TW202332436A - 治療用化合物 - Google Patents
治療用化合物 Download PDFInfo
- Publication number
- TW202332436A TW202332436A TW111146299A TW111146299A TW202332436A TW 202332436 A TW202332436 A TW 202332436A TW 111146299 A TW111146299 A TW 111146299A TW 111146299 A TW111146299 A TW 111146299A TW 202332436 A TW202332436 A TW 202332436A
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- pyrazol
- pyridin
- benzyl
- dihydro
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 244
- 230000001225 therapeutic effect Effects 0.000 title abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 66
- 125000001072 heteroaryl group Chemical group 0.000 claims description 54
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 25
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 19
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 15
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- ILJOYZVVZZFIKA-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;hydrate Chemical compound O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 ILJOYZVVZZFIKA-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- AHUXCBVCMJGTTD-UHFFFAOYSA-N tert-butyl 3-bromo-6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine-5-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN2N=CC(Br)=C21 AHUXCBVCMJGTTD-UHFFFAOYSA-N 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QKSQWQOAUQFORH-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonylimino]carbamate Chemical compound CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C QKSQWQOAUQFORH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005985 thienyl[1,3]dithianyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000003813 thumb Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003371 toe Anatomy 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 108091008023 transcriptional regulators Proteins 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- INQOMBQAUSQDDS-FIBGUPNXSA-N trideuterio(iodo)methane Chemical compound [2H]C([2H])([2H])I INQOMBQAUSQDDS-FIBGUPNXSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本發明的實施例係關於經取代之雜環衍生物治療用化合物,包含該等化合物的組合物,以及該等化合物及組合物用於藉由抑制蛋白質(諸如組蛋白)的乙醯離胺酸區域的溴結構域介導的識別來實現表觀遺傳調節的用途。該等組合物及方法可用於治療由異常細胞信號傳導介導的疾病,諸如發炎病症、癌症及腫瘤疾病。本文所描述的特定化合物展示出與BRD4相比對CBP的選擇性抑制活性。
Description
本申請案主張於2017年4月18日提出申請之美國臨時申請案第62/486,894號及於2018年4月13日提出申請之美國臨時申請案第62/657,456號之權益,此等美國臨時申請案之內容藉此以引用之方式全部併入本文。
本文所描述之實施例提供用於治療癌症、腫瘤疾病、發炎或免疫病症的組合物、調配物及方法。
需要有效治療由異常組蛋白脫乙醯化介導的疾病及病症,諸如發炎病症、癌症及腫瘤疾病。
本文提供了經取代之雜環衍生物治療用化合物及包含該等化合物的醫藥組合物。本文所描述的經取代之雜環衍生化合物係基於吡啶酮及相關雜環結構,此等吡啶酮大體在4位置及5位置處被取代。具體而言,在5位置處用視情況經取代之含N雜芳基(諸如噁唑、吡唑或三唑)取代吡啶酮。
標的化合物及組合物係用於藉由抑制與異常細胞訊號傳導相關聯的蛋白質(諸如組蛋白)的乙醯基離胺酸區域的溴結構域介導的識別來實現表觀遺傳調節。更特定而言,與抑制溴結構域4 (bromain domain 4; BRD4)活性相比,本文的至少一些實施例提供對環狀AMP反應結合蛋白(cyclic AMP-responsive element-binding protein; CREB)結合蛋白(CBP或CREBBP)活性的選擇性抑制。此外,標的化合物及組合物係用於治療由異常細胞訊號傳導介導的疾病,諸如發炎病症及癌症,諸如前列腺癌、乳腺癌、膀胱癌、肺癌、黑素瘤等。
至少一個實施例提供具有式I之結構的化合物:
式I
其中式I之化合物視情況為其醫藥學上可接受的鹽,且其中:
X6為N或CR
7,其中R
7為氫、鹵素、烷基或烷氧基;
R
2為氫、烷基、芳基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基;
R
5為氫、鹵素、-CN、-N(R
22)
2、-NH(R
22)、-N(R
22)SO
2R
21、-N(R
22)SO
2N(R
22)
2、-N(R
22)CO(R
22)、-N(R
22)CO
2R
21、-N(R
22)CON(R
22)
2、-OC(O)N(R
22)
2、-C(O)N(R
22)
2、-OW、-NW、-SW、-SO
2W,或視情況經取代之烷基、芳基、芳烷基、雜芳基、雜芳基烷基、環烷基、環烷基烷基、雜環基或雜環基烷基,其中
W為至少一個氫、-N(R
22)
2,或視情況經取代之烷基、芳基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基;
R
6為氫、鹵素、-CN、烷基、環烷基、環烷基烷基、芳基、芳烷基、雜芳基、雜芳基烷基、雜環基、雜環基烷基、-OR
22或-N(R
22)
2;
或R
5及R
6共同形成視情況經取代之5員或6員環;
R
A為視情況經取代之含N雜芳基;
其中每個R
22獨立地選自氫、烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基。
在至少一個實施例中,X6為CH。在至少一個實施例中,X6為CF。在至少一個實施例中,R
2為甲基。在至少一個實施例中,R
6為氫。
在至少一個實施例中,R
A為視情況經取代之五員含N雜芳基。在至少一個實施例中,R
A為視情況經取代之吡唑。在至少一個實施例中,R
A為視情況經取代之哌啶基吡唑。在至少一個實施例中,R
A為環戊基吡唑。在至少一個實施例中,R
A為視情況經取代之咪唑。在至少一個實施例中,R
A為視情況經取代之噁唑。在至少一個實施例中,R
A為視情況經取代之異噁唑。在至少一個實施例中,R
A為視情況經取代之三唑。
在至少一個實施例中,R
A選自:
其中X為鍵、CH
2、CHR或CRR';
其中R及R'獨立地為鹵素、鹵化物或烷基;
R
1為氫、烷基、芳基、芳烷基、烷氧基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基;以及R
13為Y-Z,其中
Y為鍵或CH(C
1-C
4烷基)及
Z為氫、鹵素、烷基、芳基、CF
2、CO
2R
22、N(R
22)或N(R
22)CO(R
22),其中
R
22為氫或烷基。
在一些實施例中,R
A為
其中
X為鍵、CH
2、CHR或CRR';其中
R及R'獨立地為鹵素、鹵化物、烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基、雜環基烷基、雜芳基、雜芳基烷基、SO
2R
21、-N(R
22)SO
2R
21;
R
1為氫、烷基、芳基、芳烷基、烷氧基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基;
R
12為氫、鹵素、-CN、烷基、環烷基或烷氧基;
每個R
13獨立地為Y-Z,其中
Y為鍵或CH(C
1-C
4烷基)及
Z為氫、鹵素、烷基、芳基、-CF
2、-NO
2、-CO
2R
22、-N(R
22),或-N(R
22)CO(R
22)、-SO
2R
21、-N(R
22)SO
2R
21、-SO
2N(R
22)
2、-N(R
22)SO
2N(R
22)
2、-CON(R
22)
2、-N(R
22)CO
2R
21、-N(R
22)CON(R
22)
2、-OC(O)N(R
22)
2、-OSO
2N(R
22)
2或-N(R
22)SO
3R
21;其中
每個R
21獨立地選自烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基;以及每個R
22獨立地選自氫、烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基;以及
R
14為氫、-CN、烷基、環烷基或烷氧基。
在至少一個實施例中,R
A為選自以下的雜芳基:
、
、
或
其中X、R
1及R
13如上文所描述。
本發明實施例之另一態樣提供式I之化合物,此化合物展示出與BRD4相比對CBP的選擇性抑制。在一個實施例中,藉由使其與式I之化合物接觸來抑制CBP的活性。
至少一個實施例提供一種包含式I之化合物及醫藥學上可接受的賦形劑的醫藥組合物。
本文所描述之實施例的另一態樣係關於一種治療有需要的患者的發炎或免疫病症的方法,此方法包含向患者投予式I之化合物或包含式I的醫藥組合物。
本文所描述之實施例的另一態樣係關於一種治療有需要的患者的腫瘤疾病或癌症的方法,此方法包含向患者投予式I之化合物或包含式I的醫藥組合物。
出於描述及揭示例如可以結合本發明實施例使用的此類公開案中描述的方法之目的,所標識的所有專利案及其他公開案明確地經由引用併入本文。僅僅是為了在本申請案的提交日期之前針對揭示內容而提供此等公開案。此方面的任何內容不應被解釋為承認發明人無權憑藉先前發明或出於任何其他原因先於此種揭示內容。所有關於日期的陳述或關於此等文件的內容的表述係基於申請人可獲得的資訊,並且不構成對此等文件的日期或內容的正確性的任何承認。
如本文及申請專利範圍中所使用的,除非上下文另有明確指示,否則單數形式包括複數形式,且反之亦然。在整個說明書中,除非另外指示,否則「包含(comprise)」、「包含(comprises)」及「包含(comprising)」被包含性地而非排他性地使用,使得所陳述的整體或整體群組可以包括一或更多個其他未陳述的整體或整體群組。除非藉由例如「...或...任一者」修飾,否則術語「或」為包括性的。當在本文中使用範圍用於諸如分子量之物理特性或諸如化學配方之化學特性時,意欲包括其中的範圍及特定實施例之所有組合及子組合。除了在操作實例中或在另外指示的情況以外,本文中使用的表示成分量或反應條件的所有數字應理解為在所有情況下皆由術語「約」修飾。術語「約」在指示數字或數值範圍時意謂所指示的數字或數值範圍為實驗變化性內(或統計實驗誤差內)的近似值,且因此數字或數值範圍可以在所述數字或數值範圍的1%與15%之間變化,可從上下文易於辨識此情況。
除非另外定義,否則與本文所描述之調配物結合使用的科學與技術術語應具有本領域普通技術人員通常理解的含義。此處使用的術語僅用於描述特定實施例之目的,而不意圖限制僅由申請專利範圍界定的本發明實施例的範疇。
定義
本文所使用之「烷基」通常係指僅由碳及氫原子組成、完全飽和、不含不飽和的雙鍵或三鍵碳的直鏈或支鏈烴鏈,具有1至15個碳原子(例如,C
1-C
15烷基)。在某些實施例中,烷基包含兩個碳原子(例如C
2烷基),例如乙基。在某些實施例中,烷基包含一個碳原子,例如甲基。在其他實施例中,烷基選自甲基、乙基、1-丙基(正丙基)、1-甲基乙基(異丙基)、1-丁基(正丁基)、1-甲基丙基(第二丁基)、2-甲基丙基(異丁基)、1,1-二甲基乙基(第三丁基)、1-戊基(正戊基)。藉由單鍵使烷基附接到分子的其餘部分。除非另有說明,否則烷基用至少一個取代基視情況取代,取代基諸如鹵素、羥基、氰基、硝基、側氧基、硫基、亞胺基、肟醯基、-OR
a、-SR
a、-OC(O)-R
a、-N(R
a)
2、-C(O)R
a、-C(O)OR
a、-C(O)N(R
a)
2、-N(R
a)C(O)OR
a、-OC(O)-N(R
a)
2、-N(R
a)C(O)R
a、-N(R
a)S(O)
tR
a(其中t為1或2)、-S(O)
tOR
a(其中t為1或2)、-S(O)
tR
a(其中t為1或2)及-S(O)
tN(R
a)
2(其中t為1或2),其中每個R
a獨立地為氫、烷基、氟烷基、碳環基、碳環基烷基、芳基、芳烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基,並且其中R
a本身如上文所描述的視情況經取代。在一些實施例中,R
a用例如鹵素、羥基、甲氧基或三氟甲基取代。此等及其他取代基在本領域中為已知的。參見例如WO 2014089364、WO 2014100463、WO 2014100818、WO 2014164708、WO 2014151945、WO 2014151106、WO 2015058160、WO 2015089192、WO 2015168466、WO 2015200709、WO 2015200843、WO 2016004105、WO 2016003917、WO 2016037005、WO 2016044342、WO 2016044138、WO 2016044429、WO 2016168682、WO 2016172618。
「烷氧基」通常係指經由式-O-烷基的氧原子鍵結的部分,其中烷基為如上文所定義的烷基;除非另有說明,否則包含烷氧基的部分如對烷基所描述的視情況經取代。
「烯基」通常係指僅由碳及氫原子組成的直鏈或支鏈烴鏈基團,含有至少一個碳-碳雙鍵且具有2至12個碳原子。在某些實施例中,烯基包含2至8個碳原子。在其他實施例中,烯基包含2至4個碳原子。藉由單鍵使烯基附接到分子的其餘部分,單鍵例如乙烯基(ethenyl)(亦即,乙烯基(vinyl))、丙-1-烯基(亦即,烯丙基)、丁-1-烯基、戊-1-烯基、戊-1,4-二烯基等。除非另有說明,否則包含烯基的部分如對烷基所描述的視情況而經取代。
「炔基」係指僅由碳及氫原子組成的直鏈或支鏈烴鏈基團,含有至少一個碳-碳三鍵,具有2至12個碳原子。在某些實施例中,炔基包含2至8個碳原子。在其他實施例中,炔基具有2至4個碳原子。藉由單鍵使炔基附接到分子的其餘部分,例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。除非另有說明,否則含有炔基的基團如對烷基所描述的視情況經取代。
「伸烷基鏈」、「伸烷基連接子」或「烷基連接子」係指將分子的其餘部分連接至基團的直鏈或支鏈二價烴鏈,僅由碳及氫組成,不含不飽和度且具有1至12個碳原子。如上下文所指示,對烷基之引用可指示此類鏈或連接子。類似地,「伸炔基鏈」係指將分子的其餘部分連接至基團的直鏈或支鏈二價烴鏈,僅由碳及氫組成,包含至少一個碳-碳三鍵且具有2至12個碳原子。此等烴鏈如對烷基所描述的視情況經取代。
「芳基」係指芳族(不飽和)單環或多環烴環系統,其中環系統中的至少一個環為完全不飽和的,亦即根據Hückel理論含有環狀離域的(4n+2)π電子的系統。大體上,芳族單環或多環烴環系統僅含有5至18個碳原子的氫及碳。示例性芳基包括苯、茀、茚滿、茚、萘滿及萘。除非另有說明,否則術語「芳基」、結構中的前綴「芳-」(諸如在「芳烷基」中)或「Phe」包括芳基,由一或更多個取代基視情況經取代,此等取代基獨立地選自鹵素、氰基、硝基;視情況經取代之烷基、烯基、炔基、氟烷基、芳基、芳烷基、芳烯基、芳炔基、碳環基、碳環基烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基;或-R
b-OR
a、-R
b-OC(O)-R
a、-R
b-OC(O)-OR
a、-R
b-OC(O)-N(R
a)
2、-R
b-N(R
a)
2、-R
b-C(O)R
a、-R
b-C(O)OR
a、-R
b-C(O)N(R
a)
2、-R
b-O-R
c-C(O)N(R
a)
2、-R
b-N(R
a)C(O)OR
a、-R
b-N(R
a)C(O)R
a、-R
b-N(R
a)S(O)
tR
a、-R
b-S(O)
tR
a、-R
b-S(O)
tOR
a或-R
b-S(O)
tN(R
a)
2,其中t為1或2,其中每個R
a獨立地為氫或烷基、氟烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基,上述之各者用鹵素、羥基、甲氧基或三氟甲基視情況取代,其中每個R
b獨立地為鍵或直鏈或支鏈烷基或伸烯基鏈,並且其中R
c為直鏈或支鏈烷基或伸烯基鏈。此等及其他取代基在本領域中為已知的。參見例如WO 2014089364、WO 2014100463、WO 2014100818、WO 2014164708、WO 2014151945、WO 2014151106、WO 2015058160、WO 2015089192、WO 2015168466、WO 2015200709、WO 2015200843、WO 2016004105、WO 2016003917、WO 2016037005、WO 2016044342、WO 2016044138、WO 2016044429、WO 2016168682、WO 2016172618。
「芳烷基」通常係指式-R
c-芳基的部分,其中R
c為烷基、烷基鏈或伸烷基鏈,且R
c亦可指伸烯基鏈或伸炔基鏈,除非後者由上下文指定或明確指示。芳烷基部分的烷基鏈部分如上文對烷基所描述的視情況經取代。芳烷基的芳基部分如上文對芳基所描述的視情況經取代。
「芳烷氧基」係指經由氧原子鍵結的芳烷基。芳烷氧基的芳基或烷基部分如上文對芳基或芳烷基所描述的視情況經取代。
「碳環基」係指僅由碳及氫原子組成的穩定的非芳族(飽和)單環、雙環或多環烴基,通常包括稠合或橋聯環系統,具有3至15個碳原子。在某些實施例中,碳環基包含3至10個碳原子。在其他實施例中,碳環基包含3至7個碳原子。藉由單鍵使碳環基附接到分子的其餘部分。碳環基可為完全飽和的或部分飽和的。完全飽和的碳環基亦可指「環烷基」。示例性單環環烷基包括環丙基、環丁基、環戊基、環己基、環庚基及環辛基。不飽和碳環基亦可指「環烯基」。示例性單環環烯基包括環戊烯基、環己烯基、環庚烯基及環辛烯基。多環碳環基包括例如金剛烷基、降莰基(norbornyl)(亦即,雙環[2.2.1]庚烷基)、降莰烯基(norbornenyl)、十氫萘基、7,7-二甲基-二環[2.2.1]-庚烷等。除非另有說明,否則術語「碳環基」包括碳環基,由獨立選擇的一或更多個取代基視情況取代,例如,如上文對芳基所描述。
「碳環基烷基」係指式-R
c-碳環基的基團,其中R
c為烷基鏈。碳環基如上文對芳基所描述的視情況經取代,且烷基如對烷基所描述的視情況經取代。類似地,「碳環基炔基」係指如上文所定義的視情況經取代的式-R
c-碳環基(其中R
c為伸炔基鏈)的基團。在一些實施例中,碳環基為環烷基,其中碳環基炔基的伸炔基鏈部分如上文對烷基鏈所定義的視情況經取代。
「碳環烷基烷氧基」係指經由氧原子鍵結的基團,具有式-O-R
c-碳環基,其中R
c為視情況經取代之烷基鏈,如對碳環基及烷基所定義的。
本文所使用之「羧酸生物類性體」係指展示出與羧酸部分相似的物理、生物及/或化學特性的官能基團或部分。羧酸生物類性體的實例包括但不限於:
、
、
、
、
、
、
、
。
「鹵基」或「鹵素」係指溴、氯、氟或碘取代基。「鹵化物」係指二元化合物,其中一部分為鹵素原子,另一部分為與鹵素相比較弱的負電性(或更多正電性)的元素或基團,諸如氟化物、氯化物、溴化物或碘化物。
「氟烷基」係指用如上文所定義的一或更多個氟取代基取代的烷基,例如三氟甲基、二氟甲基、氟甲基、2,2,2-三氟乙基、1-氟甲基-2-氟乙基等。氟烷基的烷基部分可如上文對烷基所定義的視情況經取代。
「雜環基」係指穩定的三員至十八員非芳族環基團,通常包含2至12個碳原子及1至6個選自氮、氧及硫的雜原子。除非另有說明,雜環基為單環、雙環、三環或四環系統,並且可包括稠合或橋聯環系統。雜環基中的雜原子可視情況經氧化。若存在,一或更多個氮原子視情況經季銨化。雜環基典型地為完全飽和的。可經由環的任何原子或藉由另一個原子或基團使雜環基團附接到分子的其餘部分。示例性雜環基包括偶氮羧基、偶氮烷基、氮丙啶基、氮雜螺環壬烯基、吖丁啶基、噻吩基[1,3]二噻烷基、1,4-二氧雜環己烷基、氫化基、咪唑啶基、嗎啉基、八氫吲哚基、八氫異吲哚基、2-側氧哌啶基、哌啶基、2-側氧吡咯啶基、oxapanenyl、1-氧雜螺[4,5]癸烷基、1,6-二氧雜螺[3,4]辛烷基、1,4-二氧雜-7-氮雜螺[4.4]壬烷基、2-氧雜-7-氮雜螺[3,5]壬烷基、2,9-二氮雜螺[5,5]十一烷-1-酮、氧雜環丁烷基、1-氧雜螺[4,4]壬烷-2-酮基、1,3,8-四氮雜螺[4,5]癸-4-酮、1,4-二硫雜-7-氮雜螺[4,4]壬烷、氧硫雜環戊烷基、噁唑烷酮基、哌嗪基、4-哌啶酮基、吡咯啶基、吡咯嗪烷基、十氫喹啉基、十氫異喹啉基、琥珀醯亞胺基、環丁碸基、環硫烷基、噻唑烷基、四氫呋喃基、四氫哌喃基、四氫噻吩基、四呋喃基、四氫哌喃基、硫代嗎啉基、二氧硫代嗎啉基、1-氧硫代嗎啉基、噻呯基、噻嗎啉基、噻唑烷二酮基、thicanyl或1,3,5-三硫雜環己烷基。除非另有說明,否則術語「雜環基」包括具有取代基的視情況經取代之雜環基,例如如對芳基所描述。
「N-雜環基」或「N-附接的雜環基」係指含有至少一個氮(含N)的雜環基,其中雜環基與分子的其餘部分的附接點係經由雜環基中的氮原子。N-雜環基如本文所描述的視情況經取代。N-雜環基的實例包括1-嗎啉基、1-哌啶基、1-哌嗪基、1-吡咯啶基、吡唑基、吡唑啶基、pyrinodyl、吡咯基、嗎啉基、咪唑啉基及咪唑啶基。
「C-雜環基」或「C-附接的雜環基」係指含有至少一個雜原子的雜環基,其中雜環基與分子的其餘部分的附接點係經由雜環基中的碳原子。C-雜環基如本文所描述的視情況經取代。C-雜環基的實例包括2-嗎啉基、2-或3-或4-哌啶基、2-哌嗪基、2-或3-吡咯啶基等。
「雜環基烷基」係指式-R
c-雜環基的基團,其中R
c為如上文所定義的烷基鏈。若雜環基為含氮雜環基,則雜環基視情況在氮原子處附接到烷基。雜環基烷基的烷基鏈及雜環基烷基的雜環基部分可各個如上文所定義的視情況經取代。
「雜環基烷氧基」係指經由式-O-R
c-雜環基的氧原子鍵結的基團,其中R
c為如上文所定義的烷基鏈。若雜環基為含氮雜環基,則雜環基視情況在氮原子處附接到烷基。雜環基烷氧基的烷基鏈如上文對烷基鏈所定義的視情況經取代;並且雜環基烷氧基的雜環基部分如上文對雜環基所定義的視情況經取代。
「雜芳基」係指衍生自三員至十八員芳族環的部分,大體包含2至17個碳原子及1至6個選自氮、氧及硫的雜原子,其中環系統中的至少一個環為完全不飽和的,亦即根據Hückel理論含有環狀離域的(4n+2)π電子的系統。雜芳基可以為單環、雙環、三環或四環系統,並且包括稠合或橋聯環系統。雜芳基中的雜原子視情況氧化。若存在,一或更多個氮原子視情況季銨化。雜芳基可經由環的任何原子附接到分子的其餘部分。除非另有說明,否則雜芳基用一或更多個取代基視情況取代,例如如對芳基所描述的。
雜芳基的實例包括氮雜卓基、吖啶基、苯并咪唑基、苯并吲哚基、1,3-苯并間二氧雜戊烯基、苯并呋喃基、苯并噁唑基、苯并[d]噻唑基、苯并噻二唑基、苯并[b][1,4]二氧呯基、苯并[b][1,4]噁嗪基、1,4-苯并二噁烷基、苯并萘并呋喃基、苯并噁唑基、苯并間二氧雜戊烯基、苯并二氧嗪基、苯并哌喃基、苯并哌喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并噻吩基)、苯并噻吩并[3,2-d]嘧啶基、苯并三唑基、苯并[4,6]咪唑并[1,2-a]-吡啶基、咔唑基、噌啉基、環戊并[d]嘧啶基、6,7-二氫-5H-環戊并[4,5]噻吩并-[2,3-d]嘧啶基、5,6-二氫苯并[h]喹啉基、5,6-二氫苯并[h]噌啉基、6,7-二氫-5H-苯并[6,7]環庚并[1,2-c]噠嗪基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、呋喃并[3,2-c]吡啶基、5,6,7,8,9,10-六氫-環辛并[d]嘧啶基、5,6,7,8,9,10-六氫環十八烷并[d]噠嗪基、5,6,7,8,9,10-六氫-環辛并[d]吡啶基、異噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、異吲哚基、吲哚啉基、異吲哚啉基、異喹啉基、吲嗪基、異噁唑基、5,8-亞甲基-5,6,7,8-四氫喹唑啉基、萘啶基、1,6-萘啶酮基、噁二唑基、2-側氧氮呯基、噁唑基、環氧乙基(oxiranyl)、5,6,6a,7,8,9,10,10a-八氫苯并[h]喹唑啉基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、呔嗪基、喋啶基、嘌呤基、吡咯基、吡唑基、吡唑并[3,4-d]-嘧啶基、吡啶基、吡哆[3,2-d]嘧啶基、吡哆[3,4-d]嘧啶基、吡嗪基、嘧啶基、噠嗪基、吡咯基、喹唑啉基、喹喏啉基、喹啉基、異喹啉基、四氫喹啉基、5,6,7,8-四氫喹唑啉基、5,6,7,8-四氫苯并[4,5]噻吩并[2,3-d]嘧啶基、6,7,8,9-四氫-5H-環庚并[4,5]噻吩并[2,3-d]嘧啶基、5,6,7,8-四氫吡啶并[4,5-c]噠嗪基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基、噻吩并[2,3-d]嘧啶基、噻吩并[3,2-d]嘧啶基、噻吩并[2,3-c]嘌呤基及噻吩基。
「N-雜芳基」係指含有至少一個氮的如上文所定義的雜芳基,其中雜芳基與分子的其餘部分的附接點為經由雜芳基環中的氮原子。N-雜芳基如對芳基所描述的視情況經取代。
「C-雜芳基」係指雜芳基,其中雜芳基與分子的其餘部分的附接點為經由雜芳基中的碳原子。C-雜芳基如對芳基所描述的視情況經取代。
「雜芳基烷基」係指-R
c-雜芳基,其中R
c如上文所定義。若雜芳基為含氮雜芳基,則雜芳基視情況在氮原子處附接到烷基。雜芳基烷基的烷基鏈如上文對烷基鏈所定義的視情況經取代;並且雜芳基烷基的雜芳基部分如上文對雜芳基所定義的視情況經取代。
「雜芳基烷氧基」係指經由氧原子鍵結的基團,並且具有式-O-R
c-雜芳基,其中R
c為烷基鏈。若雜芳基為含氮雜芳基,則雜芳基視情況在氮原子處附接到烷基。雜芳基烷氧基的伸烷基鏈如上文對烷基鏈所定義的視情況經取代。雜芳基烷氧基的雜芳基部分如上文對雜芳基所定義的視情況經取代。
「可選」或「視情況」意謂隨後描述的事件或情況可能發生或可能不發生,並且描述包括事件或情況發生的情況以及事件或情況不發生的情況。例如,「視情況經取代之芳基」意謂芳基可被取代或可不被取代,並且該描述包括經取代之芳基及不具有取代基的芳基。在部分、基團或取代基的列表中,在列表開頭處使用「視情況經取代之」指示且列表中的所有成員皆視情況經取代。通常,除非上下文或明確的語言另有說明,否則本文所描述的化學基團或基團視情況經取代。
本文所描述的吡唑吡啶酮化合物可含有一或更多個不對稱中心,且因此可產生對映異構物、非對映異構物及其他立體異構形式,就絕對立體化學而言,可定義為(R)-或(S)-。除非另有說明,否則此等化合物的所有立體異構形式皆在本揭示內容中設想。當本文所描述的化合物含有烯烴雙鍵時,且除非另有說明,否則對化合物的引用包括E及Z幾何異構物(例如順式或反式)的「幾何異構物」。同樣,所有可能的異構物,以及此等的外消旋及光學純形式,以及所有的互變異構形式皆包括在內。術語「位置異構物」係指中心環周圍的結構異構物,諸如苯環周圍的鄰位、間位及對位異構物。立體異構物可以藉由本領域已知的手段及方法分離,例如對掌性HPLC。因此,本文提供的化合物包括各種立體異構物及其混合物,並且包括「對映異構物」,此係指兩種立體異構物,此兩種立體異構物的分子結構為彼此不可重疊的鏡像。
「互變異構物」係指其中質子從分子的一個原子移位到同一分子的另一個原子的分子係可能的。在某些實施例中,本文呈現的化合物可存在為互變異構物。在可能存在互變異構的情況下,可能存在互變異構物的化學平衡,但互變異構物的確切比例取決於諸如物理狀態、溫度、溶劑及pH等因素。互變異構平衡的一些實例包括:
此外,在一些實施例中,吡唑吡啶酮化合物含有非天然比例的原子同位素或包括包含同位素富集原子的化合物。設想用
2H、
3H、
11C、
13C、
14C、
15C、
12N、
13N、
15N、
16N、
16O、
17O、
14F、
15F、
16F、
17F、
18F、
33S、
34S、
35S、
36S、
35Cl、
37Cl、
79Br、
81Br、
125I同位取代。本發明化合物的所有同位素變體無論是否為放射性皆涵蓋在本發明實施例的範疇內。在某些實施例中,本文揭示的化合物具有用
2H原子取代的一些或全部
1H原子。含氘化合物的合成方法在本領域中為已知的。氘化起始原料容易獲得且經歷本文所描述的合成方法以提供含氘取代之雜環衍生化合物的合成。含氘試劑可從化學供應商(例如,Aldrich Chemical Co.)商購獲得。適用於親核取代反應的氘轉移試劑(諸如碘甲烷-d3(CD3I))易於獲得且可用於在親核取代反應條件下將氘取代之碳原子轉移至反應基質。此外,氘化鋰鋁(LiAlD
4)可用於在還原條件下將氘轉移至反應基質。可以使用氘氣及鈀催化劑來減少不飽和碳-碳鍵聯及執行芳基碳-鹵素鍵的還原性取代。因此,在一個實施例中,本文所描述的化合物含有至少一個氘原子,諸如1、2、3、4、5或6個氘原子。在另一個實施例中,本文揭示的化合物用氘原子完全取代且不含不可交換的
1H原子。
此外,本文所描述的吡唑吡啶酮化合物可以作為「前藥」生產或配製。前藥係在投予時可為無活性的,但在生理條件下或藉由水解(亦即,在活體內)轉化成生物學活性化合物的化合物;因此前藥為生物活性化合物的醫藥學上可接受的前驅物。前藥化合物可提供受試者內的溶解性、組織相容性或延遲釋放的優點。前藥亦指使用共價鍵結的載劑,當向受試者投予此類前藥時,其在體內釋放活性化合物。活性化合物的前藥可藉由修飾活性化合物中存在的官能基團來製備,使得修飾在常規操作或在活體內裂解成母體活性化合物。例如,前藥包括其中羥基、胺基或巰基與任何基團鍵結的化合物,當將活性化合物的前藥投予哺乳動物受試者時,分別裂解形成游離羥基、游離胺基或游離巰基。前藥的實例包括活性化合物中的醇或胺官能基團的乙酸酯、羧酸酯、甲酸酯及苯甲酸酯衍生物。參見例如Bundgard,DESIGN OF PRODRUGS,在7-9, 21-24 (Elsevier, Amsterdam, 1985);Higuchi等人,Pro drugs as Novel Delivery Systems, 14 A.C.S. Symposium Series;BIOREVERSIBLE CARRIERS IN DRUG DESIGN (Roche (編著), Am. Pharm. Assoc. and Pergamon Press; 1987)。
另外,本文所描述的吡唑吡啶酮化合物可作為醫藥學上可接受的鹽來生產或提供。此等化合物中任何一種的醫藥學上可接受的鹽意欲包括任何及所有醫藥學上適宜的鹽形式,包括醫藥學上可接受的鹽,諸如酸及鹼加成鹽,如本領域中眾所周知的。參見例如WO 2014089364、WO 2014100463、WO 2014100818、WO 2014164708、WO 2014151945、WO 2014151106、WO 2015058160、WO 2015089192、WO 2015168466、WO 2015200709、WO 2015200843、WO 2016004105、WO 2016003917、WO 2016037005、WO 2016044342、WO 2016044138、WO 2016044429、WO 2016168682、WO 2016172618。
因此,如本文所使用,對式I的吡唑吡啶酮化合物的引用在彼參考中包括其醫藥學上可接受的鹽、水合物、溶劑合物、N-氧化物、立體異構物、互變異構物、放射性同位素富集或氘化形式或其前藥。
本發明實施例的吡唑吡啶酮化合物可根據本文的一般合成途徑且更具體地如本文實例中所描述製備。通常,本文提供的吡唑吡啶酮化合物以實質上純的形式製備,其中含有小於約5%,或小於約1%,或小於約0.1%的其他有機小分子,諸如未反應的中間體或例如在一或更多個合成步驟中產生的合成副產物。
在某些實施例中,吡唑吡啶酮化合物可以作為純化合物投予。在其他實施方式中且一般而言,將吡唑吡啶酮化合物與醫藥學上可接受的載劑(在本文中亦稱為醫藥學上適宜的(或可接受的)賦形劑、生理上適宜的(或可接受的)賦形劑或生理上適宜的(或可接受的)載劑)組合,此醫藥學上可接受的載劑係基於選定的投藥途徑及標準醫藥實踐來選擇。參見例如REMINGTON: SCI. & PRACTICE OF PHARM. 第21版 (Gennaro (編著) Mack Pub. Co., Easton, Pa., US, 2005)。
本文所使用之「治療(treatment)」或「治療(treating)」,或「緩解」或「改善」在本文中可互換使用。此等術語係指獲得有益或期望結果的方法,包括但不限於治療益處或預防益處。「治療益處」係指根除或改善所治療的潜在病症。而且,經由根除或改善與潜在病症相關的一或更多種生理症狀來實現治療益處,使得在患者中觀察到改善,儘管患者仍可能患有潜在的病症。為了預防益處,可以將組合物投予處於發展特定疾病的風險的患者,或投予報告患有疾病的一或更多種生理症狀的患者,即使可能尚未對該疾病作出診斷。
本文描述了經取代之吡唑吡啶酮化合物,此等化合物為與諸如腫瘤生長、癌症或發炎症狀之疾病相關的無活性細胞生長調節途徑的抑制劑。此等化合物及包含此等化合物的組合物可用於治療癌症及腫瘤疾病。因此,本文所描述的化合物可用於治療癌症,例如膀胱癌、乳腺癌、Burkitt氏淋巴瘤、肺癌、NUT中線癌、黑素瘤或前列腺癌。
一個實施例提供式I的化合物,
式I
其中式I之化合物視情況為其醫藥學上可接受的鹽,且其中:
X6為CH或C-F;
R
2為氫,或烷基;
R
5為氫或視情況經取代之烷基、環烷基、雜環基、雜環烷基、芳基、雜芳基、-OW、-NW、-SW或-SO
2W其中
W為視情況經取代之烷基、環烷基、雜環基、雜環烷基、芳基、芳烷基、雜芳基或雜芳烷基;
R
6為氫、鹵素、鹵化物或視情況經取代之烷基或烷氧基;以及
R
A為視情況經取代之雜芳基。
在至少一個實施例中,X6為CH。
在至少一個實施例中,R
6為氫。在至少一個實施例中,R
6為甲基。
在至少一個實施例中,R
2為烷基,諸如甲基。
在至少一個實施例中,R
5為視情況經取代之芳基。在一些實施例中,R
5為未取代之苯基。
在至少一個實施例中,R
5為視情況經取代之雜芳基,諸如異噁唑基吡咯基、嗎啉基或四氫哌喃基。在一些實施例中,R
5為視情況經取代之N-吡咯基。在特定實施例中,R
5為未取代之N-吡咯基。在特定實施例中,R
5為用甲基乙醯亞胺取代之N-吡咯基。
在一些實施例中,R
5為經取代之雜環基,其中取代基可為羧酸、乙酸甲酯、甲磺醯基、丙基乙醯胺、磺醯基、甲基乙醯胺或二甲基乙醯胺。
在至少一個實施例中,R
5為視情況經取代之烷基,諸如甲基。在一些實施例中,R
5為經取代之烷基,其中取代基可為例如乙酸甲酯、甲磺醯基、丙基乙醯胺、磺醯基、甲基乙醯胺或二甲基乙醯胺。
在至少一個實施例中,R
5為視情況經取代之環烷基,諸如環丁基或環丙基。
在至少一個實施例中,R
5為-OW,其中W為視情況經取代之烷基,諸如乙基。在一些實施例中,W為經取代之烷基,其中取代基為羧酸、氰基、羥基或吡啶基。
在至少一個實施例中,R
5為-SW,其中W可為視情況經取代之烷基、苯基、羧酸、烷基乙醯胺。
在至少一個實施例中,R
5為-SO
2W,其中W為烷基。
在至少一個實施例中,R
A為視情況經取代之五員含N雜芳基。在至少一個實施例中,R
A為視情況經取代之吡唑基。在至少一個實施例中,R
A為視情況經取代之哌啶基吡唑。在至少一個實施例中,R
A為環戊基吡唑。在至少一個實施例中,R
A為視情況經取代之咪唑。在至少一個實施例中,R
A為視情況經取代之噁唑。在至少一個實施例中,R
A為視情況經取代之異噁唑。在至少一個實施例中,R
A為視情況經取代之三唑。
在一些實施例中,R
A為:
,
其中X為鍵、CH
2、CHR或CRR',其中
R及R'獨立地為氫、鹵素或視情況經取代之烷基;
R
1為氫或視情況經取代之烷基、芳基、芳烷基、烷氧基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳基烷基或-SO
2W;以及
R
13為-Y-Z,其中
Y選自鍵或CH(C
1-C
4烷基),及
Z選自氫、鹵素、烷基、芳基、-CF
2、-CO
2R
22、-N(R
22)或-N(R
22)CO(R
22),其中R
22為氫或烷基。
在至少一個實施例中,X為CHR,其中R為C
1-C
5烷基,諸如乙基、甲基或環丙基。
在R
13之至少一個實施例中,Y為鍵且Z為氫。在R
13之至少一個實施例中,Y為鍵且Z為甲基。
在至少一個實施例中,R
1為-SO
2Me或甲基乙醯胺。
在至少一個實施例中,R
1為視情況經取代之芳基,諸如苄基或苯基。在至少一個實施例中,R
1為經取代之苄基或苯基。在一些實施例中,R
1為用諸如溴基、氯基、氟基、二氟基之鹵基取代的苄基或苯基;用諸如二氟甲基之鹵烷基取代的苄基或苯基;用諸如乙基、甲基、丙基、異丙基或環丙基之C
1-C
5烷基取代的苄基或苯基;用氰基取代的苄基或苯基;用諸如甲氧基之烷氧基取代的苄基或苯基;用羧酸酯取代的苄基或苯基,以使得R
1為苯甲酸酯;或用諸如吡唑基或甲基吡唑基之視情況經取代之雜芳基取代的苄基或苯基。
在至少一個實施例中,R
1為視情況經取代之環基部分,諸如環己基或環丙基。在其中R
1為經取代之環基部分之實施例中,取代基可為胺基、氰基、二甲胺基、如二氟基之鹵素、羥基、甲氧基、甲基。
在至少一個實施例中,R
1為視情況經取代之雜環基,諸如嗎啉基或四氫哌喃基。
在至少一個實施例中,R
1為視情況經取代之雜芳基,諸如視情況經取代之吡啶基。在至少一個實施例中,R
1為視情況經取代之雜芳基烷基,諸如吡啶基乙基或哌啶基。在一些實施例中,R
1為經取代之雜芳基烷基,其中取代基為例如甲磺醯基或磺醯基。
在一些實施例中,R
1為視情況經取代之C
1-C
5烷基,諸如異丁基、乙基、甲基、丙基、環丙基、環丙基甲基、異丙基。
在一些實施例中,R
1為經取代之C
1-C
5烷基,其中取代基可為例如乙酸甲酯、甲磺醯基、丙基乙醯胺、磺醯基、甲基乙醯胺或二甲基乙醯胺。
在一些實施例中,R
A選自:
或
、
、
、
、
、
、
、
或
其中
X為鍵、CH
2、CHR或CRR';其中
R及R'獨立地為氫、鹵素或視情況經取代之烷基;以及
R
1為氫或視情況經取代之烷基、芳基、芳烷基、烷氧基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基、雜芳基烷基或-SO
2W,
其中W為C
1-C
4烷基,且其中R
1如上文所描述。
在式I之化合物的至少一個實施例中,X6為CH,R
2為甲基,R
6為H,R
5為N-吡咯基,及R
A為苄基吡唑基;在特定實施例中,此化合物為5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡咯-1-基)吡啶-2(1H)-酮。
在式I之化合物的至少一個實施例中,X6為CH,R
2為甲基,R
6為H,R
5為異丙氧基,及R
A為苯基乙基吡唑基。
在式I之化合物的至少一個實施例中,其中X6為CH,R
2為甲基,R
6為H,R
5為H,及R
A為:
,
其中X為CHR,其中R
13為甲基;及R
1為氯苄基。在式I之化合物的至少一個實施例中,其中X6為CH,R
2為甲基,R
6為H,R
5為H,及R
A為環丙基(苯基)甲基吡唑基。
在特定實施例中,式I之化合物為表1之化合物:
表 1 | ||
實例 | 結構 | 名稱 |
1 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
2 | 5-(1-(環丙基(苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
3 | 2-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈 | |
4 | 3-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈 | |
5 | 1-甲基-5-(1-(吡啶-2-基甲基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
6 | 5-(1-(4-氟苄基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
7 | 5-(1-苄基-1H-吡唑-4-基)-1,4-二甲基吡啶-2(1H)-酮 | |
8 | 4-(1-苄基-1H-吡唑-4-基)-2-甲基異喹啉-1(2H)-酮 | |
9 | 4-(1-苄基-1H-吡唑-4-基)-2-甲基-2,6-萘啶-1(2H)-酮 | |
10 | 5-(1-苄基-1H-吡唑-4-基)-1-乙基吡啶-2(1H)-酮 | |
11 | 5-(1-(1-(3-(二氟甲基)苯基)乙基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮 | |
12 | 1-甲基-5-(苯基(1-甲基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
13 | 5-(1-苄基-1H-吡唑-4-基)-1,3-二甲基-吡啶-2(1H)-酮 | |
14 | ( S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
15 | ( R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
16 | 3-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈 | |
17 | 1,3-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶‑2(1H)-酮 | |
18 | 5-(1-(環丙基(苯基)甲基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮 | |
19 | 5-(1-(1-(2-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
20 | 1-甲基-5-(1-(1-(間甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
21 | 4-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
22 | 1-甲基-5-(1-(1-(鄰甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
23 | 5-(1-(1-(3-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
24 | 1-甲基-5-(1-(1-(吡啶-3-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
25 | 4-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈 | |
26 | 3-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
27 | 5-(1-(1-(2-甲氧基苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
28 | 5-(1-(1-(3-甲氧基苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
29 | 1-甲基-5-(1-(1-(吡啶-4-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
30 | 1,3,4-三甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
31 | 3-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
32 | 3-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
