JP7158416B2 - 抗腫瘍免疫応答を改善するための組成物および方法 - Google Patents
抗腫瘍免疫応答を改善するための組成物および方法 Download PDFInfo
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- WEMQMWWWCBYPOV-UHFFFAOYSA-N s-indacene Chemical compound C=1C2=CC=CC2=CC2=CC=CC2=1 WEMQMWWWCBYPOV-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007727 signaling mechanism Effects 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
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000002731 stomach secretion inhibitor Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960000187 tissue plasminogen activator Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000023750 transforming growth factor beta production Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 239000008243 triphasic system Substances 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229950005972 urelumab Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-M valerate Chemical class CCCCC([O-])=O NQPDZGIKBAWPEJ-UHFFFAOYSA-M 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000012808 vapor phase Substances 0.000 description 1
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Description
「アミノカルボニル」は、-C(O)NH2置換基を指す。
「カルボキシル」は、-CO2H置換基を指す。
「カルボニル」は、-C(O)-、-(CO)-または-C(=O)-基を指す。すべての表記は、本明細書内で交換可能に使用される。
「シアノ」は、-C≡N置換基を指す。
「シアノアルキレン」は、-(アルキレン)C≡N置換基を指す。
「アセチル」は、-C(O)CH3置換基を指す。
「ヒドロキシ」または「ヒドロキシル」は、OH置換基を指す。
「ヒドロキシアルキレン」は、-(アルキレン)OH置換基を指す。
「オキソ」は、=O置換基を指す。
「チオ」または「チオール」は、-SH置換基を指す。
「低級アルキル」は、上記で定義されたアルキルと同じ意味を有するが、1~4k所の炭素原子を有する(C1-C4アルキル)。
本明細書で使用する場合、「真核生物開始因子-4A」として知られている「eIF4A」は、RNAリモデリングに関与する7つの高度に保存されたアミノ酸モチーフによって特徴づけられるATP依存性へリカーゼの「DEADボックス」ファミリーのメンバーを指す。eIF4Aは、RNA依存性ATPaseおよびATP依存性RNAヘリカーゼとして機能し、特定のタンパク質を合成するために大半の細胞mRNAの翻訳を認識および開始するeIF4F(真核生物開始因子4F)複合体の一部としてリボゾームへのmRNA結合を促進する。eIF4A、eIF4EおよびeIF4Gで構成される機能的なeIF4F複合体は、高度に構造化された5’-UTRまたはIRES要素を含むmRNAの翻訳に関与している。特に、eIF4Fは、eIF4Eを介してmRNAの5’末端のキャップ構造を認識し、eIF4Aのヘリカーゼ活性を介して、5’-UTR領域の二次構造を解き、eIF4GとeIF3との間の相互作用を介して43S複合体を結合する。例えば、Marintchevら, 細胞,136:447-460,2009年およびParsyanら,Nat.Rev.Mol.cell Biol.12:235-245,2012年を参照。eIF4Aは、mRNAのサブセットの翻訳を選択的に調節する。この選択性は、mRNAの5’-UTR内に見られる構造要素と配列認識モチーフの結果であると考えられている。eIF4Aファミリーには、3つのメンバー:eIF4AI、eIF4AII、およびeIF4AIIIがある。特定の実施形態では、eIF4Aは人のeIF4Aを指す。eIF4Aの過剰発現は、リンパ腫、肺癌、卵巣癌、乳癌などの様々な癌の予後不良と関連する。
(式(I)中、
Xは、CR6R7、O、S、NH、N(C1-C8)アルキル、C(O)、C=CR6R7、N(CO)R8、S(O)またはS(O)2であり、
Yは、5員ヘテロアリールまたは6員アリールまたはヘテロアリールであり、
R1およびR2は、独立に、アリール、ヘテロシクリル、ヘテロアリールまたはシクロアルキルであり、
R3a、R3b、R4aおよびR4bは、独立に、H、ハロゲン、CN、C1~C8(アルキル)、(C1~C8)ハロアルキル、C2~C8(アルケニル)、(C2~C8)アルキニル、OR9、NHR9、NR9R9、[(C1~C8)アルキレン]OR9、[(C1~C8)アルキレン]NHR9、[(C1~C8)アルキレン]NR9R9、C(O)R8、C(O)NHR9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NHR9、C(O)[(C1~C8)アルキレン]NR9R9、CO2R9、C(S)NHR9、C(S)NR9R9、SR9、S(O)R9、SO2R9、SO2NHR9、SO2NR9R9、NH(CO)R8、NR9(CO)R8、NH(CO)NHR9、NH(CO)NR9R9、NR9(CO)NHR9、NR9(CO)NR9R9、P(O)(OH)(OR9)、P(O)(OR9)(OR9)、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクロイルであり、
R3aおよびR3b、ならびに、R4aおよびR4bは、独立に、結合してオキソもしくはアルケニル、またはシクロアルキルもしくはヘテロシクリル環を形成し;または
R3aおよびR4a、R3bおよびR4bまたはR4aおよびR5は、それらが結合している炭素原子と共にシクロアルキルまたはヘテロシクリル環を形成し、または
R2およびR3aは、それらが結合している炭素原子と共にに環式環系を形成し、
R5は、H、ハロゲン、OH、CN、N3、SR9、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルキニル、NHC(O)(C1~C8)アルキルまたはヘテロアリールであり、
R6およびR7は、独立に、H、CN、ハロゲン、OR9、SR9、(C1~C8)アルキル、NH(R9)またはNR9R9であり、
R8は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、シクロアルキル、O(シクロアルキル)、ヘテロシクリル、O(ヘテロシクリル)、アリール、O(アリール)、ヘテロアリールまたはO(ヘテロアリール)であり、
R9は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、シクロアルキル、ヘテロシクリル、[(C1-C8)アルキレン]ヘテロシクリル、アリール、[(C1~C8)アルキレン]アリールまたはヘテロアリールであり、
ここで、2つのR9は、ともにNR9R9、[(C1~C8)アルキレン]NR9R9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NR9R9、C(S)NR9R9、SO2NR9R9、NH(CO)NR9R9またはNR9(CO)NR9R9の窒素原子に結合し、ヘテロシクリル環を任意に形成し、
任意のアルキル、アルケニル、シクロアルキル、ヘテロシクリル、ヘテロアリールまたはアリールは、OH、CN、SH、SO2NH2、SO2(C1~C4)アルキル、SO2NH(C1~C4)アルキル、ハロゲン、NH2、NH(C1~C4)アルキル、N[(C1~C4)アルキル]2、C(O)NH2、COOH、COOMe、アセチル、(C1~C8)アルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルケニル、(C2~C8)アルキニル、ハロアルキル、チオアルキル、シアノメチレン、アルキルアミニル、NH2-C(O)-アルキレン、NH(Me)-C(O)-アルキレン、CH2-C(O)-低級アルキル、C(O)-低級アルキル、アルキルカルボニルアミニル、CH2-[CH(OH)]m-(CH2)p-OH、CH2-[CH(OH)]m-(CH2)p-NH2またはCH2-アリール-アルコキシから選択される1、2、または3の基で任意に置換されてもよく、または
任意のアルキル、シクロアルキルまたはヘテロシクリルは、オキソで任意に置換され、
「m」および「p」は、1、2、3、4、5または6であり、
Yが6員アリールである場合、XはOではない)
の化合物、もしくはその立体異性体、互変異性体、またはその薬学的に許容される塩である。
(ここで、
A1は、NまたはCR10であり、
A2は、NまたはCR11であり、
A3は、NまたはCR12であり、
A4は、NまたはCR13であり、
R10、R11、R12およびR13は、独立に、H、ハロゲン、C1~C8(アルキル)、(C1~C8)ハロアルキル、C(O)O(C1~C8)アルキル、C(O)(C1~C8)アルキル、SO2(C1~C8)アルキル、C2~C8(アルケニル)、(C2~C8)アルキニル、OR9、NHR9、NR9R9、CN、[(C1~C8)アルキレン]OR9、[(C1~C8)アルキレン]NHR9、[(C1~C8)アルキレン]NR9R9、C(O)R8、C(O)NHR9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NHR9、C(O)[(C1~C8)アルキレン]NR9R9、CO2R9、C(S)NHR9、C(S)NR9R9、SR9、S(O)R9、SO2R9、SO2NHR9、SO2NR9R9、NH(CO)R8、NR9(CO)R8、NH(CO)NHR9、NH(CO)NR9R9、NR9(CO)NHR9、NR9(CO)NR9R9、P(O)(OH)(OR9)、P(O)(OR9)(OR9)、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリルである)である。
(ここで、任意のB1、B2およびB3の2つは、CR14およびNであり、残りのB環原子は、N(R15)またはSであり、R14は、H、CN、ハロゲン、OR9、SR9、(C1~C8)アルキル、C(O)O(C1~C8)アルキル、C(O)(C1~C8)アルキル、SO2(C1~C8)アルキル、SO2NR9R9、C(O)NR9R9、NR9R9またはNR9C(O)R8であり、R15はHまたは(C1~C8)アルキルである)
である。
Rac-(5aR,6S,7R,8R,8aS)-8,8a-ジヒドロキシ-3-メトキシ-5a-(4-メトキシフェニル)-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 1F)、
(5aR,6S,7R,8R,8aS)-3-シアノ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.2F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.3F)、
(5aR,6S,7R,8R,8aS)-3-シアノ-8,8a-ジヒドロキシ-5a-(4-メトキシフェニル)-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.4F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-5a-(4-メトキシフェニル)-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.5F)、
(5aR,6S,7R,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-3-メトキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.6F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a-(p-tolイル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.7F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a-(4-(トリフルオロメチル)フェニル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.8F)、
(5aR,6S,7R,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd.No.9F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-フルオロフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd.No.10F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-クロロフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd.No.11F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-N,N-ジメチル-5a-(4-(メチルスルホニル)フェニル)-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd.No.12F)、
Rac-(1R,2R,3S,3aR,8bS)-6-シアノ-3a-(4-シアノフェニル)-1,8b-ジヒドロキシ-N,N-ジメチル-3-フェニル-2,3,3a,8b-テトラヒドロ-1H-ベンゾ[b]シクロペンタ[d]チオフェン-2-カルボキサミド(Cpd.No.13F)、
Rac-(5aR,6S,7R,8R,8aS)-3-シアノ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-カルボキサミド(Cpd.No.14F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-シアノフェニル)-4b,5-ジヒドロキシ-2-メトキシ-N,N-ジメチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-b]ピリジン-6-カルボキサミド(Cpd.No.15F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-(ジフルオロメチル)フェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.16F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a-(4-(トリフルオロメトキシ)フェニル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.17F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.18F)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-カルボキサミド(Cpd.No.19F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N-メチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.20F)、
Rac-メチル (4aR,5S,6R,7R,7aS)-4a-(4-シアノフェニル)-7,7a-ジヒドロキシ-2-メチル-5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキシレート(Cpd.No.21F)、
Rac-(5aR,6S,7R,8S,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-スルホンアミド(Cpd.No.22F)、
(4aR,5S,6R,7R,7aS)-4a-(4-シアノフェニル)-7,7a-ジヒドロキシ-N,N,2-トリメチル5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキサミド(Cpd.No.23F)、
Rac-メチル (5aR,6R,6aS,7aS,7bR)-3-クロロ-5a-(4-シアノフェニル)-7b-ヒドロキシ-6-フェニル-5a,7,7a,7b-テトラヒドロシクロプロパ[4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-6a(6H)-カルボキシレート(Cpd.No.24F)、
Rac-メチル(5aR,6R,6aS,7aS,7bR)-3-クロロ-5a-(4-シアノフェニル)-7b-ヒドロキシ-6-フェニル-5a,7,7a,7b-テトラヒドロシクロプロパ[4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-6a(6H)-カルボキシレート(Cpd.No.25F)、
Rac-4-((5aR,6S,7R,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-7-(オキサゾール-2-イル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル(Cpd.No.26F)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボチオアミド(Cpd.No.27F)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボチオアミド(Cpd.No.28F)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-シアノフェニル)-3,8,8a-triヒドロキシ-N,N-ジメチル-6-フェニル-2-(トリフルオロメチル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.29F)、
