TW202317559A - 作為ron抑制劑之新穎尿素衍生物化合物 - Google Patents
作為ron抑制劑之新穎尿素衍生物化合物 Download PDFInfo
- Publication number
- TW202317559A TW202317559A TW111123537A TW111123537A TW202317559A TW 202317559 A TW202317559 A TW 202317559A TW 111123537 A TW111123537 A TW 111123537A TW 111123537 A TW111123537 A TW 111123537A TW 202317559 A TW202317559 A TW 202317559A
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- TW
- Taiwan
- Prior art keywords
- pyrazole
- pyridin
- trifluoromethyl
- dihydro
- imidazo
- Prior art date
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- -1 urea derivative compound Chemical class 0.000 title claims description 191
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- 229910052760 oxygen Inorganic materials 0.000 claims description 48
- 239000001301 oxygen Substances 0.000 claims description 48
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 46
- 229910052731 fluorine Inorganic materials 0.000 claims description 45
- 150000003839 salts Chemical class 0.000 claims description 31
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical group 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 150000003573 thiols Chemical class 0.000 claims description 4
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 150000003230 pyrimidines Chemical class 0.000 claims description 3
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- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004968 peroxymonosulfuric acids Chemical class 0.000 description 1
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- ITYLVGSRFWGZFJ-UHFFFAOYSA-N tert-butyl n-[4-(2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl]carbamate Chemical compound FC1=CC(NC(=O)OC(C)(C)C)=CC=C1OC1=CC=NC(N)=C1N ITYLVGSRFWGZFJ-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000006276 transfer reaction Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
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- Animal Behavior & Ethology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本發明關於作為蛋白質激酶抑制劑,特別是RON抑制劑之新穎化合物。
Description
本發明關於作為蛋白質激酶抑制劑之新穎化合物。具體而言,本發明關於作為RON抑制劑之新穎化合物。
相關申請案之交互參照
本申請案請求於2021年6月24日向韓國智慧財產局申請之韓國專利申請案第10-2021-0082700號之權益,其揭露之內容係以引用方式全文併入本文中。
已知至少有400種蛋白質激酶催化從三磷酸腺苷(ATP)至蛋白質受質之磷酸基轉移反應(phosphoryl transfer reaction)。在磷酸基轉移至的目標蛋白質中,特異性胺基酸係酪胺酸、絲胺酸、或蘇胺酸,因此蛋白質激酶通常被稱為蛋白質酪胺酸激酶(PTK)或絲胺酸/蘇胺酸激酶(STK)。
該等蛋白質激酶構成結構上相關群組之大家族,負責控制細胞內各種訊號傳導路徑。訊號傳導路徑包括許多藉由將磷酸基轉移至目標蛋白質的其他訊號傳導路徑。此等磷酸化事件作用為分子開/關(on/off)開關,其可調控目標蛋白質或蛋白質複合物之生物功能。在訊號傳導路徑中適當的蛋白質激酶功能係活化或去活化代謝酶、調控蛋白質、受體、細胞骨架蛋白質、離子通道及離子幫浦、轉錄因子等。由於蛋白質磷酸化之控制缺陷所致之不受控的訊號傳導係與許多疾病有關,包括炎症、癌症、過敏/氣喘、免疫系統疾病、中樞神經系統疾病、血管生成等。
幾乎所有激酶均包括類似的250至300個胺基酸的催化結構域。激酶可藉由其磷酸化之受質來分類,且已經識別出大致上對應於此等激酶家族之各者的序列基序。
與此同時,亦將源自南特之受體(receptor originated from nante, RON)(其係酪胺酸蛋白質激酶受體中之一者)稱為巨噬細胞刺激1受體(macrophage stimulating 1 receptor, MST1R),且已有報導其促進癌症細胞之侵襲及轉移。亦已知在許多腫瘤類型中出現RON之過度表現。
在腫瘤細胞中活化酪胺酸蛋白質激酶(諸如RON)增加腫瘤細胞之增殖、侵襲、及轉移,且增加腫瘤細胞對凋亡及細胞毒性療法之抗性。為此,靶向酪胺酸蛋白質激酶(諸如RON)之選擇性小分子激酶調節劑有望對治療其中RON受體等之活化在原發性腫瘤及繼發性轉移之進展上具有關鍵作用的癌症具有治療潛力。因此,對於選擇性抑制RON(酪胺酸蛋白質中之一者)之激酶活性的各種抑制劑正在持續進行研究中。
技術問題
本發明之態樣提供具有蛋白質激酶抑制活性之新穎化合物。
本發明之另一態樣提供可用於預防或治療癌症之化合物。
本發明之又另一態樣提供可用於預防或治療免疫相關之疾病之化合物。
本發明之又另一態樣提供可用作RON抑制劑之化合物。
技術解決方案
為了達到上述目的,
根據本發明之態樣,提供下式1之吡啶衍生物化合物或其醫藥上可接受之鹽。
在式1中,
上述X係O,
上述Y係氫、鹵素、C
1-C
6烷基、或C
3-C
6環烷基,
上述R
1係氫、C
1-C
6烷基、C
3-C
12環烷基、或C
2-C
11雜環烷基,
上述R
2係氫或C
1至C
6烷基,
上述A係-Ar或-(CH
2)n-Ar,其中Ar係經取代或未經取代之C
6-C
10芳基、或經取代或未經取代之包括1至4個選自由氮、硫、及氧所組成之群組的雜環原子的5員雜芳基,其中取代基係選自下列中之一或多者:鹵素、胺、C
1-C
6烷基、C
3-C
12環烷基、經鹵素取代之C
1-C
6烷基、C
6-C
10芳基、C
1-C
6烷氧基、C
1-C
6烷硫基、羥基、羧酸、C
1-C
6烷羰基、C
1-C
6烷氧羰基、C
1-C
6烷羰氧基、硝基、氰基、胺甲醯基、尿素、硫醇基、及NR
3R
4,且上述n係1至3之整數,
上述R
3及R
4各自獨立地係氫或C
1-C
6烷基,
上述B係C
3-C
19雜芳基或經取代之C
3-C
19雜芳基,其中取代基係鹵素、C
1-C
6烷基、C
3-C
7環烷基、經鹵素取代之C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
11雜環烷基、 C
3-C
11雜環烯基、或C
6-C
10芳基,
其中鹵素係選自由下列所組成之群組:F、Cl、Br、及I。
根據本發明之另一態樣,提供醫藥組成物,其包括上述式1之化合物或其醫藥上可接受之鹽、及醫藥上可接受之載劑。
有利效果
根據本發明,一種新穎化合物或其醫藥上可接受之鹽,其藉由抑制蛋白質激酶、特別是RON受體之蛋白質激酶活性而可用於治療各種免疫媒介之疾病,包括抗癌劑,但本發明不限於此。
根據一個態樣,本發明提供上述所定義之式1之新穎尿素衍生物化合物或其醫藥上可接受之鹽。
在本發明中,化合物包括但不限於式1之化合物、其立體異構物(諸如鏡像異構物及非鏡像異構物)、溶劑合物、及前藥。
在式1中,
上述X係O,
上述Y係氫、鹵素、C
1-C
6烷基、或C
3-C
6環烷基,
上述R
1係氫、C
1-C
6烷基、C
3-C
12環烷基、或C
2-C
11雜環烷基,
上述R
2係氫或C
1-C
6烷基,
上述A係-Ar或-(CH
2)n-Ar,其中Ar係經取代或未經取代之C
6-C
10芳基、或經取代或未經取代之包括1至4個選自由氮、硫、及氧所組成之群組的雜環原子的5員雜芳基,其中取代基係選自下列中之一或多者:鹵素、胺、C
1-C
6烷基、C
3-C
12環烷基、經鹵素取代之C
1-C
6烷基、C
6-C
10芳基、C
1-C
6烷氧基、C
1-C
6烷硫基、羥基、羧酸、C
1-C
6烷羰基、C
1-C
6烷氧羰基、C
1-C
6烷羰氧基、硝基、氰基、胺甲醯基、尿素、硫醇基、及NR
3R
4,且上述n係1至3之整數,
上述R
3及R
4各自獨立地係氫或C
1-C
6烷基,
上述B係C
3-C
19雜芳基或經取代之C
3-C
19雜芳基,其中取代基係鹵素、C
1-C
6烷基、C
3-C
7環烷基、經鹵素取代之C
1-C
6烷基、C
1-C
6烷氧基、C
3-C
11雜環烷基、 C
3-C
11雜環烯基、或C
6-C
10芳基,
其中鹵素係選自由下列所組成之群組:F、Cl、Br、及I。
在本說明書中,術語「取代(substitution)」意指將與結構中之碳原子結合的氫原子改變成另一個取代基,且取代發生之位置不受限制,只要其係氫原子被取代之位置(亦即取代基可取代之位置)即可,且當在二或更多個位置處取代時,二或更多個取代基可係彼此相同或不同。
在本說明書中,除非另有定義,否則「取代基(substituent)」可係選自由下列所組成之群組中之一或多者:氘、鹵素、羥基、C
1-C
10烷基、C
3-C
12環烷基、 C
1-C
10烷氧基、C
5-C
12芳氧基、C
1-C
10烷硫氧基(alkylthioxy)、C
5-C
12芳硫氧基(arylthioxy)、C
1-C
10烷磺醯氧基(alkylsulfoxy)、C
5-C
12芳磺醯氧基(arylsulfoxy)、 C
1-C
10鹵烷基、C
2-C
20烯基、C
0-C
10胺、腈、硝基、亞醯胺、醯胺、側氧基、羰基、羧酸、胺甲醯基、酯、C
5-C
12芳基、及C
5-C
12雜芳基。
