mg; 0.79 mmol; 1.00 eq.)に、水酸化カリウム(66.20 mg; 1.18 mmol; 1.50 eq.)及び水 (0.60 ml)を添加した。反応混合物を50℃に2時間加熱した。反応物を濃縮し、そして凍結乾燥して、粗製の所望の生成物をグレイ固形分として提供した。
N-[3-(3,3-ジメチル-モルホリン-4-カルボニル)-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-8-イルメチル]-アセトアミド (175)
1H-NMR (DMSO-d6): δ 7.91-7.76 (m, 2H), 7.28-7.22 (m, 1H), 6.74-6.61 (m, 2H), 5.37-5.26 (m, 2H), 4.14 (s, 0.5H), 3.96 (d, 3.5H), 3.84-3.69 (m, 5H), 3.42 (s, 2H), 2.05 (s, 0.5H), 1.91 (s, 0.5H), 1.86 - 1.76 (m, 3H), 1.42 (s, 6H)。m/z = 497 [M+H]+
8-シアノ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸tert-ブチル-メチル-アミド (12)
1H NMR (400 MHz, CDC13) δ 7.54 (ddd, J= 4.7, 4.1, 2.4 Hz, 2H), 7.19 (dd, J= 5.0, 1.5 Hz, 1H), 6.97 (s, 1H), 6.62 (s, 1H), 5.58 (s, 2H), 3.92 (s, 3H), 3.28 (s, 3H), 1.53 (s, 9H)。m/z = 423 [M+H]+
7-メトキシ-8-(1-メチル-1H-ピロール-3-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (2-ヒドロキシ-1-ヒドロキシメチル-1-メチル-エチル)-アミド (179)
1H-NMR (DMSO-d6): δ 8.06 (s, 1H), 7.90 (s, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.79 (s, 1H), 6.71 (s, 1H), 6.63 (s, 1H), 5.77 (s, 1H), 5.49 (s, 2H), 4.95 (s, 2H), 3.83 (s, 3H), 3.65-3.56 (m, 5H), 3.53-3.45 (m, 2H), 1.30 (s, 3H)。m/z = 495 [M+H]+
7-メトキシ-8-(1-メチル-1H-ピラゾール-3-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (2-ヒドロキシ-1-ヒドロキシメチル-1-メチル-エチル)-アミド (185)
1H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.85 (d, 1H), 7.60 (s, 1H), 7.41 (s, 1H), 7.32 (s, 2H), 6.76 (s, 1H), 6.49 (s, 1H), 5.53 (s, 2H), 4.95 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.66-3.57 (m, 2H), 3.53-3.45 (m, 2H), 1.30 (s, 3H)。m/z = 496 [M+H]+
7-メトキシ-8-(テトラヒドロ-フラン-3-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 tert-ブチル-メチル-アミド (194)
1H-NMR (DMSO-d6): δ 7.95 (dd, 1H), 7.84 (dd, 1H), 7.32 (dd, 1H), 6.69 (s, 1H), 6.60 (s, 1H), 5.34 (d, 2H), 3.85 (t, 1H), 3.79 (s, 3H), 3.71 - 3.57 (m, 2H), 3.43 (五重項, 1H), 3.21 - 3.15 (m, 4H), 2.10 - 2.00 (m, 1H), 1.56-1.40 (m, 10H)。 m/z = 468 [M+H]+
7-メトキシ-8-(テトラヒドロ-フラン-2-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 tert-ブチル-メチル-アミド (201)
1H-NMR (DMSO-d6): δ 7.93 (dd, 1H), 7.82 (dd, 1H), 7.30 (dd, 1H), 6.75 (s, 1H), 6.66 (s, 1H), 5.33 (q, 2H), 4.90 (dd, 1H), 3.77 (s, 3H), 3.65-3.58 (m, 2H), 3.17 (s, 3H), 2.18 - 2.07 (m, 1H), 1.85- 1.74 (m, 1H), 1.70 - 1.59 (m, 1H), 1.50- 1.40 (m, 10H)。 m/z = 468 [M+H]+
7-メトキシ-8-(1-メチル-1H-ピラゾール-3-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (1S,3S)-3-アミノ-シクロペンチルエステル (180)