Rac-4-((5aR,6S,7S,8R,8aS)-7-(アミノメチル)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル(Cpd.No.30F)、
Rac-(5aR,6R,6aS,7aS,7bR)-3-クロロ-5a-(4-シアノフェニル)-7b-ヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,7a,7b-テトラヒドロシクロプロパ[4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-6a(6H)-カルボキサミド(Cpd.No.31F)、
Rac-(5aR,6S,7R,8aR)-3-クロロ-5a-(4-シアノフェニル)-8a-ヒドロキシ-N,N-ジメチル-8-オキソ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド(Cpd.No.32F)、
Rac-(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N,8-トリメチル6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 33Fa)およびRac-(5aR,6S,7R,8S,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N,8-トリメチル6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 33Fb)、
Rac-(5aR,6S,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8-メチレン-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-オール (Cpd. No. 34F)、
Rac-(5aR,6R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8a-ヒドロキシ-8-メトキシ-N,N-ジメチル-6-フェニル-5a,8a-ジヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 35F)、
Rac-(4aR,5S,6R,7R,7aS)-3-クロロ-4a-(4-シアノフェニル)-7,7a-ジヒドロキシ-N,N,2-トリメチル5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキサミド (Cpd. No. 36F)、
Rac-(4aR,5S,6R,7R,7aS)-4a-(4-ブロモフェニル)-3-クロロ-7,7a-ジヒドロキシ-N,N,2-トリメチル5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキサミド (Cpd. No. 37F)、
Rac-(5aR,6S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-6,7-ジヒドロスピロ[シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,2’-オキセタン]-8a(5aH)-オール (Cpd. No. 38F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-7-((メチルアミノ)メチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 39F)、
Rac-4-((5aR,6S,7R,8R,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 40Fa)、 rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 40Fb)、 および rac-4-((5aR,6S,7S,8S,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 40Fc)
Rac-4-((5aR,6S,7R,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 41Fa)、 rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 41Fb)、 および rac-4-((5aR,6S,7S,8S,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 41Fc)、
Rac-(1R,2R,3S,3aR,8bS)-8b-アジド-1-ヒドロキシ-6-メトキシ-3a-(4-メトキシフェニル)-N,N-ジメチル-3-フェニル-2,3-ジヒドロ-1H-シクロペンタ[b]ベンゾフラン-2-カルボキサミド (Cpd. No. 42F)、
Rac-メチル (5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8a-フルオロ-8-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキシレート (Cpd. No. 43F)、
Rac-(1R,2R,3S,3aR,8bS)-8b-アミノ-1-ヒドロキシ-6-メトキシ-3a-(4-メトキシフェニル)-N,N-ジメチル-3-フェニル-2,3,3a,8b-テトラヒドロ-1H-シクロペンタ[b]ベンゾフラン-2-カルボキサミド (Cpd. No. 44F)、
Rac-(1R,2R,3S,3aR,8bS)-8b-アセトアミド-1-ヒドロキシ-6-メトキシ-3a-(4-メトキシフェニル)-N,N-ジメチル-3-フェニル-2,3,3a,8b-テトラヒドロ-1H-シクロペンタ[b]ベンゾフラン-2-カルボキサミド (Cpd. No. 45F)、
Rac-ジメチル 2-[[(5aR,6S,7R,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8a-ヒドロキシ-8-オキソ-6-フェニル-6,7-ジヒドロシクロペンタ[4,5]フロ[1,2-b]ピリジン-7-イル]メチル]プロパンジオエート(propanedioate) (Cpd. No. 46F)、
Rac-(5aR,6S,8S,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8a-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8-カルボニトリル (Cpd. No. 47F)、
Rac-(5aR,6S,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8-エチニル6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-ol (Cpd. No. 48F)、
Rac-メチル (5aR,6S,7R,8R,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8-シアノ-8a-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキシレート (Cpd. No. 49F)、
Rac-メチル (5aR,6S,7R,8R,8aR)-3-クロロ-8-シアノ-5a-(4-シアノフェニル)-8a-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキシレート (Cpd. No. 50F)、
Rac-(5aR,6S,7R,8R,8aR)-3-クロロ-8-シアノ-5a-(4-シアノフェニル)-8a-ヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 51F)、
Rac-(5aR,6S,7R,8R,8aR)-3-クロロ-8-シアノ-5a-(4-シアノフェニル)-8a-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 52F)、
Rac-(3aR,3bS,8aR,9R,9aR)-8a-(4-ブロモフェニル)-6-クロロ-3b-ヒドロキシ-9-フェニル-1,3a,3b,8a,9,9a-ヘキサヒドロ-2H-オキサゾールo[4’’,5’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-2-オン (Cpd. No. 53F)、
Rac-4-((3aR,3bS,8aR,9R,9aR)-6-クロロ-3b-ヒドロキシ-2-オキソ-9-フェニル-1,2,3a,3b,9,9a-ヘキサヒドロ-8aH-オキサゾールo[4’’,5’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-8a-イル)ベンゾニトリル (Cpd. No. 54F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-(ヒドロキシメチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 55F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-7-(ヒドロキシメチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 56F)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-メチル-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 57F)、
Rac-メチル (5aR,6S,8S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-フルオロ-8,8a-ジヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキシレート (Cpd. No. 58F)、
Rac-メチル (5aR,6S,8S,8aS)-3-クロロ-5a-(4-シアノフェニル)-7-フルオロ-8,8a-ジヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキシレート (Cpd. No. 59F)、
Rac-(2aS,3S,3aR,8bS,8cR)-3a-(4-ブロモフェニル)-6-クロロ-3-フェニル-2a,3,3a,8c-テトラヒドロオキセト(oxeto)[3’’,2’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-8b(2H)-オール (Cpd. No. 60F)、
Rac-(2aS,3S,3aR,8bS,8cR)-3a-(4-ブロモフェニル)-6-クロロ-3-フェニル-2a,3,3a,8c-テトラヒドロオキセト[3’’,2’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-8b(2H)-オール (Cpd. No. 61F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-(メトキシメチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 62F)、
Rac-(1aS,3S,3aR,8bS)-3a-(4-ブロモフェニル)-6-クロロ-3-フェニル-1a,2,3,3a-テトラヒドロ-オキシレノ(oxireno)[2’’,3’’:1’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン (Cpd. No. 63F)、
(4bS,5R,6R,7S,7aR)-7a-(4-シアノフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N,N-ジメチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 64F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-(アミノメチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 65F)、
4-((4bS,5R,6S,7S,7aR)-6-((ジメチルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 66F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-6-(ピペラジン-1-イルメチル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 67F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((4-メチルピペラジン-1-イル)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 68F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((メチルアミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 69F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((エチルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)シクロヘキサ-1,3-ジエン-1-カルボニトリル (Cpd. No. 70F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-(アゼチジン-1-イルメチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 71F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-6-(ピロリジン-1-イルメチル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 72F)、
4-((4bS,5R,6S,7S,7aR)-6-((ジエチルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 73F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((エチル(メチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 74F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-6-(((2-ヒドロキシエチル)(メチル)アミノ)メチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 75F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((ベンジル(メチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 76F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((ベンジルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 77F)、
Rac-4-((5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-6-(((ピリジン-3-イルメチル)アミノ)メチル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 78F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-6-(((2-ヒドロキシエチル)アミノ)メチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 79F)、
Rac-(4aR,5S,6R,7R,7aS)-4a-(4-シアノフェニル)-7,7a-ジヒドロキシ-2-イソプロピル-N,N-ジメチル-5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキサミド (Cpd. No. 80F)、
4-((3aR,4R,4aR,9bS,9cR)-9b-ヒドロキシ-9-メトキシ-2-オキソ-4-フェニル-2,3,3a,4,9b,9c-ヘキサヒドロ-4aH-オキサゾールo[4’’,5’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[2,3-c]ピリジン-4a-イル)ベンゾニトリル (Cpd. No. 81F)、
Rac-(4aR,5S,6R,7R,7aS)-3-シアノ-4a-(4-シアノフェニル)-7,7a-ジヒドロキシ-N,N,2-トリメチル5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキサミド (Cpd. No. 82F)、
4-((5aR,6S,7R,8S,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-7-(ピロリジン-1-イルスルホニル)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 83F)、
Rac-(5aR,6S,7R,8S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-(メチルスルホニル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 84F)、
Rac-4-((5aR,6S,7R,8S,8aS)-3-クロロ-8,8a-ジヒドロキシ-7-(メチルスルホニル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 85F)、