在本說明書中,「烷基(alkyl)」可係直鏈或支鏈,且較佳地具有1至20個碳原子,除非另有定義。其實施例可包括甲基、乙基、丙基、正丙基、異丙基、丁基、正丁基、異丁基、三級丁基、二級丁基、1-甲基丁基、乙基丁基、戊基、正戊基、異戊基、新戊基、三級戊基、己基、正己基、甲基戊基、2-甲基戊基、4-甲基-2-戊基、3,3-二甲基丁基、2-乙基丁基、庚基、正庚基、1-甲基己基、環戊基甲基、環己基甲基、辛基、正辛基、三級辛基、1-甲基庚基、2-乙基己基、2-丙基戊基、正壬基、2,2-二甲基庚基、1-乙基丙基、二甲基丙基、異己基、2-甲基戊基、4-甲基己基、5-甲基己基等,但不限於此。
在本說明書中,「環烷基(cycloalkyl)」可意指環狀飽和烴,且較佳地具有3至20個碳原子,除非另有定義。其實施例可包括環丙基、環丁基、環戊基、3-甲基環戊基、2,3-二甲基環戊基、環己基、3-甲基環己基、4-甲基環己基、2,3-二甲基環己基、3,4,5-三甲基環己基、4-三級丁基環己基、環庚基、環辛基等,但不限於此。
在本說明書中,「烷氧基(alkoxy)」可係直鏈、支鏈、或環狀,且較佳地具有1至20個碳原子,除非另有定義。其實施例可包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、三級丁氧基、二級丁氧基、正戊氧基、新戊氧基、異戊氧基、正己氧基、3,3-二甲基丁氧基、2-乙基丁氧基、正辛氧基、正壬氧基、正癸氧基、苄氧基、對甲基苄氧基等,但不限於此。
在本說明書中,「烯基(alkenyl)」可係直鏈或支鏈,且較佳地具有2至20個碳原子,除非另有定義。其實施例可包括乙烯基、1-丙烯基、異丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、3-甲基-1-丁烯基、1,3-丁二烯基、烯丙基、1-苯基乙烯-1-基、2-苯基乙烯-1-基、2,2-二苯基乙烯-1-基、2-苯基-2-(萘-1-基)乙烯-1-基、2,2-雙(二苯-1-基)乙烯-1-基、芪基(stilbenyl group)、苯乙烯基等,但不限於此。
在本說明書中,「芳基(aryl)」可係單芳基(monoaryl)、聯芳基(biaryl)、或三或更多個環之多環芳基(polycyclic aryl),且當包括二或更多個環狀結構時,各環可經稠合或以螺環接(spiro)形式包括,且較佳地具有5至12個碳原子,除非另有定義。其實施例可包括苯基、聯苯基、聯三苯基、萘基、蒽基、菲基、芘基、苝基等,但不限於此。
在本說明書中,「雜環原子(heterocyclic atom)」意指環中包括非碳原子。除非另有定義,否則雜環原子可包括一或多個選自氧、氮、硒、及硫之原子。
在本說明書中,「雜環烷基(heterocycloalkyl)」可意指包括雜原子之環狀飽和烴,且較佳地具有2至20個碳原子,除非另有定義。
在本說明書中,「雜芳基(heteroaryl)」可意指包括雜環原子之芳族烴。雜芳基可係單環或多環,且當包括二或更多個環狀結構時,各環可經稠合或以螺環接(spiro)形式包括,且較佳地具有5至12個碳原子,除非另有定義。其實施例可包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、㗁唑基、㗁二唑基、吡啶基、聯吡啶基(bipyridyl group)、嘧啶基、三𠯤基、三唑基、吖啶基、嗒𠯤、吡𠯤、喹啉基、喹唑啉基、喹㗁啉基、呔𠯤基、吡啶并嘧啶基(pyrido pyrimidyl group)、吡啶并吡𠯤基(pyrido pyrazinyl group)、吡𠯤并吡𠯤基(pyrazino pyrazinyl group)、異喹啉基、吲哚基、咔唑基(carbazolyl group)、苯并㗁唑基(benzoxazolyl group)、苯并咪唑基(benzimidazolyl group)、苯并噻唑基(benzothiazolyl group)等,但不限於此。
根據具體實施例,本發明提供下述式2之新穎尿素衍生物化合物或其醫藥上可接受之鹽。
取代基係與式1中之定義相同。
根據具體實施例,在上述式1中,上述A可係-Ar或-(CH
2)n-Ar,其中上述Ar係經取代或未經取代之 C
6-C
10芳基或經取代或未經取代之5員雜芳基。此時,就結構A而言,術語「芳基」不僅意指其中A係單價官能基的結構(亦即其中上述式1中之B係氫的結構),且當上述B具有非氫的結構時,上述Ar可係經取代或未經取代之 C
6-C
10亞芳基或經取代或未經取代之5員雜亞芳基。
根據具體實施例,在上述式1中,上述A可係經取代或未經取代之5員雜芳基,且具體而言,可包括至少二個雜環原子。此時,所包括之雜環原子可係相同或彼此不同,但不限於此。
根據另一具體實施例,在上述式1中,上述Ar可包括至少一個氮原子作為雜環原子,且可進一步包括至少一個選自氮及硫之雜環原子。
根據另一具體實施例,上述Ar可包括一或二個選自由吡唑、咪唑、及噻唑所組成之群組的雜芳基,其中雜芳基可係經取代或未經取代,且經取代之雜芳基具有之取代基可係鹵素、胺、C
1-C
6烷基、C
3-C
12環烷基、經鹵素取代之C
1-C
6烷基、C
6-C
10芳基、C
1-C
6烷氧基、C
1-C
6烷硫基、羥基、羧酸、C
1-C
6烷羰基、C
1-C
6烷氧羰基、C
1-C
6烷羰氧基、硝基、氰基、胺甲醯基、尿素、硫醇基、及NR
3R
4。此時,上述R
3及R
4係如上述所定義。
根據另一具體實施例,在上述式1中,上述A可係經取代或未經取代之C
6-C
10芳基,且具體而言,可係經取代或未經取代之苯基。此時,經取代之苯基具有之取代基可係選自鹵素及經鹵素取代之C
1-C
6烷基中之一或多者。更具體而言,經取代之苯基具有之取代基可係選自氟、溴、及三氟甲基中之一或多者。
根據另一具體實施例,在上述式1中,上述A可係-(CH
2)n-Ar,其中n可係1至3之整數,且例如,n可係1。
根據具體實施例,在上述式1中,上述B可係嘧啶、經取代之嘧啶、嗒𠯤、經取代之嗒𠯤、或喹啉,其中取代基可係鹵素、C
1-C
3烷基、鹵化C
1-C
3烷基、C
3-C
5環烷基、C
4-C
6雜環烯基、或C
1-C
3烷氧基。
根據具體實施例,在上述式1中,上述Y係氟。
根據具體實施例,在上述式1中,上述R
1係C
1-C
6烷基、C
3-C
6環烷基、或C
4-C
6雜環烷基。
根據另一具體實施例,在上述式1中,上述R
1係氫、甲基、乙基、異丙基、環戊基、或四氫呋喃基。
根據具體實施例,在上述式1中,上述R
2係氫。
根據具體實施例,在上述式1之化合物可係選自由下列所組成之群組:
5-乙基-N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺,
5-乙基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-5-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺,
N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(3-氯吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(5-氯吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(3-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(5-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(4-氯吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(4-溴吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(4-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(6-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(3-溴吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(異喹啉-1-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(6-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(吡啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-甲基嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(3-乙基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(4-乙基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(4-環丙基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(4-(3,6-二氫-2H-哌喃-4-基)吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嗒𠯤-3-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-甲基嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
1-(3-乙氧基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
N-(3-氟-4-((2-側氧基-1-(四氫呋喃-3-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
及
N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺,
且其結構係如下表1中所示:
在本發明中,「醫藥上可接受之鹽(pharmaceutically acceptable salt)」包括常用於形成鹼金屬鹽及形成游離酸或游離鹼之加成鹽的鹽。此類鹽之性質並不重要,但應係醫藥上可接受的。適用於式1之化合物之醫藥上可接受之酸加成鹽可從無機酸或有機酸製備。無機酸之實施例可括鹽酸、氫溴酸、氫碘酸、硝酸、碳酸、硫酸、及磷酸。合適的有機酸可選自脂族、脂環族、芳族、芳基脂族、雜環族、羧酸、及磺酸類之有機酸,且其實施例可括甲酸、乙酸、己二酸、丁酸、丙酸、丁二酸、乙醇酸、葡萄糖酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、葡萄糖醛酸、順丁烯二酸、反丁烯二酸、丙酮酸、天門冬胺酸、麩胺酸、苯甲酸、鄰胺苯甲酸(anthranilic acid)、甲磺酸(mesylic acid)、4-羥基苯甲酸、苯乙酸、杏仁酸、撲酸(embonic acid/pamoic acid)、甲烷磺酸、乙烷磺酸、乙烷二磺酸(ethanedisulfonic acid)、苯磺酸、泛酸(pantothenic acid)、2-羥基乙烷磺酸、甲苯磺酸、磺胺酸(sulfanilic acid)、環己基胺基磺酸(cyclohexylaminosulfonic acid)、樟腦酸、樟腦磺酸(camphorsulfonic acid)、二葡萄糖酸(digluconic acid)、環戊烷丙酸(cyclopentanepropionic acid)、十二烷基磺酸(dodecylsulfonic acid)、葡糖庚酸(glucoheptanoic acid)、甘油膦酸(glycerophosphonic acid)、庚酸、己酸、2-羥基-乙磺酸、菸鹼酸、2-萘磺酸、草酸、棕櫚酸(palmoic acid)、果膠酯酸、過硫酸、2-苯基丙酸、苦味酸、三甲基乙酸(pivalic acid)、丙酸、丁二酸、酒石酸、硫氰酸、甲磺酸、十一酸、硬脂酸、海藻酸(algenic acid)、β-羥基丁酸、水楊酸、半乳糖二酸、及半乳糖醛酸(galacturonic acid)。適用於式1之化合物之醫藥上可接受之鹼加成鹽可係金屬鹽,例如,從鋁、鈣、鋰、鎂、鉀、鈉、或鋅製備之鹽,或從有機鹼製備之鹽,該等有機鹼包括經取代之胺(包括一級胺、二級胺、或三級胺)及環胺,例如,咖啡因、精胺酸、二乙胺、N-乙基哌啶、組胺酸、還原葡糖胺、異丙基胺、離胺酸、嗎啉、N-乙基嗎啉、哌𠯤、哌啶、三乙基胺、或三甲基胺。此等鹽可藉由一般方法從本發明之對應化合物製備,諸如將合適的酸或鹼與式1之化合物反應。當鹼性基團及酸性基團存在於相同分子中時,式1之化合物亦可形成內鹽。