33 | 2-甲基-4-(1-(1-苯基乙基)-1H-吡唑-4-基)-2,5,6,7-四氫-1H-環戊[c]吡啶-1-酮 | |
34 | 1,3-二甲基-5-(5-甲基-1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
35 | 5-(1-苄基-1H-吡唑-4-基)-1-(二氟甲基)-4-苯基吡啶-2(1H)-酮 | |
36 | 4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
37 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-甲磺醯基-吡咯啶-1-基)-1-甲基-1H-吡啶-2-酮 | |
38 | 4-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
39 | 4-乙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
40 | 4-(吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
41 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1--基)吡啶-2(1H)-酮 | |
42 | 1-甲基-4-(甲胺基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
43 | 1-甲基-4-嗎啉基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
44 | 1-甲基-4-((1-甲基-1H-吡唑-3-基)甲氧基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
45 | ( R)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
46 | ( S)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
47 | ( S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | |
48 | 4-異丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
49 | 4-環丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
50 | 4-((1-乙醯基吖丁啶-3-基)氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
51 | 4-(環戊氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
52 | 4-(環己氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
53 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | |
54 | 1-甲基-4-(3-甲基吖丁啶-1-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
55 | ( R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | |
56 | 4-(苄氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
57 | 1-甲基-4-苯氧基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
58 | 4-(3-甲氧基吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
59 | 4-環丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
60 | ( S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | |
61 | ( R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | |
62 | 4-乙氧基-1-甲基-5-(1-(1-(對甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
63 | 5-(1-(1-([1,1'-聯苯基]-4-基)乙基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
64 | 5-(1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
65 | 4-乙氧基-1-甲基-5-(1-(4-甲苄基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
66 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-1-基)-吡啶-2(1H)-酮 | |
67 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-嗎啉基吡啶-2(1H)-酮 | |
68 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡咯-1-基)吡啶-2(1H)-酮 | |
69 | 4-乙氧基-1-甲基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮 | |
70 | 甲基-2-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯 | |
71 | 甲基3-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯 | |
72 | ( R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)乙醯胺 | |
73 | (S)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)乙醯胺 | |
74 | ( R)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-甲酸 | |
75 | ( S)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-甲酸 | |
76 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺 | |
77 | 甲基1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸鹽 | |
78 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N,N-二甲基-1H-吡咯-3-甲醯胺 | |
79 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | |
80 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-腈 | |
81 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-乙基-1H-吡咯-3-甲醯胺 | |
82 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-異丙基-1H-吡咯-3-甲醯胺 | |
83 | 1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-(1H-吡咯-1-基)吡啶-2(1H)-酮 | |
84 | 1-(1-甲基-5-(1-甲基-1H-吡唑-4-基)-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | |
85 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺 | |
86 | 1-(5-(1-(環丙基甲基)-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | |
87 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-吡咯啶-1-基-1H-吡啶-2-酮 | |
88 | N-{2-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-環戊基}-乙醯胺 | |
89 | N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基甲基}-乙醯胺 | |
90 | N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基甲基}-乙醯胺 | |
91 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2,2,2-三氟乙氧基)吡啶-2(1H)-酮 | |
92 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3,3,3-三氟丙氧基)吡啶-2(1H)-酮 | |
93 | 1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-甲基乙醯胺 | |
94 | 5-(1-苄基-1H-吡唑-4-基)-4-(1H-咪唑-1-基)-1-甲基吡啶-2(1H)-酮 | |
95 | 5-(5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
96 | 4-乙氧基-1-甲基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
97 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
98 | 5-(1-(2,6-二氯苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
99 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2-甲基肼基)吡啶-2(1H)-酮 | |
100 | 4-乙氧基-1-甲基-5-(1-{1-[4-(1-甲基-1H-吡唑-4-基)-苯基]-乙基}-1H-吡唑-4-基)-1H-吡啶-2-酮 | |
101 | 4-乙氧基-5-[1-(4-異丙基-苄基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | |
102 | 4-乙氧基-1-甲基-5-(1-(4-(1-甲基-1H-吡唑-4-基)苄基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
103 | 5-(1-(4-(1H-吡唑-4-基)苄基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
104 | 4-乙氧基-1-甲基-5-(1-(1-(3-(1-甲基-1H-吡唑-4-基)苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
105 | 5-(1-(3-溴苄基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
106 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-( 鄰甲苯基)吡啶-2(1H)-酮 | |
107 | 1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | |
108 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
109 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-3-基)吡啶-2(1H)-酮 | |
110 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮 | |
111 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-( 間甲苯基)吡啶-2(1H)-酮 | |
112 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-( 對甲苯基)吡啶-2(1H)-酮 | |
113 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-甲氧基苯基)-1-甲基吡啶-2(1H)-酮 | |
114 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-5-基)吡啶-2(1H)-酮 | |
115 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮 | |
116 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-2-基)吡啶-2(1H)-酮 | |
117 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-3-基)吡啶-2(1H)-酮 | |
118 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-氯苯基)-1-甲基吡啶-2(1H)-酮 | |
119 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基吡啶-2(1H)-酮 | |
120 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-甲氧基苯基)-1-甲基吡啶-2(1H)-酮 | |
121 | 5-(1-苄基-1H-吡唑-4-基)-4-(異噁唑-3-基)-1-甲基吡啶-2(1H)-酮 | |
122 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | |
123 | 5-(1-苄基-1H-吡唑-4-基)-4-(2-氯苯基)-1-甲基吡啶-2(1H)-酮 | |
124 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-[4,4'-聯吡啶]-2(1H)-酮 | |
125 | 5-(1-環己基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
126 | 1-甲基-4-苯基-5-(1-(四氫-2H-哌喃-4-基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
127 | 1-甲基-5-(1-(1-(甲磺醯基)哌啶-4-基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | |
128 | 1-甲基-4-苯基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
129 | 1-甲基-5-(1-((甲磺醯基)甲基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | |
130 | 1-甲基-5-(1-(2-嗎啉基乙基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | |
131 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[2,4'-聯吡啶]-2'(1'H)--酮 | |
132 | 5-(1-乙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
133 | 1-甲基-4-苯基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮 | |
134 | N-甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-1H-吡唑-1-基)乙醯胺 | |
135 | N,N-二甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙醯胺 | |
136 | 5-(1,3-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
137 | 5-(1-異丁基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
138 | 5-(1-異丙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
139 | 1-甲基-4-苯基-5-(1-丙基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
140 | 甲基2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-1H-吡唑-1-基)乙酸酯 | |
141 | 2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-N-丙基乙醯胺 | |
142 | 4-環戊基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
143 | 4-環己基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
144 | 4-環丙基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
145 | 1-甲基-4-苯基-5-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
146 | 5-(1-(環丙基甲基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
147 | 5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-4-(4-三氟甲基-苯基)-1H-吡啶-2-酮 | |
148 | 4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-N-甲基-苯甲醯胺 | |
149 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-氟苯基)-1-甲基吡啶-2(1H)-酮 | |
150 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)苯甲腈 | |
151 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)苯甲醯胺 | |
152 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-4-基)吡啶-2(1H)-酮 | |
153 | 4-(4-氯-苯基)-5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-1H-吡啶-2-酮 | |
154 | 4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲酸 | |
155 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)苯甲酸 | |
156 | 4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲腈 | |
157 | 5-(1-(環己基甲基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
158 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙醯胺 | |
159 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙酸 | |
160 | 5-(1-苄基-1H-吡唑-4-基)-4-(1-(二氟甲基)-1H-吡唑‑4-基)-1-甲基吡啶-2(1H)-酮 | |
161 | 5-(1-苄基-1H-吡唑-4-基)-4-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
162 | 5-(5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
163 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙腈 | |
164 | 5-(1,5-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶‑2(1H)-酮 | |
165 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-丙氧基-1H-吡啶-2-酮 | |
166 | 3-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-丙酸 | |
167 | [5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-乙腈 | |
168 | 5-(1-苄基-1H-吡唑-4-基)-4-乙基硫基-1-甲基-1H-吡啶-2-酮 | |
169 | [5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基硫基]-乙酸 | |
170 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-((甲胺基)氧基)吡啶-2(1H)-酮 | |
171 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-乙氧基-1-甲基-1H-吡啶-2-酮 | |
172 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-甲基吡咯啶-3-磺醯胺 | |
173 | (R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)-1,1,1-三氟甲磺醯胺 | |
174 | (R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)甲磺醯胺 | |
175 | 4-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
176 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-異丙基-苯甲腈 | |
177 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲氧基-苯甲腈 | |
178 | 2-氯-6-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
179 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲基-苯甲腈 | |
180 | 4-乙氧基-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | |
181 | 4-乙氧基-1-甲基-5-(1-(1-(甲磺醯基)哌啶-3-基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
182 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲腈 | |
183 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈 | |
184 | 4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
185 | 5-(1-苄基-3-硝基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
186 | 5-(3-胺基-1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | |
187 | N-[1-苄基-4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-基]-乙醯胺 | |
188 | 5-(1-苄基-1H-吡唑-4-基)-4-(2-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮 | |
189 | 5-(1-苄基-1H-吡唑-4-基)-4-(2,6-二甲基-苯基)-1-甲基-1H-吡啶-2-酮 | |
190 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-苯基-1H-吡啶-2-酮 | |
191 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-(4-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮 | |
192 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-(1-甲基-1H-吡唑-4-基)-1H-吡啶-2-酮 | |
193 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮 | |
194 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮 | |
195 | 5-(1-苄基-1H-吡唑-4-基)-1,6-二甲基-1H-吡啶-2-酮 | |
196 | 3-二甲胺基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮 | |
197 | 3-環丙基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮 | |
198 | 1-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-甲酸乙酯 | |
199 | 2-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-2H-吡唑-3-甲酸乙酯 | |
200 | 4-胺基-5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
201 | 3-((5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)胺基)丙酸 | |
202 | 2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
203 | 2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
204 | 2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
205 | 2-[4-(1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | |
206 | 2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
207 | 2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
208 | 2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | |
209 | 2-[4-(1,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
210 | 2-[4-(5,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
211 | 2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
212 | 2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
213 | 2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
214 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
215 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
216 | 2-{4-[4-(3-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
217 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲酸 | |
218 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲醯胺 | |
219 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-N-甲基-苯甲醯胺 | |
220 | 2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | |
221 | 2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | |
222 | 2-[4-(1'-環丙基-1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | |
223 | 2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
224 | 2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
225 | 2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸 | |
226 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | |
227 | 2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | |
228 | 2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | |
229 | 2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | |
230 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | |
231 | 2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | |
232 | 2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | |
233 | 2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
234 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
235 | 2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
236 | 2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
237 | 2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
238 | 2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
239 | 2-(4-(1,1',5-三甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
240 | 2-(4-(5-氟-1'-甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
241 | 2-{4-[4-(3-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
242 | 2-(4-(5-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
243 | 2-(4-(4-(3,4-二甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
244 | 2-{4-[4-(2-甲氧基-嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
245 | 2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
246 | 2-{4-[1-甲基-6-側氧-4-(3,4,5-三甲氧基-苯基)-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | |
247 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲酸 | |
248 | 4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
249 | 2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸 | |
250 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-1-甲基-4-((1-甲基-1H-吡唑-4-基)甲氧基)吡啶-2(1H)-酮 | |
251 | 3-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
252 | 4-乙氧基-5-(1-(2-氟苯基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | |
253 | 4-乙氧基-1-甲基-5-(1-(吡啶-2-基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
254 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
255 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
256 | 2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
257 | 2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
258 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈 | |
259 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲酸 | |
260 | 4-甲氧基-2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
261 | 4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | |
262 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | |
263 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | |
264 | 4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
265 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲腈 | |
266 | 4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | |
267 | 4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | |
268 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸 | |
269 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸 | |
270 | 4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | |
271 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲酸 | |
272 | 4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲酸 | |
273 | 2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-6-氟-苯甲腈 | |
274 | 2-氟-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
275 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-6-氟-苯甲腈 | |
276 | 2-氯-6-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | |
277 | 2-氯-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
278 | 2-氟-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
279 | 2-氯-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
280 | 2-氯-6-(4-(4-(2-乙基嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
281 | 2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
282 | 2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | |
283 | 2-(4-(1-甲基-4-(2-嗎啉基乙氧基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
284 | 5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮 | |
285 | 5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-6-甲氧基-1'-甲基-1'H-[3,4']聯吡啶基-2'-酮 | |
286 | 4-(4-氯-苯基)-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | |
287 | 5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮 | |
288 | N-氰基-2-(4-(4-(4-氟苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | |
289 | N-氰基-2-(4-(1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | |
290 | N-氰基-2-(4-(4-(4-甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | |
291 | 2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-N-氰基苯甲醯胺 | |
292 | N-氰基-2-(4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺 | |
293 | N-氰基-2-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺 | |
294 | N-氰基-2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺 | |
295 | N-氰基-2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | |
296 | N-氰基-2-(4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺 | |
297 | 5-(1-(2-(1H-四唑-5-基)苯基)-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基吡啶-2(1H)-酮 | |
298 | 4-(4-甲氧基-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | |
299 | 4-(4-氟-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | |
300 | 1-甲基-4-(1-甲基-1H-吡唑-4-基)-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | |
301 | 4-環丙基-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | |
302 | N-{2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苄醯基}-甲磺醯胺 | |
303 | 乙磺酸2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲醯胺 | |
304 | N-[(二甲胺基)磺醯基]-{2-[4-(4-環丙基-1-甲基-6-側氧(3-氫吡啶))吡唑基]苯基}羧醯胺 | |
305 | 3-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈 | |
306 | 4-甲氧基-3-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | |
307 | 3-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | |
308 | 6-甲氧基-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮. | |
309 | 1-甲基-4-(2-(甲胺基)嘧啶-5-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
310 | 1,1'-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | |
311 | 4-(2-(乙胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
312 | 4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | |
313 | 6-(3-(二甲胺基)丙氧基)-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮 | |
314 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | |
315 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮 | |
316 | 5'-(1-(2-氯苯基)-1H-吡唑-4-基)-6-甲氧基-1',5-二甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | |
317 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-2'-甲氧基-1-甲基-[4,4'-聯吡啶]-2(1H)-酮 | |
318 | 5-(1-(2-氟苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | |
319 | 5'-(1-(2-氟苯基)-1H-吡唑-4-基)-6-甲氧基-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | |
320 | 5-(1-(2-氟苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮 | |
321 | 5-(1-(2-羥基環己基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | |
322 | 2-氯-6-[4-[4-[2-(環丙基胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
323 | 2-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
324 | 2-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
325 | 2-氯-6-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
326 | 2-氯-6-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
327 | 2-氯-6-(4-(4-(2-((環丙基甲基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
328 | 2-氯-6-(4-(4-(2-(二甲胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
329 | 2-氯-6-(4-(4-(2-(環戊基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
330 | 2-氯-6-(4-(1-甲基-6-側氧-4-(2-(吡咯啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
331 | 2-氯-6-(4-(4-(2-(異丙基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
332 | 2-氯-6-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
333 | 2-[4-[4-[2-(乙胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | |
334 | 2-[4-[4-[2-(二甲胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | |
335 | 2-氯-6-(4-(1-甲基-4-(2-嗎啉基嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
336 | 2-氟-6-[4-[1-甲基-6-側氧-4-(2-吡咯啶-1-基嘧啶-5-基)-3-吡啶]吡唑-1-基]苯甲腈 | |
337 | 2-氯-6-(4-(1-甲基-4-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
338 | 2-氯-6-(4-(1-甲基-6-側氧-4-(2-(哌啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | |
339 | 2-氯-6-[4-[4-[6-(異丙基胺基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]-吡唑-1-基]苯甲腈 | |
340 | 2-氯-6-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
341 | 2-氯-6-(4-(1'-甲基-6-(甲胺基)-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
342 | 2-氯-6-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
343 | 2-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | |
344 | 2-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | |
345 | 2-氯-6-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}苯甲腈 | |
346 | 2-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)-6-氟苯甲腈 | |
347 | 2-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}-6-氟苯甲腈 | |
348 | 2-氯-6-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)苯甲腈 | |
349 | 2-氯-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | |
350 | 2-氟-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | |
351 | 2-氟-6-(4-(6-(異丙基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
352 | 2-氯-6-[4-[4-[6-(環戊氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
353 | 2-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | |
354 | 2-氯-6-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
355 | 2-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
356 | 2-氯-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
357 | 2-氯-6-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
358 | 2-氟-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
359 | 2-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | |
360 | 2-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | |
361 | 2-[4-[4-[6-(環戊氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | |
362 | 2-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | |
363 | 2-氯-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
364 | 2-氯-6-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
365 | 2-氯-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
366 | 2-氯-6-[4-[4-(6-環丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
367 | 2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | |
368 | 2-氟-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
369 | 2-氯-6-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
370 | 2-氯-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
371 | 2-氯-6-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
372 | 2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | |
373 | 2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
374 | 2-[4-[4-(6-環丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | |
375 | 2-氟-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
376 | 2-氯-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
377 | 2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
378 | 2-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | |
379 | 2-氯-6-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
380 | 2-環丙基-6-[4-[1-甲基-4-(1-甲基-2-側氧-4-吡啶)-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
381 | 2-環丙基-6-[4-[4-[1-(環丙基甲基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
382 | 2-環丙基-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
383 | 2-環丙基-6-(4-(6-甲氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
384 | 2-環丙基-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
385 | 2-環丙基-6-[4-[1-甲基-6-側氧-4-(2-側氧-1-丙基-4-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | |
386 | 2-環丙基-6-[4-[4-(1-乙基-2-側氧-4-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
387 | 2-環丙基-6-[4-[4-[6-(2-氟乙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
388 | 2-環丙基-6-(4-(1'-環丙基-1-甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲腈 | |
389 | 2-環丙基-6-[4-[4-[1-(2-氟乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
390 | 2-環丙基-6-[4-[4-[1-(2-羥基乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | |
391 | 2-環丙基-6-(4-(6-(環丙基甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | |
392 | 4-乙氧基-5-(5-甲磺醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-1-甲基-1H-吡啶-2-酮 | |
393 | 5-(5-乙醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-4-乙氧基-1-甲基-1H-吡啶-2-酮 | |
394 | 1-甲基-4-苯基-5-(5-苯基噁唑-2-基)吡啶-2(1H)-酮 | |
395 | 1-甲基-5-(1-甲基-5-苯基-1H-吡唑-3-基)-4-苯基吡啶-2(1H)-酮 | |
396 | 1-甲基-4-苯基-5-(2-苯基噁唑-4-基)吡啶-2(1H)-酮 | |
397 | 1-甲基-4-苯基-5-(2-苯基噁唑-5-基)吡啶-2(1H)-酮 |
在一些實施例中,式I之化合物選自:
5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮;
2-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈;
3-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈;
1-甲基-5-(1-(吡啶-2-基甲基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(4-氟苄基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1,4-二甲基吡啶-2(1H)-酮;
4-(1-苄基-1H-吡唑-4-基)-2-甲基異喹啉-1(2H)-酮;
4-(1-苄基-1H-吡唑-4-基)-2-甲基-2,6-口奈啶基-1(2H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-乙基吡啶-2(1H)-酮;
5-(1-(1-(3-(二氟甲基)苯基)乙基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮;
1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(環丙基(苯基)甲基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
(S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
(R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
3-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈;
1,3-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(環丙基(苯基)甲基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮;
5-(1-(1-(2-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
1-甲基-5-(1-(1-(間甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-5-(1-(1-(鄰甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(1-(3-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
1-甲基-5-(1-(1-(吡啶-3-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈;
3-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(1-(2-甲氧基苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
5-(1-(1-(3-甲氧基苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
1-甲基-5-(1-(1-(吡啶-4-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1,3,4-三甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
3-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
3-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
2-甲基-4-(1-(1-苯基乙基)-1H-吡唑-4-基)-2,5,6,7-四氫-1H-環戊[c]吡啶-1-酮;
1,3-二甲基-5-(5-甲基-1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-(二氟甲基)-4-苯基-吡啶-2(1H)-酮;
4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-乙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-(吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮;
1-甲基-4-(甲胺基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-4-嗎啉基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-4-((1-甲基-1H-吡唑-3-基)甲氧基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
(R)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
(S)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
(S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮;
4-異丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-環丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-((1-乙醯基吖丁啶-3-基)氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-(環戊氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-(環己氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮;
1-甲基-4-(3-甲基吖丁啶-1-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
(R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮;
4-(苄氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-4-苯氧基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-(3-甲氧基吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-環丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
(S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮;
(R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮;
4-乙氧基-1-甲基-5-(1-(1-(對甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)酮;
5-(1-(1-([1,1'-聯苯基]-4-基)乙基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮;
4-乙氧基-1-甲基-5-(1-(4-甲苄基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-1-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-嗎啉基吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡咯-1-基)吡啶-2(1H)-酮;
4-乙氧基-1-甲基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮;
甲基2-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯;
甲基3-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯;
(R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-基)乙醯胺;
(S)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-基)乙醯胺;
(R)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-甲酸;
(S)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-甲酸;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡咯-3-甲酸甲酯
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N,N-二甲基-1H-吡咯-3-甲醯胺;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-腈;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-乙基-1H-吡咯-3-甲醯胺;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-異丙基-1H-吡咯-3-甲醯胺;
1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-(1H-吡咯-1-基)吡啶-2(1H)-酮
1-(1-甲基-5-(1-甲基-1H-吡唑-4-基)-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺;
1-(5-(1-(環丙基甲基)-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-吡咯啶-1-基-1H-吡啶-2-酮;
N-{2-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-環戊基}-乙醯胺;
N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基甲基}-乙醯胺;
N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基甲基}-乙醯胺;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2,2,2-三氟乙氧基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3,3,3-三氟丙氧基)吡啶-2(1H)-酮;
1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-甲酸甲基醯胺;
5-(1-苄基-1H-吡唑-4-基)-4-(1H-咪唑-1-基)-1-甲基-吡啶-2(1H)-酮;
5-(5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-4-乙氧基-1-甲基-吡啶-2(1H)-酮;
4-乙氧基-1-甲基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(2-氯苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基-吡啶-2(1H)-酮;
5-(1-(2,6-二氯苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基-吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2-甲基肼基)吡啶-2(1H)-酮;
4-乙氧基-1-甲基-5-(1-{1-[4-(1-甲基-1H-吡唑-4-基)-苯基]-乙基}-1H-吡唑-4-基)-1H-吡啶-2-酮;
4-乙氧基-5-[1-(4-異丙基-苄基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮;
4-乙氧基-1-甲基-5-{1-[4-(1-甲基-1H-吡唑-4-基)-苄基]-1H-吡唑-4-基}-1H-吡啶-2-酮;
4-乙氧基-1-甲基-5-{1-[4-(1H-吡唑-4-基)-苄基]-1H-吡唑-4-基}-1H-吡啶-2-酮;
4-乙氧基-1-甲基-5-(1-(1-(3-(1-甲基-1H-吡唑-4-基)苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(3-溴苄基)-1H-吡唑-4-基)-4-乙氧基-1-甲基-吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-鄰甲苯基-1H-吡啶-2-酮;
1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-3-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(間甲苯基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(對甲苯基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(3-甲氧基苯基)-1-甲基-吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-5-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-2-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-3-基)吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(3-氯苯基)-1-甲基-吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基-吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(4-甲氧基苯基)-1-甲基-吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(異噁唑-3-基)-1-甲基吡啶-2(1H)-酮;
5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(2-氯苯基)-1-甲基-吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-[4,4'-聯吡啶]-2(1H)-酮;
5-(1-環己基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮;
1-甲基-4-苯基-5-(1-(四氫-2H-哌喃-4-基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-5-(1-(1-(甲磺醯基)哌啶-4-基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮;
1-甲基-4-苯基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-5-(1-((甲磺醯基)甲基)-1H-吡唑-4-基)-4-苯基-吡啶-2(1H)-酮;
1-甲基-5-(1-(2-嗎啉基乙基)-1H-吡唑-4-基)-4-苯基-吡啶-2(1H)-酮;
5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[2,4'-聯吡啶]-2'(1'H)-酮;
5-(1-乙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮;
1-甲基-4-苯基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮;
N-甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙醯胺;
N,N-二甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙醯胺;
5-(1,3-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮;
5-(1-異丁基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮;
5-(1-異丙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮;
1-甲基-4-苯基-5-(1-丙基-1H-吡唑-4-基)吡啶-2(1H)-酮;
甲基2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙酸酯
2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-N-丙基乙醯胺;
4-環戊基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-環己基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-環丙基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮;
1-甲基-4-苯基-5-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2(1H)-酮;
5-(1-(環丙基甲基)-1H-吡唑-4-基)-1-甲基-4-苯基-吡啶-2(1H)-酮;
5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-4-(4-三氟甲基-苯基)-1H-吡啶-2-酮;
4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-N-甲基-苯甲醯胺;
5-(1-苄基-1H-吡唑-4-基)-4-(4-氟苯基)-1-甲基-吡啶-2(1H)-酮;
4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)苯甲腈;
4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)苯甲醯胺;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-4-基)吡啶-2(1H)-酮;
4-(4-氯-苯基)-5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-1H-吡啶-2-酮;
4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲酸;
4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-苯甲酸;
4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲腈;
5-(1-(環己基甲基)-1H-吡唑-4-基)-1-甲基-4-苯基-吡啶-2(1H)-酮;
2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡唑-1-基)乙醯胺;
2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡唑-1-基)乙酸;
5-(1-苄基-1H-吡唑-4-基)-4-(1-(二氟甲基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
5-(5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-1-甲基-4-苯基-吡啶-2(1H)-酮;
2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡唑-1-基)乙腈;
5-(1,5-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-丙氧基-1H-吡啶-2-酮;
3-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-丙酸;
[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-乙腈;
5-(1-苄基-1H-吡唑-4-基)-4-乙基硫基-1-甲基-1H-吡啶-2-酮;
[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基硫基]-乙酸;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-((甲胺基)氧基)吡啶-2(1H)-酮;
5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-乙氧基-1-甲基-1H-吡啶-2-酮;
1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-甲基吡咯啶-3-磺醯胺;
(R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)-1,1,1-三氟甲磺醯胺;
(R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)甲磺醯胺;
5-(1-苄基-1H-吡唑-4-基)-4-(3-甲磺醯基-吡咯啶-1-基)-1-甲基-1H-吡啶-2-酮;
2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-異丙基-苯甲腈;
2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲氧基-苯甲腈;
2-氯-6-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲基-苯甲腈;
4-乙氧基-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮;
4-乙氧基-1-甲基-5-(1-(1-(甲磺醯基)哌啶-3-基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲腈;
2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈;
4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
5-(1-苄基-3-硝基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮;
5-(3-胺基-1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮;
N-[1-苄基-4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-基]-乙醯胺;
5-(1-苄基-1H-吡唑-4-基)-4-(2-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮;
5-(1-苄基-1H-吡唑-4-基)-4-(2,6-二甲基-苯基)-1-甲基-1H-吡啶-2-酮;
5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-苯基-1H-吡啶-2-酮;
5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-(4-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮;
5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-(1-甲基-1H-吡唑-4-基)-1H-吡啶-2-酮;
5-(1-苄基-1H-吡唑-4-基)-1-甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮;
5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮;
5-(1-苄基-1H-吡唑-4-基)-1,6-二甲基-1H-吡啶-2-酮;
3-二甲胺基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮;
3-環丙基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮;
1-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-甲酸乙酯;
2-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-2H-吡唑-3-甲酸乙酯;
4-胺基-5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
3-((5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)胺基)丙酸;
2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
2-[4-(1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸;
2-[4-(1,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-[4-(5,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
2-{4-[4-(3-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲酸;
4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲醯胺;
4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-N-甲基-苯甲醯胺;
2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(1'-環丙基-1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸;
2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸;
2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸;
2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸;
2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸;
2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸;
2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸;
2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸;
2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(1,1',5-三甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(5-氟-1'-甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-{4-[4-(3-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
2-(4-(5-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(4-(3,4-二甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-{4-[4-(2-甲氧基-嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-{4-[1-甲基-6-側氧-4-(3,4,5-三甲氧基-苯基)-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈;
2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲酸;
4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸;
5-(1-(2-氯苯基)-1H-吡唑-4-基)-1-甲基-4-((1-甲基-1H-吡唑-4-基)甲氧基)吡啶-2(1H)-酮;
3-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
4-乙氧基-5-(1-(2-氟苯基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮;
4-乙氧基-1-甲基-5-(1-(吡啶-2-基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈;
2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲酸;
4-甲氧基-2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈;
2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈;
2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈;
4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲腈;
4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈;
4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸;
2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸;
2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸;
4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸;
2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲酸;
4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲酸;
2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-6-氟-苯甲腈;
2-氟-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-6-氟-苯甲腈;
2-氯-6-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈;
2-氯-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
2-氟-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(2-乙基嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺;
2-(4-(1-甲基-4-(2-嗎啉基乙氧基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮;