(5aR,6S,7R,8S,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-7-(メチルスルホニル)-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-3-カルボニトリル (Cpd. No. 86F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)(モルホリノ)メタノン (Cpd. No. 87F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N-メチル-7-フェニル-N-(2,2,2-トリフルオロエチル)-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 88F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-N-シクロプロピル-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 89F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-N-(2,2,2-トリフルオロエチル)-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 90F)、
Rac-(5aR,6S,8S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7,7-ジフルオロ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 91F)、
Rac-(5aR,6R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-5a,6-ジヒドロスピロ[シクロペンタ[4,5]フロ[3,2-b]ピリジン-7,1’-シクロプロパン]-8,8a(8H)-ジオール (Cpd. No. 92F)、
Rac-(5aR,6S,7R,8S,8aS)-7-(ベンジルスルホニル)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 93F)、
Rac-4-((5aR,6S,7R,8S,8aS)-7-(ベンジルスルホニル)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 94F)、
(4bS,5R,6R,7S,7aR)-7a-(4-シアノフェニル)-4b,5-ジヒドロキシ-N,N-ジメチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 95F)、
Rac-(4bS,5R,6R,7S,7aR)-4-シアノ-7a-(4-シアノフェニル)-4b,5-ジヒドロキシ-N,N-ジメチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 96F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4-クロロ-4b,5-ジヒドロキシ-N,N-ジメチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 97F)、
(4bS,5R,6R,7S,7aR)-4-クロロ-7a-(4-シアノフェニル)-4b,5-ジヒドロキシ-N,N-ジメチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 98F)、
Rac-(4aR,5S,6R,7R,7aS)-4a-(4-シアノフェニル)-7,7a-ジヒドロキシ-2-(4-メトキシベンジル)-N,N-ジメチル-5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキサミド (Cpd. No. 99F)、
Rac-(4aR,5S,6R,7R,7aS)-4a-(4-シアノフェニル)-7,7a-ジヒドロキシ-N,N-ジメチル-5-フェニル-2,4a,5,6,7,7a-ヘキサヒドロシクロペンタ[4,5]フロ[3,2-c]ピラゾール-6-カルボキサミド (Cpd. No. 100F)、
Rac-(4bS,5S,6R,7S,7aR)-7a-(4-ブロモフェニル)-4-メトキシ-6-(メチルスルホニル)-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 101F)、
4-((4bS,5S,6R,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-(メチルスルホニル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 102F)、
4-((4bS,5R,6S,7S,7aR)-6-((ジメチルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 103F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 104F)、
(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-3-カルボニトリル (Cpd. No. 105F)、
(4bS, 5R, 6S, 7S, 7aR)-7a-(4-(ジフルオロメチル)フェニル)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 106F)、
(4bS,5R,6S,7S,7aR)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 107F)、
(5aR,6S,7R,8R,8aS)-3-クロロ-5a-(4-(ジフルオロメチル)フェニル)-7-((ジメチルアミノ)メチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 108F)、
(5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-6-フェニル-5a-(4-(トリフルオロメチル)フェニル)-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 109F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-(モルホリノメチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 110F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-N-(2,2-ジフルオロエチル)-4b,5-ジヒドロキシ-4-メトキシ-N-メチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 111F)、
4-((4bS,5R,6S,7S,7aR)-6-(((2,2-ジフルオロエチル)(メチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 112F)、
4-((4bS,5R,6S,7S,7aR)-6-((4,4-ジフルオロピペリジン-1-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 113F)、
Rac-((1R,5S)-8-アザビシクロ[3.2.1]オクタ-8-イル)((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)メタノン (Cpd. No. 114F)、
4-((4bS,5R,6S,7S,7aR)-6-(((2,2-ジフルオロエチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 115F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-N-(2,2-ジフルオロエチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 116F)、
Rac-(4bS,5S,6R,7S,7aR)-7a-(4-ブロモフェニル)-4-メトキシ-7-フェニル-6-((2,2,2-トリフルオロエチル)スルホニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 117F)、
Rac-4-((4bS,5S,6R,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-6-(フェニルスルホニル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 118F)、
Rac-4-((4bS,5S,6R,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-6-(ピリジン-2-イルスルホニル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 119F)、
4-((4bR,5R,7S,7aR)-4b-ヒドロキシ-5-(ヒドロキシメチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 120F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)(3,3-ジフルオロアゼチジン-1-イル)メタノン (Cpd. No. 121F)、
4-((4bS,5R,6S,7S,7aR)-6-((3,3-ジフルオロアゼチジン-1-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル) ベンゾニトリル (Cpd. No. 122F)、
Rac-(5aR,6S,7R,8S,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N-メチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-スルホンアミド (Cpd. No. 123F)、
Rac-(5aR,6S,7R,8S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-N-メチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-スルホンアミド (Cpd. No. 124F)、
Rac-(5aR,6S,7R,8S,8aS)-3-クロロ-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-N-メチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-スルホンアミド (Cpd No. 125F)、
4-((4bS,5S,6R,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-(モルホリノスルホニル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 126F)、
Rac-(5aR,6S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 127F)、
Rac-4-((5aR,6S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 128F)、
Rac-(5aR,6S,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8a-ヒドロキシ-6-フェニル-5a,6,7,8a-テトラヒドロ-8H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8-オン (Cpd. No. 129F)、
Rac-(5aR,6S,8S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 130F)、
Rac-4-((5aR,6S,8S,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 131F)、
Rac-N’-((5aR,6S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8a-ヒドロキシ-6-フェニル-5a,6,7,8a-テトラヒドロ-8H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8-イリデン)-4-メチルベンゼンスルホノヒドラジド (Cpd. No. 132F)、
Rac-(5aR,6S,8aR)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-5a,6-ジヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-オール (Cpd. No. 133F)、
Rac-メチル (4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキシレート (Cpd. No. 134F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)(4,4-ジフルオロピペリジン-1-イル)メタノン (Cpd. No. 135F)、
Rac-メチル (5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-カルボキシレート (Cpd. No. 136F)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-カルボキサミド (Cpd. No. 137F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 138F)、
(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 139F)、
4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 140F)、
Rac-4-((5aR,6S,7S,8R,8aS)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 141F)、
Rac-(5aR,6S,7S,8R,8aS)-3-クロロ-5a-(4-クロロフェニル)-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 142F)、
Rac-(5aR,6S,7S,8R,8aS)-3-クロロ-5a-(4-(ジフルオロメチル)フェニル)-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 143F)、
Rac-(5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a-(4-(トリフルオロメチル)フェニル)-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 144F)、
(5aR,6S,7S,8R,8aS)-5a-(4-クロロフェニル)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 145F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(ジフルオロメチル)フェニル)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 146F)、
(5aR,6S,7S,8R,8aS)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a-(4-(トリフルオロメチル)フェニル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 147F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(ジフルオロメチル)フェニル)-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 148F)、
Rac-(5aR,6S,7S,8R,8aS)-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a-(4-(トリフルオロメチル)フェニル)-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 149F)、
Rac-4-((5aR,6S,7S,8R,8aS)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-3-(メチルアミノ)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 150F)、
(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-7-(モルホリノメチル)-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 151F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-7-(モルホリノメチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 152F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3,3-ジフルオロピロリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 153F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3,3-ジフルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 154F)、