在本發明中,「溶劑合物(solvate)」可包括水合物、具有有機溶劑之溶劑合物,該等有機溶劑諸如甲醇、乙醇、2-丙醇、1,2-丙二醇、1,3-丙二醇、正丁醇、1,4-丁二醇、三級丁醇、乙酸、丙酮、乙酸丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、甲基乙基酮、2-戊酮、四氫呋喃、乙腈、氯仿、甲苯、及其混合物。
根據另一態樣,本發明提供醫藥組成物,其包括上述所定義之式1之新穎化合物或其醫藥上可接受之鹽、及醫藥上可接受之載劑。
該醫藥組成物可用於預防或治療蛋白質激酶媒介之疾病,但本發明之用途不限於此等疾病。
在一個具體實施例中,醫藥組成物可用於預防或治療RON媒介之疾病。
根據本發明之醫藥組成物包括治療有效量的上述式1之化合物或其醫藥上可接受之鹽。
在一個具體實施例中,疾病可係選自由下列所組成之群組的癌症:肺癌、乳癌、結腸直腸癌、腎臟癌、胰臟癌、頭部癌、子宮頸癌、遺傳性乳突狀腎細胞癌(hereditary papillary renal cell carcinoma)、小兒肝細胞癌(pediatric hepatocellular carcinoma)、及胃癌,但不限於此。
在另一具體實施例中,疾病可係選自由下列所組成之群組的免疫疾病:發炎病症、心血管疾病、病毒誘導之疾病、循環系統疾病、纖維增生疾病(fibro-proliferative disease)、及痛覺(pain sensation),但不限於此。
對於治療上述疾病,可將醫藥組成物投予至有需要預防或治療上述疾病之個體。
在本說明書中,術語「預防(prevention)」意指降低感染疾病或病症之風險,且其意指藉由在暴露於或易患該疾病但尚未患有該疾病或展現出該疾病之症狀的患者中預防該疾病之一種以上臨床症狀之進展來抑制或延遲疾病發作的任何行動。
在本說明書中,術語「治療(treatment)」意指減輕疾病或病症,且其意指藉由阻止或降低疾病或其一或多種臨床症狀之進展來降低或有益地改變疾病之症狀的任何行動。
在本說明書中,術語「載劑(carrier)」意指促進將化合物引入細胞或組織中的化合物。醫藥組成物可藉由使用醫藥上可接受之載劑調配以單位劑量形式來製備,或可藉由引入到多劑量容器中來製備。此時,配方可呈於油或水性介質中之溶液、懸浮液、或乳劑之形式,或可呈萃取物、粉劑、顆粒劑、錠劑、膠囊、或凝膠(例如,水凝膠)之形式,且可額外地含有分散劑或穩定劑。
此外,包括在醫藥組成物中之由式1表示之化合物或其醫藥上可接受之鹽可被載運於醫藥上可接受之載劑中,諸如膠體懸浮液、粉劑、生理食鹽水、脂質、脂質體、微球、或奈米球粒子。上述可與輸送裝置形成複合物或與其結合,且可使用所屬技術領域中已知之輸送系統而在體內載運,該等輸送系統諸如脂質、脂質體、微粒、金、奈米粒子、聚合物、縮合反應器(condensation reactor)、多醣、聚胺基酸、樹枝狀分子(dendrimer)、皂苷、吸收增強物質(adsorption enhancing substance)、或脂肪酸。
此外,醫藥上可接受之載劑可包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、澱粉、阿拉伯膠、橡膠、磷酸鈣、海藻酸鹽、明膠、矽酸鈣、微晶纖維素、聚乙烯吡啶酮、織維素、水、糖漿、甲基纖維素、羥基苯甲酸甲酯、羥基苯甲酸丙酯、滑石粉、硬脂酸鎂、礦物油等,其等一般用於配方中,但不限於此。此外,除了上述組分之外,可額外地包括潤滑劑、潤濕劑、甜味劑、調味劑、乳化劑、懸浮劑、防腐劑等。
根據本發明之醫藥組成物可在臨床上投予時口服或腸胃外投予且可以一般醫藥配方之形式使用。亦即,本發明之醫藥組成物可在實際臨床上投予時以各種口服及腸胃外配方投予,且當調配時,使用常用稀釋劑或賦形劑(諸如填料、摻和劑、黏合劑、潤濕劑、崩散劑、界面活性劑等)製備。口服投予之固體配方包括錠劑、丸劑、酸液(acids)、顆粒劑、膠囊等,且此類固體配方係藉由在草藥萃取物或草藥發酵產物中混合至少一種賦形劑(例如,澱粉、碳酸鈣、蔗糖或乳糖、明膠等)來製備。此外,除了簡單賦形劑之外,亦使用潤滑劑諸如硬脂酸鎂滑石粉。口服投予之液體配方可包括懸浮液、內服液劑(internal liquid)、乳劑、糖漿等,且除了常用的簡單稀釋劑水及液態石蠟之外,亦可包括各種賦形劑諸如潤濕劑、甜味劑、調味劑、香氛劑、防腐劑等。腸胃外投予之配方包括無菌水性溶液、非水性溶劑、懸浮劑、乳劑、冷凍乾燥配方、及栓劑。非水性溶劑及懸浮液之實施例可包括丙二醇、聚乙二醇、植物油(諸如橄欖油)、及注射用酯諸如油酸乙酯。作為栓劑之基質材料,可使用witepsol、聚乙烯二醇、tween 61、可可脂、月桂脂(laurin fat)、甘油、明膠等。
當醫藥組成物係用於臨床目的投予時,式1之化合物或其醫藥上可接受之鹽之有效劑量可視下列因素而變化,諸如調配方法、投予模式、患者的年齡、體重、性別、病理病況、及飲食、投予時間、投予途徑、排泄率、藥物混合(drug mixing)、及反應敏感度,但大致上,醫藥組成物每1 kg成年患者體重可投予0.01至20 mg/天、較佳地1至10 mg/天,且可依醫師或藥劑師之判斷以固定的時間間隔每天分數次,較佳地每天2至3次投予。
在另一態樣中,本發明提供用於治療蛋白質激酶媒介之疾病、特別是RON媒介之疾病之方法,該方法包括向個體投予治療有效量的上述式1之化合物或其醫藥上可接受之鹽。
在另一態樣中,本發明提供用於抑制RON受體之活性之方法,該方法包括向個體投予治療有效量的上述式1之化合物或其醫藥上可接受之鹽。
在本說明書中,術語「治療有效量(therapeutically effective amount)」意指藉由各配方本身在治療期間達成降低疾病之嚴重程度及其發作頻率之目的,但避免一般與其他療法相關之有害副作用的各配方之量。舉例而言,用於腫瘤治療之有效劑係在延長患者之生存期,抑制與腫瘤相關之快速增殖細胞之生長、或腫瘤消退方面有效。
在下文中,本發明之例示化合物可根據下列方法製備,但本發明之化合物係不限於該製備方法。
製備實施例
1
。
7-(4-
胺基
-2-
氟苯氧基
)-1-
異丙基
-1,3-
二氫
-2H-
咪唑并
[4,5-b]
吡啶
-2-
酮
在下文中,製備實施例1之化合物係根據下述反應式1製備。
反應式1。
步驟1)將三級丁基(3-氟-4-羥基苯基)胺甲酸酯4-胺基-2-氟苯酚(10 g, 79 mmol)溶解於THF (100 mmol)中,然後加入Boc-酐(34.3 g, 158 mmol),並將混合物在室溫下攪拌12小時。
將反應混合物濃縮,並將殘餘物藉由管柱層析法純化,以獲得標題化合物(13 g,產率:72%)。
MS
m/z:228[M+H]。
步驟2)三級丁基(4-((2-胺基-3-硝基吡啶-4-基)氧基)-3-氟苯基)胺甲酸酯
將在上述步驟1中獲得之化合物三級丁基(3-氟-4-羥基苯基)胺甲酸酯(12.5 g, 55 mmol)及4-氯-3-硝基吡啶-2-胺(9.55 g, 55 mmol)溶解於60 mL的DMSO中,然後在0°C下加入NaH (2.64 g, 66 mmol),並將混合物在100°C下攪拌12小時。將反應混合物用乙酸乙酯稀釋,用水及鹽水洗滌,然後濃縮。將殘餘物藉由管柱層析法純化,以獲得標題化合物(15 g,產率:75%)。
MS
m/z:365[M+H]。
步驟3)三級丁基(4-((2,3-二胺基吡啶-4-基)氧基)-3-氟苯基)胺甲酸酯
在室溫下將在上述步驟2中獲得之三級丁基(4-((2-胺基-3-硝基吡啶-4-基)氧基)-3-氟苯基)胺甲酸酯溶解於甲醇/THF混合溶劑中,然後加入Pd/C,並將混合物在氫條件(hydrogen condition)下攪拌12小時。將反應混合物通過矽藻土(celite)過濾器過濾,然後濃縮。將殘餘物藉由管柱層析法純化,以獲得標題化合物(11.5 g,產率:84%)。
MS
m/z:335[M+H]。
步驟4)三級丁基(4-((2-胺基-3-(乙氧基羰基)胺基)吡啶-4-基)氧基)-3-氟苯基)胺甲酸酯
將在上述步驟3中獲得之化合物三級丁基(4-((2,3-二胺基吡啶-4-基)氧基)-3-氟苯基)胺甲酸酯(10 g, 29.9 mmol)及吡啶(4.73 g, 59.8 mmol)溶解於THF中,然後在0°C下緩慢加入氯甲酸乙酯(3.57 g, 32.9 mmol)。將混合物攪拌12小時,然後將反應混合物用乙酸乙酯稀釋,用水及鹽水洗滌,然後濃縮。將殘餘物藉由管柱層析法純化,以獲得標題化合物(4.5 g,產率:37%)。
MS
m/z:407[M+H]。
步驟5)乙基(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)胺甲酸酯
將在上述步驟4中獲得之化合物三級丁基(4-((2-胺基-3-(乙氧基羰基)胺基)吡啶-4-基)氧基)-3-氟苯基)胺甲酸酯(3.5 g, 8.61 mmol)溶解於TFA/DCM 1:5混合溶劑中並在室溫下攪拌5小時。將反應混合物用乙酸乙酯稀釋,用水及鹽水洗滌,並藉由管柱層析法純化,以獲得標題化合物(1.9 g,產率:72%)。
MS
m/z:307[M+H]。
步驟6)乙基(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)(異丙基)胺甲酸酯
將在上述步驟5中獲得之化合物乙基(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)胺甲酸酯(1.9 g, 6.2 mmol)溶解於DMF中,然後在0°C下加入NaH (0.273 g, 6.82 mmol),接著緩慢加入2-溴丙烷(0.84 g, 6.82 mmol)。將混合物攪拌12小時,然後將反應混合物用乙酸乙酯稀釋,用水及鹽水洗滌,然後濃縮。將殘餘物藉由管柱層析法純化,以獲得標題化合物(1.25 g,產率:58%)。
MS
m/z:349[M+H]。
步驟7)7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
將在上述步驟6中獲得之化合物乙基(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)(異丙基)胺甲酸酯(1.25 g, 3.59 mmol)及乙氧化鈉(0.488 g, 7.18 mmol)溶解於乙醇中並將混合物在微波條件及120°C下攪拌4小時。將水添加至反應混合物使混合物結晶,從而獲得標題化合物(1.0 g,產率:92%)。
1H NMR (500 MHz, MeOH-d
4) δ 7.76 (d, 1H), 7.03 (t, 1H), 6.62 (dd, 1H), 6.57(dd, 1H), 6.33 (d, 1H), 5.02 (m, 1H), 1.58 (s, 3H), 1.07 (s, 3H);