DCM (10.00 ml; 156.01 mmol; 127.06 eq.)中に懸濁された8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (500.00 mg; 1.23 mmol; 1.00 eq.)に、(1S,3S)-3-アミノ-シクロペンタノールヒドロクロリド(253.43 mg; 1.84 mmol; 1.50 eq.)、[(ベンゾトリアゾール-1-イルオキシ)-ジメチルアミノ-メチレン]-ジメチル-アンモニウムテトラフルオロボレート(788.43 mg; 2.46 mmol; 2.00 eq.)及びエチル-ジイソプロピルアミン (0.61 ml; 3.68 mmol; 3.00 eq.)を添加した。反応物を室温にて1時間撹拌した。混合物を濃縮して、そしてフラッシュクロマトグラフィーにより精製し、8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 ((1S,3S)-3-ヒドロキシ-シクロペンチル)-アミド及び8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (1S,3S)-3-アミノ-シクロペンチルエステルの混合物(合計247 mg, 41 %)を白色固形分として提供した。
8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 ((1S,3S)-3-ヒドロキシ-シクロペンチル)-アミド及び8-ブロモ-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (1S,3S)-3-アミノ-シクロペンチルエステル(120.00 mg; 0.24 mmol; 1.00 eq.)の混合物に、1-メチル-3-(4,4,5,5-テトラメチル-[1,3,2]ジオキサボロラン-2-イル)-1H-ピラゾール (76.37 mg; 0.37 mmol; 1.50 eq.)、酢酸パラジウム (2.75 mg; 0.01 mmol; 0.05 eq.)、ジシクロヘキシル-(2',6'-ジメトキシ-ビフェニル-2-イル)-ホスファン(10.05 mg; 0.02 mmol; 0.10 eq.)、炭酸カリウム(101.46 mg; 0.73 mmol; 3.00 eq.)、ジオキサン(4.00 ml)及び水(0.40 ml)を添加した。反応混合物を140℃で18時間加熱した。混合物を濃縮して、その一部分をフラッシュクロマトグラフィー(KPNH, 80〜100 % EtOAc/ヘキサン、0〜20 % MeOH/EtOAc) により精製し、7-メトキシ-8-(1-メチル-1H-ピラゾール-3-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 ((1S,3S)-3-ヒドロキシ-シクロペンチル)-アミド (78 mg, 65 %)を白色固形分として提供した。粗材料の残部を逆相分取-HPLC (35〜45 % CH3CN、H2O中0.1 % NH4OH中)により精製し、7-メトキシ-8-(1-メチル-1H-ピラゾール-3-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 (1S,3S)-3-アミノ-シクロペンチルエステル(5 mg, 4.2 %)を白色固形分として提供した。
1H-NMR (DMSO-d6): δ 7.94 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.33 (s, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 5.38 (s, 2H), 4.96 (s, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 3.63 (s, 1H), 1.32 (d, 12H)。m/z = 492 [M+H]+
7-メトキシ-8-(1-メチル-1H-ピロール-3-イル)-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3- c]ピラゾール-3-カルボン酸 (1S,3S)-3-アミノ-シクロペンチルエステル(181)
1H-NMR (DMSO-d6): δ 8.01 (s, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 7.01 (s, 1H), 6.88 (s, 1H), 6.72 (s, 1H), 6.64 (s, 1H), 5.81 (s, 1H), 5.34 (s, 2H), 4.98 (s, 1H), 4.09 (s, 5H), 3.84 (s, 3H), 3.59 (s, 4H), 1.48 - 1.14 (m, 12H)。m/z = 491 [M+H]+
7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸 tert- ブチル-メチル-アミド (133)
1H-NMR (DMSO-d6): δ 7.94 (dd, 1H), 7.81 (dd, 1H), 7.32 (dd, 1H), 6.67 (d, 1H), 6.62 (d, 1H), 6.47 (dd, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.17 (s, 3H), 1.44 (s, 9H)。m/z = 398 [M+H]+
(2-メトキシメチル-2-メチル-ピロリジン-1-イル)-(7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-イル)-メタノン (183)