Rac-(5aR,6S,7S,8R,8aS)-7-((tert-ブチルアミノ)メチル)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 155F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-7-((4-フルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 156aF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((4-フルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 156bF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((4-フルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 156cF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-7-((4,4-ジフルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 157aF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((4,4-ジフルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 157bF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((4,4-ジフルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 157cF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 158aF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 158bF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 158cF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-7-((ジエチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 159aF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジエチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 159bF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((ジエチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 159cF)、
Rac-(5aR,6S,7R,8S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-7-(ピリジン-2-イルthio)-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 160aF)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-7-(ピリジン-2-イルthio)-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 160bF)、
Rac-メチル (1aS,2R,3S,3aR,8bS)-3a-(4-ブロモフェニル)-6-クロロ-3-フェニル-1a,2,3,3a-テトラヒドロ-オキシレノ[2’’,3’’:1’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-2-カルボキシレート (Cpd. No. 161F)、
Rac-(5aR,6S,8R,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8-(ヒドロキシメチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-オール (Cpd. No. 162F)、
Rac-(5aR,6S,7R,8S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-7-(ピリジン-2-イルスルホニル)-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 163F)、
Rac-4-((5aR,6S,7R,8S,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-7-(ピリジン-2-イルスルホニル)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 164F)、
Rac-(5aR,6S,8S,8aR)-8-(アミノメチル)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-オール (Cpd. No. 165)、
Rac-(5aR,6S,8S,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8-(ヒドロキシメチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-オール (Cpd. No. 166F)、
Rac-4-((5aR,6S,8R,8aR)-3-クロロ-8a-ヒドロキシ-8-(ヒドロキシメチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 167F)、
Rac-4-((5aR,6S,8S,8aR)-3-クロロ-8a-ヒドロキシ-8-(ヒドロキシメチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 168F)、
Rac-(2aR,3S,3aR,8bS,8cR)-3a-(4-ブロモフェニル)-6-クロロ-8b-ヒドロキシ-3-フェニル-3,3a,8b,8c-テトラヒドロオキセト[3’’,2’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[3,2-b]ピリジン-2(2aH)-オン (Cpd. No. 169F)、
Rac-(4bR,5R,6R,7S,7aR)-5-(アミノメチル)-7a-(4-ブロモフェニル)-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 170F)、
Rac-4-((4bR,5R,6R,7S,7aR)-5-(アミノメチル)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 171F)、
Rac-(4bR,5R,7S,7aR)-5-(アミノメチル)-7a-(4-ブロモフェニル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 172F)、
Rac-4-((4bR,5R,7S,7aR)-5-(アミノメチル)-4b-ヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 173F)、
Rac-(5aR,6S,8R,8aR)-8-(アミノメチル)-5a-(4-ブロモフェニル)-3-クロロ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-オール (Cpd. No. 174F)、
Rac-4-((5aR,6S,8R,8aR)-8-(アミノメチル)-3-クロロ-8a-ヒドロキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 175F)、
Rac-(5aR,6S,8R,8aR)-8-(アミノメチル)-5a-(4-シアノフェニル)-8a-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-3-カルボニトリル (Cpd. No. 176F)、
Rac-(5aR,6S,8R,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8-(モルホリノメチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8a-オール (Cpd. No. 177F)、
Rac-4-((5aR,6S,8R,8aR)-3-クロロ-8a-ヒドロキシ-8-(モルホリノメチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 178F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-6-(ヒドロキシメチル)-4-メトキシ-5-(モルホリノメチル)-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 179F)、
Rac-4-((4bR,5R,6R,7S,7aR)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-5-(モルホリノ-メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 180F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-5-(((2,2-ジフルオロエチル)アミノ)メチル)-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 181F)、
Rac-4-((4bR,5R,6R,7S,7aR)-5-(((2,2-ジフルオロエチル)アミノ)メチル)-4b-ヒドロキシ-6-(ヒドロキシル-メチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 182F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-6-(ヒドロキシメチル)-4-メトキシ-5-((4-メチルピペラジン-1-イル)メチル)-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 183F)、
Rac-4-((4bR,5R,6R,7S,7aR)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-5-((4-メチル-ピペラジン-1-イル)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 184F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-6-(ヒドロキシメチル)-4-メトキシ-5-((オキセタン-3-イルアミノ)メチル)-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 185F)、
Rac-4-((4bR,5R,6R,7S,7aR)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-5-((オキセタン-3-イルアミノ)-メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)-ベンゾニトリル (Cpd. No. 186F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5-(((ピリジン-4-イルメチル)アミノ)メチル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 187F)、
Rac-4-((4bR,5R,6R,7S,7aR)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5-(((ピリジン-4-イルメチル)アミノ)メチル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 188F)、
Rac-4-((5aR,6S,7R,8S,8aS)-3-クロロ-8,8a-ジヒドロキシ-6-フェニル-7-(ピリジン-2-イルthio)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 189F)、
Rac-(5aR,6S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8-エチニル8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 190F)、
Rac-(5aR,6S,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-N,N-ジメチル-6-フェニル-8-(プロプ(prop)-1-イン(yn)-1-イル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-7-カルボキサミド (Cpd. No. 191F)、
Rac-(4bR,7S,7aR)-7a-(4-ブロモフェニル)-4b-ヒドロキシ-4-メトキシ-N,N-ジメチル-5-オキソ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 192F)、
Rac-メチル (4bS,5R,6R,7aR)-4b,5-ジヒドロキシ-7a-(4-ヨードフェニル)-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキシレート (Cpd. No. 193F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((4-アセチルピペラジン-1-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 194F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-(((2,2-ジフルオロエチル)アミノ)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 195F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-(((2,2-ジフルオロエチル)アミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 196F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-(((2,2-ジフルオロエチル)アミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 197F)、
4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-7-((4-メチルピペラジン-1-イル)メチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 198aF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-7-((4-メチルピペラジン-1-イル)メチル)-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 198bF)、
Rac-(5aR,6S,7R,8R,8aR)-5a-(4-ブロモフェニル)-3-クロロ-7-(ヒドロキシメチル)-1-メトキシ-8-(モルホリノメチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8a-オール (Cpd. No. 199F)、
Rac-(5aR,6S,7R,8R,8aR)-5a-(4-シアノフェニル)-8a-ヒドロキシ-7-(ヒドロキシメチル)-1-メトキシ-8-(モルホリノメチル)-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 200F)、
Rac-(4bR,5R,6R,7S,7aR)-5-((2-オキサ-6-アザスピロ[3.3]へプタン-6-イル)メチル)-7a-(4-ブロモフェニル)-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 201F)、
Rac- 4-((4bR,5R,6R,7S,7aR)-5-((2-オキサ-6-アザスピロ[3.3]へプタン-6-イル)メチル)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 202F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-6-(ヒドロキシメチル)-4-メトキシ-5-((((1-メチル-1H-ピラゾール-5-イル)メチル)アミノ)メチル)-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 203F)、
Rac-4-((4bR,5R,6R,7S,7aR)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-5-((((1-メチル-1H-ピラゾール-5-イル)メチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 204F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-5-((ジメチルアミノ)メチル)-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 205F)、
Rac-4-((4bR,5R,6R,7S,7aR)-5-((ジメチルアミノ)メチル)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 206F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3,3-ジフルオロアゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 207aF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((3,3-ジフルオロアゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 207bF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-(((2,2-ジフルオロエチル)(メチル)アミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 208aF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-(((2,2-ジフルオロエチル)(メチル)アミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 208bF)、