MS
m/z:303[M+H]。
製備實施例
2
。
7-(4-
胺基
-2-
氟苯氧基
)-1-
乙基
-1,3-
二氫
-2H-
咪唑并
[4,5-b]
吡啶
-2-
酮
標題化合物(63 mg,產率:56%)係以類似於製備實施例1之方式,藉由在製備實施例1之步驟6中使用碘乙烷而非2-溴丙烷來獲得。
MS
m/z:289[M+H]。
製備實施例
3
。
7-(4-
胺基
-2-
氟苯氧基
)-1-
甲基
-1,3-
二氫
-2H-
咪唑并
[4,5-b]
吡啶
-2-
酮
標題化合物(90 mg,產率:74%)係以類似於製備實施例1之方式,藉由在製備實施例1之步驟6中使用碘甲烷而非2-溴丙烷來獲得。
MS
m/z:275[M+H]。
製備實施例
4
。
7-(4-
胺基
-2-
氟苯氧基
)-1-
環戊基
-1,3-
二氫
-2H-
咪唑并
[4,5-b]
吡啶
-2-
酮
標題化合物(150 mg,產率:86%)係以類似於製備實施例1之方式,藉由在製備實施例1之步驟6中使用環戊基溴化物而非2-溴丙烷來獲得。
MS
m/z:329[M+H]。
製備實施例
5
。
7-(4-
胺基
-2-
氟苯氧基
)-1,3-
二氫
-2H-
咪唑并
[4,5-b]
吡啶
-2-
酮
在下文中,製備實施例5之化合物係根據下述反應式2製備。
反應式2。
步驟1)三級丁基(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)胺甲酸酯
將三級丁基(4-((2,3-二胺基吡啶-4-基)氧基)-3-氟苯基)胺甲酸酯(250 mg, 0.75 mmol)溶解於THF中,並將混合物冷卻至0°C。加入三光氣(225 mg, 0.75 mmol),並將混合物在0°C下攪拌30分鐘。加入飽和NaHCO
3,並將混合物用乙酸乙酯萃取三次。將有機層用鹽水洗滌並濃縮,並將殘餘物藉由管柱層析法純化,以獲得標題化合物(85 mg,產率:32%)。
MS
m/z:361[M+H]。
步驟2)7-(4-胺基-2-氟苯氧基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
將在上述步驟1中獲得之化合物三級丁基(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)胺甲酸酯(80 mg, 0.22 mmol) 溶解於3 ml的DCM中,並加入1.5 ml的TFA。將反應混合物在室溫下攪拌2小時。將反應混合物濃縮,用乙酸乙酯稀釋,並用飽和NaHCO
3洗滌。將有機層用鹽水洗滌並濃縮,以獲得標題化合物(40 mg,產率:69%)。
MS
m/z:261[M+H]。
製備實施例
6
。
1-(3-
甲基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧酸
在下文中,製備實施例6之化合物係根據下述反應式3製備。
反應式3。
步驟1)乙基2-(乙氧基亞甲基)-4,4,4-三氟-3-側氧丁酸酯
將乙基4,4,4-三氟-3-側氧丁酸酯(2.0 g, 10.9 mmol)及三乙氧基甲烷(2.0 g, 14.1 mmol)溶解於乙酸酐(3.3 g, 32.6 mmol)中,並將混合物在130°C下攪拌4小時。將反應混合物濃縮,以獲得標題化合物(2.0 g,產率:77%)。
MS
m/z:241[M+H]。
步驟2)乙基1-(3-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸酯
將在上述步驟1中獲得之化合物乙基2-(乙氧基亞甲基)-4,4,4-三氟-3-側氧丁酸酯(0.5 g, 2.1 mmol)及2-肼基-4-甲基吡啶(0.23 g, 1.9 mmol)溶解於6 ml的乙醇中並將混合物在60°C下攪拌12小時。將反應混合物用乙酸乙酯及水萃取並濃縮。將殘餘物藉由管柱層析法純化,以獲得標題化合物(0.38 g,產率:56%)。
1H NMR (500 MHz, CDCl
3) δ 8.46 (d, 1H), 8.20 (s, 1H), 7.77 (d, 1H), 7.43 (dd, 1H), 4.41 (q, 2H), 2.19 (s, 3H), 1.41 (t, 3H); MS
m/z: 300[M+H]。
步驟3)1-(3-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸
在上述步驟2中獲得之化合物乙基1-(3-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸酯(0.38 g, 1.3 mmol)溶解於4 ml乙醇中,然後在室溫下加入2 ml的6N氫氧化鈉溶液,並將混合物攪拌1小時。將藉由將冰水添加至反應產物中所形成之固體過濾,以獲得標題化合物(0.31 g,產率:90%)。
1H NMR (500 MHz, DMSO-d
6) δ 13.42 (brs, 1H), 8.46 (d, 1H), 8.31 (s, 1H), 8.02 (d, 1H), 7.62 (dd, 1H), 2.12 (s, 3H); MS
m/z: 272[M+H]。
實施例
1.5-
乙基
-N-(3-
氟
-4-((2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
嘧啶
-5-
基
)-1H-
吡唑
-4-
羧醯胺
在下文中,實施例1之化合物係根據下述反應式4製備。
反應式4
將在上述製備實施例5中獲得之化合物7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮(20 mg, 0.07 mmol)、5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸(20 mg, 0.08 mmol)、及HATU (40 mg, 0.10 mmol)溶解於2 mL的DMF中,然後加入DIPEA (17 μl, 0.10 mmol),並將混合物在室溫下攪拌12小時。將反應混合物用乙酸乙酯稀釋,用水及鹽水洗滌,然後濃縮。將殘餘物藉由prep-HPLC純化(0.1%甲酸於水/乙腈中),以獲得標題化合物(24 mg,產率:65%)。
1H NMR (500 MHz, DMSO-d
6) δ 11.42 (brs, 1H), 11.28 (brs, 1H), 10.23 (s, 1H), 9.38 (s, 1H), 9.13 (s, 2H), 8.46 (s, 1H), 7.99 (m, 1H), 7.78 (d, 1H), 7.59 (m, 1H), 7.39 (t, 1H), 6.37 (d, 1H), 3.05 (q, 2H), 1.13 (t, 3H); MS
m/z: 461[M+H]。
實施例
2.5-
乙基
-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
嘧啶
-5-
基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(9 mg,產率:22%)係以類似於實施例1之方式,藉由使用在製備實施例1中獲得之7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮而非根據實施例1之7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (brs, 1H), 10.24 (s, 1H), 9.38 (s, 1H), 9.13 (s, 2H), 8.46 (d, 1H), 8.01 (m, 1H), 7.82 (d, 1H), 7.60 (m, 1H), 7.43 (t, 1H), 6.41 (d, 1H), 4.91 (m, 1H), 3.05 (q, 2H), 1.49 (d, 6H), 1.13 (t, 3H); MS
m/z: 503[M+H]。
實施例
3
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(15 mg,產率:21%)係以類似於實施例2之方式,藉由使用1-(吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.90 (s, 1H), 8.63 (d, 1H), 8.39 (s, 1H), 8.15 (t, 1H), 7.93 (dd, 1H), 7.84 (d, 1H), 7.81 (d, 1H), 7.65 (d, 1H), 7.55 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 542[M+H]。
實施例
4
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
嘧啶
-5-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(35 mg,產率:49%)係以類似於實施例2之方式,藉由使用1-(吡啶-5-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.91 (s, 1H), 9.46 (s, 1H), 9.20 (s, 2H), 8.53 (s, 1H), 7.94 (dd, 1H), 7.81 (d, 1H), 7.58 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 543[M+H]。
實施例
5
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-
甲基
-1-(
嘧啶
-5-
基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(17 mg,產率:26%)係以類似於實施例2之方式,藉由使用5-甲基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.24 (s, 1H), 9.33 (s, 1H), 9.16 (s, 2H), 8.46 (s, 1H), 7.98 (dd, 1H), 7.81 (d, 1H), 7.61 (d, 1H), 7.43 (t, 1H), 6.40 (d, 1H), 4.88 (m, 1H), 2.67 (s, 3H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 489[M+H]。
實施例
6
。
N-(4-((1-
環戊基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)-3-
氟苯基
)-5-
乙基
-1-(
嘧啶
-5-
基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(27 mg,產率:47%)係以類似於實施例1之方式,藉由使用在製備實施例4中獲得之7-(4-胺基-2-氟苯氧基)-1-環戊基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮而非根據實施例1之7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮來獲得。
1H NMR (400 MHz, DMSO-d