1H-NMR (DMSO-d6): δ 7.95 (s, 1H), 7.82 (s, 1H), 7.32 (s, 1H), 6.69 - 6.60 (m, 2H), 6.49-6.44 (m, 1H), 5.43 (s, 2H), 4.05 (s, 1H), 3.90-3.79 (m, 2H), 3.73 (s, 3H), 3.59-3.52 (m, 1H), 2.16 -2.07 (m, 1H), 1.88-1.72(m, 2H), 1.68-1.58 (m, 1H), 1.42 (s, 3H)。m/z = 443 [M+H]+
(3,3-ジメチル-モルホリン-4-イル)-(7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3- c]ピラゾール-3-イル)-メタノン (128)
LCMS: m/z =すべて[M+H]+, HPLC保持時間= 3.65 分
7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3,8-ジカルボン酸 8-アミド3-(tert-ブチル-メチル-アミド) (50)
工程1: 8-カルバモイル-7-メトキシ-1-チオフェン-3-イル-1,4-ジヒドロ-クロメノ[4,3-c]ピラゾール-3-カルボン酸
1H NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.71 (s, 1H), 7.69 - 7.56 (m, 1H), 7.26 (d, J= 4.9 Hz, 1H), 6.79 (s, 1H), 5.46 (s, 2H), 3.98 (s, 3H), 3.23 (s, 3H), 1.54 (s, 9H)。m/z = 441 [M+H]+
例47
以下の化合物を例1に開示された手順と類似の手順を用いて調製した。
N-(1,3-ジヒドロキシ-2メチルプロパン-2-イル)-7-メトキシ-N-メチル-8-(1-メチル-1H-ピラゾール-3-イル)-1-(チオフェン-3-イル-1,4-ジヒドロクロメノ[4,3-c]ピラゾール-3-カルボキサミド (217)
CHO FSHR細胞+ EC20FSHにおける環式AMP産生のEC50 (アッセイA)
1ウェルあたり2500のCho-FSHR-LUC-1-1-43細胞を5 μlのフェノールレッドを含まないDMEM/F12 + 1% FBS中に播種した。細胞を384ウェルの固体の白色低体積プレート(Greiner 784075)にMultidropにより播種した。DMEM/F12 + 0.1 % BSA中の2X EC20FSH/IBMX、100 μlをマルチドロップにより、384のウェルプレート中でスタンプされた試験化合物2 μlに添加する(化合物を1:50に希釈する)ことにより、細胞をアッセイした。最終FSH濃度は0.265 pMであり、そして最終IBMX濃度は200 μMであった。化合物プレートマップは下記のとおりであった:カラム1:2 μlのDMSO; カラム2: 2 μlのDMSO; カラム3〜12及び13〜24: 2 μlの試験化合物(100% DMSO中で1:4希釈)、又は、2 μlのFSH(DMEM/F12+0.1% BSA中で1:4希釈)。FSHの出発濃度は50 nMであった(最終濃度は0.5 nMであった)。さらに、カラム23は0.5 nMの最終濃度で2 μlのEC100FSH 参照(100X) (DMEM/F12 + 0.1% BSA中で希釈)を含み、そしてカラム24は2 μlの1 mM AS707664/2参照化合物2を含んだ。5 μlの化合物+ EC20 FSH混合物を細胞プレートに移した(5 μlの細胞媒体に1:2希釈)。プレートを37℃で1時間インキュベートした。10 μlの混合HTRF (CisBio # 62AM4PEC)試薬を1ウェルあたり添加し、そして室温で1時間インキュベートした。cAMP HTRF -低体積384ウェルプロトコールを用いてEnvisionでプレートを読んだ。読み出し情報は計算蛍光比(665 nm / 620 nm)であった。百分率(%)で示された値はFSH標準の最大応答に対するアゴニストの特定の濃度での%効果(応答)を示す。結果は下記に提供される。
ラット顆粒層 EC50FSH (アッセイB)
アッセイをYanofsky ら (2006) Allosteric activation of the follicle-stimulating hormone (FSH) receptor by selective, non-peptide agonists(本発明の開示中に参照により取り込むJBC 281(19): 13226-13233)の教示に従って行った。結果を下記に提供する。
+ > 5 μM;
++ >l〜5 μM;
+++ > 0.1〜1 μM;
++++ < 0.1 μM。
医薬製剤
(A)注射バイアル:本発明に係る活性成分100g及びリン酸水素二ナトリウム5gの3lの二回蒸留した水中の溶液を、2N塩酸を用いてpH 6.5に調節し、無菌ろ過し、注射バイアル中に移し、無菌状態で凍結乾燥し、そして無菌条件下でシールする。各注射バイアルは5 mgの活性成分を含む。
Claims (20)
- 式Iの化合物又はその医薬上許容されうる塩、
YはO, S又はNRであり、
ZはO, S, SO, S02又はNであり、ZがO, S, SO又はS02であるときには、pは0であり、
各Rは、独立して、水素、C1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、又は、