5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-6-甲氧基-1'-甲基-1'H-[3,4']聯吡啶基-2'-酮;
4-(4-氯-苯基)-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮;
5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮;
N-氰基-2-(4-(4-(4-氟苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺;
N-氰基-2-(4-(1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺;
N-氰基-2-(4-(4-(4-甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺;
2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-N-氰基苯甲醯胺;
N-氰基-2-(4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺;
N-氰基-2-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺;
N-氰基-2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺;
N-氰基-2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺;
N-氰基-2-(4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺;
5-(1-(2-(1H-四唑-5-基)苯基)-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基吡啶-2(1H)-酮;
4-(4-甲氧基-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮;
4-(4-氟-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮;
1-甲基-4-(1-甲基-1H-吡唑-4-基)-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮;
4-環丙基-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮;
N-{2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苄醯基}-甲磺醯胺;
乙磺酸2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲醯胺;
N-[(二甲胺基)磺醯基]-{2-[4-(4-環丙基-1-甲基-6-側氧(3-氫吡啶))吡唑基]苯基}羧醯胺;
3-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈;
4-甲氧基-3-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈;
3-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈;
6-甲氧基-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮;
1-甲基-4-(2-(甲胺基)嘧啶-5-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
1,1'-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮;
4-(2-(乙胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮;
6-(3-(二甲胺基)丙氧基)-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮;
5-(1-(2-氯苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮;
5-(1-(2-氯苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮;
5'-(1-(2-氯苯基)-1H-吡唑-4-基)-6-甲氧基-1',5-二甲基-[3,4'-聯吡啶]-2'(1'H)-酮;
5-(1-(2-氯苯基)-1H-吡唑-4-基)-2'-甲氧基-1-甲基-[4,4'-聯吡啶]-2(1H)-酮;
5-(1-(2-氟苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮;
5'-(1-(2-氟苯基)-1H-吡唑-4-基)-6-甲氧基-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮;
5-(1-(2-氟苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮;
5-(1-(2-羥基環己基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮;
2-氯-6-[4-[4-[2-(環丙基胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(2-((環丙基甲基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(2-(二甲胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(2-(環戊基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(1-甲基-6-側氧-4-(2-(吡咯啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(4-(2-(異丙基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-[4-[4-[2-(乙胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈;
2-[4-[4-[2-(二甲胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈;
2-氯-6-(4-(1-甲基-4-(2-嗎啉基嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氟-6-[4-[1-甲基-6-側氧-4-(2-吡咯啶-1-基嘧啶-5-基)-3-吡啶]吡唑-1-基]苯甲腈;
2-氯-6-(4-(1-甲基-4-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(1-甲基-6-側氧-4-(2-(哌啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-[4-[4-[6-(異丙基胺基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]-吡唑-1-基]苯甲腈;
2-氯-6-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(1'-甲基-6-(甲胺基)-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈
2-氯-6-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈;
2-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈;
2-氯-6-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}苯甲腈;
2-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)-6-氟苯甲腈;
2-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}-6-氟苯甲腈;
2-氯-6-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)苯甲腈;
2-氯-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈;
2-氟-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈;
2-氟-6-(4-(6-(異丙基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-[4-[4-[6-(環戊氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈;
2-氯-6-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈
2-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-氟-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈;
2-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈;
2-[4-[4-[6-(環戊氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈;
2-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈;
2-氯-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-氯-6-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-氯-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-[4-[4-(6-環丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈;
2-氟-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-氯-6-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈;
2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-[4-[4-(6-環丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈;
2-氟-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-氯-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈;
2-氯-6-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-環丙基-6-[4-[1-甲基-4-(1-甲基-2-側氧-4-吡啶)-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-環丙基-6-[4-[4-[1-(環丙基甲基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-環丙基-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-環丙基-6-(4-(6-甲氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-環丙基-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
2-環丙基-6-[4-[1-甲基-6-側氧-4-(2-側氧-1-丙基-4-吡啶)-3-吡啶]吡唑-1-基]苯甲腈;
2-環丙基-6-[4-[4-(1-乙基-2-側氧-4-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-環丙基-6-[4-[4-[6-(2-氟乙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-環丙基-6-(4-(1'-環丙基-1-甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲腈;
2-環丙基-6-[4-[4-[1-(2-氟乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-環丙基-6-[4-[4-[1-(2-羥基乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈;
2-環丙基-6-(4-(6-(環丙基甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈;
4-乙氧基-5-(5-甲磺醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-1-甲基-1H-吡啶-2-酮;
5-(5-乙醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-4-乙氧基-1-甲基-1H-吡啶-2-酮;
1-甲基-4-苯基-5-(5-苯基噁唑-2-基)吡啶-2(1H)-酮;
1-甲基-5-(1-甲基-5-苯基-1H-吡唑-3-基)-4-苯基吡啶-2(1H)-酮;
1-甲基-4-苯基-5-(2-苯基噁唑-4-基)吡啶-2(1H)-酮;或
1-甲基-4-苯基-5-(2-苯基噁唑-5-基)吡啶-2(1H)-酮。
在一些實施例中,本文揭示的經取代之雜環衍生化合物具有表2中提供的結構。
經取代之雜環衍生化合物的製備
表 2 | |||
根據本領域熟習技術者已知的有機合成技術製作本文所描述的反應中使用的化合物,從可商購的化學品及/或從化學文獻中所描述的化合物開始製作。「可商購的化學品」係自標準商業來源獲得,包括Acros Organics (Pittsburgh, Pa., US)、Aldrich Chemical (Milwaukee, Wis., US;包括Sigma Chemical與Fluka)、Apin Chemicals Ltd. (Milton Park, UK)、Avocado Research (Lancashire, UK)、BDH Inc. (Toronto, CA)、Bionet (Cornwall, UK)、Chemservice Inc. (West Chester, Pa., US)、Crescent Chemical Co. (Hauppauge, N.Y., US)、Eastman Organic Chemicals、Eastman Kodak Company (Rochester, N.Y., US)、Fisher Scientific Co. (Pittsburgh, Pa., US)、Fisons Chemicals (Leicestershire, UK)、Frontier Scientific (Logan, Utah, US)、ICN Biomedicals, Inc. (Costa Mesa, Cal., US)、Key Organics (Cornwall, UK)、Lancaster Synthesis (Windham, N.H., US)、Maybridge Chemical Co. Ltd. (Cornwall, UK)、Parish Chemical Co. (Orem, Utah, US)、Pfaltz & Bauer, Inc. (Waterbury, Conn., US)、Polyorganix (Houston, Tex., US)、Pierce Chemical Co. (Rockford, Ill., US)、Riedel de Haen AG (Hanover, DE)、Spectrum Quality Product, Inc. (New Brunswick, N.J., US)、TCI America (Portland, Or., US)、Trans World Chemicals, Inc. (Rockville, Md., US)及Wako Chemicals USA, Inc. (Richmond, Va., US)。
經由各種參考書及資料庫來識別本領域普通技術者已知的方法。適宜參考書及論文詳述了用於製備本文所描述的化合物的反應物的合成,或提供了描述此製備的參考文獻。參見例如SYNTHETIC ORGANIC CHEM. (John Wiley & Sons, Inc., N.Y.);Sandler等人,ORGANIC FUNCTIONAL GROUP PREP.,第二版,(Academic Press, N.Y., 1983);House, MODERN SYNTHETIC REACTIONS,第二版,(W.A. Benjamin, Inc., Menlo Park, Calif., 1972);Gilchrist, HETEROCYCLIC CHEM.,第二版,(John Wiley & Sons, N.Y., 1992);March, ADVANCED ORGANIC CHEM.: REACTIONS, MECHANISMS & STRUCTURE,第四版,(Wiley-Interscience, N.Y., 1992)。本領域已知額外適宜參考文獻,此等參考文獻詳述了用於製備本文所描述的化合物的反應物的合成,或提供了描述此製備的參考文獻。參見例如Fuhrhop & Penzlin, ORGANIC SYNTH.: CONCEPTS, METHODS, STARTING MAT'LS,第二修訂與擴增版,(John Wiley & Sons, ISBN: 3 527-29074-5, 1994);HOFFMAN, ORGANIC CHEM., INTERMEDIATE TEXT (Oxford Univ. Press, ISBN 0-19-509618-5, 1996);Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS: GUIDE TO FUNCTIONAL GROUP PREPARATIONS,第二版,(Wiley-VCH, ISBN: 0-471-19031-4, 1999);March, ADVANCED ORGANIC CHEM.: REACTIONS, MECHANISMS, & STRUCTURE,第四版,(John Wiley & Sons, ISBN: 0-471-60180-2, 1992); MODERN CARBONYL CHEM. (Otera (編著), Wiley-VCH, ISBN: 3-527-29871-1, 2000);Patai, PATAI'S 1992 GUIDE TO CHEM. OF FUNCTIONAL GROUPS (Interscience ISBN: 0-471-93022-9, 1992);Solomons, ORGANIC CHEM.,第七版,(John Wiley & Sons, ISBN: 0-471-19095-0, 2000);Stowell, INTERMEDIATE ORGANIC CHEM.,第二版,(Wiley-Interscience, ISBN: 0-471-57456-2, 1993);INDUSTRIAL ORGANIC CHEM.: STARTING MATERIALS & INTERMEDIATES: ULLMANN'S ENCYCLOPEDIA (John Wiley & Sons, ISBN: 3-527-29645-X, 1999),在8卷中;ORGANIC REACTIONS (1942-2000) (John Wiley & Sons),在超過55卷中;CHEM. FUNCTIONAL GROUPS (John Wiley & Sons),在73卷中。
特定及類似反應物亦可經由美國化學學會的化學文摘服務(the Chemical Abstract Service of the American Chemical Society)製備的已知化學品的指數來識別,此等化學文摘服務可在大多數公共及大學圖書館中以及經由線上資料庫(美國華盛頓特區美國化學學會)。目錄中已知但不可商購的化學品可由定制化學合成室製備,其中許多標準化學供應廠(例如,上文列出的彼等)提供定制合成服務。用於製備及選擇本文所描述的經取代之雜環衍生化合物的醫藥鹽的參考文獻為Stahl & Wermuth, HANDBOOK OF PHARMACEUTICAL SALTS (Verlag Helvetica Chimica Acta, Zurich, DE, 200)2。
用於合成經取代之雜環衍生物的一般方法亦為已知的。參見例如WO 2009158396;WO 200563768;WO 2006112666;Briet等人,58 Tetrahedron 5761 (2002);WO 200877550;WO 200877551;WO 200877556;WO 200712421;WO 200712422;US200799911;WO 200877550;Havera等人,42 J. Med. Chem. 3860 (1999);WO 200429051;US20090054434。經取代之雜環衍生物合成的額外實例為已知的。參見例如WO 2012/171337;WO 2011/044157;WO 2009/097567;WO 2005/030791;EP 203216;Becknell等人,21 Bioorg. Med. Chem. Letts. 7076 (2011);Svechkarev等人,Visnik Kharkivs'kogo Natsional'nogo Univ. im. V. N. Karazina, 770:201 (2007);Coskun等人,35 Synth. Commun. 2435 (2005);Alvarez等人,15 Sci. Synth. 839 (2005);Kihara等人,53 Heterocycl. 359 (2000);Couture等人,7 J. Chem. Soc'y, Perkin Transact. 1: Org. Bio-Org. Chem. 789 (1999);Kihara等人,48 Heterocycles 2473 (1998);Couture等人,52 Tetrahed. 4433 (1996);Couturre等人,37 Tetrahed. Lett. 3697 (1996);Natsugari等人,38 J. Med. Chem. 3106 (1995);Moehrle等人,321 Archiv Pharm. 759 (Weinheim, DE) 321:759 (1988);Gore等人,3 J. Chem. Soc'y, Perkin Transact. 1: Org. Bio-Org. Chem. 481 (1972-1999) (1988);Narasimhan等人,3 J. Chem. Soc'y, Chem. Commun. 191 (1987);Henry等人,40 J. Org. Chem. 1760 (1975);Berti, 90 Gazzetta Chim. Italiana 559 (1960);Berti等人,49 Annal. Chim. 2110 (Rome, IT; 1959);Berti等人,49 Annal. Chim. 1253 (Rome, IT;1959);WO 2012000595;Couture等人,52 Tetrahed. 4433 (1996);WO 2010069504;WO 2010069504;WO 2006030032;WO 2005095384;US20050222159;WO 2013064984;Mishra等人,2013 Eur. J. Org. Chem. 693 (2013);Vachhani等人,69 Tetrahed. 359 (2013);Xie等人,45 Eur. J. Med. Chem. 210 (2010);Mukaiyama等人,15 Bioorg. Med. Chem. 868 (2007);JP2005/089352;Wang等人,9 Molec. 574 (2004);WO 2000023487;US20060287341;CN103183675;Hares等人,32 Egyptian J. Pharm. Sci. 303 (1991);DE2356005;DE2133898;DE2133998;美國專利案第3,816,422號;DE2011970;Staehle等人,8 Justus Liebigs Annalen der Chem. 1275 (1973)。
在一些實施例中,本文揭示的經取代之雜環衍生化合物藉由下文在流程1-8中描述的一般合成途徑製備。此等流程意欲對本領域熟習技術者為示例性,並非限制性的。本文揭示或本領域熟習技術者易於獲得用於合成經取代之雜環衍生化合物的額外方法。
本發明實施例的吡唑吡啶酮化合物可根據以下流程中描述的一般合成途徑製備:
流程 1
在前述流程1中提供了用於製備本文所描述的一些經取代之衍生化合物的方法。使5-溴吡啶-2(1H)-酮衍生物(1-1)在鹼性條件下經歷用烷基鹵化物的烷基化以提供相關的5-溴-1-烷基吡啶-2(1H)-酮衍生物(1-2)。化合物1-2與適宜的鹵化物進一步鈀催化的交叉偶合反應提供化合物1-3。
流程 2
以上流程2中提供了用於製備本文所描述的一些經取代之衍生化合物的方法。使5-溴-4-氯吡啶-2(1H)-酮(2-1)在鹼性條件下經歷用烷基鹵化物的烷基化以提供相關的5-溴-4-氯-1-烷基吡啶-2(1H)-酮衍生物(2-2)。化合物2-2與適宜的鹵化物的鈀催化的交叉偶合反應提供化合物2-3。化合物2-3與適宜的鹵化物進一步鈀催化的交叉偶合反應提供化合物2-4。或者,2-3在鹼性條件下經歷用適宜的醇或胺或硫醇的取代,以提供化合物2-4。
流程 3
以上流程3中提供了用於製備本文所描述的一些經取代之衍生化合物的方法。遵照兩步順序將5-溴-4-氯吡啶-2(1H)-酮(3-1)轉化為相關化合物3-2。更具體地說,(1)在鹼性條件下用烷基鹵化物烷基化,(2)在鹼性條件下用適宜的醇或胺或硫醇取代,提供化合物3-2。化合物3-2與適宜的鹵化物進一步鈀催化的交叉偶合反應提供化合物3-3。
流程 4
在上述每個反應程序或流程中,各種取代基可選自本文另外教示的各種取代基。
醫藥組合物
在某些實施例中,如本文所描述的經取代之雜環衍生化合物作為純化學品投予。在其他實施例中,本文所描述的經取代之雜環衍生化合物與醫藥學上適宜的或可接受的載劑(在本文中亦稱為醫藥學上適宜的(或可接受的)賦形劑、生理上適宜的(或可接受的)賦形劑或生理上適宜的(或可接受的)載劑)組合,此醫藥學上適宜的或可接受的載劑係基於選定的投藥途徑及標準醫藥實踐來選擇,例如在REMINGTON: SCIENCE & PRACTICE OF PHARMACY,第21版,(Gennaro (編著) Mack Pub. Co., Easton, Pa. US(2005))中。
因此,本文提供了醫藥組合物,此醫藥組合物包含至少一種經取代之雜環衍生化合物,諸如式I的化合物,對此種化合物的引用包括其立體異構物、醫藥學上可接受的鹽、水合物、溶劑合物或N-氧化物,以及一或更多種醫藥學上可接受的載劑。若載劑與組合物的其他成分相容且對組合物的受體(亦即,受試者)無害,則載劑(或賦形劑)為可接受的或適宜的。
一個實施例提供了包含式I化合物及醫藥學上可接受的賦形劑的醫藥組合物。在某些實施例中,如本文所描述的經取代之雜環衍生化合物實質上為純的,因為其包含小於約5%,或小於約1%,或小於約0.1%的其他有機小分子,諸如污染中間體或例如在合成方法的一或更多個步驟中產生的副產物。
適宜的口服劑型包括例如片劑、丸劑、小藥囊或者硬或軟明膠、甲基纖維素或易於溶解在消化道中的另一適宜材料的膠囊。使用適宜的無毒固體載劑,包括例如醫藥等級的甘露糖醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、滑石粉、纖維素、葡萄糖、蔗糖、碳酸鎂等。參見例如REMINGTON, 2005。
根據患者(例如,人類)的狀況,亦即疾病階段、一般健康狀況、年齡及醫學領域的熟習技術者將用於判定劑量的其他因素,包含至少一種本文所描述的經取代之雜環衍生化合物的組合物的劑量可為不同。
如醫學領域熟習技術者所決定的,可以適合於待治療(或預防)之疾病的方式投予醫藥組合物。合適的劑量及適宜的投藥持續時間及頻率將由諸如患者狀況、患者疾病的類型與嚴重程度、活性成分的特定形式及投藥方法等因素決定。通常,合適的劑量及治療方案提供足以提供治療或預防益處的量的組合物(例如改善的臨床結果,諸如更頻繁的完全或部分緩解,或更長時間的無疾病及/或總體存活,或症狀嚴重程度的減輕。最佳劑量一般可使用實驗模型及/或臨床試驗來決定。最佳劑量可取決於患者的身體質量、重量或血容量。
口服劑量通常在每日約1.0 mg至約1000 mg,1至4次或更多的範圍內。
溴結構域抑制及 cAMP 反應結合蛋白
組蛋白乙醯化通常與基因轉錄的活化有關,因為已知修飾藉由改變靜電來放鬆DNA與組蛋白八聚物的相互作用。除了此物理變化之外,已知特定蛋白質結合至組蛋白內的乙醯化離胺酸殘基以讀取表觀遺傳密碼。溴結構域為蛋白中的小(約110個胺基酸)不同結構域,在組蛋白的上下文中已知通常但非排他性地結合至乙醯化離胺酸。已知大約五十種蛋白含有溴結構域,並且它們在細胞內具有一系列功能,包括蛋白的溴結構域與外端(bromodomain and extra-terminal; BET)家族以及cAMP反應結合蛋白(cyclic AMP-responsive element-binding protein; CREB)結合蛋白(CBP)。
CBP及其旁系同源物p300為高度同源、普遍存在、通用的轉錄共活化因子蛋白,此等蛋白對於發育及許多其他生理過程係必需的。除了參與轉錄事件之外,已知共活化因子蛋白有助於諸如DNA修復、RNA剪接之其他過程。Janknecht, 17 Histol. Histopathol. 657 (2002)。
人CBP蛋白含有2442個胺基酸。在CBP中已經鑑定了幾個結構及功能結構域,包括溴結構域(bromodomain; BRD),三個半胱胺酸-組胺酸富集的區域(CH1、CH2及CH3)以及組蛋白乙醯轉移酶(histone acetyltransferase; HAT)結構域。在許多與染色質相關的蛋白質中發現的溴結構域被認為起組蛋白結合模體的作用。已知此三個半胱胺酸/組胺酸的結構域可作為眾多轉錄調節因子的對接模組。CH2結構域部分位於HAT結構域內。基於序列同源性資料,CH2區域的一部分已被歸類為植物同源域(plant homeodomain; PHD)型鋅指,此種鋅指主要發現於在染色質等級上起作用的蛋白質中。Kalkhoven等人,22 Molec. Cell. Biol. 1961 (2002)。
溴結構域由約110個胺基酸組成,此等胺基酸排列在由藉由螺旋間環連接的四個α-螺旋(αZ、αA、αB、αC)組成的特徵性結構中,稱為BRD折疊。已知溴結構域特異性結合至乙醯化離胺酸。Hay等人,136 J. Am. Chem. Soc. 9308 (2014)。人溴結構域家族由61個成員組成,其中有代表組蛋白乙醯轉移酶轉錄共活化因子的兩個不同的亞組,諸如含單個溴結構域的CBP/p300及通常含有兩個串聯溴結構域的BET家族蛋白,諸如BRD4。亦已知BRD4及CBP的溴結構域分別作為轉錄共活化劑及染色質組織劑起不同的作用。Plotnikov等人,22 Structure 353 (2014)。
最近的研究闡明了人CBP蛋白結合的離胺酸-乙醯化組蛋白H4胜肽的溴結構域-PHD串聯模組的結構。在此研究中使用兩種不同的組蛋白H4胜肽,此等胜肽含有相同的H4殘基5-25,但攜帶不同的離胺酸乙醯化位點,亦即,離胺酸殘基20在H4K20ac的情況下乙醯化且離胺酸殘基12及16在H4K12ac/K16ac的情況下乙醯化。結構分析揭示了BRD4的溴結構域與CBP的溴結構域之間的各種區別。例如,觀察到與偏好二乙醯化組蛋白H4序列的BRD4溴結構域不同,CBP溴結構域表明明顯偏好單乙醯化H4序列模體。此研究進一步提供了對CBP及BRD4的溴結構域單獨及二乙醯化組蛋白H4識別的不同模式的見解。不受任何具體理論的束縛,假設CBP的溴結構域與BRD4的溴結構域之間的差異將有助於識別選擇性靶向CBP的溴結構域的抑制劑。
CBP蛋白已與各種臨床症狀相關聯。CBP在人體中的單倍不足導致Rubinstein-Taybi綜合症,其特徵在於智力遲鈍、顱面畸形,以及闊拇指及大腳趾。已經顯示小鼠中CBP的雜合缺失導致包括造血系統在內的多種組織中的缺陷。由染色體易位導致的CBP功能改變亦導致白血病的形成。CBP蛋白亦被牽涉在以p53突變為特徵的人類癌症中發揮作用。回應於細胞應激,p53經歷C及N末端區域的翻譯後修飾,包括C末端區域的乙醯化(例如,K382 pf p53處的離胺酸乙醯化),此導致經由其溴結構域招募CBP。CBP-p53乙醯化離胺酸相互作用反過來對p53誘導的p21介導的G1細胞週期停滯至關重要。
因此,假設抑制CBP溴結構域且由此抑制p53介導的p21活化在癌症及其他疾病中具有重要的臨床應用,其中已知高度活躍的p53發揮作用,諸如阿茲海默症、帕金森氏症、亨廷頓氏病脊髓疾病、多發性硬化症、缺血性腦損傷、感染性及自體免疫性疾病以及心肌局部缺血。Hay等人,2014。此外,研究表明CBP的序列化係由擴展的聚麸醯胺酸重複引起的神經退化性疾病的根本原因之一,諸如亨廷頓氏病、齒狀核紅核蒼白球丘腦下部萎縮、脊髓延髓肌萎縮及1、2、3、6、7及12型脊髓小腦性共濟失調。Janknecht, 2002。
近年來,溴結構域的治療靶向被認為是人類惡性及發炎疾病中重要的潛在治療模式。Muller等人,13 Expert Rev. Molec. Med. e29 (2011);Filippakopoulos & Knapp, 13 Nat. Rev. Drug Discov. 337 (2014)。溴結構域的抑制劑藉由抑制抗炎基因的表現而展示出抗炎活性。例如,Th17細胞藉由介導受感染區域中的嗜中性粒細胞及巨噬細胞的募集而在宿主免疫反應中起重要作用。有人提出,Th17細胞的異常調節為多種發炎及自體免疫病症的病因中的一個組成部分。據瞭解,Th17細胞在自體免疫及發炎過程中發揮作用,但最近Th17細胞因其在腫瘤免疫學中的作用而受到了新的關注。Zou & Restifo, 10 Nat. Rev. Immunol. 248 (2010);Coffelt等人,522 Nature 345 (2015)。Th17細胞為產生IL-17A、IL17F、IL-21、IL-22及GM-CSF的T輔助細胞的子集。Th17細胞已被認為是諸如強直性脊柱炎(ankylosing spondylitis; AS)、牛皮癬與牛皮癬關節炎(psoriasis and psoriatic arthritis; PSA)、類風濕性關節炎、克羅恩氏病及多發性硬化症(multiple sclerosis; MS)之自體免疫性疾病的關鍵效應子。JQ1,一種溴及外端域(bromo and extraterminal domain; BET)溴結構域抑制劑,顯示出減少了膠原誘導的關節炎及實驗性自體免疫性腦脊髓炎,其他兩種牽涉Th17的人類發炎疾病。Belkina等人,190 J. Immunol. 3670 (2013)。蘇金單抗(secukinumab),一種抗IL-17A抗體,顯示出改善了強直性脊柱炎。Baeten等人,382 Lancet 1705 (2013)。除了支援TH17細胞在此等發炎疾病中的重要性之外,此發現加強了對能夠靶向TH17細胞因子產生的新藥物的搜尋。
另外,調節性T細胞(Treg)經常募集並積聚在腫瘤內,此導致癌細胞的免疫逃避。此等腫瘤內調節性T細胞降低效應T細胞的反應,此係藉由免疫系統清除腫瘤細胞的主要障礙。增強對腫瘤的免疫反應的一種方法為特異性抑制調節性T細胞募集或腫瘤內積聚,此種方法稱為癌症免疫療法。Dougan & Dranoff, 27 Ann. Rev. Immunol. 83 (2009);Mellman等人,480 Nature 480 (2011);Curiel, 117 J. Clinical. Invest. 1167 (2007);Nishikawa & Sakaguchi, 27 Curr. Op. Immunol. 1 (2014)。
已顯示CBP為調節性T細胞生物學中的關鍵組分,並且暗示其對於從初始T細胞分化Treg係必需的。具體而言,在小鼠調節性T細胞中CBP的缺失導致Treg抑制功能受損並且在鼠癌症模型中減少腫瘤生長。Liu等人,19 Nat. Med. 1173 (2013);Liu等人,34 Molec. Cel. Biol. 3993 (2014)。CBP溴結構域包含非常適合結合抑制劑的疏水口袋,而溴結構域上的表面及環狀殘基的多樣性允許藉由藥理學試劑選擇性靶向。Muller等人,13 Exp. Rev. Mol. Med. e29 (2011);Hay等人,2014。此等特徵使CBP成為免疫治療的理想靶點。為了支援此種方法,Th17細胞因子的產生被CBP溴結構域抑制所破壞。Ghosh等人,291 J. Biol. Chem. 13014 (2016);Hammitzsch等人,112 PNAS 10768 (2015)。
CBP抑制劑的活性可導致Treg分化及功能受損,從而釋放癌症中效應子反應的抑制且可能重新發揮抗腫瘤免疫性。因此,單獨地或與補充癌症免疫療法結合,此等抑制劑可以加強腫瘤根除,諸如經由抗體介導的查核點抑制逆轉細胞毒性CD8+T細胞耗竭。Brahmer等人,366 NEJM 2455 (2012);Topalian等人,366 NEJM 2443 (2012);Hodi等人,363 NEJM 711 (2010)。其他CBP抑制劑已經在白血病治療的背景下進行了研究。Picaud等人,75 Cancer Res. 1 (2015)。
因此,在至少一個實施例中,本文揭示的式I之化合物能夠抑制生物樣本中CBP或其突變體或同源物的活性;並且此特徵對於本領域熟習技術者眾所周知的各種目的是有用的。此類目的的實例包括但不限於生物檢定、輸血、器官移植、生物樣本儲存。
在至少一個實施例中,本文揭示的式I之化合物能夠抑制患者中的CBP蛋白或其突變體或同源物的活性;具體而言,例如,在包括向有需要的患者投予式I之化合物或包含該化合物的醫藥組合物的方法中。
至少一個實施例提供了在生物樣本中抑制CBP蛋白或其突變體或同源物的方法,包括使生物樣本與本文揭示的化合物接觸的步驟。一些實施例提供了用於治療有需要的患者中由CBP蛋白質(諸如BET蛋白)介導的病症的方法,包括向患者投予式I之化合物或包含式I之化合物的醫藥組合物。
根據此等方法可治療的疾病及病症包括但不限於癌症及其他增殖性病症、阿茲海默症、帕金森氏症、亨廷頓氏病脊髓疾病、多發性硬化症、缺血性腦損傷、感染性及自體免疫性疾病、齒狀核紅核蒼白球丘腦下部萎縮、脊髓延髓肌萎縮與1、2、3、6、7及12型脊髓小腦性共濟失調、病毒感染及心肌局部缺血。因此,一個態樣為治療患有疾病、病症或其症狀的受試者的方法,此方法包括向受試者投予本文的化合物或組合物。在一個實施例中,用實施例的化合物及醫藥學上可接受的載劑、佐劑或媒介物治療人類患者,其中該化合物以可量測地抑制患者中的CBP蛋白質活性的量存在。
實施例進一步提供了治療患有本文揭示的症狀、疾病、病症或疾病之一者的受試者(諸如人類)的方法。該方法包含向需要此種治療的受試者投予治療有效量的一或更多種所提供的化合物,此等化合物藉由抑制CBP蛋白且通常藉由調節基因表現起作用來誘導各種細胞效應,特別是誘導或抑制基因表現,從而阻止細胞增殖,誘導細胞分化及/或誘導凋亡。
實施例進一步提供了調節本文揭示的症狀、疾患、病症或疾病,特別是癌症、發炎疾病或病毒性疾病中的活體內蛋白質甲基化、基因表現、細胞增殖、細胞分化或凋亡的治療方法,此方法包含向需要此種治療的受試者投予藥理活性及治療有效量的一或更多種本文所描述的化合物。
在某些實施例中,本文揭示的化合物治療或改善發炎或自體免疫病症。在一些態樣中,發炎或自體免疫性病症包括但不限於強直性脊柱炎(ankylosing spondylitis; AS)、牛皮癬與牛皮癬關節炎(psoriasis and psoriatic arthritis; PSA)、類風濕性關節炎、克羅恩氏病及多發性硬化症(multiple sclerosis; MS)。
在一些實施例中,本文揭示的化合物抑制Th17細胞功能。在一些態樣中,實施例提供抑制細胞因子分泌的式I之化合物,諸如但不限於IL-17A分泌。
在一些實施例中,本文揭示的化合物用於免疫腫瘤學治療。在一些態樣中,所揭示的化合物損害調節性T細胞分化及功能。在一些態樣中,使用所揭示的化合物減少了腫瘤中調節性T細胞的募集或積聚。在一些態樣中,使用所揭示的化合物降低了癌症背景下效應細胞的抑制。
本文提供的實施例進一步係關於藉由向需要此種治療的哺乳動物,特別是人類投予有效量的式I之化合物來治療或改善癌症或另一種增殖性病症的方法。在一些實施例中,藉由此等方法治療的疾病為癌症。
在某些實施例中,癌症為成人T細胞白血病/淋巴瘤、乳腺癌、腦癌或肺癌。
在一些實施例中,本文揭示的化合物治療或預防病毒感染,諸如皰疹病毒、人類乳突病毒、腺病毒、痘病毒及其他DNA病毒。
一個實施例提供了調節細胞中基因轉錄的方法,此方法包含將含溴結構域的蛋白質暴露於式I之化合物。一個實施例提供了抑制蛋白質的乙醯離胺酸區域的溴結構域介導的識別的方法,此方法包含將溴結構域暴露於式I之化合物。
一個實施例提供了調節細胞中基因轉錄的方法,此方法包含將CBP暴露於式I之化合物。一個實施例提供了抑制蛋白質的乙醯離胺酸區域的CBP介導的識別的方法,此方法包含將CBP暴露於式I之化合物。
至少一個實施例提供了針對CBP展示出比針對BRD4更低的IC
50的式I之化合物。在一個具體實施例中,式I之化合物為例如5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡咯-1-基)吡啶-2(1H)-酮。
治療方法
本發明實施例的一個態樣提供了治療有需要的患者的癌症的方法,包含向患者投予如本文所描述的式I之化合物或包含式I之化合物的醫藥組合物。
鑒於本揭示內容,其他實施例及用途對於本領域熟習技術者來說將是顯而易見的。提供以下實例僅僅是作為各種實施例的說明,而不應被解釋為以任何方式限制本發明。
實例 I. 化學合成
除非另有說明,否則試劑與溶劑以從商業供應商處收到的方式使用。無水溶劑及烘箱乾燥的玻璃器皿用於對水分及/或氧敏感的合成轉化。產出率並未最佳化。反應時間為近似的且並未最佳化。除非另有說明,否則在矽膠上執行管柱層析及薄層色譜(thin layer chromatography; TLC)。色譜以ppm (δ)給出,且偶合常數(J)以赫茲記錄。對於
1H NMR譜,將溶劑峰用作參考峰。
實例 1:5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
流程5
步驟 1:1-苄基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑
將4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(3.0 g, 15.5 mmol)、溴甲基-苯(3.2 g, 18.7 mmol)及K
2CO
3(4.3 g, 31.2 mmol)在DMF (30 mL)中之混合物在室溫下攪拌隔夜。在用EtOAc (50 mL)及H
2O (50 mL)稀釋後,分離有機層,以及用鹽水(50 mL)洗滌,用Na
2SO
4乾燥,過濾,並在真空中濃縮。藉由管柱層析法在矽膠上用PE/EtOAc (5:1)溶離來純化殘餘物,得到呈淺黃色固體的化合物1-苄基-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(3.5 g, 12.3 mmol),產率為79%。
1H NMR (400 MHz, CDCl
3): δ 7.81 (s, 1H), 7.66 (s, 1H), 7.37-7.29 (m, 3H), 7.24-7.22 (m, 2H), 5.30 (s, 2H), 1.29 (s, 12H). LCMS (M+H)
+285.
步驟 2:5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
在N
2下將1-苄基-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(140 mg, 0.495 mmol)、5-溴-1H-吡啶-2-酮(100 mg, 0.495 mmol)、Pd(PPh
3)
4(60 mg, 0.049 mmol)及Na
2CO
3(104 mg, 0.990 mmol)在二噁烷(5 mL)與H
2O (1 mL)中之混合物加熱至90℃經歷5小時。隨後,用EtOAc (60 mL)及H
2O (50 mL)稀釋混合物。將有機相用鹽水(60 mL)洗滌,用Na
2SO
4乾燥,過濾,並在真空下濃縮。藉由製備HPLC純化殘餘物,得到呈黃色油的5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮(60 mg, 0.22 mmol),產率為44%。
1H NMR (400 MHz, CD
3OD): δ 7.96 (s, 1H), 7.38-7.31 (m, 2 H), 7.38-7.28 (m, 6H), 6.58 (d, J=9.3 Hz, 1H), 5.22 (s, 2H), 3.59 (s, 3H). LCMS (M+H)
+266.