6) δ 11.68 (s, 1H), 10.20 (s, 1H), 9.33 (s, 1H), 9.08 (s, 1H), 7.94 (dd, 1H), 7.78 (d, 1H), 7.56 (d, 1H), 7.39 (t, 1H), 6.36 (d, 1H), 4.95 (m, 1H), 2.98 (q, 2H), 2.05 (m, 2H), 1.94 (m, 2H), 1.71 (m, 2H), 1.56 (m, 2H), 1.07 (t, 3H); MS
m/z: 529[M+H]。
實施例
7
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(3-
氟吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(22 mg,產率:40%)係以類似於實施例2之方式,藉由使用1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.90 (s, 1H), 8.56 (d, 1H), 8.50 (s, 1H), 8.23 (t, 1H), 7.93 (dd, 1H), 7.87 (m, 1H), 7.81 (d, 1H), 7.57 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 560[M+H]。
實施例
8
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(3-
甲基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(35 mg,產率:48%)係以類似於實施例2之方式,藉由使用1-(3-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.84 (s, 1H), 8.49 (d, 1H), 8.43 (s, 1H), 8.04 (d, 1H), 7.94 (dd, 1H), 7.81 (d, 1H), 7.63 (dd, 1H), 7.58 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.88 (m, 1H), 2.17 (s, 3H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 556[M+H]。
實施例
9
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(5-
甲基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(14 mg,產率:19%)係以類似於實施例2之方式,藉由使用1-(5-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.67 (s, 1H), 10.88 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 7.95 (m, 2H), 7.91 (d, 1H), 7.80 (d, 1H), 7.55 (d, 1H), 7.45 (t, 1H), 6.40 (d, 1H), 4.87 (m, 1H), 2.42 (s, 3H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 556[M+H]。
實施例
10
。
1-(3-
氯吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(37 mg,產率:49%)係以類似於實施例2之方式,藉由使用1-(3-氯吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.70 (s, 1H), 10.88 (s, 1H), 8.67 (d, 1H), 8.51 (s, 1H), 8.41 (d, 1H), 7.94 (dd, 1H), 7.82 (m, 2H), 7.58 (d, 1H), 7.46 (t, 1H), 6.42 (d, 1H), 4.88 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 576[M+H]。
實施例
11
。
1-(5-
氯吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(8 mg,產率:11%)係以類似於實施例2之方式,藉由使用1-(5-氯吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.70 (s, 1H), 10.91 (s, 1H), 8.73 (d, 1H), 8.41 (s, 1H), 8.30 (dd, 1H), 7.92 (d, 1H), 7.81 (d, 1H), 7.55 (s, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.78 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 576[M+H]。
實施例
12
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1-(3-(
三氟甲基
)
吡啶
-2-
基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(29 mg,產率:36%)係以類似於實施例2之方式,藉由使用1-(3-(三氟甲基)吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.88 (s, 1H), 8.99 (d, 1H), 8.67(d, 1H), 8.51 (s, 1H), 8.02 (dd, 1H), 7.94 (d, 1H), 7.81 (d, 1H), 7.59 (d, 1H), 7.46 (t, 1H), 6.41 (t, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 610[M+H]。
實施例
13
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1-(5-(
三氟甲基
)
吡啶
-2-
基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(27 mg,產率:34%)係以類似於實施例2之方式,藉由使用1-(5-(三氟甲基)吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (400 MHz, DMSO-d
6) δ 11.66 (s, 1H), 10.94 (s, 1H), 9.04 (s, 1H), 8.54 (dd, 1H), 8.43 (s 1H), 8.19 (d, 1H), 7.87 (dd, 1H), 7.77 (d, 1H), 7.50 (d, 1H), 7.42 (t, 1H), 6.37 (d 1H), 4.83 (m, 1H), 1.45 (s, 3H), 1.43 (s, 3H); MS
m/z: 610[M+H]。
實施例
14
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(4-
甲基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(43 mg,產率:59%)係以類似於實施例2之方式,藉由使用1-(4-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.89 (s, 1H), 8.46 (d, 1H), 8.37 (s, 1H), 7.93 (dd, 1H), 7.91 (d, 1H), 7.81 (d, 1H), 7.68 (s, 1H), 7.56 (d, 1H), 7.47-7.44 (m, 2H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 556[M+H]。
實施例
15
。
1-(4-
氯吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(40 mg,產率:53%)係以類似於實施例2之方式,藉由使用1-(4-氯吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.93 (s, 1H), 8.62 (d, 1H), 8.42 (s, 1H), 8.05 (d, 1H), 7.92 (d, 1H), 8.81 (d, 1H), 7.55 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 576[M+H]。
實施例
16
。
1-(4-
溴吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(40 mg,產率:49%)係以類似於實施例2之方式,藉由使用1-(4-溴吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.93 (s, 1H), 8.53 (d, 1H), 8.42 (s, 1H), 8.16 (d, 1H), 7.94-7.91 (m, 2H), 7.81 (d, 1H), 7.55 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 620[M], 622[M+2]。
實施例
17
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1-(4-(
三氟甲基
)
吡啶
-2-
基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(44 mg,產率:55%)係以類似於實施例2之方式,藉由使用1-(4-(三氟甲基)吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.96 (s, 1H), 8.93 (d, 1H), 8.47 (s, 1H), 8.25 (s, 1H), 8.06 (d, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 6.42 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 610[M+H]。
實施例
18
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(6-
甲基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(30 mg,產率:41%)係以類似於實施例2之方式,藉由使用1-(6-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 10.89 (s, 1H), 8.35 (s, 1H), 8.03 (t, 1H), 7.92 (d, 1H), 7.81 (d, 1H), 7.55 (d, 1H), 7.50-7.44 (m, 2H), 6.41 (d, 1H) 4.87 (m, 1H), 2.54 (s, 3H), 1.49 (s, 3H), 1.48(s, 3H); MS
m/z: 556[M+H]。
實施例
19
。
1-(3-