Rac-(5aR,6S,7R,8R,8aR)-5a-(4-ブロモフェニル)-3-クロロ-8-((ジメチルアミノ)メチル)-7-(ヒドロキシメチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8a-オール (Cpd. No. 209F)、
Rac-(5aR,6S,7R,8R,8aR)-5a-(4-シアノフェニル)-8-((ジメチルアミノ)メチル)-8a-ヒドロキシ-7-(ヒドロキシメチル)-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 210F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3-フルオロアゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 211aF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((3-フルオロアゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 211bF)、
(5aR,6S,7S,8R,8aS)-7-(アゼチジン-1-イルメチル)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 212F)、
Rac-(5aR,6S,7R,8R,8aR)-5a-(4-シアノフェニル)-8-((4,4-ジフルオロピペリジン-1-イル)メチル)-8a-ヒドロキシ-7-(ヒドロキシメチル)-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 213F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-((3,3-ジメチルモルホリノ)メチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8,8a-ジオール (Cpd. No. 214F)、
Rac-((5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-イル)(3-(ジフルオロメチル)アゼチジン-1-イル)メタノン (Cpd. No. 215F)、
Rac-((5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-イル)(3-(ジフルオロメチル)アゼチジン-1-イル)メタノン (Cpd. No. 216F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((3-(ジフルオロメチル)アゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 217F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3-(ジフルオロメチル)アゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 218F)、
Rac-((5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-イル)(1,1-ジフルオロ-4-アザスピロ[2.3]ヘキサン-4-イル)メタノン (Cpd. No. 219F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-7-((1,1-ジフルオロ-4-アザスピロ[2.3]ヘキサン-4-イル)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 220F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((1,1-ジフルオロ-4-アザスピロ[2.3]ヘキサン-4-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 221F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((1,1-ジフルオロ-4-アザスピロ[2.3]ヘキサン-4-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 222F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-1-メトキシ-7-((メチルアミノ)メチル)-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 223F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-7-((メチルアミノ)メチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 224F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-7-((メチルアミノ)メチル)-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 225F)、
Rac-(4bR,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-5-((tert-ブチルアミノ)メチル)-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 226F)、
Rac-(5aR,6S,7R,8S,8aR)-5a-(4-ブロモフェニル)-3-クロロ-7-((ジメチルアミノ)メチル)-8a-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8-カルボニトリル (Cpd. No. 227F)、
Rac-(5aR,6S,7R,8S,8aR)-3-クロロ-5a-(4-シアノフェニル)-7-((ジメチルアミノ)メチル)-8a-ヒドロキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-b]ピリジン-8-カルボニトリル (Cpd. No. 228F)、
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-8,8a-ジヒドロキシ-1,3-ジメトキシ-N,N-ジメチル-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-カルボキサミド (Cpd. No. 229F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-ブロモフェニル)-7-((ジメチルアミノ)メチル)-1,3-ジメトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 230F)、
4-((5aR,6S,7S,8R,8aS)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1,3-ジメトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 231F)、
Rac-4-((5aR,6S,7S,8R,8aS)-7-((ジエチルアミノ)メチル)-8,8a-ジヒドロキシ-1,3-ジメトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 232F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((メチル(2,2,2-トリフルオロエチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 233F)、
Rac-(4bR,5R,7S,7aR)-7a-(4-(アミノメチル)フェニル)-5-(ヒドロキシメチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-オール (Cpd. No. 234F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)(2-オキサ-6-アザスピロ[3.3]へプタン-6-イル)メタノン (Cpd. No. 235F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((2-オキサ-6-アザスピロ[3.3]へプタン-6-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 236F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N-メチル-N-(オキセタン-3-イル)-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 237F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((メチル(オキセタン-3-イル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 238F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N-(オキセタン-3-イル)-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 239F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((オキセタン-3-イルアミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 240F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((((1-メチル-1H-ピラゾール-5-イル)メチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 241F)、
Rac-4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((((1-メチル-1H-ピラゾール-5-イル)メチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 242F)、
4-((4bS,5R,6S,7S,7aR)-6-((tert-ブチル(メチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 243F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((シクロプロピルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 244F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-N-シクロプロピル-4b,5-ジヒドロキシ-4-メトキシ-N-メチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 245F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-((シクロプロピル(メチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 246F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-N-(2-フルオロエチル)-4b,5-ジヒドロキシ-4-メトキシ-N-メチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 247F)、
4-((4bS,5R,6S,7S,7aR)-6-(((2-フルオロエチル)(メチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 248F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N-メチル-N-((1-メチル-1H-ピラゾール-5-イル)メチル)-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 249F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((メチル((1-メチル-1H-ピラゾール-5-イル)メチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 250F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-N-(2-ヒドロキシ-2-メチルプロピル)-4-メトキシ-N-メチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 251F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-6-(((2-ヒドロキシ-2-メチルプロピル)(メチル)アミノ)メチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 252F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-N-(2-ヒドロキシ-2-メチルプロピル)-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 253F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-6-(((2-ヒドロキシ-2-メチルプロピル)アミノ)メチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 254F)、
Rac-(4bS,5R,6S,7S,7aR)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-7a-(p-tolイル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 255F)、
(4bS,5R,6S,7S,7aR)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-7a-(p-tolイル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 256F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)(ピペリジン-1-イル)メタノン (Cpd. No. 257F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-6-(ピペリジン-1-イルメチル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 258F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-(((2-フルオロエチル)アミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 259F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N-(2-メトキシエチル)-N-メチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 260F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-(((2-メトキシエチル)(メチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 261F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N-(2-メトキシエチル)-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 262F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-(((2-メトキシエチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル hydrochloride (Cpd. No. 263F)、
Rac-((1R,5S)-3-オキサ-8-アザビシクロ[3.2.1]オクタ-8-イル)((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)メタノン (Cpd. No. 264F)、
4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-オキサ-8-アザビシクロ[3.2.1]オクタ-8-イル) メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ [4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 265F)、
Rac-((1R,5S)-3-オキサ-6-アザビシクロ[3.1.1]へプタン-6-イル)((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)メタノン (Cpd. No. 266F)、
Rac-4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-3-オキサ-6-アザビシクロ[3.1.1]へプタン-6-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 267F)、
4-((4bS,5R,6S,7S,7aR)-6-(((1R,5S)-8-アザビシクロ[3.2.1]オクタ-8-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 268F)、
Rac-(3aR,4R,4aR,9bS,9cR)-4a-(4-(ジフルオロメチル)フェニル)-9b-ヒドロキシ-9-メトキシ-4-フェニル-3,3a,4,4a,9b,9c-ヘキサヒドロ-2H-オキサゾールo[4’’,5’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[2,3-c]ピリジン-2-オン (Cpd. No. 269F)、