同一の原子上の2つのR基が該原子と一緒に結合して、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環を形成し、その各々は場合により置換されていてよく、
環Aは縮合C3-10アリール、縮合3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する縮合3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する縮合5〜6 員単環式ヘテロアリール環であり、
R1は-OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R又は-N(R)2であり、
R2は-R、ハロゲン、-ハロアルキル、-OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R又は-N(R)2であり、
R3は水素、C1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、
各R4は独立して、-R, ハロゲン、-ハロアルキル、-OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R又は-N(R)2であり、
R5はC1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、
R6は水素、C1-6脂肪族、C3-10アリール、3〜8員飽和又は部分不飽和炭素環、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜7員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する5〜6 員単環式ヘテロアリール環であり、その各々は場合により置換されていてよく、
又は、R5及びR6は、その各々が結合している原子と一緒に、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜8員複素環、又は、窒素、酸素又は硫黄から独立して選ばれる1〜4個のヘテロ原子を有する3〜8 員ヘテロアリール環を形成し、その各々は場合により置換されていてよく、
nは0, 1又は2であり、そして
pは0又は1である)。 - XはOである、請求項1記載の化合物。
- YはOである、請求項1記載の化合物。
- ZはNである、請求項1記載の化合物。
- 環Aはフェニルである、請求項1記載の化合物。
- R1は-ORであり、そしてRはC1-6脂肪族である、請求項1記載の化合物。
- R2は水素、Br, CN,
- R3は
- R5はメチル、t-ブチル、-CD3、
- ZはNであり、そしてZ, R5及びR6により形成される環は
- R6は水素、メチル、t-ブチル又は-CD3である、請求項1記載の化合物。
- 式I-f:
- 式I-h:
- 表1から選ばれる、請求項1記載の化合物。
- 請求項1記載の化合物及び医薬上許容されうるアジュバント、キャリア又はビヒクルを含む、医薬組成物。
- 患者又は生物学的サンプルにおけるFSHR又はその変異体の活性を調節するための方法であって、請求項1記載の化合物又はその生理学的に許容されうる塩を前記患者に投与するか、又は、該化合物又はその生理学的に許容されうる塩と前記生物学的サンプルを接触させる工程を含む、方法。
- FSHR-媒介障害の治療を必要とする患者において該障害を治療するための方法であって、前記患者に請求項1記載の化合物を投与する工程を含む、方法。
- 対象における受胎障害を治療するための方法であって、前記対象に請求項1記載の化合物又はその生理学的に許容されうる塩を投与する工程を含む、方法。
- FSHR-媒介障害の予防的又は治療的処置のための医薬の製造のための、請求項1記載の化合物又はその生理学的に許容されうる塩の使用。
- 請求項1記載の式Iの化合物の製造方法であって、
式(II)
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JP2023536442A (ja) | 2020-07-29 | 2023-08-25 | 江蘇恒瑞医薬股▲ふん▼有限公司 | オキサアザスピロ環系誘導体、その調製方法及びその医薬的応用 |
AU2022367432A1 (en) | 2021-10-14 | 2024-05-02 | Incyte Corporation | Quinoline compounds as inhibitors of kras |
WO2024044778A2 (en) * | 2022-08-26 | 2024-02-29 | Celmatix Inc. | Novel modulators of fshr and uses thereof |
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03505204A (ja) * | 1988-06-20 | 1991-11-14 | フアルミタリア・カルロ・エルバ・エツセ・エルレ・エルレ | 3環式3―オキソ―プロパンニトリル誘導体およびその調製方法 |
JP2005510466A (ja) * | 2001-09-19 | 2005-04-21 | ファルマシア・コーポレイション | 炎症の治療のための置換されたピラゾロ化合物 |
WO2008035356A2 (en) * | 2006-09-20 | 2008-03-27 | Glenmark Pharmaceuticals Limited | Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation |
US20100216785A1 (en) * | 2009-02-25 | 2010-08-26 | Neuroscienze Pharmaness S.C. A.R.L. | Pharmaceutical compositions |
JP2010195785A (ja) * | 2009-02-25 | 2010-09-09 | Neuroscienze Pharmaness Scarl | 医薬化合物 |
JP2012528105A (ja) * | 2009-05-27 | 2012-11-12 | エム・エス・ディー・オス・ベー・フェー | 受胎障害治療用のfsh受容体アゴニストとしての(ジヒドロ)イミダゾイソ(5,1−a)キノリン |
JP2013500948A (ja) * | 2009-07-31 | 2013-01-10 | エム・エス・ディー・オス・ベー・フェー | ジヒドロベンゾインダゾール |
JP2013510825A (ja) * | 2009-11-13 | 2013-03-28 | メルク セローノ ソシエテ アノニム | 三環式ピラゾールアミン誘導体 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5547975A (en) * | 1994-09-20 | 1996-08-20 | Talley; John J. | Benzopyranopyrazolyl derivatives for the treatment of inflammation |
PT1102763E (pt) | 1998-08-07 | 2005-01-31 | Applied Research Systems | Mimeticos fsh para o tratamento da infertilidade |
EP1307193A1 (en) | 2000-07-27 | 2003-05-07 | Affymax Research Institute | Agonists of follicle stimulating hormone activity |
SE0102404D0 (sv) * | 2001-07-04 | 2001-07-04 | Active Biotech Ab | Novel immunomodulating compounds |
ZA200505734B (en) * | 2003-02-07 | 2006-12-27 | Daiichi Seiyaku Co | Pyrazole Derivative |
DE602004028800D1 (en) | 2003-02-07 | 2010-10-07 | Daiichi Sankyo Co Ltd | Pyrazolderivat |
WO2009010824A1 (en) * | 2007-07-13 | 2009-01-22 | Glenmark Pharmaceuticals, S.A. | Dihydrochromenopyrazole derivatives as vanilloid receptor ligands |
CN101910170A (zh) * | 2007-10-22 | 2010-12-08 | 记忆药物公司 | 用于治疗疾病的烟碱性乙酰胆碱受体的(1,4-二氮杂双环[3.2.2]壬-6-烯-4-基)-杂环基-甲酮配体 |
JP2012506848A (ja) * | 2008-10-27 | 2012-03-22 | グラクソ グループ リミテッド | グルタミン酸受容体モジュレーターとしての三環式化合物 |
-
2014
- 2014-06-24 SG SG11201509411VA patent/SG11201509411VA/en unknown
- 2014-06-24 BR BR112015030387-0A patent/BR112015030387B1/pt active IP Right Grant
- 2014-06-24 EP EP14739013.2A patent/EP3013832B1/en active Active
- 2014-06-24 ES ES14739013T patent/ES2849434T3/es active Active
- 2014-06-24 JP JP2016521900A patent/JP6625973B2/ja active Active
- 2014-06-24 KR KR1020167000707A patent/KR102318498B1/ko active IP Right Grant
- 2014-06-24 CN CN201480046771.2A patent/CN105473596B/zh active Active
- 2014-06-24 RU RU2016101958A patent/RU2663898C2/ru active
- 2014-06-24 US US14/900,209 patent/US10081637B2/en active Active
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-
2016
- 2016-06-13 HK HK16106787.6A patent/HK1218757A1/zh unknown
-
2018