溴吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(43 mg,產率:52%)係以類似於實施例2之方式,藉由使用1-(3-溴吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.87 (s, 1H), 8.69 (d, 1H), 8.53-8.50 (m, 2H), 7.94 (dd, 1H), 7.81 (d, 1H), 7.71 (dd, 1H), 7.59 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H) 1.48 (s, 3H); MS
m/z: 620[M], 622[M+2]。
實施例
20
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
異喹啉
-1-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(45 mg,產率:58%)係以類似於實施例2之方式,藉由使用1-(異喹啉-1-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.70 (s, 1H), 10.92 (s, 1H), 8.59-8.56 (m, 2H), 8.25-8.22 (m, 2H), 7.99-7.96 (m, 2H), 7.84-7.81 (m, 2H), 7.47 (t, 1H), 6.42 (d, 1H), 4.88 (m, 1H), 1.50 (s, 3H), 1.48 (s, 3H); MS
m/z: 592[M+H]。
實施例
21
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(5-
氟吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(15 mg,產率:21%)係以類似於實施例2之方式,藉由使用1-(5-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.70 (brs, 1H), 10.91 (s, 1H), 8.68 (d, 1H), 8.40 (s, 1H), 8.12 (td, 1H), 7.96-7.91 (m, 2H), 7.81 (d, 1H), 7.55 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 560[M+H]。
實施例
22
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1-(6-(
三氟甲基
)
吡啶
-2-
基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(27 mg,產率:34%)係以類似於實施例2之方式,藉由使用1-(6-(三氟甲基)吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.97 (s, 1H), 10.98 (s, 1H), 8.48-8.44 (m, 2H), 8.24 (d, 1H), 8.15 (d, 1H), 7.91 (dd, 1H), 7.81 (s, 1H), 7.54 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 610[M+H]。
實施例
23
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
吡啶
-3-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(36 mg,產率:50%)係以類似於實施例2之方式,藉由使用1-(吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.88 (s, 1H), 8.84-8.81 (m, 2H), 8.44 (s, 1H), 8.10 (d, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.70 (dd, 1H), 7.57 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 542[M+H]。
實施例
24
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
吡啶
-4-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(36 mg,產率:50%)係以類似於實施例2之方式,藉由使用1-(吡啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.90 (s, 1H), 8.87 (d, 1H), 8.46 (s, 1H), 7.92 (dd, 1H), 7.81 (d, 1H), 7.68 (d, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 542[M+H]。
實施例
25
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
嘧啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(19 mg,產率:35%)係以類似於實施例2之方式,藉由使用1-(嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.70 (s, 1H), 10.93 (s, 1H), 9.09 (d, 2H), 8.43 (s, 1H), 7.93 (d, 1H), 7.82-7.81 (m ,2H), 7.56 (d, 1H), 7.46 (t, 1H), 6.42 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.48 (s, 3H); MS
m/z: 543[M+H]。
實施例
26
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(4-
甲基嘧啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(10 mg,產率:18%)係以類似於實施例2之方式,藉由使用1-(4-甲基嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.61 (s, 1H), 10.92 (s, 1H), 8.90 (d, 1H), 8.40 (s, 1H), 7.92 (d, 1H), 7.81 (d, 1H), 7.68 (d, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 2.61 (s, 3H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 557[M+H]。
實施例
27
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
嘧啶
-4-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(23 mg,產率:43%)係以類似於實施例2之方式,藉由使用1-(嘧啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 11.01 (s, 1H), 9.29 (s, 1H), 9.12 (d, 1H), 8.50 (s, 1H), 8.07 (d, 1H), 7.91 (dd, 1H), 7.81 (d, 1H), 7.53 (d, 1H), 7.46 (t, 1H), 6.42 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 543[M+H]。
實施例
28
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(3-
甲氧基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(39 mg,產率:52%)係以類似於實施例2之方式,藉由使用1-(3-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (400 MHz, DMSO-d
6) δ 11.66 (s, 1H), 10.77 (s, 1H), 8.35 (s, 1H), 8.67 (d, 1H), 7.90 (d, 1H), 7.82 (d, 1H), 7.77 (d, 1H), 7.68 (dd, 1H), 7.54 (d, 1H), 7.42 (t, 1H), 6.36 (d, 1H), 4.83 (m, 1H), 3.82 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H); MS
m/z: 572[M+H]。
實施例
29
。
1-(3-
乙基吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(40 mg,產率:53%)係以類似於實施例2之方式,藉由使用1-(3-乙基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (400 MHz, DMSO-d
6) δ 11.71 (s, 1H), 10.85 (s, 1H), 8.50 (dd, 1H), 8.43 (s, 1H), 8.09 (d, 1H), 7.95 (dd, 1H), 7.81 (d, 1H), 7.67 (dd, 1H), 7.59 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 2.48 (q, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 1.10 (t, 3H); MS
m/z: 570[M+H]。
實施例
30
。
1-(4-
乙基吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(34 mg,產率:45%)係以類似於實施例2之方式,藉由使用1-(4-乙基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.70 (s, 1H), 10.91 (s, 1H), 8.50 (d, 1H), 8.38 (s, 1H), 7.93 (dd, 1H), 7.81 (d, 1H), 7.69 (s, 1H), 7.56 (d, 1H), 7.51 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 2.80 (q, 2H), 1.49 (s, 3H), 1.47 (s, 3H), 2.87 (t, 3H); MS
m/z: 570[M+H]。
實施例
31
。
1-(4-
環丙基吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(29 mg,產率:38%)係以類似於實施例2之方式,藉由使用1-(4-環丙基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
,1H NMR (500 MHz, DMSO-d