Rac-(4bS,5R,6R,7R,7aR)-6-アミノ-7a-(4-(ジフルオロメチル)フェニル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 270F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-クロロフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N,N-ジメチル-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 271F)、
(4bS,5R,6S,7S,7aR)-7a-(4-クロロフェニル)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 272F)、
Rac-(6-オキサ-3-アザビシクロ[3.1.1]へプタン-3-イル)((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)メタノン (Cpd. No. 273F)、
4-((4bS,5R,6S,7S,7aR)-6-((6-オキサ-3-アザビシクロ[3.1.1]へプタン-3-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 274F)、
Rac-(3aR,4S,4aR,9bS,9cR)-4a-(4-ブロモフェニル)-9b-ヒドロキシ-9-メトキシ-4-フェニル-3,3a,4,4a,9b,9c-ヘキサヒドロ-2H-furo[3’’,2’’:4’,5’]シクロペンタ[1’,2’:4,5]フロ[2,3-c]ピリジン-2-オン (Cpd. No. 275F)、
Rac-4-((4bS,5R,6R,7S,7aR)-6-(2-(ジメチルアミノ)エチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 276F)、
Rac-(4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-N-メチル-7-フェニル-N-(ピリジン-3-イルメチル)-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 277F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-6-((メチル(ピリジン-3-イルメチル)アミノ)メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 278F)、
Rac-((4bS,5R,6R,7S,7aR)-7a-(4-ブロモフェニル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)(3,3-ジフルオロピロリジン-1-イル)メタノン (Cpd. No. 279F)、
4-((4bS,5R,6S,7S,7aR)-6-((3,3-ジフルオロピロリジン-1-イル)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 280F)、
Rac-((4bS,5R,6R,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-イル)(モルホリノ)メタノン (Cpd. No. 281F)、
(4bS,5R,6S,7S,7aR)-4-メトキシ-6-(モルホリノメチル)-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 282F)、
Rac-(4bS,5R,6S,7S,7aR)-4-メトキシ-6-((4-メチルピペラジン-1-イル)メチル)-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 283F)、
(4bS,5R,6S,7S,7aR)-4-メトキシ-6-((4-メチルピペラジン-1-イル)メチル)-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 284F)、
Rac-(4bS,5R,6R,7S,7aR)-N-(2,2-ジフルオロエチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-4b,6,7,7a-テトラヒドロ-5H-シクロペンタ[4,5]フロ[2,3-c]ピリジン-6-カルボキサミド (Cpd. No. 285F)、
(4bS,5R,6S,7S,7aR)-6-(((2,2-ジフルオロエチル)アミノ)メチル)-4-メトキシ-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 286F)、
Rac-4-((4bS,5R,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-5-(モルホリノメチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 287F)、
(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3,3-ジフルオロアゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 288F)、
Rac-(4bR,7S,7aR)-4-メトキシ-5-(モルホリノメチル)-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b-ol (Cpd. No. 289F)、
4-((4bS,5R,6S,7S,7aR)-6-((tert-ブチルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 290F)、
4-((4bS,5R,6S,7S,7aR)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-6-(((2,2,2-トリフルオロエチル)アミノ)メチル)-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 291F)、
Rac-(5aR,6S,7S,8R,8aS)-7-(アミノメチル)-5a-(4-ブロモフェニル)-3-クロロ-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 292F)、
Rac-(5aR,6S,7S,8R,8aS)-7-(アミノメチル)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 293F)、
Rac-4-((5aR,6S,7S,8R,8aS)-7-(アミノメチル)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 294F)、 ならびに
Rac-(5aR,6S,7R,8R,8aS)-5a-(4-ブロモフェニル)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-7-カルボン酸 (Cpd. No. 295F)。
(5aR,6S,7S,8R,8aS)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a-(4-(トリフルオロメチル)フェニル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 147F)、
4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-7-((4-メチルピペラジン-1-イル)メチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 198aF)、
(5aR,6S,7S,8R,8aS)-7-(アゼチジン-1-イルメチル)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 212F)、
(5aR,6S,7S,8R,8aS)-5a-(4-クロロフェニル)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 145F)、
Rac-(5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a-(4-(トリフルオロメチル)フェニル)-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 144F)、
Rac-(5aR,6S,7S,8R,8aS)-3-クロロ-5a-(4-(ジフルオロメチル)フェニル)-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 143F)、
Rac-(5aR,6S,7S,8R,8aS)-3-クロロ-5a-(4-クロロフェニル)-7-((ジメチルアミノ)メチル)-1-メトキシ-6-フェニル-5a,6,7,8-テトラヒドロ-8aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-8,8a-ジオール (Cpd. No. 142F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-(((2,2-ジフルオロエチル)アミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 196F)、
(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 139F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((3,3-ジフルオロアゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 207bF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-7-(モルホリノメチル)-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 152F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((4,4-ジフルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 157bF)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 158bF)、
4-((5aR,6S,7S,8R,8aS)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1,3-ジメトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 231F)、
Rac-4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジエチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 159bF)、
4-((5aR,6S,7S,8R,8aS)-3-クロロ-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-6,7,8,8a-テトラヒドロ-5aH-シクロペンタ[4,5]フロ[3,2-c]ピリジン-5a-イル)ベンゾニトリル (Cpd. No. 140F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-(ジフルオロメチル)フェニル)-7-((ジメチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 146F)、
(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-7-(モルホリノメチル)-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 151F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-(((2,2-ジフルオロエチル)アミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 197F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3,3-ジフルオロアゼチジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 207aF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((4,4-ジフルオロピペリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 157cF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((3,3-ジフルオロピロリジン-1-イル)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 153F)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-7-((ジエチルアミノ)メチル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 159cF)、
Rac-(5aR,6S,7S,8R,8aS)-5a-(4-シアノフェニル)-8,8a-ジヒドロキシ-1-メトキシ-6-フェニル-7-(ピロリジン-1-イルメチル)-5a,7,8,8a-テトラヒドロ-6H-シクロペンタ[4,5]フロ[3,2-c]ピリジン-3-カルボニトリル (Cpd. No. 158cF)、
Rac-4-((4bR,5R,6R,7S,7aR)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-5-(モルホリノ-メチル)-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 180F)、
Rac-4-((4bR,5R,6R,7S,7aR)-5-((ジメチルアミノ)メチル)-4b-ヒドロキシ-6-(ヒドロキシメチル)-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 206F)、
4-((4bS,5R,6S,7S,7aR)-6-((ジメチルアミノ)メチル)-4b,5-ジヒドロキシ-4-メトキシ-7-フェニル-4b,5,6,7-テトラヒドロ-7aH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-7a-イル)ベンゾニトリル (Cpd. No. 66F)、
(4bS,5R,6S,7S,7aR)-7a-(4-クロロフェニル)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 272F)、
(4bS,5R,6S,7S,7aR)-7a-(4-(ジフルオロメチル)フェニル)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 106F)、ならびに
(4bS,5R,6S,7S,7aR)-6-((ジメチルアミノ)メチル)-4-メトキシ-7-フェニル-7a-(4-(トリフルオロメチル)フェニル)-5,6,7,7a-テトラヒドロ-4bH-シクロペンタ[4,5]フロ[2,3-c]ピリジン-4b,5-ジオール (Cpd. No. 107F)から選択される。
特定の実施形態では、本開示は、高炎症性リンパ球の非炎症性固形腫瘍への浸潤を促進するために、eIF4A阻害剤を投与することを含む、癌などの過剰増殖性障害を射治療する方法を提供する。本明細書で使用される用語「抗腫瘍リンパ球」は、抗腫瘍活性を有する白血球を指す。抗腫瘍活性には、例えば、腫瘍の成長の防止もしくは遅延させること、または腫瘍の退行を引き起こすこと、腫瘍細胞の死をもたらす細胞毒性活性、または腫瘍細胞の成長、移動、分裂、栄養素の代謝、または他の細胞との間で信号を送受信する腫瘍細胞の能力を低下させることを含んで成る。抗腫瘍リンパ球は、例えば、CD8+(「エフェクター」)T細胞およびCD4+(「ヘルパー」)T細胞を含む腫瘍抗原特異的T細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT細胞(NK-T細胞)、B細胞、およびプラズマ細胞を含む。
非分裂フィーダー細胞は、ガンマ線照射されたPBMCフィーダー細胞を含み得る。PBMCには、約3000~3600radの範囲のガンマ線を照射できる。リンパ球とフィーダー細胞を培地に加える順序は、必要に応じて逆にすることができる。培養物は通常、リンパ球の成長に適した温度などの条件下でインキュベートすることができる。例えば、ヒトT細胞の増殖の場合、温度は一般に少なくとも約25℃、好ましくは少なくとも約30℃、より好ましくは約37℃である。
特定の実施形態では、本開示は、eIF4A阻害剤を投与して抗腫瘍リンパ球(すなわち、内因性、または非内因性のリンパ球)の腫瘍への浸潤を促進することにより、非炎症性腫瘍などの過剰増殖性疾患を処理する方法を提供する。例えば、有効量のeIF4A阻害剤を投与すると、以前は浸潤していなかった抗腫瘍リンパ球による腫瘍の浸潤が生じたり、抗腫瘍リンパ球による腫瘍の浸潤が約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%、約100%、約200%、約300%、約400%、約500%、約1000%、それより多くまで増加することがある。抗腫瘍リンパ球による浸潤、または抗腫瘍活性は、例えば、抗腫瘍リンパ球の既知のマーカー(例えば、CD8、CD4、CD3、または異種もしくは合成表面マーカータンパク質)の免疫組織化学染色を使用して、レポータータンパク質(例えば、抗腫瘍リンパ球によって発現する蛍光タンパク質)のイメージング、または生体内イメージング技術(例えば、MRI、またはPETなど)、またはリンパ球抗腫瘍活性を示すサイトカイン標識の測定レベル(例えば、IL-6、IL-8、IL-10、TNF-α、MCP1、IL-1β、IL-15およびIFN-γ)によって、または腫瘍細胞死の標識としての免疫原性細胞死マーカーのレベル測定(例えば、Tesniereら,Cell Death and Differentiation 15:3(2008)参照;Wollerら,Front. Oncol. 4:188(2014)も参照)により、決定できる。
(式I中、
Xは、CR6R7、O、S、NH、N(C1~C8)アルキル、C(O)、C=CR6R7、N(CO)R8、S(O)またはS(O)2であり、