- 2018-08-22 US US16/108,414 patent/US11365199B2/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH03505204A (ja) * | 1988-06-20 | 1991-11-14 | フアルミタリア・カルロ・エルバ・エツセ・エルレ・エルレ | 3環式3―オキソ―プロパンニトリル誘導体およびその調製方法 |
JP2005510466A (ja) * | 2001-09-19 | 2005-04-21 | ファルマシア・コーポレイション | 炎症の治療のための置換されたピラゾロ化合物 |
WO2008035356A2 (en) * | 2006-09-20 | 2008-03-27 | Glenmark Pharmaceuticals Limited | Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and process for their preparation |
US20100216785A1 (en) * | 2009-02-25 | 2010-08-26 | Neuroscienze Pharmaness S.C. A.R.L. | Pharmaceutical compositions |
JP2010195785A (ja) * | 2009-02-25 | 2010-09-09 | Neuroscienze Pharmaness Scarl | 医薬化合物 |
JP2012528105A (ja) * | 2009-05-27 | 2012-11-12 | エム・エス・ディー・オス・ベー・フェー | 受胎障害治療用のfsh受容体アゴニストとしての(ジヒドロ)イミダゾイソ(5,1−a)キノリン |
JP2013500948A (ja) * | 2009-07-31 | 2013-01-10 | エム・エス・ディー・オス・ベー・フェー | ジヒドロベンゾインダゾール |
JP2013510825A (ja) * | 2009-11-13 | 2013-03-28 | メルク セローノ ソシエテ アノニム | 三環式ピラゾールアミン誘導体 |
Non-Patent Citations (2)
Title |
---|
"RN 1348894-85-8", DATABASE REGISTRY[ONLINE], JPN7018001428, 5 December 2011 (2011-12-05) * |
"RN 1349331-00-5", DATABASE REGISTRY[ONLINE], JPN7018001427, 6 December 2011 (2011-12-06) * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2017524733A (ja) * | 2014-06-23 | 2017-08-31 | トコフェレックス, インコーポレイテッド | Fshrのモジュレータとしてのピラゾール化合物およびその使用 |
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US10081637B2 (en) | 2018-09-25 |
BR112015030387A8 (pt) | 2019-12-24 |
RU2663898C2 (ru) | 2018-08-13 |
JP6625973B2 (ja) | 2019-12-25 |
US11365199B2 (en) | 2022-06-21 |
BR112015030387A2 (pt) | 2017-07-25 |
SG11201509411VA (en) | 2015-12-30 |
RU2016101958A (ru) | 2017-07-28 |
CA2912921A1 (en) | 2014-12-31 |
KR20160021817A (ko) | 2016-02-26 |
US20180354965A1 (en) | 2018-12-13 |
CA2912921C (en) | 2021-05-18 |
AU2014302712B2 (en) | 2018-11-29 |
HK1218757A1 (zh) | 2017-03-10 |
ES2849434T3 (es) | 2021-08-18 |
KR102318498B1 (ko) | 2021-10-27 |
MX2015016825A (es) | 2016-04-18 |
IL243226A0 (en) | 2016-02-29 |
EP3013832B1 (en) | 2020-11-04 |
BR112015030387B1 (pt) | 2021-02-09 |
IL243226B (en) | 2019-10-31 |
ZA201508514B (en) | 2019-07-31 |
KR20210114561A (ko) | 2021-09-23 |
EP3013832A1 (en) | 2016-05-04 |
NZ714201A (en) | 2021-02-26 |
CN105473596B (zh) | 2019-04-30 |
CN105473596A (zh) | 2016-04-06 |
US20160152626A1 (en) | 2016-06-02 |
RU2016101958A3 (ja) | 2018-03-29 |
WO2014209980A1 (en) | 2014-12-31 |
AU2014302712A1 (en) | 2015-12-03 |
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