實例 2:5-(1-(環丙基(苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
步驟 1:4-溴-1-(環丙基(苯基)甲基)-1H-吡唑
向冷卻至0℃的4-溴-1H-吡唑(200 mg, 1.36 mmol)、環丙基(苯基)甲醇(405 mg, 2.72 mmol)及PPh
3(720 mg, 2.72 mmol)在無水THF (6 ml)中之混合物逐滴添加偶氮二羧酸二第三丁酯(0.4 ml, 2.72 mmol)。將反應在微波反應器中於150℃加熱15分鐘。隨後冷卻至室溫,並在減壓下濃縮。藉由矽膠管柱層析法(0-30% EtOAc/Hex)純化殘餘物,得到呈澄清油的標題化合物(160 mg, 42%)。
步驟 2:5-(1-(環丙基(苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
將來自步驟1之標題化合物(60 mg, 0.22 mmol)及1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-2(1H)-酮(61 mg, 0.26 mmol)溶於二噁烷(0.5 mL)中。向此溶液添加Pd(PPh
3)
4(12.5 mg, 0.011 mmol)及Na
2CO
3(在水中2 M,0.22 mL)。將反應在微波中於120℃加熱20分鐘。在減壓下移除溶劑。將殘餘物溶於MeOH (2 mL),經由矽藻土過濾,並藉由製備HPLC(10%至100% MeCN/水,0.1% FA)純化,得到標題化合物(11 mg,17%產率)。
1H NMR (CD
3OD, 400 MHz) δ 8.15 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.32-7.26 (m, 5H), 6.55 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.8 Hz, 1H), 3.60 (s, 3H), 1.76-1.70 (m, 1H), 0.83-0.73 (m, 2H), 0.58-0.45 (m, 2H). LCMS (M+H)
+306.
實例 3-13、
17及
19-35係使用適當的吡啶酮及鹵化物以與實例1類似的多步驟方式來製備的。實例14-16及18係使用適當的吡啶酮及鹵化物以與實例2類似的多步驟方式來製備的,且在表3中展示:
實例 36:4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮
流程6
步驟 1:4-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮
表 3 | ||||
實例 | 結構 | 名稱 | 1H NMR ppm (δ) | MS (M+H) |
3 | 2-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈 | (DMSO- d 6 , 400 MHz) δ 8.25 (s, 1H), 8.07 (d, J=1.0 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.72 (s, 1H), 7.72-7.64 (m, 2H), 7.56-7.53 (m, 2H), 7.30 (d, J=7.8 Hz, 1H), 6.44 (d, J=9.3 Hz, 1H), 5.53 (s, 2H), 3.44 (s, 3H) | 291 | |
4 | 3-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈 | (DMSO- d 6 , 400 MHz) δ 8.12 (s, 1H), 8.01 (s, 1H), 7.80-7.68 (m, 2H), 7.68-7.65 (m, 2H), 7.63-7.56 (m, 2H), 6.43 (d, J=9.3 Hz, 1H), 5.40 (s, 2H), 3.50 (s, 3H) | 291 | |
5 | 1-甲基-5-(1-(吡啶-2-基甲基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.53 (m, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.83-7.77 (m, 3H), 7.36-7.35 (m, 1H), 7.34 (m, 1H), 6.60 (d, J=9.3 Hz, 1H), 5.46 (s, 2H), 3.60 (s, 3H) | 267 | |
6 | 5-(1-(4-氟苄基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.96 (s, 1H), 7.92 (s, 1H), 7.74-7.75 (m, 2H), 7.31-7.28 (m, 2H), 7.09-7.05 (m, 2H), 6.59 (d, J=9.3 Hz, 1H), 5.32 (s, 2H), 3.59 (s, 3H) | 284 | |
7 | 5-(1-苄基-1H-吡唑-4-基)-1,4-二甲基-吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.50 (s, 1H), 7.37-7.33 (m, 4H), 7.26-7.25 (m, 2H), 7.16 (s, 1H), 6.46 (s, 1H), 5.33 (s, 2H), 3.52 (s, 3H), 2.14 (s, 3H) | 280 | |
8 | 4-(1-苄基-1H-吡唑-4-基)-2-甲基異-喹啉-1(2H)-酮 | (CDCl 3, 400 MHz) δ 8.50 (d, J=7.6 Hz, 1H), 7.66-7.62 (m, 3H), 7.50-7.49 (m, 2H), 7.40-7.26 (m, 5H), 7.04 (s, 1H), 5.38 (s, 2H), 3.62 (s, 3H) | 316 | |
9 | 4-(1-苄基-1H-吡唑-4-基)-2-甲基-2,6-口奈啶-1(2H)-酮 | (CD 3OD, 400 MHz) δ 9.06 (s, 1H), 8.66 (d, J=5.3 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H), 8.01 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.36-7.31 (m, 5 H), 5.44 (s, 2H), 3.65 (s, 3H) | 317 | |
10 | 5-(1-苄基-1H-吡唑-4-基)-1-乙基吡啶-2(1H)-酮 | (CDCl 3, 300 MHz) δ 7.64 (s, 1H), 7.45-7.33 (m, 6H), 7.24 (s, 2H), 6.61 (d, J=9.0 Hz, 1H), 5.33 (s, 2H), 4.01 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H) | 280 | |
11 | 5-(1-(1-(3-(二氟-甲基)苯基)乙基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.05 (s, 1H), 7.83 (s, 2H), 7.67 (s, 1H), 7.45-7.38 (m, 4H), 6.87 (s, 0.25H), 6.73 (s, 0.5H), 6.59 (s, 0.25H), 5.68-5.64 (m, 1H), 3.59 (s, 3H), 2.15 (s, 3H), 1.92 (d, J=7.0 Hz, 3H) | 343 | |
12 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.15 (s, 1H), 8.01 (d, J=2.5 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J=2.5 Hz, 1H), 7.35-7.22 (m, 5H), 5.59-5.57 (m, 1H), 3.43 (s, 3H), 1.81 (d, J=7.0 Hz, 3H) | 280 | |
13 | 5-(1-苄基-1H-吡唑-4-基)-1,3-二甲基-吡啶-2(1H)-酮 | (CDCl 3, 300 MHz) δ 7.64 (s, 1H), 7.45 (s, 1H), 7.41-7.31 (m, 4H), 7.28-7.26 (m, 3H), 5.33 (s, 2H), 3.58 (s, 3H), 2.19 (s, 3H) | 280 | |
14 | ( S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.01 (s, 1H), 7.92 (s, 1H), 7.78-7.76 (m, 2H), 7.34-7.23 (m, 5H), 6.59 (d, J=9.3 Hz, 1H), 5.59 (m, 1H), 3.59 (s, 3H), 1.90 (d, J=7.1 Hz, 3H) | 281 | |
15 | (R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.02 (s, 1H), 7.92 (s, 1H), 7.78-7.76 (m, 2H), 7.34-7.23 (m, 5H), 6.59 (d, J= 9.3 Hz, 1H), 5.59 (m, 1H), 3.59 (s, 3H), 1.90 (d, J= 7.1 Hz, 3H) | 281 | |
16 | 3-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.09 (s, 1H), 7.94 (d, J=2.5 Hz, 1H), 7.81-7.77 (m, 2H), 7.66-7.53 (m, 4H), 6.60 (d, J=9.3 Hz, 1H), 5.68 (m, 1H), 3.60 (s, 3H), 1.92 (d, J=7.1 Hz, 3H) | 305 | |
17 | 1,3-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.00 (s, 1H), 7.77-7.75 (m, 2H), 7.66 (d, J=0.9 Hz, 1H), 7.34-7.23 (m, 5H), 5.59 (m, 1H), 3.59 (s, 3H), 2.19 (s, 3H), 1.90 (d, J=7.1 Hz, 3H) | 294 | |
18 | 5-(1-(環丙基(苯基)甲基)-1H-吡唑-4-基)-1,3-二甲基-吡啶-2(1H)‑酮 | (CD 3OD, 400 MHz) δ 8.15 (s, 1H), 7.80 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.32-7.26 (m, 5H), 4.66 (d, J= 9.8 Hz, 1H), 3.60 (s, 3H), 2.16 (s, 3H), 1.76-1.70 (m, 1H), 0.83-0.73 (m, 2H), 0.58-0.45 (m, 2H) | 319 | |
19 | 5-(1-(1-(2-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基-吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.65 (s, 1H), 7.53 (s, 1H), 7.47-7.46 (m, 1H), 7.40-7.38 (m, 2H), 7.24-7.22 (m, 2H), 7.17-7.15 (m, 1H), 6.62 (d, J= 9.2 Hz, 1H), 5.96 (q, J= 6.8 Hz, 1H), 3.76 (s, 3H), 1.93 (d, J= 7.2 Hz, 3H) | 314 | |
20 | 1-甲基-5-(1-(1-(間甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.62 (s, 1H), 7.46-7.43 (m, 2H), 7.38 (d, J=2.4 Hz, 1H), 7.26-7.24 (d, J=7.6 Hz, 1H), 7.13-7.11 (m, 1H), 7.06-7.04 (m, 2H), 6.61-6.59 (d, J=9.2 Hz, 1H), 5.48 (q, J=6.8 Hz, 1H), 3.57 (s, 3H), 2.34 (s, 3H), 1.91 (d, J=7.6 Hz, 3H) | 294 | |
21 | 4-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.23 (d, J= 9.9 Hz, 1H), 8.08 (d, J= 1.0 Hz, 1H), 7.74 (s, 1H), 7.35-7.25 (m, 5H), 6.31 (d, J= 13 Hz, 1H), 5.75-5.63 (m, 1H), 3.44 (s, 3H), 1.82 (d, J= 7.0 Hz, 1H) | 299 | |
22 | 1-甲基-5-(1-(1-( 鄰甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.61 (s, 1H), 7.44-7.29 (m, 3H), 7.24-7.20 (m, 4H), 6.60-6.58 (m, 1H), 5.75 (q, J= 6.8 Hz, 1H), 3.57 (s, 3H), 2.30 (s, 3H), 1.87 (d, J=6.4 Hz, 3H) | 295 | |
23 | 5-(1-(1-(3-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基-吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.63 (s, 1H), 7.48 (s, 1H), 7.5 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.29-7.27 (m, 2H), 7.21 (s, 1H), 7.12-7.09 (m, 1H), 6.61 (d, J=9.2 Hz, 1H), 5.49 (q, J=6.8 Hz, 1H), 3.58 (s, 3H), 1.91 (d, J=7.2 Hz, 3H) | 314 | |
24 | 1-甲基-5-(1-(1-(吡啶-3-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 8.61-8.58 (m, 2H), 7.68 (s, 1H), 7.60-7.55 (m, 2H), 7.49-7.43 (m, 2H), 7.32-7.30 (m, 1H), 6.64 (d, J= 9.2 Hz, 1H), 5.60 (q, J= 6.8 Hz, 1H), 3.62 (s, 3H), 2.01 (d, J= 7.6 Hz, 3H) | 281 | |
25 | 4-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈 | (CDCl 3, 400 MHz) δ 7.65 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.52 (s, 1H), 7.46-7.44 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.41-7.40 (m, 1H), 7.28 (d, J=8.8 Hz, 2H), 6.61 (d, J=9.2 Hz, 1H), 5.57 (q, J=6.8 Hz, 1H), 3.56 (s, 3H), 1.94 (d, J= 6.8 Hz, 3H) | 305 | |
26 | 3-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.03 (s, 1H), 7.78-7.76 (m, 2H), 7.67-7.62 (m, 1H), 7.34-723 (m, 5H), 5.57 (q, J= 7.2 Hz, 1H), 3.64 (s, 3H), 1.89 (d, J= 7.2 Hz, 3H) | 298 | |
27 | 5-(1-(1-(2-甲氧基-苯基)乙基)-1H-吡唑-4-基)-1-甲基-吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.61 (s, 1H), 7.50 (s, 1H), 7.47-7.44 (m, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.29-7.25 (m, 1H), 7.07-7.05 (m, 1H), 6.95-6.89 (dd, J=7.5, 6.8 Hz, 2H), 6.60 (d, J=9.2 Hz, 1H), 5.95 (q, J=6.8 Hz, 1H), 3.86 (s, 3H), 3.57 (s, 3H), 1.87 (d, J=7.2 Hz, 3H) | 310 | |
28 | 5-(1-(1-(3-甲氧基-苯基)乙基)-1H-吡唑-4-基)-1-甲基-吡啶-2(1H)--酮 | (CDCl 3, 400 MHz) δ 7.62 (s, 1H), 4.46-7.43 (m, 2H), 7.38-7.37 (d, J=2.4 Hz, 1H), 7.29-7.26 (m, 1H), 6.85-6.84 (m, 2H), 6.78-6.77 (m, 1H), 6.61-6.59 (d, J=9.6 Hz, 1H), 5.49 (q, J=6.8 Hz, 1H), 3.79 (s, 3H), 3.57 (s, 3H), 1.92 (d, J=6.8 Hz. 3H) | 310 | |
29 | 1-甲基-5-(1-(1-(吡啶-4-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 8.59-8.57 (m, 2H), 7.66 (s, 1H), 7.54 (s, 1H), 7.48-7.45 (dd, J=9.2 Hz, 2.8 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.07-1.06 (d, J=5.6 Hz, 2H), 6.64-6.61 (d, J=9.6 Hz, 1H), 5.53 (q, J=6.8 Hz, 1H), 3.59 (s, 3H), 1.94 (d, J=6.8 Hz, 3H) | 281 | |
30 | 1,3,4-三甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | CD 3OD, 400 MHz) δ 7.79 (s, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.37-7.31 (m, 2H), 7.30-7.24 (m, 3H), 5.61 (q, J=7.2 Hz, 1H), 3.56 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H), 1.90 (d, J=7.2 Hz, 3H) | 308 | |
31 | 3-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.06 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 7.79 (s, 1H), 7.37-7.24 (m, 5H), 5.60 (q, J=7.2 Hz, 1H), 3.64 (s, 3H), 1.91 (d, J=7.2 Hz, 3H) | 314 | |
32 | 3-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.07 (s, 1H), 7.80 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.35-7.23 (m, 5H), 7.13 (d, J=2.0 Hz, 1H), 5.59 (q, J=7.2 Hz, 1H), 3.87 (s, 3H), 3.60 (s, 3H) 1.90 (d, J=6.8 Hz, 3H) | 310 | |
33 | 2-甲基-4-(1-(1-苯基乙基)-1H-吡唑-4-基)-2,5,6,7-四氫-1H-環戊[c]吡啶-1-酮 | (CD 3OD, 400 MHz) δ 7.90 (s, 1H), 7.69 (s, 2H), 7.35-7.24 (m, 5H), 5.60 (q, J=6.8 Hz, 1H), 3.59 (s, 3H), 2.99 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 2.10-2.07 (m, J=7.6 Hz, 2H), 1.90 (d, J=7.2 Hz, 3H) | 320 | |
34 | 1,3-二甲基-5-(5-甲基-1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.57 (s, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.39 (s, 1H), 7.33-7.18 (m, 5H), 5.65-5.63 (m, 1H), 3.45 (s, 3H), 2.22 (s, 3H), 2.02 (s, 3H), 1.80 (d, J=6.9 Hz, 3H) | 308 | |
35 | 5-(1-苄基-1H-吡唑-4-基)-1-(二氟甲基)-4-苯基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.97 (s, 0.25H), 7.82 (0.5H), 7.75 (s, 1H), 7.67 (0.25H), 7.37-7.06 (m. 12H), 6.51 (s, 1H), 5.19 (s, 2H) | 378 |
用氮氣淨化5-溴-4-氯-1-甲基吡啶-2(1H)-酮(100 mg, 0.45 mmol)及1-(1-苯基乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑(160 mg, 0.54 mmol)、Pd(dppf)Cl
2-CH
2Cl
2(35 mg, 0.04 mmol)及
K3PO
4(190 mg, 0.9 mmol)在二噁烷(3 ml)及水(3滴)中之混合物,加蓋並加熱至80℃經歷2小時。將反應冷卻並經由矽藻土過濾,在減壓下移除溶劑,並且藉由製備HPLC純化所得殘餘物,得到呈白色形式的標題化合物(70mg, 50%)。 1H NMR (400 MHz, CD
3OD): δ 8.08 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.33-7.26 (m, 5H), 6.64 (s, 1H), 5.75 (s, 1H), 5.65-5.63 (m, 1H), 3.44 (s, 3H), 1.82 (d, J=7.0 Hz, 3H). LCMS (M+H)
+314.
步驟 2:5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
在無水THF (0.5 mL)中的4-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮(50 mg, 0.16 mmol)添加異丙醇(0.5 mL),繼之以NaH (16 mg, 0.4 mmol)。將反應在微波反應器中於100℃加熱20分鐘。移除溶劑,並藉由製備HPLC純化殘餘物,得到呈黃色油的5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮(17 mg, 0.05 mmol),產率為31%。
1H NMR (400 MHz, CD
3OD): 7.91 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.35-7.25 (m, 5H), 5.99 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 4.72-4.66 (m, 1H), 3.52 (s, 3H), 1.89 (d, J=7.2 Hz, 3H), 1.36 (d, J=6.0 Hz, 6H). LCMS (M+H)
+338.
實例 37:5-(1-苄基-1H-吡唑-4-基)-4-(3-甲磺醯基-吡咯啶-1-基)-1-甲基-1H-吡啶-2-酮
將5-(1-苄基-1H-吡唑-4-基)-4-氯-1-甲基-1H-吡啶-2-酮(100 mg, 0.334 mmol)、3-甲磺醯基-吡咯啶(60 mg, 0.403 mmol)、Pd-NHC (22 mg, 0.034 mmol)及Cs
2CO
3(269 mg, 0.825 mmol)在二噁烷/H
2O (5 mL/1 mL)中之混合物在N
2下於120℃攪拌12小時。將反應冷卻至室溫,用含水飽和NH
4Cl (50 mL)稀釋,並用DCM (25 mL×3)萃取。將合併的有機層用鹽水(15 mL×5)洗滌,用Na
2SO
4乾燥,並過濾。藉由製備HPLC純化殘餘物,得到呈無色油的標題化合物。
1H NMR (CD
3OD, 400 MHz) δ 7.80 (s, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.37-7.28 (m, 6H), 5.36 (s, 2H), 3.87-3.84 (m, 1H), 3.60-3.58 (m, 1H), 3.57 (s, 3H), 3.48-3.36 (m, 2H), 3.22-3.18 (m, 1H), 2.90 (s, 3H), 2.33-2.27 (m, 2H). LCMS (M+H)
+413.
表4中的
實例 38-46、
48-53、
56-57、
59-71、
76-86、
91-92及
94-99係使用適當的親核試劑及經取代之吡唑以與實例36類似的多步驟方式來製備的。實例
47、
54-55、
58、
72-75、
87-90及
93係使用適當的胺及經取代之吡唑以與實例37類似的多步驟方式來製備的。
實例 100:4-乙氧基-1-甲基-5-(1-{1-[4-(1-甲基-1H-吡唑-4-基)-苯基]-乙基}-1H-吡唑-4-基)-1H-吡啶-2-酮
流程 7 步驟 1:1-溴-4-(1-溴-乙基)-苯
表 4 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
38 | 4-氯-1-甲基-5-(1-(1-苯基-乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.08 (s, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.33-7.26 (m, 5H), 6.64 (s, 1H), 5.75 (s, 1H), 5.65-5.63 (m, 1H), 3.44 (s, 3H), 1.82 (d, J=7.0 Hz, 3H) | 314 | |
39 | 4-乙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.98 (s, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.35-7.25 (m, 5H), 5.61-5.59 (m, 1H), 4.03 (q, J=6.8 Hz, 2H), 3.37 (s, 3H), 1.81 (d, J=7.0 Hz, 3H), 1.35 (t, J=6.9 Hz, 3H) | 324 | |
40 | 4-(吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.74 (s, 1H), 7.49 (s, 1H), 7.32-7.25 (m, 6H), 5.60 (m, 1H), 5.29 (s, 1H), 3.67-3.63 (m, 4H), 3.42 (s, 3H), 2.16-2.13 (m, 2H), 1.90 (d, J=7.1 Hz, 3H) | 335 | |
41 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.34-7.25 (m, 6H), 5.62-5.58 (m, 2H), 3.43 (s, 3H), 3.02-2.98 (m, 4H), 1.89 (d, J=7.2 Hz, 3H), 1.78-1.75 (m, 4H) | 349 | |
42 | 1-甲基-4-(甲基-胺基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.83 (s, 1H), 7.56 (s, 1H), 7.33-7.28 (m, 6H), 5.60-5.59 (m, 1H), 5.51 (s, 1H), 3.42 (s, 3H), 2.75 (s, 3H), 1.91 (d, J=7.1 Hz, 3H) | 309 | |
43 | 1-甲基-4-嗎啉基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.62 (s, 1H), 7.57 (s, 1H), 7.38-7.31 (m, 3H), 7.25-7.24 (m, 2H), 7.23 (s, 1H), 5.98 (s, 1H), 5.53 (q, J=6.8 Hz, 1H), 3.54-3.50 (m, 4H), 3.48 (s, 3H), 3.83-3.80 (m, 4H), 1.93 (d, J=6.8 Hz, 3H) | 365 | |
44 | 1-甲基-4-((1-甲基-1H-吡唑-3-基)甲氧基)-5-(1-(1-苯基-乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.95 (s, 1H), 7.86 (s, 1H), 7.76 (s, 1H), 7.58 (s, 1H), 7.31-7.26 (m, 3H), 7.16-7.14 (m, 2H), 6.33 (d, J=2.4 Hz, 1H), 6.16 (s, 1H), 5.52 (m, 1H), 5.09 (s, 2H), 3.87 (s, 3H), 3.52 (s, 3H), 1.81 (d, J=7.1 Hz, 3H) | 390 | |
45 | (R)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.91 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.35-7.25 (m, 5H), 5.99 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 4.72-4.66 (m, 1H), 3.52 (s, 3H), 1.89 (d, J=7.2 Hz, 3H), 1.36 (d, J=6.0 Hz, 6H) | 338 | |
46 | (S)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz), δ 7.91 (s, 1H), 7.84 (s, 1H), 7.79 (s, 1H), 7.35-7.33 (m, 2H), 7.27-7.26 (m, 3H), 6.00 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 4.70-4.67 (m, 1H), 3.52 (s, 3H), 1.90 (d, J=7.6 Hz, 3H), 1.36 (d, J=6.0 Hz, 6H) | 338 | |
47 | (S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1‑基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.34-7.25 (m, 6H), 5.62-5.58 (m, 2H), 3.43 (s, 3H), 3.02-2.98 (m, 4H), 1.89 (d, J=7.2 Hz, 3H), 1.78-1.75 (m, 4H) | 349 | |
48 | 4-異丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.91 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.36-7.23 (m, 5H), 5.99 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 3.81 (d, J=6.4 Hz, 2H), 2.08-2.05 (m, 1H), 1.88 (d, J=7.2 Hz, 3H), 0.97 (d, J=6.4 Hz, 6H) | 352 | |
49 | 4-環丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.94 (s, 1H), 7.84 (s, 1H), 7.80 (s, 1H), 7.36-7.25 (m, 5H), 5.84 (s, 1H), 5.59 (q, J=6.8 Hz, 1H), 4.80-4.73 (m, 1H), 3.52 (s, 3H), 2.54-2.46 (m, 2H), 2.17-2.10 (m, 2H), 1.89 (d, J=7.2 Hz, 3H), 1.85-1.73 (m, 2H) | 350 | |
50 | 4-((1-乙醯基吖丁啶-3-基)氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.97 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.37-7.26 (m, 5H), 5.73 (s, 1H), 5.61 (q, J=6.8 Hz, 1H), 5.11-5.08 (m, 1H), 4.66-4.61 (m, 1H), 4.43-4.38 (m, 1H), 4.21-4.18 (m, 1H), 3.98-3.95 (m, 1H), 3.51 (s, 3H), 1.90 (d, J=6.8 Hz, 3H), 1.89 (s, 3H) | 393 | |
51 | 4-(環戊氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.85 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.37-7.25 (m, 5H), 5.98 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 4.89-4.86 (m, 1H), 3.52 (s, 3H), 1.98-1.91 (m, 2H), 1.88 (d, J=7.2 Hz, 3H), 1.83-1.78 (m, 2H), 1.70-1.63 (m, 4H) | 364 | |
52 | 4-(環己氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.90 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.37-7.23 (m, 5H), 6.00 (s, 1H), 5.59 (q, J=7.2 Hz, 1H), 4.49-4.47 (m, 1H), 3.52 (s, 3H) 1.94-1.93 (m, 2H), 1.89 (d, J=7.2 Hz, 3H), 1.69-1.66 (m, 2H), 1.62-1.53 (m, 3H), 1.48-1.30 (m, 3H) | 378 | |
53 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.95 (s, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.34-7.27 (m, 3H), 7.24 (s, 2H), 7.18-7.16 (m, 2H), 6.67 (s, 1H), 6.41-6.40 (m, 1H), 5.50 (q, J=7.2 Hz, 1H), 3.64 (s, 3H), 1.80 (d, J=7.2 Hz, 3H) | 346 | |
54 | 1-甲基-4-(3-甲基吖丁啶-1-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | CD 3OD, 400 MHz), δ 7.72 (s, 1H), 7.47 (s, 1H), 7.34-7.26 (m, 5H), 7.24 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 5.28 (s, 1H), 3.75-3.72 (m, 2H), 3.41 (s, 3H), 3.30-3.15 (m, 2H), 2.56-2.54 (m, 1H), 1.90 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H) | 349 | |
55 | (R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.73 (s, 1H), 7.48 (s, 1H), 7.34-7.25 (m, 6H), 5.62-5.58 (m, 2H), 3.43 (s, 3H), 3.02-2.98 (m, 4H), 1.89 (d, J= 7.2 Hz, 3H), 1.78-1.75 (m, 4H) | 349 | |