Yは、5員ヘテロアリールまたは6員アリールまたはヘテロアリールであり、
R1およびR2は、独立して、アリール、ヘテロシクリル、ヘテロアリールまたはシクロアルキルであり、
R3a、R3b、R4aおよびR4bは、独立して、H、ハロゲン、CN、C1~C8(アルキル)、(C1~C8)ハロアルキル、C2~C8(アルケニル)、(C2~C8)アルキニル、OR9、NHR9、NR9R9、[(C1~C8)アルキレン]OR9、[(C1~C8)アルキレン]NHR9、[(C1~C8)アルキレン]NR9R9、C(O)R8、C(O)NHR9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NHR9、C(O)[(C1~C8)アルキレン]NR9R9、CO2R9、C(S)NHR9、C(S)NR9R9、SR9、S(O)R9、SO2R9、SO2NHR9、SO2NR9R9、NH(CO)R8、NR9(CO)R8、NH(CO)NHR9、NH(CO)NR9R9、NR9(CO)NHR9、NR9(CO)NR9R9、P(O)(OH)(OR9)、 P(O)(OR9)(OR9)、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリルであり、
R3aおよびR3b、ならびにR4aおよびR4bは、独立して、結合してオキソもしくはアルケニル、またはシクロアルキルもしくはヘテロシクリル環を形成し、または
R3aおよびR4a、R3bおよびR4bまたはR4aおよびR5は、それらが結合している炭素原子と共にシクロアルキルまはたヘテロシクリル環を形成し、または
R2およびR3aは、それらが結合している炭素原子と共に二環式環系を形成し、
R5は、H、ハロゲン、OH、CN、N3、SR9、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2-C8)アルキニル、NHC(O)(C1~C8)アルキルまたはヘテロアリールであり、
R6およびR7は、独立して、H、CN、ハロゲン、OR9、SR9、(C1~C8)アルキル、NH(R9)またはNR9R9であり、
R8は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、シクロアルキル、O(シクロアルキル)、ヘテロシクリル、Oヘテロシクリル)、アリール、O(アリール)、ヘテロアリールまたはO(ヘテロアリール)であり、
R9は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、シクロアルキル、ヘテロシクリル、[(C1~C8)アルキレン]ヘテロシクリル、アリール、[(C1~C8)アルキレン]アリールまたはヘテロアリールであり、
NR9R9、[(C1~C8)アルキレン]NR9R9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NR9R9、C(S)NR9R9、SO2NR9R9、NH(CO)NR9R9またはNR9(CO)NR9R9の2つのR9は、それらが結合している窒素原子と共にヘテロシクリル環を任意に形成し、
任意のアルキル、アルケニル、シクロアルキル、ヘテロシクリル、ヘテロアリールまたはアリールは、OH、CN、SH、SO2NH2、SO2(C1~C4)アルキル、SO2NH(C1~C4)アルキル、ハロゲン、NH2、NH(C1~C4)アルキル、N[(C1~C4)アルキル]2、C(O)NH2、COOH、COOMe、アセチル、(C1-C8)アルキル、O(C1-C8)アルキル、O(C1-C8)ハロアルキル、(C2-C8)アルケニル、(C2-C8)アルキニル、ハロアルキル、チオアルキル、シアノメチレン、アルキルアミニル、NH2-C(O)‐アルキレン、NH(Me)-C(O)-アルキレン、CH2-C(O)-低級アルキル、C(O)-低級アルキル、アルキルカルボニルアミニル、CH2-[CH(OH)]m-(CH2)p-OH、CH2-[CH(OH)]m-(CH2)p-NH2またはCH2-アリール-アルコキシから選択される1、2、または3の基で任意に置換してもよく、または
任意のアルキル、シクロアルキルまたはヘテロシクリルは、オキソで任意に置換されてもよく
「m」および「p」は、1、2、3、4、5または6であり、および
Yが6員アリールである場合、XはOではない)
もしくはその立体異性体、互変異性体、またはその薬学的に許容される塩
によるeIF4A 阻害剤の治療的有効量を投与することを含含んで成る。
(ここで、
A1は、NまたはCR10であり、
A2は、NまたはCR11であり、
A3は、NまたはCR12であり、
A4は、NまたはCR13であり、および
R10、R11、R12およびR13は、独立して、H、ハロゲン、C1-C8(アルキル)、 (C1-C8)ハロアルキル、C(O)O(C1-C8)アルキル、C(O)(C1-C8)アルキル、SO2(C1-C8)アルキル、C2-C8(アルケニル)、(C2-C8)アルキニル、OR9、NHR9、NR9R9、CN、[(C1-C8)アルキレン]OR9、[(C1-C8)アルキレン]NHR9、[(C1-C8)アルキレン]NR9R9、C(O)R8、C(O)NHR9、C(O)NR9R9、C(O)[(C1-C8)アルキレン]NHR9、C(O)[(C1-C8)アルキレン]NR9R9、CO2R9、C(S)NHR9、C(S)NR9R9、SR9、S(O)R9、SO2R9、SO2NHR9、SO2NR9R9、NH(CO)R8、NR9(CO)R8、NH(CO)NHR9、NH(CO)NR9R9、NR9(CO)NHR9、NR9(CO)NR9R9、P(O)(OH)(OR9)、P(O)(OR9)(OR9)、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリルである)
である。
(ここで、B1、B2およびB3のうちの任意の2つはare CR14およびNであり、その残りはB環原子は、N(R15)またはSであり、R14は、H、CN、ハロゲン、OR9、SR9、(C1~C8)アルキル、C(O)O(C1~C8)アルキル、C(O)(C1~C8)アルキル、SO2(C1~C8)アルキル、SO2NR9R9、C(O)NR9R9、NR9R9またはNR9C(O)R8であり、R15はHまたは(C1-C8)アルキルである)である。
に係るeIF4A阻害剤、もしくはその立体異性体、互変異性体、または薬学的に許容される塩を投与することを含んで成る。
(式(I)中、
Xは、CR6R7、O、S、NH、N(C1~C8)アルキル、C(O)、C=CR6R7、N(CO)R8、S(O)またはS(O)2であり、
Yは、5員ヘテロアリールまたは6員アリールまたはヘテロアリールであり、
R1およびR2は、独立して、アリール、ヘテロシクリル、ヘテロアリールまたはシクロアルキルであり、
R3a、R3b、R4aおよびR4bは、独立して、H、ハロゲン、CN、C1~C8(アルキル)、(C1~C8)ハロアルキル、C2~C8(アルケニル)、(C2~C8)アルキニル、OR9、NHR9、NR9R9、[(C1~C8)アルキレン]OR9、[(C1~C8)アルキレン]NHR9、[(C1~C8)アルキレン]NR9R9、C(O)R8、C(O)NHR9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NHR9、C(O)[(C1~C8)アルキレン]NR9R9、CO2R9、C(S)NHR9、C(S)NR9R9、SR9、S(O)R9、SO2R9、SO2NHR9、SO2NR9R9、NH(CO)R8、NR9(CO)R8、NH(CO)NHR9、NH(CO)NR9R9、NR9(CO)NHR9、NR9(CO)NR9R9、P(O)(OH)(OR9)、P(O)(OR9)(OR9)、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリルであり、
R3aおよびR3b、ならびにR4aおよびR4bは、独立して、結合してオキソもしくはアルケニル、またはシクロアルキルもしくはヘテロシクリル環を形成し、または
R3aおよびR4a、R3bおよびR4bまたはR4aおよびR5は、それらが結合している炭素原子と共にシクロアルキルまたはヘテロシクリル環を形成し、または
R2およびR3aは、それらが結合している炭素原子と共に二環式環系を形成し、
R5は、H、ハロゲン、OH、CN、N3、SR9、(C1~C8)アルキル、(C1~C8)ハロアルキ、 O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルキニル、NHC(O)(C1~C8)アルキルまたはヘテロアリールであり、
R6およびR7は、独立して、H、CN、ハロゲン、OR9、SR9、(C1~C8)アルキル、NH(R9)またはNR9R9であり、
R8は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、シクロアルキル、O(シクロアルキル)、ヘテロシクリル、Oヘテロシクリル)、アリール、O(アリール)、ヘテロアリールまたはO(ヘテロアリール)であり、
R9は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、シクロアルキル、ヘテロシクリル、[(C1~C8)アルキレン]ヘテロシクリル、アリール、[(C1~C8)アルキレン]アリールまたはヘテロアリールであり、
NR9R9、[(C1-C8)アルキレン]NR9R9、C(O)NR9R9、C(O)[(C1-C8)アルキレン]NR9R9、C(S)NR9R9、SO2NR9R9、NH(CO)NR9R9またはNR9(CO)NR9R9、の2つのR9とそれらが結合している窒素原子は、ヘテロシクリル環を任意に形成し、
任意のアルキル、アルケニル、シクロアルキル、ヘテロシクリル、ヘテロアリール またはアリールは、OH、CN、SH 、SO2NH2、SO2(C1~C4)アルキル、SO2NH(C1~C4)アルキル、ハロゲン、NH2、NH(C1~C4)アルキル、N[(C1~C4)アルキル]2、C(O)NH2、COOH、COOMe、アセチル、(C1~C8)アルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルケニル、(C2~C8)アルキニル、ハロアルキル、チオアルキル、シアノメチレン、アルキルアミニル、NH2-C(O)-アルキレン、NH(Me)-C(O)-アルキレン、CH2-C(O)-低級アルキル、C(O)-低級アルキル、アルキルカルボニルアミニル、CH2-[CH(OH)]m-(CH2)p-OH、CH2-[CH(OH)]m-(CH2)p-NH2またはCH2-アリール-アルコキシから選択される1、2、または3の基で任意に置換され、または
任意のアルキル、シクロアルキルまたはヘテロシクリルは、オキソで任意に置換され、
「m」および「p」は、1、2、3、4、5または6であり、
Yが6員アリールである場合、XはOではない)
の化合物もしくはその立体異性体、互変異性体、またはその薬学的に許容される塩から選択されるeIF4A阻害剤の有効量を投与することを含んで成る。
別の態様では、本開示は、被験体の非炎症性固形腫瘍を治療するための薬剤の製造における本明細書に記載のeIF4A阻害剤のいずれかの使用を提供する。別の態様では、本開示は、非炎症性固形腫瘍に関連する癌を治療するための医薬品の製造における、本明細書に記載のeIF4A阻害剤の使用を提供する。特定の実施形態では、本開示の医薬の製造に有用なeIF4A阻害剤は、(a)ロカグラメートまたはその誘導体、または(b)式I:
(式(I)中、
Xは、CR6R7、O、S、NH、N(C1~C8)アルキル、C(O)、C=CR6R7、N(CO)R8、S(O)またはS(O)2であり、
Yは、5員ヘテロアリールまたは6員アリールまたはヘテロアリールであり、
R1およびR2は、独立して、アリール、ヘテロシクリル、ヘテロアリールまたはシクロアルキルであり、
R3a、R3b、R4aおよびR4bは、独立して、H、ハロゲン、CN、C1~C8(アルキル)、(C1~C8)ハロアルキル、C2~C8(アルケニル)、(C2~C8)アルキニル、OR9、NHR9、NR9R9、[(C1~C8)アルキレン]OR9、[(C1~C8)アルキレン]NHR9、[(C1~C8)アルキレン]NR9R9、C(O)R8、C(O)NHR9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NHR9、C(O)[(C1~C8)アルキレン]NR9R9、CO2R9、C(S)NHR9、C(S)NR9R9、SR9、S(O)R9、SO2R9、SO2NHR9、SO2NR9R9、NH(CO)R8、NR9(CO)R8、NH(CO)NHR9、NH(CO)NR9R9、NR9(CO)NHR9、NR9(CO)NR9R9、P(O)(OH)(OR9)、P(O)(OR9)(OR9)、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリルであり、
R3aおよびR3b、ならびにR4aおよびR4bは、独立して、結合してオキソもしくはアルケニル、またはシクロアルキルもしくはヘテロシクリル環を形成し、または
R3aおよびR4a、R3bおよびR4bまたはR4aおよびR5は、それらが結合している炭素原子と共にシクロアルキルまたはヘテロシクリル環を形成し、または
R2およびR3aは、それらが結合している炭素原子と共に二環式環系を形成し、
R5は、H、ハロゲン、OH、CN、N3、SR9、(C1~C8)アルキル、(C1~C8)ハロアルキ、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルキニル、NHC(O)(C1~C8)アルキルまたはヘテロアリールであり、
R6およびR7は、独立して、H、CN、ハロゲン、OR9、SR9、(C1~C8)アルキル、NH(R9)またはNR9R9であり、
R8は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、シクロアルキル、O(シクロアルキル)、ヘテロシクリル、Oヘテロシクリル)、アリール、O(アリール)、ヘテロアリールまたはO(ヘテロアリール)であり、
R9は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、シクロアルキル、ヘテロシクリル、[(C1~C8)アルキレン]ヘテロシクリル、アリール、[(C1~C8)アルキレン]アリールまたはヘテロアリールであり、
NR9R9、[(C1-C8)アルキレン]NR9R9、C(O)NR9R9、C(O)[(C1-C8)アルキレン]NR9R9、C(S)NR9R9、SO2NR9R9、NH(CO)NR9R9またはNR9(CO)NR9R9、の2つのR9とそれらが結合している窒素原子は、ヘテロシクリル環を任意に形成し、
任意のアルキル、アルケニル、シクロアルキル、ヘテロシクリル、ヘテロアリール またはアリールは、OH、CN、SH、SO2NH2、SO2(C1~C4)アルキル、SO2NH(C1~C4)アルキル、ハロゲン、NH2、NH(C1~C4)アルキル、N[(C1~C4)アルキル]2、C(O)NH2、COOH、COOMe、アセチル、(C1~C8)アルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルケニル、(C2~C8)アルキニル、ハロアルキル、チオアルキル、シアノメチレン、アルキルアミニル、NH2-C(O)-アルキレン、NH(Me)-C(O)-アルキレン、CH2-C(O)-低級アルキル、C(O)-低級アルキル、アルキルカルボニルアミニル、CH2-[CH(OH)]m-(CH2)p-OH、CH2-[CH(OH)]m-(CH2)p-NH2またはCH2-アリール-アルコキシから選択される1、2、または3の基で任意に置換され、または
任意のアルキル、シクロアルキルまたはヘテロシクリルは、オキソで任意に置換され、
「m」および「p」は、1、2、3、4、5または6であり、
Yが6員アリールである場合、XはOではない)
に従った化合物もしくはその立体異性体、互変異性体、またはその薬学的に許容される塩を含んで成る。
実施例1
eIF4A阻害剤の腫瘍間質リモデリングへの影響
Cmp1およびCmp2は、5 ’非翻訳領域(UTR)内の特定のポリプリンモチーフを有するmRNAへのeIF4A結合の可逆的強化を介してeIF4Aを調節する強力で配列選択的なeIF4A阻害剤である。腫瘍性タンパク質の発現は、タンパク質合成のレベルで厳密に制御されており、eIF4A、eIF4E、eIF4Gで構成される複合体である真核生物の翻訳開始因子4F(eIF4F)によって大きく制御されている。eIF4Fは、40SリボソームサブユニットへのmRNAの補充を触媒して、48S開始複合体を形成する。翻訳開始因子eIF4Aは、RNAデュプレックスのATP依存性巻き戻しを触媒するATP依存性ヘリカーゼの「DEADボックス」ファミリーのメンバーであり、開始コドンに遭遇するまで5’-UTR内の43Sリボソーム複合体スキャンを促進する。
TGFβでの24時間処理による線維芽細胞の筋線維芽細胞への形質転換を、TGFβ誘導筋線維芽細胞分化マーカー、平滑筋アクチン(αSMA)の発現、およびI型コラーゲンなどの細胞外マトリックス成分の産生によって評価した。24時間TGFβ処理後のウエスタンブロットによるα-SMAタンパク質レベルの分析により、線維芽細胞形質転換に対応するα-SMAの増加、および細胞外マトリックスプロコラーゲン産生の増加が確認された。細胞とTGFβおよびeIF4A阻害剤(Cmp1またはCmp2)の共インキュベーションにより、α-SMAタンパク質レベルが用量依存的に低下し、Cmp1またはCmp2濃度がより高い場合のα-SMAとβ-アクチンの比率は、形質転換されていない未処理の線維芽細胞の比率に近づいた(図1)。eIF4A阻害剤(Cmp1またはCmp2)による治療は、細胞外マトリックスの成分であるプロコラーゲンI型分泌の増加もブロックした(図2Aおよび2B)。
筋線維芽細胞へのTGFβ媒介線維芽細胞の形質転換の特徴は、α-SMAおよびコラーゲンなどの細胞外マトリックス成分の増加である。eIF4A阻害剤Cmp1またはCmp2とTGFβの同時投与は、α平滑筋アクチンの阻害からわかるように、線維芽細胞から筋線維芽細胞への形質転換をブロックした。Cmp1およびCmp2は、1型プロコラーゲンのレベルの増加の阻害によって証明されるように、分化中に上方制御される細胞外マトリックス成分の産生を阻害することも観察された。
筋線維芽細胞へのTGFβ媒介線維芽細胞の形質転換の特徴は、α-SMAおよびコラーゲンなどの細胞外マトリックス成分の増加である。eIF4A阻害剤Cmp1またはCmp2とTGFβの同時投与は、α平滑筋アクチンの阻害からわかるように、線維芽細胞から筋線維芽細胞への形質転換をブロックした。Cmp1およびCmp2は、1型プロコラーゲンのレベルの増加の阻害によって証明されるように、分化中に上方制御される細胞外マトリックス成分の産生を阻害することも観察された。