6) δ 11.71 (s, 1H), 10.90 (s, 1H), 8.41 (d, 1H), 8.37 (s, 1H), 7.93 (d, 1H), 7.81 (d, 1H), 7.57-7.55 (m, 2H), 7.46 (t, 1H), 7.30 (d, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 2.16 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H), 1.17 (m, 2H), 0.95 (m, 2H); MS
m/z: 582[M+H]。
實施例
32
。
1-(4-(3,6-
二氫
-2H-
哌喃
-4-
基
)
吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(10 mg,產率:16%)係以類似於實施例2之方式,藉由使用1-(4-(3,6-二氫-2H-哌喃-4-基)吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
MS
m/z:624[M+H]。
實施例
33
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(4-
甲氧基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(36 mg,產率:48%)係以類似於實施例2之方式,藉由使用1-(4-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
,1H NMR (500 MHz, DMSO-d
6) δ 11.71 (s, 1H), 10.90 (s, 1H), 8.43 (d, 1H), 8.37 (s, 1H), 7.93 (dd, 1H), 7.81 (d, 1H), 7.55 (d, 1H), 7.46 (t, 1H), 7.36 (d, 1H), 7.22 (dd, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 3.34 (s, 3H), 1.49 (s, 3H), 1.47 (s, 3H).
MS
m/z:572[M+H]。
實施例
34
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(5-
甲氧基吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(26 mg,產率:34%)係以類似於實施例2之方式,藉由使用1-(5-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.71 (s, 1H), 10.87 (s, 1H), 8.34-8.32 (m, 2H), 7.93 (dd, 1H), 7.81 (d, 1H), 7.76-7.70 (m, 2H), 7.56 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 3.94 (s, 3H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 572[M+H]。
實施例
35
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(
嗒
𠯤
-3-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(34 mg,產率:47%)係以類似於實施例2之方式,藉由使用1-(嗒𠯤-3-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
MS
m/z:543[M+H]。
實施例
36
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(5-
甲基嘧啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(28 mg,產率:38%)係以類似於實施例2之方式,藉由使用1-(5-甲基嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (brs, 1H), 10.92 (s, 1H), 8.92-8.88 (m, 2H), 8.41 (s, 1H), 7.93 (dd, 1H), 7.81 (d, 1H), 7.56 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 2.42 (s, 3H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 557[M+H]。
實施例
37
。
1-(3-
乙氧基吡啶
-2-
基
)-N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(20 mg,產率:26%)係以類似於實施例2之方式,藉由使用1-(3-乙氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.70 (s, 1H), 10.79 (s, 1H), 8.41 (s, 1H), 8.19 (d, 1H), 7.95 (d, 1H), 7.85 (d, 1H), 7.81 (d, 1H), 7.69 (dd, 1H), 7.58 (d, 1H), 7.45 (t, 1H), 6.40 (d, 1H), 4.87 (m, 1H), 4.18 (m, 2H), 1.49 (s, 3H), 1.48 (s, 3H), 1.22 (t, 3H); MS
m/z: 572[M+H]。
實施例
38
。
N-(3-
氟
-4-((1-
異丙基
-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(4-
氟吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(10 mg,產率:18%)係以類似於實施例2之方式,藉由使用1-(4-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧酸而非根據實施例2之5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧酸來獲得。
1H NMR (500 MHz, DMSO-d
6) δ 11.69 (s, 1H), 10.94 (s, 1H), 8.68 (dd, 1H), 8.42 (s, 1H), 7.92 (dd, 1H), 7.87 (dd, 1H), 7.81 (d, 1H), 7.62 (m, 1H), 7.55 (d, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.87 (m, 1H), 1.49 (s, 3H), 1.47 (s, 3H); MS
m/z: 560[M+H]。
實施例
39
。
N-(3-
氟
-4-((2-
側氧基
-1-(
四氫
-2H-
哌喃
-4-
基
)-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(3-
氟吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(28 mg, 53%)係以類似於實施例7之方式,藉由使用7-(4-胺基-2-氟苯氧基)-1-(四氫-2H-哌喃-4-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮而非根據實施例7之7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮來獲得。
1H NMR (500 MHz, DMSO-d6) δ 11.77 (brs, 1H), 10.91 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.21 (t, 1H), 7.95 (m, 3H), 7.59 (m, 1H), 7.48 (t, 1H), 6.43 (d, 1H), 4.71 (m, 1H), 3.97 (m, 2H), 3.42 (m, 2H), 2.44 (m, 2H), 1.74 (m, 2H); MS m/z : 602[M+H]。
實施例
40
。
N-(3-
氟
-4-((2-
側氧基
-1-(
四氫呋喃
-3-
基
)-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(3-
氟吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(31 mg, 58%)係以類似於實施例7之方式,藉由使用7-(4-胺基-2-氟苯氧基)-1-(四氫呋喃-3-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮而非根據實施例7之7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮來獲得。
1H NMR (500 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.90 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.21 (t, 1H), 7.94 (d, 1H), 7.88 (m, 2H), 7.58 (m, 1H), 7.48 (m, 1H), 6.43 (d, 1H), 5.30 (m, 1H), 4.01 (m, 1H), 3.94 (m, 3H), 2.42 (m, 1H), 2.28 (m, 1H); MS m/z : 588[M+H]。
實施例
41
。
N-(3-
氟
-4-((1-(1-
甲基哌啶
-4-
基
)-2-
側氧基
-2,3-
二氫
-1H-
咪唑并
[4,5-b]
吡啶
-7-
基
)
氧基
)
苯基
)-1-(3-
氟吡啶
-2-
基
)-5-(
三氟甲基
)-1H-
吡唑
-4-
羧醯胺
標題化合物(8 mg, 15%)係以類似於實施例7之方式,藉由使用7-(4-胺基-2-氟苯氧基)-1-(1-甲基哌啶-4-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮而非根據實施例7之7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮來獲得。
1H NMR (500 MHz, DMSO-d6) δ 11.75 (brs, 1H), 10.91 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.23 (t, 1H), 7.94 (m, 3H), 7.58 (m, 1H), 7.46 (t, 1H), 6.41 (d, 1H), 4.42 (m, 1H), 2.88 (m, 2H), 2.51 (m, 2H), 2.15 (s, 3H), 1.97 (m, 2H), 1.71 (m, 2H); MS m/z : 615[M+H]。
實驗實施例
1
。評估對
RON
及
MET
之抑制活性
[1-1]
評估對
RON
之抑制活性