56 | 4-(苄氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.89 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.46-7.42 (m, 2H), 7.40-7.35 (m, 3H), 7.31-7.24 (m, 3H), 7.14-7.10 (m, 2H), 6.15 (s, 1H), 5.50 (q, J=7.2 Hz, 1H), 5.15 (s, 2H), 3.54 (s, 3H), 1.77 (d, J=7.2 Hz, 3H) | 386 | |
57 | 1-甲基-4-苯氧基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.50-7.48 (m, 2H), 7.34-7.22 (m, 6H), 7.18-7.14 (m, 2H), 5.65-5.55 (m, 2H), 3.54 (s, 3H), 1.88 (d, J=7.2 Hz, 3H) | 372 | |
58 | 4-(3-甲氧基吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.34-7.25 (m, 6H), 5.60 (q, J=6.8 Hz, 1H), 5.34 (s, 1H), 4.07-4.04 (m, 1H), 3.80-3.76 (m, 2H), 3.46-3.42 (m, 5H), 3.17 (s, 3H), 1.90 (d, J=7.2 Hz, 3H) | 365 | |
59 | 4-環丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CDCl 3, 400 MHz) δ 7.64 (s, 1H), 7.53 (s, 1H), 7.37-7.28 (m, 4H), 7.26-7.22 (m, 2H), 6.37 (s, 1H), 5.51 (q, J=6.8 Hz, 1H), 3.74-3.71 (m, 1H), 3.52 (s, 3H), 1.91 (d, J=7.2 Hz, 3H), 0.88-0.80 (m, 2H), 0.77-0.74 (m, 2H) | 336 | |
60 | (S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.94 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.34-7.27 (m, 3H), 7.23 (s, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.67 (s, 1H), 6.41-6.40 (m, 1H), 5.50-5.48 (m, 1H), 3.64 (s, 3H), 1.80 (d, J=7.1 Hz, 3H) | 346 | |
61 | (R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.94 (s, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.34-7.27 (m, 3H), 7.23 (s, 1H), 7.17 (d, J=7.5 Hz, 1H), 6.67 (s, 1H), 6.41-6.40 (m, 1H), 5.50-5.48 (m, 1H), 3.64 (s, 3H), 1.80 (d, J=7.1 Hz, 3H) | 346 | |
62 | 4-乙氧基-1-甲基-5-(1-(1-(對甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.89 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.15 (m, 5H), 5.98 (s, 1H), 5.54-5.48 (m, 1H), 4.11 (q, J=5.0 Hz, 2H), 3.51 (s, 3H), 2.30 (s, 3H), 1.87 (d, J=7.0 Hz, 3H), 1.42 (t, J=6.9 Hz, 3H) | 338 | |
63 | 5-(1-(1-([1,1'-聯苯基]-4-基)乙基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.04 (s, 1H), 7.92 (s, 1H), 7.76 (s, 1H), 7.63-7.56 (m, 4H), 7.48-7.41 (m, 4H), 7.38-7.37 (m, 1H), 5.83 (s, 1H), 5.69-5.68 (m, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.36 (s, 3H), 1.87 (d, J=7.0 Hz, 3H), 1.33 (t, J=6.9 Hz, 3H) | 400 | |
64 | 5-(1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.97 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.37-7.24 (m, 5H), 5.84 (s, 1H), 5.33 (s, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.37 (s, 3H), 1.36 (t, J=6.9 Hz, 3H) | 310 | |
65 | 4-乙氧基-1-甲基-5-(1-(4-甲苄基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.93 (s, 1H), 7.91 (s, 1H), 7.73 (s, 1H), 7.15 (s, 4H), 5.84 (s, 1H), 5.26 (s, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.37 (s, 3H), 2.27 (s, 2H), 1.36 (t, J=6.9 Hz, 3H) | 324 | |
66 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.93 (s, 1H), 7.66 (s, 1H), 7.58 (s, 1H), 7.33-7.17 (m, 7H), 6.67 (s, 1H), 6.40-6.39 (m, 1H), 5.25 (s, 2H), 3.63 (s, 3H) | 332 | |
67 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-嗎啉基-吡啶‑2(1H)‑酮 | (CD 3OD, 400 MHz) δ 7.92 (s, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 7.35-7.25 (m, 5H), 5.96 (s, 1H), 5.36 (s, 2H), 3.54-3.53 (m, 4H), 3.49 (s, 3H), 2.86-2.84 (m, 4H) | 351 | |
68 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡咯-1-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.89 (s, 1H), 7.32-7.24 (m, 3H), 7.24 (s, 1H), 7.18-7.14 (m, 3H), 6.67 (d, J=2.2 Hz, 2H), 6.46 (s, 1H), 6.19-6.18 (m, 2H), 5.23 (s, 2H), 3.61 (s, 3H) | 331 | |
69 | 4-乙氧基-1-甲基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.99 (s, 1H), 7.88 (s, 2H), 5.92 (s, 1H), 4.07 (q, J=6.8 Hz, 2H), 1.39 (t, J=6.8 Hz, 3H) | 220 | |
70 | 甲基 2-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯 | (CD 3OD, 400 MHz) δ 8.02 (d, J=7.7 Hz, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.51-7.49 (m, 2H), 7.43-7.39 (m, 1H), 5.99 (s, 1H), 5.76 (s, 2H), 4.05 (q, J=7.0 Hz, 2H), 3.90 (s, 3H), 3.52 (s, 3H), 1.44 (t, J=6.9 Hz, 3H) | 368 | |
71 | 甲基 3-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯 | (CD 3OD, 400 MHz) δ 7.99 (s, 1H), 7.95 (d, J=7.2 Hz, 1H), 7.92 (s, 1H), 7.49 (d, J=3.2 Hz, 1H), 7.49-7.47 (m, 3H), 5.99 (s, 1H), 5.42 (s, 2H), 4.12 (q, J=7.0 Hz, 2H), 3.88 (s, 3H), 3.52 (s, 3H), 1.45 (t, J=7.0 Hz, 3H) | 368 | |
72 | ( R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)乙醯胺 | (CD 3OD, 400 MHz) δ 7.77 (s, 1H), 7.54 (d, J=7.2 Hz, 2H), 7.37-7.25 (m, 6H), 5.37 (s, 2H), 4.26-4.23 (m, 1H), 3.57 (s, 3H), 3.39-3.35 (m, 2H), 3.26-3.20 (m, 1H), 3.00-2.96 (m, 1H), 2.09-2.04 (m, 1H), 1.90 (s, 3H), 1.88-1.81 (m, 1H) | 392 | |
73 | ( S)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)乙醯胺 | (CD 3OD, 400 MHz) δ 7.62 (s, 1H), 7.41 (s, 1H), 7.26-7.14 (m, 6H), 5.53 (s, 1H), 5.26 (s, 2H), 4.13-4.11 (m, 1H), 3.33 (s, 3H), 3.21-3.10 (m, 2H), 3.03-3.02 (m, 1H), 2.81-2.78 (m, 1H), 1.95-1.90 (m, 1H), 1.80 (s, 3H), 1.71-1.67 (m, 1H) | 392 | |
74 | ( R)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-甲酸 | (CD 3OD, 400 MHz) δ 7.78 (s, 1H), 7.56-7.55 (m, 2H), 7.37-7.25 (m, 6H), 5.38 (s, 2H), 3.59 (s, 3H), 3.38-3.34 (m, 2H), 3.26-3.19 (m, 2H), 3.08-3.04 (m, 1H), 2.13-2.09 (m, 2H) | 379 | |
75 | ( S)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-甲酸 | (CD 3OD, 400 MHz) δ (s, 1H), 7.52 (s, 1H), 7.36-7.24 (m, 6H), 5.64 (s, 1H), 5.36 (s, 2H), 3.44 (s, 3H), 3.26-3.24 (m, 2H), 3.15-3.09 (m, 2H), 2.99-2.95 (m, 1H), 2.08-2.02 (m, 2H). | 379 | |
76 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺 | (CD 3OD, 400 MHz) δ 7.94 (s, 1H), 7.31-7.14 (m, 8H), 6.73 (d, J=2.4 Hz, 1H), 6.59 (d, J=1.6 Hz, 1H), 6.53 (s, 1H), 5.22 (s, 2H), 3.62 (s, 3H), 2.84 (s, 3H) | 388 | |
77 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡咯-3-甲酸甲酯 | (DMSO- d 6 , 400 MHz) δ 8.05 (s, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.37-7.28 (m, 4H), 7.25 (s, 1H), 7.14 (s, 1H), 7.11 (d, J=1.8 Hz, 1H), 6.86-6.84 (m, 1H), 6.53-6.52 (m, 1H), 6.47 (s, 1H), 5.24 (s, 2H), 3.70 (s, 3H), 3.50 (s, 3H) | 389 | |
78 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N,N-二甲基-1H-吡咯‑3羧醯胺 | (CD 3OD, 400 MHz) δ 7.93 (s, 1H), 7.31-7.28 (m, 3H), 7.24 (s, 1H), 7.20-7.15 (m, 3H), 7.06 (d, J=1.9 Hz, 1H), 6.79-6.78 (m, 1H), 6.55 (s, 1H), 6.49-6.48 (m, 1H), 5.24 (s, 2H), 3.62 (s, 3H), 2.99 (s, 6H) | 402 | |
79 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | (DMSO- d 6 , 400 MHz) δ 12.0 (br s, 1H), 8.03 (s, 1H), 7.32-7.26 (m, 5H), 7.15 (s, 1H), 7.11 (d, J=7.0 Hz, 1H), 6.85-6.84 (m, 1H), 6.49-6.46 (m, 2H), 5.76 (s, 1H), 5.25 (s, 2H), 3.49 (s, 3H) | 375 | |
80 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-腈 | (CD 3OD, 400 MHz) δ 7.93 (s, 1H), 7.39-7.26 (m, 4H), 7.18-7.15 (m, 3H), 6.82-6.81 (m, 1H), 6.55 (s, 1H), 6.48 (d, J=1.6 Hz, 1H), 6.47 (d, J=1.6 Hz, 1H), 5.25 (s, 2H), 3.49 (s, 3H) | 356 | |
81 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶‑4-基)-N-乙基-1H-吡咯-3-甲醯胺 | (DMSO- d 6 , 400 MHz) δ 8.03 (s, 1H), 7.09-7.88 (m, 1H), 7.34-7.27 (m, 4H), 7.26-7.10 (m, 3H), 6.75 (s, 1H), 6.59-6.58 (m, 1H), 6.41 (s, 1H), 5.24 (s, 2H), 3.49 (s, 3H), 3.21 (q, J=6.8 Hz, 2H), 1.07 (t, J=1.0 Hz, 3H) | 402 | |
82 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-異丙基-1H-吡咯-3-甲醯胺 | (DMSO- d 6 , 400 MHz) δ 8.03 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.34-7.26 (m, 4H), 7.12-7.10 (m, 3H), 6.72-6.71 (m, 1H), 6.61-6.60 (m, 1H), 6.40 (s, 1H), 5.25 (s, 2H), 4.06-4.01 (m, 1H), 3.49 (s, 3H), 1.12 (d, J=6.6 Hz, 6H) | 416 | |
83 | 1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-(1H-吡咯-1-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.97 (s, 1H), 7.20 (s, 1H), 6.94 (s, 1H), 6.76-6.74 (m, 2H), 6.35 (s, 1H), 6.18-6.17 (m, 2H), 3.75 (s, 3H), 3.49 (s, 3H) | 255 | |
84 | 1-(1-甲基-5-(1-甲基-1H-吡唑-4-基)-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡咯-3-甲酸 | (CD 3OD, 400 MHz) δ 7.93 (s, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 6.76-6.75 (m, 1H), 6.62 (d, J=1.5 Hz, 1H), 6.61 (d, J=1.5 Hz, 1H), 6.55 (s, 1H), 3.82 (s, 3H), 3.64 (s, 3H) | 299 | |
85 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺 | (DMSO- d 6 , 400 MHz) δ 8.03 (s, 1H), 7.41 (s, 1H), 7.35-7.26 (m, 5H), 7.13-7.11 (m, 3H), 6.90 (s, 1H), 6.77-6.76 (m, 1H), 6.58-6.57 (m, 1H), 6.41 (s, 1H), 5.25 (s, 2H), 3.49 (s, 3H) | 374 | |
86 | 1-(5-(1-(環丙基甲基)-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | (DMSO- d 6 , 400 MHz) δ 8.06 (s, 1H), 7.30-7.29 (m, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.84-6.83 (m, 2H), 6.53-6.51 (m, 1H), 6.47 (s, 1H), 3.98 (d, J=7.1 Hz, 2H), 3.51 (s, 3H), 0.49-0.44 (m, 2H), 0.27-0.23 (m, 2H) | 339 | |
87 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-吡咯啶-1-基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.70 (s, 1H), 7.49 (s, 1H), 734-7.25 (m, 6H), 5.61 (s, 1H), 5.34 (s, 2H), 3.42 (s, 3H), 3.03-3.00 (m, 4H), 1.79-1.76 (m, 4H) | 335 | |
88 | N-{2-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-環戊基}-乙醯胺 | (CD 3OD, 400 MHz) δ 7.77 (s, 1H), 7.54 (d, J=7.2 Hz, 2H), 737-7.25 (m, 6H), 5.37 (s, 2H), 4.26-4.23 (m, 1H), 3.57 (s, 3H), 3.39-3.35 (m, 2H), 3.26-3.20 (m, 1H), 3.00-2.96 (m, 1H), 2.09-2.04 (m, 1H), 1.90 (s, 3H), 1.88-1.81 (m, 1H). | 392 | |
89 | N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基甲基}-乙醯胺 | (CD 3OD, 400 MHz) δ 7.71 (s, 1H), 7.51 (s, 1H), 7.38-7.29 (m, 6H), 5.65 (s, 1H), 5.35 (s, 2H), 3.44 (s, 3H), 3.14-3.04 (m, 5H), 2.83-2.79 (m, 1H), 2.31-2.28 (m, 1H), 1.94-1.89 (m, 4H), 1.56-1.51 (m, 1H) | 406 | |
90 | N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基-甲基}-乙醯胺 | (CD 3OD, 400 MHz) δ 7.70 (s, 1H), 7.50 (s, 1H), 7.37-7.26 (m, 6H), 5.61 (s, 1H), 5.35 (s, 2H), 3.42 (s, 3H), 3.15-3.01 (m, 5H), 2.81-2.77 (m, 1H), 2.30-2.26 (m, 1H), 1.93-1.89 (m, 4H), 1.56-1.51 (m, 1H). | 406 | |
91 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2,2,2-三氟-乙氧基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.00 (s, 1H), 7.85 (s, 1H), 7.70 (s, 1H), 7.35-7.29 (m, 3H), 7.25-7.23 (m, 2H), 6.03 (s, 1H), 5.32 (s, 2H), 4.84 (q, J=8.4 Hz, 2H), 3.40 (s, 3H) | 364 | |
92 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3,3,3-三氟丙-氧基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.98-7.95 (m, 2H), 7.74 (s, 1H), 7.34-7.22 (m, 5H), 5.95 (s, 1H), 5.31 (s, 2H), 4.24-4.21 (m, 2H), 3.38 (s, 3H), 2.88-2.65 (m, 2H) | 378 | |
93 | 1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-甲基乙醯胺 | (CD 3OD, 400 MHz) δ (s, 1H), 7.50 (s, 1H), 7.35-7.23 (m, 6H), 5.62 (s, 1H), 5.34 (s, 2H), 3.43 (s, 3H), 3.22-3.16 (m, 3H), 3.10-3.03 (m, 1H), 2.87-2.83 (m, 1H), 2.70 (s, 3H), 2.02-1.95 (m, 2H) | 392 | |
94 | 5-(1-苄基-1H-吡唑-4-基)-4-(1H-咪唑-1-基)-1-甲基-吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.14 (s, 1H), 8.04 (s, 1H), 7.70 (s, 1H), 7.36 (s, 1H), 7.35-7.30 (m, 3H), 7.28-7.26 (m, 2H), 7.14 (s, 1H), 7.09 (s, 1H), 6.50 (s, 1H), 5.25 (s, 2H), 3.50 (s, 3H) | 332 | |
95 | 5-(5,6-二氫-4H-吡咯并[1,2-b]-吡唑-3-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.60 (s, 1H), 7.56 (s, 1H), 5.84 (s, 1H), 4.06-4.02 (m, 4H), 3.52 (s, 3H), 2.93-2.90 (m, 2H), 2.55-2.53 (m, 2H), 1.35 (t, J=7.0 Hz, 3H) | 260 | |
96 | 4-乙氧基-1-甲基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.61 (s, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.54-7.50 (m, 2H), 7.33-7.30 (m, 1H), 5.90 (s, 1H), 4.12 (q, J=6.9 Hz, 2H), 3.41 (s, 3H), 1.44 (t, J=7.0 Hz, 3H) | 296 | |
97 | 5-(1-(2-氯-苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基-吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.33 (s, 1H), 8.08 (s, 1H), 8.07 (s, 1H), 7.71-7.63 (m, 2H), 7.53-7.48 (m, 2H), 5.89 (s, 1H), 4.08 (q, J=6.9 Hz, 2H), 3.41 (s, 3H), 1.41 (t, J=7.0 Hz, 3H) | 330 | |
98 | 5-(1-(2,6-二氯苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基-吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz), δ 8.14 (s, 1H), 8.08 (s, 1H), 8.07 (s, 1H), 7.73-7.71 (m, 2H), 7.62-7.58 (m, 2H), 4.09 (q, J=6.9 Hz, 2H), 3.41 (s, 3H), 1.38 (t, J=7.0 Hz, 3H) | 364 | |
99 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2-甲基-肼基)-吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.89 (s, 1H), 7.58 (s, 1H), 7.36 (s, 1H), 7.30 (s, 1H), 7.28-7.22 (m, 5H), 6.08 (s, 1H), 5.33 (s, 2H), 3.32 (s, 3H), 2.63 (s, 3H) | 310 |
將1-(4-溴-苯基)-乙醇(1g, 5 mmol)在HBr (15 mL)中之混合物加熱至90℃經歷5小時。將混合物冷卻至室溫,注入水(5 mL),並用醚(5 mL×3)萃取。將有機層在真空下濃縮,且用層析法矽膠PE:EtOAc (50:1)純化殘餘物,得到呈無色油的1-溴-4-(1-溴-乙基)-苯(900 mg, 3.4 mmol),產率為68%。
1H NMR (300 MHz, CDCl
3): δ 7.50 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.1 Hz 2H), 5.18 (q, J=7.8 Hz 1H), 2.05 (d, J=6.9 Hz 3H).
步驟 2:5-{1-[1-(4-溴-苯基)-乙基]-1H-吡唑-4-基}-4-乙氧基-1-甲基-1H-吡啶-2-酮
將4-乙氧基-1-甲基-5-(1H-吡唑-4-基)-1H-吡啶-2-酮(50 mg, 0.22 mmol)、1-溴-4-(1-溴-乙基)-苯(72 mg, 0.27 mmol)及K
2CO
3(63 mg, 0.45 mmol)在DMF (5 mL)中之混合物加熱至60℃隔夜。將反應冷卻至室溫,注入含水NH
4Cl (5 mL),並用DCM (5 mL×3)萃取。將有機層用Na
2SO
4乾燥,過濾,並在真空中濃縮濾液。藉由製備TLC、DCM:MeOH (30:1)純化殘餘物,得到呈黃色油的5-{1-[1-(4-溴-苯基)-乙基]-1H-吡唑-4-基}-4-乙氧基-1-甲基-1H-吡啶-2-酮(15 mg, 0.037 mmol),產率為16%。
步驟 3:4-乙氧基-1-甲基-5-(1-{1-[4-(1-甲基-1H-吡唑-4-基)-苯基]-乙基}-1H-吡唑-4-基)-1H-吡啶-2-酮
將5-{1-[1-(4-溴-苯基)-乙基]-1H-吡唑-4-基}-4-乙氧基-1-甲基-1H-吡啶-2-酮(26 mg, 0.06 mmol)、1-甲基-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(16.2 mg, 0.04 mmol)、Na
2CO
3(14 mg, 0.12 mmol)及Pd(PPh
3)
4在二噁烷/水(2 mL/0.2 mL)中之混合物在微波中於130℃攪拌3小時。將反應冷卻至室溫,注入含水NH
4Cl (5 mL),並用DCM (5 mL×3)萃取。將有機層用Na
2SO
4乾燥,過濾,並在真空下濃縮濾液。藉由製備TLC (DCM:MeOH (20:1)純化殘餘物,得到呈無色油的4-乙氧基-1-甲基-5-(1-{1-[4-(1-甲基-1H-吡唑-4-基)-苯基]-乙基}-1H-吡唑-4-基)-1H-吡啶-2-酮(8 mg, 0.02 mmol),產率為31%。
1H NMR (400 MHz, MeOD): δ 7.94 (d, J=3.6 Hz, 2H), 7.84 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 5.98 5.98 (s, 1H), 5.58 (q, J=6.8 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.91 (s, 3H), 3.52 (s, 3H), 1.91 (d, J=7.2 Hz, 3H), 1.42 (t, J=6.4 Hz, 3H). LCMS (M+H)
+404.
實例 101-105係使用適當的鹵化物及硼酸衍生物以與實例100類似的多步驟方式來製備的,並呈現於表5中。
實例 106:5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-鄰甲苯基-1H-吡啶-2-酮
流程8
步驟 1:1-苄基-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑
表 5 | ||||
實例 | 結構 | IUPAC 名稱 | 1HNMR(ppm) | MS (M+H) |
101 | 4-乙氧基-5-[1-(4-異丙基-苄基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.89 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 7.24-7.18 (m, 4H), 6.02 (s, 1H), 5.30 (s, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.54 (s, 3H), 2.92-2.85 (m, 1H), 1.41 (t, J=6.8 Hz, 3H), 1.22 (d, J=7.2 Hz, 6H) | 352 | |
102 | 4-乙氧基-1-甲基-5-{1-[4-(1-甲基-1H-吡唑-4-基)-苄基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.94 (d, J=4.0 Hz, 2H), 7.84 (s, 1H), 7.80 (d, J=4.8 Hz, 2H), 7.53 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 5.99 (s, 1H), 5.30 (s, 2H), 4.10 (q, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.52 (s, 3H), 1.42 (t, J=7.0 Hz, 3H) | 390 | |
103 | 4-乙氧基-1-甲基-5-{1-[4-(1H-吡唑-4-基)-苄基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.94 (br, 3H), 7.85 (s, 1H), 7.81 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.27 (d, J=7.6 Hz, 2H), 5.99 (s, 1H), 5.34 (s, 2H), 4.11 (q, J=6.8 Hz, 2H), 3.53 (s, 3H), 1.42 (t, J=7.2 Hz, 3H) | 376 | |
104 | 4-乙氧基-1-甲基-5-(1-(1-(3-(1-甲基-1H-吡唑-4-基)苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.97 (s, 1H), 7.93 (s, 1H), 7.84 (s, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.48-7.46 (m, 2H), 7.34-7.31 (m, 1H), 7.11-7.09 (m, 1H), 5.98 (s, 1H), 5.60-5.59 (m, 1H), 4.11 (q, J=6.8 Hz, 2H), 3.90 (s, 3H), 3.51 (s, 3H), 1.92 (d, J=7.1 Hz, 3H), 1.40 (t, J=7.2 Hz, 3H) | 403 | |
105 | 5-(1-(3-溴-苄基)-1H-吡唑-4-基)-4-乙氧基-1-甲基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) 7.98 (s, 1H), 7.85 (s, 1H), 7.82 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.41 (s, 1H), 7.29-7.24 (m, 2H), 6.00 (s, 1H), 5.35 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.53 (s, 3H), 1.45 (t, J=7.2 Hz, 3H) | 388 |
將4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(3.5 g, 18.2 mmol)、溴甲基-苯(3.2 g, 18.7 mmol)及K
2CO
3(4.5 g, 32.6 mmol)在DMF (30 mL)中之混合物在室溫下攪拌隔夜。用CH
2Cl
2(50 mL)及H
2O (50 mL)稀釋反應混合物。將有機層分離,以及用鹽水(50 mL)洗滌,用Na
2SO
4乾燥,過濾,並在真空下濃縮。藉由管柱層析法在矽膠上用PE:EtOAc (5:1)溶離來純化殘餘物,得到呈淺黃色固體的化合物1-苄基-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(2.8 g, 9.8 mmol),產率為54%。
1H NMR (400 MHz, CDCl
3): δ 7.81 (s, 1H), 7.66 (s, 1H), 7.37-7.29 (m, 3H), 7.24-7.22 (m, 2H), 5.30 (s, 2H), 1.29 (s, 12H). LCMS (M+H)
+285.
步驟 2:5-(1-苄基-1H-吡唑-4-基)-4-氯-1-甲基-1H-吡啶-2-酮
將1-苄基-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(2.4 g, 8.5 mmol)、5-溴-4-氯-1-甲基-1H-吡啶-2-酮(1.9 g, 8.5 mmol)、Pd(dppf)Cl
2(622 mg, 0.85 mmol)及
K3PO
4(4.7 g, 21.2 mmol)在二噁烷/H
2O (20/4 mL)中之混合物在80℃攪拌4小時。隨後用DCM (50 mL)及H
2O (50 mL)稀釋反應混合物;將有機層分離,以及用鹽水(50 mL)洗滌,用Na
2SO
4乾燥,過濾,並在真空中濃縮。藉由管柱層析法在矽膠上用PE:EtOAc (1:3)溶離來純化殘餘物,得到呈灰色固體的化合物5-(1-苄基-1H-吡唑-4-基)-4-氯-1-甲基-1H-吡啶-2-酮(1.2 g, 0.4 mmol),產率為47%。LCMS (M+H)
+300.
在N
2下將5-(1-苄基-1H-吡唑-4-基)-4-氯-1-甲基-1H-吡啶-2-酮(50 mg, 0.167 mmol)、2-甲苯基硼酸(28 mg, 0.206 mmol)、Pd(PPh
3)
4(20 mg, 0.017 mmol)及Na
2CO
3(44 mg, 0.418 mmol)在二噁烷(5 mL)與H
2O (1 mL)中之混合物加熱至90℃經歷5小時。隨後,用CH
2Cl
2(60 mL)及H
2O (50 mL)稀釋混合物;將有機相用鹽水(60 mL)洗滌,用Na
2SO
4乾燥,過濾,並在真空中濃縮。藉由製備TLC純化殘餘物,得到呈褐色油的化合物5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-鄰甲苯基-1H-吡啶-2-酮(57 mg, 0.160 mmol),產率為96%。
1H NMR (400 MHz, DMSO-
d6): δ 7.95 (s, 1H), 7.30-7.22 (m, 5H), 7.16 (d, J=7.2 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 7.01 (d, J=6.0 Hz, 2H), 6.96 (d, J=6.4 Hz, 2H), 6.19 (s, 1H), 5.13 (s, 2H), 3.51 (s, 3H), 1.90 (s, 3H). LCMS (M+H)
+356.