TGFβおよび細胞外マトリクス産生に対するEIF4A阻害の効果
簡単に説明すると、線維芽細胞(Lonza#CC-2512;すべての実験に細胞継代番号2~5を使用)を播種し(0日目)、10%ウシ胎児血清(FBS)、ペニシリン、ストレプトマイシンおよびグルタマックス(Invitrogen)を添加したダルベッコ変法イーグル培地(DMEM)、37℃、5%CO2の加湿インキュベーターで一晩培養した。1日目に、細胞をリン酸緩衝生理食塩水(PBS)で洗浄し、その後、ペニシリン、ストレプトマイシン、およびグルタマックスを補充した新鮮な無血清DMEMで72時間インキュベートした。4日目に、細胞を洗浄した後、10 ng / mlTGFβを含む新鮮な無血清DMEMを添加し、24時間培養した。5日目に、細胞を洗浄した後、eIF4A阻害剤Cmp1(0、1.2、3.7、11.1、33.3または100 nM)を含む新鮮な無血清DMEMを添加し、培養した。コントロールには未処理の細胞が含まれていた。eIF4A阻害剤の添加後48時間で、300ulの培地を回収し、遠心分離して細胞破片をペレット化し、-80℃で凍結した。培地中のTGFβ1は、製造元の指示に従って、ヒトTGF-B1 ELISAキット(R&D System DY240-05)を使用して定量した。プロコラーゲン1型Cペプチド(PIPC)レベルは、(PIP)EIAキット(Clontech、Cat。No. MK101)を使用して、製造元の指示に従って分析した。
筋線維芽細胞は、形質転換成長因子-βの外因性添加を使用して分化および活性化された。事前に形成された筋線維芽細胞からのTGFβ分泌を阻害するCmp1の能力をELISA分析により評価した。図3Aに示すように、eIF4A阻害剤Cmp1による筋線維芽細胞の48時間の処理により、用量依存的に分泌TGFβのレベルが低下した。Cmp1処理によるTGFβの阻害は、プロコラーゲンI型レベルの対応する用量依存的減少をもたらした(図3B)。
事前に形成された筋線維芽細胞は、機密の(secrete)TGFβを分泌し、I型コラーゲンなどの細胞外マトリックス成分の継続的な発現をもたらします。事前に形成された筋線維芽細胞をeIF4A阻害剤(Cmp1)で処理すると、TGFβとプロコラーゲンI型の分泌が阻害され、eIF4Aの阻害がTGFβとコラーゲン産生を調節することで腫瘍間質リモデリングを変更できることが示された。これらのデータは、eIF4A阻害がT細胞の局在化と腫瘍への浸潤に影響を及ぼす可能性があることを示している。
腫瘍浸潤リンパ球に対するCMP1の影響
間質に富む腫瘍タイプ(例えば、膵管腺癌)は、治療が非常に難しい癌である。可溶性サイトカイン、成長因子、プロテアーゼ、および細胞外マトリックスの成分の複雑なネットワークは、腫瘍微小環境内で協調的に相互作用し、がん細胞の増殖、浸潤、早期転移を維持および促進し、治療抵抗性を媒介する。T細胞の局在と移動は、抗腫瘍免疫監視の前提条件である。T細胞は腫瘍よりも間質に効率的に蓄積することがわかり、間質細胞外マトリックスがT細胞の移動を制御する上で重要な役割を果たしている。細胞外マトリックス成分の阻害は、腫瘍へのT細胞浸潤を増加させ、間質細胞外マトリックスがT細胞の位置付けと移動を制御することにより抗腫瘍免疫に影響することを示している。
CMP1の免疫細胞浸潤を調節する能力は、マウスKPC-3腫瘍モデルで生体内でIHC分析により評価された(図4A)。ビヒクルで処理した腫瘍サンプルでは、最小限のCD3-またはCD8-陽性T細胞が検出された。0.3mg/kgQ2Dまたは1mg/kgQ1WのCmp1を17日間投与すると、KPC-3腫瘍サンプルのCD3+T細胞が大幅に増加した(図4B)。1mg/kgQ1WCmp1で処理した動物でも、CD8+T細胞の有意な増加が観察された(図4C)。
間質細胞外マトリックスは、T細胞の局在と移動を制御することにより、抗腫瘍免疫に影響を及ぼすことが示されている。eIF4A阻害剤は、TGFβレベルの減少を通じて間質細胞外マトリックスを変化させ、I型コラーゲンレベルのダウンレギュレーションをもたらすことが観察された。Cmp1による膵臓KPC-3腫瘍モデルの生体内治療により、腫瘍内のCD3+およびCD8+T細胞が増加しました。これらの結果は、Cmp1が細胞外マトリックスを変化させ、免疫応答の誘発に重要な腫瘍浸潤リンパ球の局在に影響を与える可能性があることを示唆している。
Claims (18)
- 対象における非炎症固形腫瘍の治療のための薬剤の製造に使用するためのeIF4A阻害剤であって、
前記eIF4A阻害剤は、式I:
(式I中、
Xは、Oであり、
Yは、6員ヘテロアリールであり、前記6員ヘテロアリールはピリジニルであり、
R1およびR2は、独立して、アリール、ヘテロシクリル、ヘテロアリールまたはシクロアルキルであり、
R3a、R3b、R4aおよびR4bは、独立して、H、ハロゲン、CN、C1~C8(アルキル)、(C1~C8)ハロアルキル、C2~C8(アルケニル)、(C2~C8)アルキニル、OR9、NHR9、NR9R9、[(C1~C8)アルキレン]OR9、[(C1~C8)アルキレン]NHR9、[(C1~C8)アルキレン]NR9R9、C(O)R8、C(O)NHR9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NHR9、C(O)[(C1~C8)アルキレン]NR9R9、CO2R9、C(S)NHR9、C(S)NR9R9、SR9、S(O)R9、SO2R9、SO2NHR9、SO2NR9R9、NH(CO)R8、NR9(CO)R8、NH(CO)NHR9、NH(CO)NR9R9、NR9(CO)NHR9、NR9(CO)NR9R9、P(O)(OH)(OR9)、P(O)(OR9)(OR9)、アリール、ヘテロアリール、シクロアルキルまたはヘテロシクリルであり、
R3a、R3b、R4aおよびR4bは、独立して、結合してオキソもしくはアルケニル、またはシクロアルキル環もしくはヘテロシクリル環を形成し、
R3aおよびR4a、R3bおよびR4bまたはR4aおよびR5は、それらが結合している炭素原子と共にシクロアルキル環またはヘテロシクリル環を形成し、
R2およびR3aは、それらが結合している炭素原子と共に二環式環系を形成し、
R5は、H、ハロゲン、OH、CN、N3、SR9、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルキニル、NHC(O)(C1~C8)アルキルまたはヘテロアリールであり、
R 8 は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、シクロアルキル、O(シクロアルキル)、ヘテロシクリル、O(ヘテロシクリル)、アリール、O(アリール)、ヘテロアリールまたはO(ヘテロアリール)であり、
R9は、H、(C1~C8)アルキル、(C1~C8)ハロアルキル、シクロアルキル、ヘテロシクリル、[(C1~C8)アルキレン]ヘテロシクリル、アリール、[(C1~C8)アルキレン]アリールまたはヘテロアリールであり、
ここで、NR9R9、[(C1~C8)アルキレン]NR9R9、C(O)NR9R9、C(O)[(C1~C8)アルキレン]NR9R9、C(S)NR9R9、SO2NR9R9、NH(CO)NR9R9またはNR9(CO)NR9R9の前記2つのR9は、それらが結合している窒素原子と共に任意にヘテロシクリル環を形成し、
任意のアルキル、アルケニル、シクロアルキル、ヘテロシクリル、ヘテロアリールまたはアリールは、OH、CN、SH、SO2NH2、SO2(C1~C4)アルキル、SO2NH(C1~C4)アルキル、ハロゲン、NH2、NH(C1~C4)アルキル、N[(C1~C4)アルキル]2、C(O)NH2、COOH、COOMe、アセチル、(C1~C8)アルキル、O(C1~C8)アルキル、O(C1~C8)ハロアルキル、(C2~C8)アルケニル、(C2~C8)アルキニル、ハロアルキル、チオアルキル、シアノメチレン、アルキルアミニル、NH2-C(O)-アルキレン、NH(Me)-C(O)-アルキレン、CH2-C(O)-低級アルキル、C(O)-低級アルキル、アルキルカルボニルアミニル、CH2-[CH(OH)]m-(CH2)p-OH、CH2-[CH(OH)]m-(CH2)p-NH2またはCH2-アリール-アルコキシから選択される1、2、もしくは3の基で任意に置換されており、または
任意のアルキル、シクロアルキルまたはヘテロシクリルは、オキソで任意に置換されており、
「m」および「p」は、1、2、3、4、5または6である)
に従った化合物、もしくは立体異性体、互変異性体、または薬学的に許容されるそれらの塩を含んで成る、eIF4A阻害剤。 - 前記eIF4A阻害剤は、経口、非経口、舌下、頬、静脈内、直接腫瘍内注射による投与、またはそれらの任意の組み合わせで投与される、請求項1または2に記載の使用のためのeIF4A阻害剤。
- 前記治療は、免疫抑制成分の阻害剤の投与をさらに含んで成る、請求項1または2に記載の使用のためのeIF4A阻害剤。
- 前記免疫抑制成分の前記阻害剤は、PD-1、PD-L1、PD-L2、LAG3、CTLA4、B7-H3、B7-H4、CD244/2B4、HVEM、BTLA、CD160、TIM3、GAL9、アデノシン、A2aR、免疫抑制性サイトカイン、IDO、アルギナーゼ、VISTA、TIGIT、PVRIG、PVRL2、KIRs、LAIR1、CEACAM-1、CEACAM-3、CEACAM-5、CD160、Treg細胞、またはそれらの任意の組合せ、の活性を阻害する、請求項4に記載の使用のためのeIF4A阻害剤。
- 前記免疫抑制成分の前記阻害剤は、抗体、もしくはその抗原結合フラグメント、融合タンパク質、小分子、RNAi分子、リボザイム、アプタマー、アンチセンスオリゴヌクレオチドまたはそれらの任意の組合せからなる群より選択される、請求項5に記載の使用のためのeIF4A阻害剤。
- 前記免疫抑制成分の前記阻害剤は、ピジリズマブ、ニボルマブ、ペンブロリズマブ、MEDI0680、AMP-224、BMS-936558 BMS-936559、デュルバルマブ、アテゾリズマブ、アベルマブ、MPDL3280A、LAG525、IMP321、IMP701、9H12、BMS-986016、イピリムマブ、トレメリムブ、アバタセプト、ベラタセプト、エノブリツズマブ、376.96、抗B7-H4抗体もしくはその抗原結合フラグメント、リリルマブ、レボ-1-メチルトリプトファン、エパカドスタット、エブセレン、インドキシモド、NLG919、1-メチル-トリプトファン(1-MT)-チラ-パザミン、N(オメガ)-ニトロ-L-アルギニンメチルエステル(L-NAME)、N-オメガ-ヒドロキシ-ノル-L-アルギニン(nor-NOHA)、L-NOHA、2(S)-アミノ-6-ボロノヘキサン酸(ABH)、S-(2-ボロノエチル)-L-システイン(BEC)、CA-170、COM902、COM701、またはそれらの抗原結合フラグメント、またはそれらの任意の組み合わせを含んで成る、請求項6に記載の使用のためのeIF4A阻害剤。
- 前記治療は、刺激性免疫チェックポイント分子のアゴニストの投与をさらに含んで成る、請求項1~7の何れかに記載の使用のためのeIF4A阻害剤。
- 刺激性免疫チェックポイント分子の前記アゴニストは、MEDI6469、MEDI6383、MEDI0562、ポマリドマイド、CDX-1127、TGN1412、CD80、CD86、CP-870,893、rhuCD40L、SGN-40、IL-2、GSK3359609、mAb88.2、JTX-2011、Icos145-1、Icos314~8、ピジリズマブ、ニボルマブ、ペンブロリズマブ、MEDI0680、AMP-224、BMS-936558 BMS-936559、デュルバルマブ、アテゾリズマブ、アベルマブ、MPDL3280A、LAG525、IMP321、IMP701、9H12、BMS-986016、イピリムマブ、トレメリムブ、アバタセプト、ベラタセプト、エノブリツズマブ、376.96、抗B7-H4抗体もしくはその抗原結合フラグメント、リリルマブ、レボ-1-メチルトリプトファン、エパカドスタット、エブセレン、インドキシモド、NLG919、1-メチル-トリプトファン(1-MT)-チラ-パザミン、N(オメガ)-ニトロ-L-アルギニンメチルエステル(L-NAME)、N-オメガ-ヒドロキシ-ノル-L-アルギニン(nor-NOHA)、L-NOHA、2(S)-アミノ-6-ボロノヘキサン酸(ABH)、S-(2-ボロノエチル)-L-システイン(BEC)、CA-170、COM902、COM701、またはそれらの抗原結合フラグメントまたはそれらの任意の組合せから選択される、請求項8に記載の使用のためのeIF4A阻害剤。
- 前記治療は、変性抗腫瘍リンパ球の投与をさらに含んで成り、
前記変性抗腫瘍リンパ球は、CD8+T細胞、CD4+T細胞またはその両方を含んで成る、請求項1~9の何れかに記載の使用のためのeIF4A阻害剤。 - 前記変性抗腫瘍リンパ球は、同種T細胞、自己T細胞、同系T細胞、またはそれらの任意の組合せから作られる、請求項10に記載の使用のためのeIF4A阻害剤。
- 前記変性抗腫瘍リンパ球は、非炎症固形腫瘍により発現される癌抗原に特異的に結合する異種受容体を含んで成る、請求項10または11に記載の使用のためのeIF4A阻害剤。
- 前記変性抗腫瘍リンパ球は、
(a)キメラ抗原受容体、異種T細胞受容体、異種高親和性T細胞受容体、またはそれらの任意の組合せを含んで成るT細胞、
(b)キメラ抗原受容体、異種T細胞受容体、異種高親和性T細胞受容体、またはそれらの任意の組合せを任意で含んで成るNK細胞、
(c)キメラ抗原受容体、異種T細胞受容体、異種高親和性T細胞受容体、またはそれらの任意の組合せを任意に含んで成るNK-T細胞、
(d)前記非炎症性固形腫瘍により発現される癌抗原に特異的な1または複数の抗体を産生するB細胞、または
(e)任意の(a)~(d)の組合せ
を含んで成る、請求項10または11に記載の使用のためのeIF4A阻害剤。 - 前記キメラ抗原受容体が、抗原ペプチドMHC複合体に特異的に結合する、および/または前記TCRが、抗原ペプチドMHC複合体に特異的に結合し、
前記抗原は、ROR1、EGFR、EGFRvIII、GD2、GD3、HPV E6、HPV E7、Her2、L1-CAM、ルイスA、ルイスY、MUC1、MUC16、PSMA、CD19、CD20、CD22、CD56、CD23、CD24、CD37、CD30、CD33、CD38、CD56、CD123、CA125、c-MET、FcRH5、WT1、葉酸受容体α、VEGF-α、VEGFR1、VEGFR2、IL-13Rα2、IL-11Rα、MAGE-A1、PSA、ephrinA2、ephrinB2、NKG2Dリガンド、NY-ESO-1、TAG-72、メソセリンまたはCEAからのものである、請求項13に記載の使用のためのeIF4A阻害剤。 - 前記治療は、前記非炎症性固形腫瘍に発現する癌抗原に特異的な抗体もしくは抗原結合フラグメント、化学療法剤、手術、放射線療法、抗癌サイトカイン、RNA干渉分子、またはそれらの任意の組合せから選択される二次療法を施すことをさらに含んで成り、
前記二次療法が、IFN-α、IL-2、IL-3、IL-4、IL-10、IL-12、IL-13、IL-15、IL-16、IL-17、IL-18、IL-21、IL-24、およびGM-CSFまたはそれらの組合せを含んで成るサイトカインを含んで成る、請求項1~11の何れかに記載の使用のためのeIF4A阻害剤。 - 前記非炎症性固形腫瘍は、肉腫、癌腫、神経膠腫、リンパ腫、またはそれらの任意の組合せを含んで成る、請求項1~15の何れかに記載の使用のためのeIF4A阻害剤。
- 前記対象は、頭頸部がん、黒色腫、膵臓がん、胆管がん、肝細胞がん、乳がん、胃がん、非小細胞肺がん、前立腺がん、食道がん、中皮腫、小細胞肺がん、結腸直腸がん、膠芽腫、またはそれらの任意の組み合わせを有するか、または有する疑いがある、請求項1~16の何れかに記載の使用のためのeIF4A阻害剤。
- 前記癌は、アスキンの腫瘍、肉腫ボトリノイド、軟骨肉腫、ユーイング肉腫、PNET、悪性血管内皮腫、悪性神経鞘腫、骨肉腫、胞巣状軟部肉腫、血管肉腫、葉状嚢胞肉腫、隆起性皮膚繊維肉腫(DFSP)、デスモイド腫瘍、線維形成性小円形細胞腫瘍、類上皮肉腫、骨外性軟骨肉腫、骨外性骨肉腫(extraskeletal osteosarcoma)、線維肉腫、消化管間質腫瘍(GIST)、血管周囲細胞腫、血管肉腫、カポジ肉腫、平滑筋肉腫、脂肪肉腫、リンパ管肉腫、リンパ肉腫、未分化多形性肉腫、悪性末梢神経鞘腫瘍(MPNST)、神経線維、横紋筋肉腫、滑膜肉腫、未分化多形性肉腫(undifferentiated pleomorphic sarcoma)、扁平上皮癌、基底細胞癌、腺癌、リニティス・プラスティカ(linitis plastic)、ビポーマ(vipoma)、胆管癌、肝細胞癌、腺様嚢胞癌、腎細胞癌、Grawitz腫瘍、上衣腫、星細胞腫、乏突起膠腫、脳幹神経膠腫、視神経膠腫、混合神経膠腫、ホジキンリンパ腫、B細胞リンパ腫、非ホジキンリンパ腫(NHL)、バーキットリンパ腫、小リンパ球性リンパ腫(SLL)、びまん性大細胞型B細胞リンパ腫、濾胞性リンパ腫、免疫芽球性大細胞リンパ腫、前駆Bリンパ芽球性リンパ腫、およびマントル細胞リンパ腫、ヴァルデンストレームマクログロブリン血症、CD37+樹状細胞リンパ腫、リンパ性リンパ腫、脾辺縁帯リンパ腫、粘膜関連(MALT)リンパ組織の結節辺縁帯B細胞リンパ腫、縦隔(胸腺)大細胞型B細胞リンパ腫、血管内大B細胞リンパ腫の、外節性辺縁帯B細胞リンパ腫、原発性滲出性リンパ腫(primary effusion lymphoma)、成人T細胞リンパ腫、節外性NK/T細胞リンパ腫、鼻型(nasal type)、腸関連T細胞リンパ腫、肝脾T細胞リンパ腫、芽球性NK細胞リンパ腫、セザリー症候群、血管免疫芽球性T細胞リンパ腫、未分化大細胞リンパ腫、またはそれらの任意の組合せを含んで成る、請求項17に記載の使用のためのeIF4A阻害剤。
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US11576933B2 (en) | 2023-02-14 |
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CN110891567B (zh) | 2024-01-09 |
BR112019024719A2 (pt) | 2020-06-16 |
KR102641269B1 (ko) | 2024-02-26 |
US20200147135A1 (en) | 2020-05-14 |
JP2020521750A (ja) | 2020-07-27 |
CA3063563A1 (en) | 2018-11-29 |
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