為了測量各實施例化合物對RON之抑制活性,使用時間解析螢光能量轉移化學(Time-Resolved Fluorescence Energy Transfer Chemistry, TR)測量各化合物之IC50。
具體而言,將化合物用100% DMSO製備成1 mM之濃度並通過3倍稀釋以逐步方式稀釋10次。將2 ul的以逐步方式稀釋之化合物添加至含有48ul的1x激酶反應緩衝液(50 mM HEPES (pH 7.4), 0.01% Tween-20, 5 mM DTT, 0.5 mM Na
3VO
4, 2 mM EGTA, 10 mM MgCl
2)之96孔盤中。
將RON蛋白質用RON儲存緩衝液(50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.5 mM EDTA, 0.02% Triton X-100)稀釋至49.3 nM之濃度。然後用1x激酶反應緩衝液再稀釋至0.4 nM之濃度。作為受質混合物,RON-特異性受質混合物(40uM ULight標記之Poly GT, 100 nM ATP)濃度為最終反應濃度的2倍。
之後,製備一384孔盤,並將2.5 μl的各實施例之稀釋化合物添加至實驗組孔之對應孔中,並將2.5 μl的4% DMSO溶液施配至高對照孔及低對照孔中。
之後,將2.5 μL的0.4 nM RON施配到高對照孔及實驗組孔中,並將2.5 μL的1x激酶反應緩衝液添加至低對照孔中,並將RON及反應緩衝液在室溫下以1000 RPM離心40秒,然後在室溫下培育20至30分鐘。然後,將5uL的受質混合物(2x)施配到所有孔中,在室溫下以1000 RPM離心40秒,然後在室溫下培育60分鐘。之後,將5 uL的30 mM EDTA添加至所有孔中以終止反應,然後在室溫下再培育5分鐘。之後,將5 uL的含有銪之4x磷酸酪胺酸抗體(Perkin Elmer)添加至所有孔中,然後在室溫下培育60分鐘。在培育之後,用視覺盤讀取器(Vison plate reader)讀取該384孔盤。此時,激發波長係340 nm,而發射波長係620 nm及665 nm。使用GraphPd Prism7程式得出各實施例化合物之IC50值。
[1-2]
評估對
MET
之抑制活性
此外,為了測量cMET之酶活性抑制,進行RON之酶活性抑制測量實驗。
具體而言,將化合物用100% DMSO製備成1 mM之濃度並通過3倍稀釋以逐步方式稀釋10次。將2 ul的以逐步方式稀釋之化合物添加至含有48ul的1x激酶反應緩衝液(50 mM HEPES (pH 7.4), 0.05% BSA, 0.005 % Tween-20, 1 mM DTT, 0.5 mM MnCl
2, 20 mM MgCl
2)之96孔盤中。
將cMET蛋白質用cMET儲存緩衝液(50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.05% Brij35, 1 mM DTT, 10%甘油)稀釋至263 nM之濃度,然後用1x激酶反應緩衝液再稀釋至2 nM之濃度。作為受質混合物,MET-特異性受質混合物(5 uM TK肽, 10 mM ATP)濃度為最終反應濃度的2倍。
之後,製備一384孔盤,並將2.5 μl的各實施例稀釋化合物添加至實驗組孔之對應孔中,並將2.5 μl的4% DMSO溶液施配至高對照孔及低對照孔中。
之後,將2.5 μL的2 nM cMET施配到高對照孔及實驗組孔中,並將2.5 μL的1x激酶反應緩衝液添加至低對照孔中,並將RON及反應緩衝液在室溫下以1000 RPM離心40秒,然後在室溫下培育20至30分鐘。然後,將5uL的受質混合物(2x)施配到所有孔中,在室溫下以1000 RPM離心40秒,然後在室溫下培育60分鐘。之後,將5 uL的90 mM EDTA添加至所有孔中以終止反應,然後在室溫下再培育5分鐘。之後,將5 uL的含有銪之4x磷酸酪胺酸抗體(Perkin Elmer)添加至所有孔中,然後在室溫下培育60分鐘。在培育之後,用視覺盤讀取器(Vison plate reader)讀取該384孔盤。此時,激發波長係340 nm,而發射波長係620 nm及665 nm。使用GraphPd Prism7程式得出各實施例化合物之IC50值。
實施例化合物之抑制活性評估結果顯示於下表2中。
(A: <50 nM, B: 50至500 nM, C: 500至5000 nM, D: >5,000 nM)
Claims (9)
- 一種下式1之尿素衍生物化合物或其醫藥上可接受之鹽: 其中在式1中, 上述X係氧, 上述Y係氫、鹵素、C 1-C 6烷基、或C 3-C 6環烷基, 上述R 1係氫、C 1-C 6烷基、或C 3-C 12環烷基、或C 2-C 11雜環烷基, 上述R 2係氫或C 1至C 6烷基, 上述A係-Ar或-(CH 2)n-Ar,其中上述Ar係經取代或未經取代之C 6-C 10芳基、或經取代或未經取代之包括1至4個選自由氮、硫、及氧所組成之群組的雜環原子的5員雜芳基,其中取代基係選自下列中之一或多者:鹵素、胺、C 1-C 6烷基、C 3-C 12環烷基、經鹵素取代之C 1-C 6烷基、 C 6-C 10芳基、C 1-C 6烷氧基、C 1-C 6烷硫基、羥基、羧酸、C 1-C 6烷羰基、C 1-C 6烷氧羰基、C 1-C 6烷羰氧基、硝基、氰基、胺甲醯基、尿素、硫醇基、及NR 3R 4,且上述n係1至3之整數, 上述R 3及R 4各自獨立地係氫或C 1-C 6烷基, 上述B係C 3-C 19雜芳基或經取代之C 3-C 19雜芳基, 其中取代基係鹵素、C 1-C 6烷基、C 3-C 7環烷基、經鹵素取代之C 1-C 6烷基、C 1-C 6烷氧基、C 3-C 11雜環烷基、 C 3-C 11雜環烯基、或C 6-C 10芳基, 其中該鹵素係選自由下列所組成之群組:F、Cl、Br、及I。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受之鹽,其中上述A係經取代或未經取代之5員雜芳基化合物。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受之鹽,其中上述B係下列之化合物:吡啶、經取代之吡啶、嘧啶、經取代之嘧啶、嗒𠯤、經取代之嗒𠯤或喹啉,其中取代基係鹵素、C 1-C 3烷基、經鹵素取代之 C 1-C 3烷基、C 3-C 5環烷基、C 4-C 6雜環烯基或C 1-C 3烷氧基。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受之鹽,其中上述Y係氟之化合物。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受之鹽,其中上述R 1係下列之化合物:氫、C 1-C 6烷基、C 3-C 6環烷基、或C 4-C 6雜環烷基。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受之鹽,其中上述R 2係氫之化合物。
- 如請求項1之尿素衍生物化合物,其中該化合物係選自由下列所組成之群組的化合物: 5-乙基-N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺, 5-乙基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-5-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺, N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-(嘧啶-5-基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(3-氯吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(5-氯吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(3-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(5-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(4-氯吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(4-溴吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(4-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(6-甲基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(3-溴吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(異喹啉-1-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1-(6-(三氟甲基)吡啶-2-基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(吡啶-3-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(吡啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-甲基嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嘧啶-4-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(3-乙基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(4-乙基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(4-環丙基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(4-(3,6-二氫-2H-哌喃-4-基)吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-甲氧基吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(嗒𠯤-3-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(5-甲基嘧啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 1-(3-乙氧基吡啶-2-基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(4-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, N-(3-氟-4-((2-側氧基-1-(四氫呋喃-3-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 及 N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(3-氟吡啶-2-基)-5-(三氟甲基)-1H-吡唑-4-羧醯胺, 或其醫藥上可接受之鹽。
- 一種醫藥組成物,其包含如請求項1至8中任一項之化合物或其醫藥上可接受之鹽、及醫藥上可接受之載劑。
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