實例 107-164係使用適當的硼酸衍生物及經取代之吡唑以與實例106類似的多步驟方式來製備的,且在表6中展示此等化合物:
表 6 | ||||
實例 | 結構 | IUPAC 名稱 | 1HNMR (ppm) | MS (M+H) |
107 | 1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.78 (s, 1H), 7.37-7.35 (m, 3H), 7.21-7.19 (m, 3H), 7.18 (s, 1H), 6.59 (s, 1H), 3.75 (s, 3H), 3.64 (s, 3H) | 266 | |
108 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.63 (s, 1H), 7.58 (s, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.36-7.25 (m, 6H), 6.61 (s, 1H), 5.33 (s, 2H), 3.76 (s, 3H), 3.57 (s, 3H) | 346 | |
109 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-3-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.94 (s, 1H), 7.50 (s, 1H), 7.34-7.30 (m, 3H), 7.28 (s, 1H), 7.20-7.12 (m, 3H), 6.56 (s, 1H), 6.36 (s, 1H), 5.21 (s, 2H), 3.64 (s, 3H), 3.35 (s, 3H) | 346 | |
110 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.94 (s, 1H), 7.50 (s, 1H), 7.33-7.31 (m, 3H), 7.21 (s, 1H), 7.15-7.12 (m, 3H), 6.56 (s, 1H), 6.36 (d, J= 1.9 Hz, 1H), 5.22 (s, 2H), 3.65 (s, 3H), 3.35 (s, 3H) | 346 | |
111 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-( 間甲苯基)-吡啶-2(1H)-酮 | (DMSO-d6, 400 MHz) δ 7.86 (s, 1H), 7.33-7.27 (m, 3H), 7.24-7.16 (m, 3H), 7.18 (d, J=7.2 Hz, 1H), 7.04 (d, J=6.4 Hz, 2H), 6.99 (s, 1H) 6.94 (d, J=7.2 Hz, 1H), 6.28 (s, 1H), 5.19 (s, 2H), 3.49 (s, 3H), 2.32 (s, 3H). | 356 | |
112 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-( 對甲苯基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.78 (s, 1H), 7.33-7.27 (m, 3H), 7.22 (s, 1H), 7.12-7.03 (m, 7H), 6.47 (s, 1H), 5.18 (s, 2H), 3.62 (s, 3H), 2.33 (s, 3H) | 356 | |
113 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-甲氧基苯基)-1-甲基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.79 (s, 1H), 7.32-7.21 (m, 5H), 7.17 (s, 1H), 7.08-7.06 (m, 2H), 6.90 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.66 (s, 1H), 6.50 (s, 1H), 5.19 (s, 2H), 3.63 (s, 3H), 3.63 (s, 3H) | 372 | |
114 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-5-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 13.0 (s, 1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.58 (s, 1H), 7.37-7.18 (m, 5H), 6.58 (s, 1H), 5.90 (s, 1H), 5.27 (s, 2H), 3.45 (s, 3H) | 332 | |
115 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.73 (s, 1H), 7.42 (s, 1H), 7.34-7.19 (m, 5H), 6.71 (s, 1H), 5.72 (s, 1H), 5.28 (s, 2H), 3.60 (s, 3H), 2.18 (s, 3H) | 346 | |
116 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-2-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.69 (s, 1H), 7.47-7.44 (m, 2H), 7.34-7.28 (m, 4H), 7.21-7.19 (m, 2H), 7.00-6.95 (m, 2H), 6.66 (s, 1H), 5.28 (s, 2H), 3.58 (s, 3H) | 348 | |
117 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-3-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.74 (s, 1H), 7.34-7.28 (m, 7H), 7.16-7.15 (m, 2H), 6.83-6.81 (m, 1H), 6.58 (s, 1H), 5.24 (s, 2H), 3.61 (s, 3H) | 348 | |
118 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-氯苯基)-1-甲基-吡啶‑2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.81 (s, 1H), 7.38-7.28 (m, 5H), 7.23 (s, 1H), 7.20 (s, 2H), 7.12 (d, J=7.2 Hz, 1H), 7.07 (d, J=7.2 Hz, 2H), 6.50 (s, 1H), 5.21 (s, 2H), 3.63 (s, 3H) | 377 | |
119 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.79 (s, 1H), 7.32-7.26 (m, 6H), 7.15-7.13 (m, 3H), 7.07 (d, J=7.2 Hz, 2H), 6.49 (s, 1H), 5.19 (s, 2H), 3.62 (s, 3H) | 377 | |
120 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-甲氧基苯基)-1-甲基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.76 (s, 1H), 7.33-7.28 (m, 3H), 7.25 (s, 1H), 7.15 (s, 1H), 7.10-7.08 (m, 4H), 6.84 (d, J=8.8 Hz, 2H), 6.47 (s, 1H), 5.12 (s, 2H), 3.79 (s, 3H), 3.61 (s, 3H) | 372 | |
121 | 5-(1-苄基-1H-吡唑-4-基)-4-(異噁唑-3-基)-1-甲基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.58 (s, 1H), 8.27 (s, 1H), 7.72 (s, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 7.35-7.30 (m, 3H), 7.23 (d, J=7.2 Hz, 2H), 6.69 (s, 1H), 5.33 (s, 2H), 3.59 (s, 3H) | 333 | |
122 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | (CD 3OD, 400 MHz) δ 8.72 (d, J=5.2 Hz, 1H), 8.66 (s, 1H), 8.15-8.12 (m, 1H), 7.89 (s, 1H), 7.76-7.73 (m, 1H), 7.35-7.30 (m, 4H), 7.27 (s, 1H), 7.13-7.11 (m, 2H), 6.66 (s, 1H), 5.22 (s, 2H), 3.65 (s, 3H) | 343 | |
123 | 5-(1-苄基-1H-吡唑-4-基)-4-(2-氯苯基)-1-甲基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.87 (s, 1H), 7.32-7.22 (m, 7H), 7.20 (s, 1H), 7.04 (s, 1H), 7.00-6.98 (m, 2H), 6.44 (s, 1H), 5.16 (s, 2H), 3.66 (s, 3H) | 377 | |
124 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-[4,4'-聯吡啶]-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.47 (d, J=6.0 Hz, 2H), 7.85 (s, 1H), 7.32-7.25 (m, 7H), 7.07 (d, J=7.6 Hz, 2H), 6.55 (s, 1H), 5.21 (s, 2H), 3.64 (s, 3H) | 343 | |
125 | 5-(1-環己基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.81 (s, 1H), 7.39-7.34 (m, 3H), 7.21-7.18 (m, 2H), 7.14 (s, 1H), 7.10 (s, 1H), 6.51 (s, 1H), 4.00-3.94 (m, 1H), 3.65 (s, 3H), 1.96-1.93 (m, 2H), 1.84-1.81 (m, 2H), 1.71-1.68 (m, 1H), 1.62-1.51 (m, 2H), 1.45-1.35 (m, 2H), 1.27-1.20 (m, 1H) | 334 | |
126 | 1-甲基-4-苯基-5-(1-(四氫-2H-哌喃-4-基) -1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.82 (s, 1H), 7.39-7.34 (m, 3H), 7.11 (s, 1H), 6.51 (s, 1H), 4.27-4.23 (m, 1H), 4.00-3.96 (m, 2H), 3.69 (s, 3H), 3.52-3.46 (m, 2H), 1.91-1.86 (m, 4H) | 336 | |
127 | 1-甲基-5-(1-(1-(甲基-磺醯基)-哌啶-4-基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | (DMSO-d6, 400 MHz) δ 7.88 (s, 1H), 7.39-7.35 (m, 3H), 7.27 (s, 1H), 7.19-7.17 (m, 2H), 6.99 (s, 1H), 6.31 (s, 1H), 4.20-4.13 (m, 1H), 3.59-3.56 (m, 2H), 3.49 (s, 3H), 2.91-2.84 (m, 5H), 2.00-1.96 (m, 2H), 1.84-1.74 (m, 2H) | 413 | |
128 | 1-甲基-4-苯基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.93 (s, 1H), 7.80 (s 1H), 7.57-7.55 (m, 2H), 7.46-7.40 (m, 5H), 7.31-7.26 (m, 3H), 7.22 (s, 1H), 6.54 (s, 1H), 3.67 (s, 3H) | 328 | |
129 | 1-甲基-5-(1-((甲基-磺醯基)-甲基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | (DMSO-d6, 400 MHz) δ 7.92 (s, 1H), 7.39-7.33 (m, 4H), 7.20-7.17 (m, 3H), 6.32 (s, 1H), 5.62 (s, 2H), 3.51 (s, 3H), 2.89 (s, 3H) | 344 | |
130 | 1-甲基-5-(1-(2-嗎-啉乙基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.80 (s, 1H), 7.39-7.34 (m, 3H), 7.25 (s, 1H), 7.22-7.20 (m, 2H), 7.11 (s, 1H), 6.50 (s, 1H), 4.15-4.12 (m, 2H), 3.65 (s, 3H), 3.63-3.60 (m, 4H), 2.67 (t, J=6.4 Hz, 2H), 2.40-2.38 (m, 4H). | 365 | |
131 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[2,4'-聯吡啶]-2'(1'H)-酮 | (CD 3OD, 400 MHz) δ 8.50 (d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.79-7.75 (m, 1H), 7.41-7.37 (m, 1H), 7.33-7.28 (m, 4H), 7.18 (s, 1H), 7.15 (s, 1H), 7.09-7.07 (m, 2H), 6.61 (s, 1H), 5.19 (s, 2H), 3.65 (s, 3H). | ||
132 | 5-(1-乙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.80 (s, 1H), 7.39-7.34 (m, 3H), 7.21-7.17 (s, 3H), 7.06 (s, 1H), 6.50 (s, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.64 (s, 3H), 1.32 (t, J=7.2 Hz, 3H) | 280 | |
133 | 1-甲基-4-苯基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ (s, 1H), 7.37-7.35 (m, 3H), 7.22-7.19 (m, 4H), 6.51 (s, 1H), 3.65 (s, 3H) | 252 | |
134 | N-甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基) 乙醯胺 | (CD 3OD, 400 MHz) δ 7.83 (s, 1H), 7.37-7.35 (m, 3H), 7.28 (s, 1H), 7.24-7.21 (m, 2H), 7.07 (s, 1H), 6.51 (s, 1H), 4.70 (s, 2H), 3.65 (s, 3H), 2.73 (s, 3H) | 333 | |
135 | N,N-二甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙醯胺 | (CD 3OD, 400 MHz) δ 7.83 (s, 1H), 7.37-7.35 (m, 3H), 7.25-7.22 (m, 3H), 7.06 (s, 1H), 6.51 (s, 1H), 4.99 (s, 2H), 3.65 (s, 3H), 3.04 (s, 3H), 2.94 (s, 3H) | 337 | |
136 | 5-(1,3-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)‑酮 | (CD 3OD, 400 MHz) δ 7.64 (s, 1H), 7.33-7.30 (m, 4H), 7.21-7.19 (m, 2H), 6.58 (s, 1H), 3.75 (s, 3H), 3.64 (s, 3H), 1.66 (s, 3H) | 280 | |
137 | 5-(1-異丁基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.80 (s, 1H), 7.38-7.33 (m, 3H), 7.21-7.19 (m, 2H), 7.16 (s, 1H), 7.08 (s, 1H), 6.51 (s, 1H), 3.78 (d, J=6.8 Hz, 2H), 3.65 (s, 3H), 2.04-1.99 (m, 1H), 0.78 (d, J=6.8 Hz, 6H). | 308 | |
138 | 5-(1-異丙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | (CDCl 3, 300 MHz) δ (s, 1H), 7.35-7.34 (m, 3H), 7.24 (s, 1H), 7.18-7.15 (m, 2H), 6.67 (s, 1H), 6.62 (s, 1H), 4.36-4.31 (m, 1H), 1.35 (d, J=6.6 Hz, 6H) | 294 | |
139 | 1-甲基-4-苯基-5-(1-丙基-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 300 MHz) δ (s, 1H), 7.39-7.35 (m, 3H), 7.23-7.20 (m, 2H), 7.14 (s, 2H), 6.52 (s, 1H), 3.97 (t, J=6.6 Hz, 2H), 3.66 (s, 3H), 1.78-1.70 (m, 2H), 0.79 (t, J=6.9 Hz, 3H) | 294 | |
140 | 甲基 2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙酸酯 | (CD 3OD, 400 MHz) δ 7.82 (s, 1H), 7.37-7.35 (m, 3H), 7.26 (s, 1H), 7.22-7.20 (m, 2H), 7.11 (s, 1H), 6.51 (s, 1H), 4.91 (s, 2H), 3.72 (s, 3H), 3.64 (s, 3H) | 324 | |
141 | 2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-1H-吡唑-1-基)-N-丙基乙醯胺 | (CD 3OD, 400 MHz) δ 7.83 (s, 1H), 7.37-7.35 (m, 3H), 7.29 (s, 1H), 7.24-7.21 (m, 2H), 7.06 (s, 1H), 6.51 (s, 1H), 4.70 (s, 2H), 3.65 (s, 3H), 3.14 (t, J=7.2 Hz, 2H), 1.52-1.48 (m, 2H), 0.92-0.88 (m, 3H) | 351 | |
142 | 4-環戊基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.68 (s, 1H), 7.57 (s, 1H), 7.50 (s, 1H), 6.56 (s, 1H), 3.94 (s, 3H), 3.58 (s, 3H), 3.13-3.04 (m, 1H), 1.93-1.88 (m, 2H), 1.81-1.78 (m, 2H), 1.65-1.59 (m, 2H), 1.57-1.50 (m, 2H) | 258 | |
143 | 4-環己基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2 (1H)-酮 | (CD 3OD, 400 MHz) δ 7.66 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 6.47 (s, 1H), 3.93 (s, 3H), 3.54 (s, 3H), 2.61-2.58 (m, 1H), 1.79-1.70 (m, 5H), 1.35-1.23 (m, 5H) | 272 | |
144 | 4-環丙基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.77 (s, 1H), 7.60 (s, 1H), 7.59 (s, 1H), 6.11 (s, 1H), 3.93 (s, 3H), 3.55 (s, 3H), 1.88-1.84 (m, 1H), 1.05-1.00 (m, 2H), 0.81-0.77 (m, 2H) | 230 | |
145 | 1-甲基-4-苯基-5-(1,3,5-三-甲基-1H-吡唑-4-基)吡啶‑2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.60 (s, 1H), 7.31-7.27 (m, 3H), 7.14-7.12 (m, 2H), 6.61 (s, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 1.91 (s, 3H) 1.81 (s, 3H) | 294 | |
146 | 5-(1-(環丙基-甲基)-1H-吡唑-4-基)-1-甲基-4-苯基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.83 (s, 1H), 7.39-7.34 (m, 3H), 7.22-7.20 (m, 2H), 7.15 (d, J=1.6 Hz, 2H), 6.51 (s, 1H), 3.84 (d, J=6.8 Hz, 2H), 3.65 (s, 3H), 1.14-1.10 (m, 1H), 0.54-0.49 (m, 2H), 0.25-0.21 (m, 2H) | 306 | |
147 | 5-(1-環丙基-甲基-1H-吡唑-4-基)-1-甲基-4-(4-三-氟甲基-苯基)-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.85 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.18 (s, 2H), 6.55 (s, 1H), 3.85 (d, J=6.8 Hz, 2H), 3.66 (s, 3H), 1.14-1.10 (m, 1H), 0.52-0.48 (m, 2H), 0.23-0.19 (m, 2H) | 374 | |
148 | 4-[5-(1-環丙基-甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-N-甲基-苯甲醯胺 | (CD 3OD, 300 MHz) δ 7.86-7.81 (m, 3H), 7.34 (d, J=7.8 Hz, 2H), 7.19 (d, J=6.9 Hz, 2H), 6.55 (s, 1H), 3.87-3.85 (m, 2H), 3.67 (s, 3H), 2.93 (s, 3H), 1.18-1.08 (m, 1H), 0.53-0.50 (m, 2H), 0.25-0.23 (m, 2H) | 363 | |
149 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-氟苯基)-1-甲基-吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.85 (s, 1H), 7.32-7.29 (m, 3H), 7.22-7.03 (m, 8H), 6.32 (s, 1H), 5.20 (s, 2H), 3.48 (s, 3H) | 360 | |
150 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)苯甲腈 | (DMSO- d 6 , 400 MHz) δ 7.90 (s, 1H), 7.79 (s, 1H), 7.77 (s, 1H), 7.36-7.28 (m, 5H), 7.19-7.17 (m, 2H), 7.03-7.01 (m, 1H), 6.36 (s, 1H), 5.19 (s, 2H), 3.49 (s, 3H) | 367 | |
151 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)苯甲醯胺 | (DMSO- d 6 , 400 MHz) δ 8.03 (s, 1H), 7.87-7.84 (m, 3H), 7.44 (s, 1H), 7.32-7.23 (m, 6H), 7.11 (s, 1H), 7.01-6.99 (m, 1H), 6.34 (s, 1H), 5.18 (s, 2H), 3.49 (s, 3H) | 385 | |
152 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 13.0 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 7.37-7.21 (m, 7H), 6.52 (s, 1H), 5.32 (s, 2H), 3.42 (s, 3H) | 332 | |
153 | 4-(4-氯-苯基)-5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.82 (s, 1H), 7.38 (d, J=8.8 Hz, 2H), 7.22-7.19 (m, 4H), 6.52 (s, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.65 (s, 3H), 1.16-1.12 (m, 1H), 0.55-0.51 (m, 2H), 0.27-0.23 (m, 2H) | 340 | |
154 | 4-[5-(1-環丙基-甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲酸 | (DMSO- d 6 , 400 MHz) δ 12.95 (br, 1H), 7.92-7.91 (m, 3H), 7.30 (d, J=8.0 Hz, 2H), 7.12 (s, 1H), 7.08 (s, 1H), 6.35 (s, 1H), 3.80 (d, J=7.2 Hz, 2H), 3.51 (s, 3H), 1.07-1.03 (m, 1H), 0.41-0.38 (m, 2H), 0.18-0.16 (m, 2H) | 350 | |
155 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)苯甲酸 | (DMSO- d 6 , 400 MHz) δ 13.0 (s, 1H), 7.89-7.87 (m, 2H), 7.28-7.26 (m, 4H), 7.16 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 6.35 (s, 1H), 5.18 (s, 2H), 3.5 (s, 3H) | 386 | |
156 | 4-[5-(1-環丙基-甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 7.85 (s, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 7.22 (s, 1H), 7.17 (s, 1H), 6.54 (s, 1H), 3.87 (d, J=7.2 Hz, 2H), 3.65 (s, 3H), 1.14-1.12 (m, 1H), 0.55-0.50 (m, 2H), 0.26-0.22 (m 2H) | 331 | |
157 | 5-(1-(環己基-甲基)-1H-吡唑-4-基)-1-甲基-4-苯基-吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.84 (s, 1H), 7.34-7.32 (m, 4H), 7.17-7.15 (m, 1H), 7.09 (s, 1H), 6.99 (s, 1H), 6.30 (s, 1H), 3.76 (m, 2H), 3.49 (s, 3H), 1.63-1.57 (m, 4H), 1.35-1.32 (m, 2H), 1.15-1.05 (m, 3H), 0.80-0.71 (m, 2H) | 384 | |
158 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡唑-1-基)乙醯胺 | (CD 3OD, 400 MHz) δ 7.65 (s, 1H), 7.59 (s, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 7.39 (s, 1H), 7.32-7.24 (m, 5H), 6.64 (s, 1H), 5.31 (s, 2H), 4.77 (s, 2H), 3.57 (s, 3H) | 389 | |
159 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙酸 | (CD 3OD, 400 MHz) δ 7.67 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 7.34-7.29 (m, 7H), 6.63 (s, 1H), 5.30 (s, 2H), 4.77 (s, 2H), 3.58 (s, 3H) | 388 | |
160 | 5-(1-苄基-1H-吡唑-4-基)-4-(1-(二氟甲基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.08 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.34-7.19 (m, 5H), 6.58 (s, 1H), 5.31 (s, 1H), 3.44 (s, 3H) | 382 | |
161 | 5-(1-苄基-1H-吡唑-4-基)-4-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)-1-甲基-吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 7.63 (s, 1H), 7.59 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 7.35-7.24 (m, 6H), 6.64 (s, 1H), 5.31 (s, 2H), 3.97 (s, 2H), 3.30 (d, J=1.4 Hz, 3H), 1.12 (s, 6H) | 404 | |
162 | 5-(5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.74 (s, 1H), 7.37-7.34 (m, 3H), 7.20-7.17 (m, 2H), 7.12 (s, 1H), 6.34 (s, 1H), 3.92 (m, 2H), 3.49 (s, 3H), 2.27-2.23 (m, 2H), 1.98-1.96 (m, 2H) | 292 | |
163 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙腈 | (DMSO- d 6 , 400 MHz) δ 7.73 (s, 1H), 7.69 (s, 1H), 7.69 (s, 1H), 7.49 (s, 1H), 7.36-7.32 (m, 4H), 7.24-7.22 (m, 2H), 6.50 (s, 1H), 5.43 (s, 2H), 5.31 (s, 2H), 3.43 (s, 3H) | 371 | |
164 | 5-(1,5-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 7.65 (s, 1H), 7.31-7.28 (m, 2H), 7.17-7.12 (m, 2H), 6.96 (s, 1H), 6.74-6.73 (m, 1H), 6.36 (s, 1H), 3.60 (s, 3H), 3.48 (s, 3H), 1.75 (s, 3H) | 280 |
表7中的
實例 165-174係使用適當的烷基或芳烷基溴化物及親核試劑以與實例36類似的多步驟方式來製備的。
實例 175:4-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮
表 7 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
165 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-丙氧基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.91 (s, 1H), 7.85 (s, 1H) 7.81 (s, 1H), 7.38-7.26 (m, 5H), 6.00 (s, 1H), 5.36 (s, 2H), 4.03 (t, J= 6.0 Hz, 2H), 3.53 (s, 3H), 1.85-1.79 (m, 2H), 0.99 (t, J =7.6 Hz, 3H). | 324 | |
166 | 3-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-丙酸 | (DMSO- d 6 , 400 MHz) δ 7.98 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.34-7.24 (m, 5H), 5.88 (s, 1H), 5.28 (s, 2H), 4.18 (t, J= 5.6 Hz, 2H), 3.38 (s, 3H), 2.75 (t, J= 5.2 Hz, 2H). | 354 | |
167 | [5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-乙腈 | (CDCl 3, 400 MHz) δ 7.64 (s, 1H), 7.55 (s, 1H), 7.37-7.33 (m, 4H), 7.27-7.26 (m, 2H), 6.01 (s, 1H), 5.33 (s, 2H), 4.75 (s, 2H), 3.54 (s, 3H). | 321 | |
168 | 5-(1-苄基-1H-吡唑-4-基)-4-乙基硫基-1-甲基-1H-吡啶-2-酮 | (CDCl 3, 400 MHz) δ 7.58 (s, 1H), 7.49 (s, 1H) 7.38-7.33 (m, 3H), 7.26-7.25 (m, 2H), 7.07 (s, 1H), 6.33 (s, 1H), 5.34 (s, 2H), 3.51 (s, 3H), 2.89 (q, J= 7.6 Hz, 2H), 1.38 (t, J= 7.6 Hz, 3H). | 326 | |
169 | [5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基硫基]-乙酸 | (DMSO- d 6 , 400 MHz) δ 7.91 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.38-7.25 (m, 5H), 6.14 (s, 1H), 5.36 (s, 2H), 3.85 (s, 2H), 3.36 (s, 3H). | 356 | |
170 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-((甲胺基)氧基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.26 (s, 1H), 7.98 (s, 1H), 7.82 (m, 1H), 7.73 (s, 1H), 7.37-7.23 (m, 5H), 6.18 (s, 1H), 5.34 (s, 2H), 2.76 (d, J= 6.5 Hz) | 311 | |
171 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-乙氧基-1-甲基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.96 (s, 1H), 7.86 (s, 1H), 7.80 (s, 1H), 6.01 (s, 1H), 4.35-4.21 (m, 2H), 4.13 (q, J= 6.8 Hz, 2H), 3.54 (s, 3H), 2.20-2.14 (m, 1H), 1.65-1.59 (m, 1H). 1.49 (t, J= 6.8 Hz, 3H), 1.44-1.37 (m, 1H). | 310 | |
172 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-甲基吡咯啶-3-磺醯胺 | (DMSO- d 6 , 400 MHz) δ 7.85 (s, 1H), 7.49 (s, 1H), 7.38-7.22 (m, 6H), 7.11-7.10 (m, 1H), 5.46 (s, 1H), 5.33 (s, 2H), 3.84 (br t, J= 6.2 Hz, 1H), 3.28 (s, 3H), 3.28-3.26 (m, 5 H), 3.02-3.02 (m, 1H), 2.55-2.51 (m, 3H), 2.11-2.07 (m, 2H) | 428 | |
173 | (R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)-1,1,1-三氟甲磺醯胺 | (DMSO- d 6 , 400 MHz) δ 9.65 (br s, 1H), 7.77 (s, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 7.27-7.16 (m, 5H), 5.32 (s, 1H), 5.26 (s, 2H), 3.93 (quin, J= 7.0 Hz, 2H), 3.22 (s, 3H), 3.20-3.05 (m, 2H), 2.95 (td, J= 7.0 Hz, 9.9 Hz, 1H), 2.80 (dd, J= 5.0 Hz, 10.7 Hz, 1H), 2.43 (td J= 1.8 Hz, 3.6 Hz, 1H), 2.07-1.92 (m, 1H), 1.70 (qd J= 6.6 Hz, 12.7 Hz, 1H) | ||
174 | (R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)甲磺醯胺 | (DMSO- d 6 , 400 MHz) δ 7.76 (s, 1H), 7.38 (s, 1H), 7.32-7.18 (m, 5H), 7.18-7.11 (m, 2H), 5.30 (s, 1H), 5.26 (s, 2H), 3.74 (sxt, J= 6.2 Hz, 1H), 3.21 (s, 3H), 3.24-3.17 (m, 1H), 3.12 (dd, J= 6.4, 10.5 Hz, 1H), 3.09-2.99 (m, 1H), 2.92 (td J= 7.2, 10.2 Hz, 1H), 2.84-2.72 (m, 4H), 1.95 (qd, J= 6.3, 12.4 Hz, 1H), 1.73-1.59 (m, 1H)H) | 428 |
藉由用甲醇代替步驟2中的異丙醇以與實例36類似的方式來製備標題化合物。
1H NMR (DMSO-d
6, 400 MHz) δ 8.03 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.31-7.23 (m, 5H), 5.87 (s, 1H), 5.61-5.59 (m, 1H), 3.80 (s, 3H), 3.33 (s, 3H), 1.81 (d, J=7.1 Hz, 3H). LCMS (M+H)
+310.
實例 176:2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-異丙基-苯甲腈
步驟 1:2-(4-碘-吡唑-1-基)-6-異丙基-苯甲腈
在N
2下向室溫的4-碘-1H-吡唑(200 mg, 1.0 mmol)在DMF (10 mL)中之溶液添加NaH (50 mg, 1.2 mmol)。將混合物攪拌30分鐘,並隨後添加2-氟-6-異丙基-苯甲腈(183 mg, 1.1 mmol)。將所得混合物在室溫下攪拌10小時。藉由添加水(45 mL)中止反應,並用DCM (15 mL×2)萃取。將合併的有機層用鹽水洗滌,用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備HPLC純化殘餘物,得到呈白色固體的標題化合物(140 mg, 0.4 mmol)。
步驟 2:5-溴-4-乙氧基-1-甲基-1H-吡啶-2-酮
向5-溴-4-氯-1-甲基-1H-吡啶-2-酮(1.0 g, 4.5 mmol)在DMF (30 mL)中之溶液添加乙醇鈉(616 mg, 9.0 mmol)。將混合物在N
2下於30℃攪拌隔夜。藉由添加水(50 mL)中止反應,並用EtOAc (25 mL×2)萃取。將合併的有機層用鹽水洗滌,用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由矽膠管柱層析法用PE/EtOAc (1:1)溶離來純化殘餘物,得到呈黃色固體的標題化合物,產率為67%。LCMS (M+H)
+232.
步驟 3:4-乙氧基-1-甲基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡啶-2-酮
向5-溴-4-乙氧基-1-甲基-1H-吡啶-2-酮(700 mg, 3.0 mmol)及聯硼酸頻那醇酯(bis(pinacolato)diboron)(1.5 g, 6.0 mmol)在二噁烷(30 mL)中之溶液添加Pd
2(dba)
3(270 mg, 0.3 mmol)、XPhos (214 mg, 0.45 mmol)及KOAc (882 mg, 9.0 mmol)。將反應混合物在N
2下於75⁰C攪拌10小時。將反應冷卻至室溫,過濾,並在減壓下濃縮。藉由矽石管柱層析法用PE/EtOAc (1:1)溶離來純化殘餘物,得到呈黃色固體的標題化合物。
1H NMR (300 MHz, CDCl
3): δ 7.53 (s, 1H), 5.75 (s, 1H), 3.91 (q, J = 6.8 Hz, 2H), 3.41 (s, 3H), 1.34 (t, J = 6.8 Hz, 3H), 1.24 (s, 12H). LCMS (M+H)
+280。
步驟 4:2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-異丙基-苯甲腈
向來自步驟1之標題化合物(140 mg, 0.4 mmol)及來自步驟3之標題化合物(174 mg, 0.6 mmol)在二噁烷(20 mL)與H
2O (4 mL)之混合物中之溶液添加Pd(dppf)Cl
2(30 mg, 0.04 mmol)及
K3PO
4(176 mg, 0.8 mmol)。將所得混合物在N
2下於60℃攪拌3小時。將反應冷卻至室溫,用水(60 mL)稀釋,並用DCM (15 mL×2)萃取。將合併的有機層用鹽水洗滌,用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備HPLC純化殘餘物,得到呈白色固體的標題化合物(70 mg, 0.19 mmol)。
1H NMR (CDCl
3, 400 MHz) δ 8.33 (s, 1H), 7.95 (s, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.58 (t, J = 6.4 Hz, 1H), 7.45 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 4.10 (q, J = 6.8 Hz, 2H), 3.57 (s, 3H), 3.55-3.49 (m, 1H), 1.51 (t, J = 7.2 Hz, 3H), 1.37 (d, J = 6.8 Hz, 6H). LCMS (M+H)
+363.
表8中的
實例 177-180係使用適當的經取代之吡唑以與實例176類似的多步驟方式來製備的。
實例 181:4-乙氧基-1-甲基-5-(1-(1-(甲磺醯基)哌啶-3-基)-1H-吡唑-4-基)吡啶-2(1H)-酮
步驟 1:3-(4-溴-1H-吡唑-1-基)-1-(甲磺醯基)哌啶
表 8 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
177 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲氧基-苯甲腈 | (CDCl 3, 400 MHz) δ 8.45 (s, 1H), 7.94 (s, 1H), 7.63 (t, J= 8.4 Hz, 1H), 7.45 (s, 1H), 7.41 (d, J= 8.0 Hz, 1H), 6.95 (d, J= 8.8 Hz, 1H), 6.01 (s, 1H), 4.10 (q, J= 7.1 Hz, 2H), 4.02 (s, 3H), 3.57 (s, 3H), 1.52 (t, J= 7.2 Hz, 3H). | 351 | |
178 | 2-氯-6-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.57 (s, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.80-7.75 (m, 2H), 7.70-7.68 (m, 1H), 6.05 (s, 1H), 4.18 (q, J =6.8 Hz 2H), 3.57 (s, 3H), 1.53 (t, J =7.2 Hz, 3H). | 355 | |
179 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲基-苯甲腈 | (CDCl 3, 400 MHz) δ 8.38 (s, 1H), 7.96 (s, 1H), 7.60-7.58 (m, 2H), 7.48 (s, 1H), 7.34-7.32 (m, 1H), 6.13 (s, 1H), 4.13 (q, J =7.2 Hz, 2H), 3.59 (s, 3H), 2.66 (s, 3H), 1.52 (t, J =6.8 Hz, 3H). | 335 | |
180 | 4-乙氧基-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | (CDCl 3, 400 MHz) δ 8.25 (dd, J= 7.6,1.2 Hz, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.79-7.75 (m, 1H), 7.69-7.65 (m, 1H), 7.53 (dd, J= 8.0,1.2 Hz, 1H), 7.45 (s, 1H), 6.01 (s, 1H), 4.09 (q, J= 7.1 Hz, 2H), 3.55 (s, 3H), 3.07 (s, 3H), 1.48 (t, J= 7.2 Hz, 3H). | 374 |
將3-(4-溴-1H-吡唑-1-基)哌啶氫氯化物(300 mg, 1.13 mmol)溶於無水吡啶(5 mL)。在0℃將DMAP(催化)及甲磺醯基氯化物(0.15 mL, 1.7 mmol)添加至溶液。將反應升溫至室溫,並攪拌30分鐘。在減壓下移除溶劑。將剩餘物溶於EtOAc (100 mL),用1N HCl (30 mL×2)、水(30 mL×2)及鹽水(30 mL)洗滌。在減壓下移除有機溶劑,並藉由矽膠管柱層析法(EtOAc/Hex 0至100%)純化殘餘物,得到呈透明固體的標題化合物(300 mg, 87%)。
步驟 2:4-乙氧基-1-甲基-5-(1-(1-(甲磺醯基)哌啶-3-基)-1H-吡唑-4-基)吡啶-2(1H)-酮
用氮氣淨化4-乙氧基-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-2(1H)-酮(50 mg, 0.18 mmol)及3-(4-溴-1H-吡唑-1-基)-1-(甲磺醯基)哌啶(45 mg, 0.22 mmol)、Pd(dppf)Cl
2-DCM (15 mg, 0.02 mmol)及K
3PO
4(76 mg, 0.36 mmol)在1,4-二噁烷(1 mL) 及水(3滴)中之混合物,加蓋並加熱至100℃經歷1小時。將反應冷卻至室溫,經由矽藻土過濾,並藉由製備HPLC(MeCN/水/0.1%甲酸)純化,得到呈白色固體的標題化合物(18 mg, 26%)。
1H NMR (DMSO-d
6, 400 MHz) δ 8.04 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 5.86 (s, 1H), 4.48-4.31 (m, 1H), 4.06 (q, J = 7.0Hz, 2H), 3.76 (dd, J = 4.2, 11.5 Hz, 1H), 3.50 (br d J = 11.6 Hz, 1H), 3.39 (s, 3H), 3.09 (dd, J = 9.9, 11.3 Hz, 1H), 2.92 (s, 3H), 2.89-2.70 (m, 1H), 2.20-1.79 (m, 3H), 1.75-1.59 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H). LCMS (M+H)
+381.
實例 182:2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲腈
步驟 1:4-甲氧基-2-[4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-吡唑-1-基]-苯甲腈
在N
2下向冷卻至0℃的4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑 (505 mg, 2.6 mmol)在DMF (5 mL)中之混合物添加NaH (258 mg, 6.5 mmol)。將反應混合物攪拌15分鐘,繼之以添加2-氟-4-甲氧基-苯甲腈(470 mg, 3.1 mmol)。將反應混合物升溫至45℃並攪拌5小時。將內容物冷卻至室溫,用冰水混合物稀釋,並用DCM (25 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮,得到呈褐色固體的標題化合物,此標題化合物用於後續步驟而無需進一步純化。
步驟 2:2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲腈
將來自步驟1之標題化合物(100 mg, 0.3 mmol)、5-溴-4-乙氧基-1-甲基-1H-吡啶-2-酮(56 mg, 0.24 mmol)、
K3PO
4(127 mg, 0.60 mmol)及Pd(dppf)Cl
2(22 mg, 0.02 mmol)在1,4-二噁烷 (5 mL)及水(1 mL)混合物中之混合物在80℃攪拌隔夜。隨後冷卻至室溫,用冰水混合它稀釋,並用DCM (25 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備TLC DCM/MeOH (15:1)純化殘餘物,得到呈白色固體的標題化合物(14 mg, 0.04 mmol)。
1H NMR (400 MHz, CDCl
3,) 8.50 (s, 1H), 7.95 (s, 1H) 7.69-7.62 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 2.4, 8.8 Hz, 1H), 6.02 (s, 1H), 4.15-4.13 (m, 2H), 3.94 (s, 3H), 3.57 (s, 3H), 1.54 (t, J = 7.2Hz, 3H). LCMS (M+H)
+351.
表9中的
實例 183-184係使用適當的經取代之吡唑以與實例182類似的多步驟方式來製備的。
實例 185:5-(1-苄基-3-硝基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮
表 9 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
183 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈 | (CD 3OD, 400 MHz) δ 8.56 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.86 (d, J= 8.8 Hz, 1H), 7.51 (t, J =8.0 Hz, 2H), 7.32 (m, 2H), 7.19 (d, J= 8.0 Hz, 2H), 7.07 (dd, J= 2.0, 8.4 Hz, 1H), 6.04 (s, 1H), 4.18-4.13 (m, 2H), 3.56 (s, 3H), 1.51 (t, J= 7.2 Hz, 3H). | 413 | |
184 | 4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (DMSO- d 6 , 400 MHz) δ 8.59 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.94 (d, J= 8.4 Hz, 1H), 7.48 (s, 1H), 7.22 (dd, J =8.4 Hz, 2.4 Hz, 1H), 5.92 (s, 1H), 4.11-4.07 (m, 3H), 3.42 (s, 3H), 1.43 (t, J= 7.2 Hz, 3H), 0.88-0.86 (m, 2H), 0.76-0.75 (m, 2H). | 377 |
用氮淨化4-乙氧基-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-2(1H)-酮(60 mg, 0.2 mmol)、1-苄基-4-溴-3-硝基-1H-吡唑 (75 mg, 0.26 mmol)、Pd(dppf)Cl
2-CH
2Cl
2(20 mg, 0.025 mmol)及
K3PO
4(90 mg, 0.43 mmol)在二噁烷 (1 mL)及水(3滴)混合物中之混合物,加蓋並加熱至100℃經歷一小時。將反應冷卻至室溫,經由矽藻土過濾,並藉由製備HPLC(MeCN/水/0.1%甲酸)純化,得到呈白色固體的標題化合物(12 mg, 16%)。
1H NMR (DMSO-d
6, 400 MHz) δ 8.06 (s, 1H), 7.72 (s, 1H), 7.36-7.22 (m, 5H), 5.79 (s, 1H), 5.39 (s, 2H), 3.83 (q, J = 6.9 Hz, 2H), 3.31 (s, 3H), 1.04 (t, J = 7.0 Hz, 3H). LCMS (M+H)
+355.
實例 186:5-(3-胺基-1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮
向0℃的來自實例185之標題化合物(0.5 g, 1.4 mmol)在MeOH (5 mL)中之混合物添加AcOH (0.5 mL)繼之以鋅粉(137 mg, 2.1 mmol)。將反應混合物在室溫下攪拌4小時,並經由矽藻土過濾。經由添加飽和NaHCO
3水溶液將濾液之pH調節至8。將混合物在減壓下濃縮,並藉由矽膠管柱層析法用DCM/MeOH (20:1)溶離來純化,得到呈紅色油的標題化合物。
1H NMR (CD
3OD, 400 MHz) δ 7.61 (s, 1H), 7.53 (s, 1H), 7.35-7.23 (m, 5H), 5.99 (s, 1H), 5.12 (s, 2H), 4.08 (q, J = 7.2 Hz, 2H), 3.51 (s, 3H), 1.38 (t, J = 6.8 Hz, 3H). LCMS (M+H)
+325.
實例 187:N-[1-苄基-4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-基]-乙醯胺
向室溫的來自實例186之標題化合物(100 mg, 0.31 mmol)在DCM (3 mL)中之溶液添加TEA (157 mg, 1.5 mmol)及乙醯基氯化物(30 mg, 0.37 mmol)。將反應混合物在室溫下攪拌隔夜。隨後注入冰水混合物,並用DCM (15 mL)萃取。將有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備HPLC純化殘餘物,得到呈白色固體的標題化合物(41 mg)。
1H NMR (400 MHz, CDCl
3): δ 7.71 (s, 1H), 7.49 (s, 1H), 7.34-7.29 (m, 5H), 5.95 (s, 1H), 5.28 (s, 2H), 4.03 (q, J = 6.8 Hz, 2H), 3.48 (s, 3H), 2.07 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). LCMS (M+H)
+367.
表10中的
實例 188-194係使用適當的烷基或芳烷基鹵化物及硼酸衍生物以與實例106類似的多步驟方式來製備的。
實例 195:5-(1-苄基-1H-吡唑-4-基)-1,6-二甲基-1H-吡啶-2-酮
步驟 1:5-溴-1,6-二甲基-1H-吡啶-2-酮
表 10 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
188 | 5-(1-苄基-1H-吡唑-4-基)-4-(2-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.76 (s, 1H), 7.35-7.30 (m, 4H), 7.19 (s, 1H), 7.13 (d, J =7.2 Hz, 1H), 7.05 (d, J =7.2 Hz, 2H), 7.01-6.97 (m, 2H), 6.81 (d, J= 8.4 Hz, 1H), 6.42 (s, 1H), 5.13 (s, 2H), 3.63 (s, 3H), 3.35 (s, 3H). | 373 | |
189 | 5-(1-苄基-1H-吡唑-4-基)-4-(2,6-二甲基-苯基)-1-甲基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 8.01 (s, 1H), 7.29-7.27 (m, 3H), 7.21 (s, 1H), 7.16 (t, J =8.0 Hz, 1H), 7.04 (d, J =8.0 Hz, 2H), 6.98-6.95 (m, 2H), 6.83 (s, 1H), 6.35 (s, 1H), 5.11 (s, 2H), 3.68 (s, 3H), 1.97 (s, 6H) | 370 | |
190 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-苯基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.82 (s, 1H), 7.39-7.33 (m, 3H), 7.22-7.19 (m, 2H), 7.17 (s, 1H), 7.16 (s, 1H), 6.51 (s, 1H), 4.12 (d, J= 7.6 Hz, 2H), 3.65 (s, 3H), 2.07-1.99 (m, 1H), 1.55-1.47 (m, 1H). 1.27-1.20 (m, 1H). | 342 | |
191 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-(4-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.78 (s, 1H), 7.21 (s, 1H), 7.18 (s, 1H), 7.13 (d, J= 8.8 Hz, 2H), 6.90 (d, J= 8.8 Hz, 2H), 6.49 (s, 1H), 4.16-4.13 (m, 2H), 3.80 (s, 3H), 3.64 (s, 3H), 2.11-2.00 (m, 1H), 1.58-1.49 (m, 1H), 1.30-1.22 (m, 1H). | 372 | |
192 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-(1-甲基-1H-吡唑-4-基)-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.64 (s, 1H), 7.55 (s, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 7.30 (s, 1H), 6.62 (s, 1H), 4.30-4.26 (m, 2H), 3.83 (s, 3H), 3.59 (s, 3H), 2.24-2.16 (m, 1H), 1.65-1.57 (m, 1H), 1.42-1.35 (m, 1H). | 346 | |
193 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮 | (CD 3OD, 400 MHz) δ 7.81 (s, 1H), 7.42 (s, 1H), 7.40 (s, 1H), 7.34-7.27 (m, 4H), 7.14-7.12 (m, 2H), 6.51(s, 1H), 6.41(s, 1H), 6.07 (d, J =9.6 Hz, 1H), 5.26 (s, 2H), 3.63 (s, 3H). | 359 | |
194 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮 | (CD 3OD, 400 MHz) δ 7.76 (s, 1H), 7.45 (s, 1H), 7.42 (d, J =2.8 Hz, 1H), 7.41 (s, 1H), 7.34-7.23 (m, 4H), 7.18-7.16 (m, 2H), 6.53(s, 1H), 6.34 (d, J =9.6 Hz, 1H), 5.28 (s, 2H), 3.61 (s, 3H). | 359 |
將5-溴-6-甲基-1H-吡啶-2-酮(500 mg, 2.66 mmol)、碘甲烷(415 mg, 2.92 mmol)及K
2CO
3(551 mg, 3.99 mmol)在DMF (8 mL)中之混合物在室溫下攪拌隔夜。用DCM (50 mL)及H
2O (50 mL)稀釋反應混合物。將有機層分離,以及用鹽水(50 mL)洗滌,用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由矽膠管柱層析法用PE/EtOAc (5:1)溶離來純化殘餘物,得到呈灰色固體的標題化合物(240 mg, 1.19 mmol)。
1H NMR (300 MHz, CDCl
3): δ 7.39 (d, J = 9.6 Hz, 1H), 6.40 (d, J = 9.6 Hz, 1H), 3.60 (s, 3H), 2.53 (s, 3H). LCMS (M+H)
+202.
步驟 2:5-(1-苄基-1H-吡唑-4-基)-1,6-二甲基-1H-吡啶-2-酮
將1-苄基-4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑 (140 mg, 0.495 mmol )、來自步驟1之標題化合物(100 mg, 0.495 mmol)、Pd(PPh
3)
4(60 mg, 0.049 mmol)及Na
2CO
3(104 mg, 0.990 mmol)在二噁烷 (5 mL)及H
2O (1 mL)中之混合物在N
2下加熱至90℃經歷5小時。將混合物冷卻至室溫,並用EtOAc (60 mL)及H
2O (50 mL)稀釋。將有機相用鹽水(60 mL)洗滌,用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備HPLC純化殘餘物,得到呈黃色油的標題化合物(60 mg, 0.22 mmol)。
1H NMR (400 MHz, CDCl
3): δ 7.48 (s, 1H), 7.39-7.32 (m, 4H), 7.30 (s, 1H), 7.27-7.26 (m, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.48 (d, J = 9.2 Hz, 1H), 5.33 (s, 2H), 3.59 (s, 3H), 2.36 (s, 3H). LCMS (M+H)
+280.
表11中的
實例 196-199係使用適當的吡唑及吡啶酮以與實例195類似的多步驟方式來製備的。
實例 200:4-胺基-5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
步驟 1:(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)胺基甲酸第三丁酯
表 11 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
196 | 3-二甲胺基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 8.02 (s, 1H), 7.76 (s, 1H), 7.50 (d, J= 2.4 Hz, 1H), 7.34-7.23 (m, 5H), 7.01 (d, J= 2.0 Hz, 1H), 5.58 (q, J= 7.2 Hz, 1H), 3.56 (s, 3H), 2.84 (s, 6H), 1.90 (d, J= 6.8 Hz, 3H). | 323 | |
197 | 3-環丙基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 8.01 (s, 1H), 7.74 (s, 1H), 7.72 (d, J= 2.4 Hz, 1H), 7.34-7.22 (m, 6H), 5.57 (q, J= 6.8 Hz, 1H), 3.59 (s, 3H), 2.07-2.03 (m, 1H), 1.89 (d, J= 7.2 Hz, 3H), 0.95-0.91 (m, 2H), 0.72-0.68 (m, 2H). | 320 | |
198 | 1-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-甲酸乙酯 | (CD 3OD, 400 MHz) δ 7.85 (s, 1H), 7.71 (s, 1H), 7.53 (s, 1H), 7.37-7.31 (m, 5H), 5.39 (s, 2H), 4.29 (q, J =6.8 Hz, 2H), 3.58 (s, 3H), 2.13 (s, 3H), 1.29 (t, J =6.8 Hz, 3H). | 352 | |
199 | 2-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-2H-吡唑-3-甲酸乙酯 | (CD 3OD, 400 MHz) δ 7.66-7.63 (m, 2H), 7.50 (s, 1H), 7.29-7.24 (m, 3H), 7.19-7.17 (m, 2H), 5.76 (s, 2H), 4.22 (q, J =7.2 Hz, 2H), 3.59 (s, 3H), 2.13 (s, 3H), 1.15 (t, J =7.2 Hz, 3H). | 352 |
將5-(1-苄基-1H-吡唑-4-基)-4-氯-1-甲基吡啶-2(1H)-酮(300 mg, 1 mmol)、胺基甲酸第三丁酯(229 mg, 2 mmol)、Pd
2(dba)
3(46 mg, 0.05 mmol)、XPhos (72 mg, 0.05 mmol)及Cs
2CO
3(456 mg, 1.4 mmol)在1,4-二噁烷(20 mL)中之溶液在氮下於95℃攪拌隔夜。在冷卻至室溫後,在減壓下移除溶劑。將殘餘物用二氯甲烷稀釋,並用鹽水洗滌。將有機相用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由矽膠管柱層析法(EtOAc)純化殘餘物,得到呈黃色固體的標題化合物(340 mg)。
步驟 2:4-胺基-5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
將來自步驟1之標題化合物(340 mg, 0.89 mmol)在1N HCl中在1,4-二噁烷(20 mL)中之溶液在室溫下攪拌12小時。在減壓下移除溶劑,得到呈黃色固體的標題化合物。
1H NMR (DMSO-d
6, 400 MHz) 8.13 (s, 1H), 7.96 (s, 1H), 7.67 (s, 1H), 7.38-7.30 (m, 5H), 6.45 (s, 1H), 5.37 (s, 2H), 3.58 (s, 3H). LCMS (M+H)
+281.
實例 201:3-((5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)胺基)丙酸
在氮下向實例200之標題化合物(100 mg, 0.36 mmol)在DMF (20 mL)中之溶液添加NaH (28 mg, 0.71 mmol, 60%)。將反應攪拌1小時。添加甲基3-溴丙烯酸酯(89 mg, 0.53 mmol),並將所得混合物攪拌2天。在減壓下濃縮反應內容物,產生殘餘物,殘餘物藉由製備HPLC純化,得到呈白色固體的標題化合物(25 mg, 0.07 mmol)。
1H NMR (CD
3OD, 400 MHz) 7.83 (s, 1H), 7.58 (s, 1H), 7.35-7.28 (m, 6H), 5.60 (s, 1H), 5.37 (s, 2H), 3.43 (s, 3H), 3.37 (t, J = 6.0 Hz, 2H), 2.52 (t, J = 6.0 Hz, 2H). LCMS (M+H)
+353.
實例 202:2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈
步驟 1:2-[4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-吡唑-1-基]-苯甲腈
將NaH (464 mg, 11.6 mmol, 60% in oil)添加至0℃的4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑(1.1 g, 5.8 mmol)在DMF (14 mL)中之溶液。將所得混合物在相同溫度下攪拌0.5小時。將2-氟-苯甲腈(0.9 g, 7.0 mmol)逐滴添加至混合物,並在40℃攪拌7小時。隨後用飽和NH
4Cl (40 mL)中止,並用DCM (30 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並濃縮。在下一步驟中直接使用粗標題化合物(1.6 g, 5.4 mmol)。
步驟 2:2-[4-(4-氯-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈
用N
2淨化步驟1之標題化合物(5.0 g, 17.0 mmol)、5-溴-4-氯-1-甲基-1H-吡啶-2-酮(3.8 g, 17.0 mmol)、Pd(dppf)Cl
2(1.2 g, 1.7 mmol)及
K3PO
4(9.0 g, 42.5 mmol)在1,4-二噁烷/水混合物(90 mL/18 mL)中之混合物,並於80℃攪拌5小時。將混合物用水(50 mL)中止,並用DCM (50 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並濃縮。藉由矽膠管柱層析法用DCM/MeOH (50:1)溶離來純化殘餘物,得到呈黃色固體的標題化合物(1.8 g, 5.8 mmol),產率為34%。
1H NMR (300 MHz, CDCl
3) δ 8.31 (s, 1H), 7.91 (s, 1H), 7.85-7.76 (m, 3H), 7.50-7.46 (m, 2H), 6.81 (s, 1H), 3.61 (s, 3H). LCMS (M+H)
+311.
步驟 3:2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈
將NaH (68 mg, 1.2 mmol, 油中60%)添加至0℃的丙-2-醇(1.1 g, 5.8 mmol)在DMF (8 mL)中之溶液。將所得混合物在相同溫度下攪拌0.5小時。將來自步驟2之標題化合物(124 mg, 0.4 mmol)添加至混合物,並於0℃攪拌0.5小時。隨後升溫至室溫,並攪拌隔夜。將反應用水(10 mL)中止,並用DCM (15 mL*3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並濃縮,得到褐色殘餘物。藉由逆相管柱層析法純化殘餘物,得到呈黃色固體的標題化合物(51 mg, 0.2 mmol)。
1H NMR (CD
3OD, 400 MHz) δ 8.54 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.93-7.91 (m, 1H), 7.84-7.80 (m, 2H), 7.59-7.55 (m, 1H), 6.06 (s, 1H), 4.80-4.74 (m, 1H), 3.57 (s, 3H), 1.44 (d, J = 6.0 Hz, 6H). LCMS (M+H)
+335.
實例 203:2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸
將2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈(30 mg,0.09 mmol)及KOH (50 mg,0.9 mmol)在水(7 mL)中之溶液在110℃攪拌3天。將pH調節至4至6,繼之以用DCM (10 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並濃縮,得到呈黃色固體的標題化合物(16 mg, 0.05 mmol)。
1H NMR (CD
3OD, 400 MHz) δ 8.16 (s, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 6.8 Hz, 1H), 7.58-7.55 (m, 2H), 6.04 (s, 1H), 4.78-4.72 (m, 1H), 3.56 (s, 3H), 1.42 (d, J = 6.0 Hz, 6H). LCMS (M+H)
+354.
實例 204:2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈
將來自實例202步驟2之標題化合物(200 mg, 0.65 mmol)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑(201 mg, 0.97 mmol)、Pd(dppf)Cl
2(48 mg, 0.07 mmol)及
K3PO
4(342 mg, 1.6 mmol)在1,4-二噁烷/水混合物(10 mL/2 mL)中之混合物用N
2純化並在100℃攪拌4小時。將混合物用水(10 mL)中止,並用DCM (7 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並濃縮。藉由製備TLC用DCM/MeOH (30:1)溶離來純化殘餘物,得到呈白色固體的標題化合物(70 mg, 0.2 mmol)。
1H NMR (300 MHz, CD
3OD) δ 8.15 (s, 1H), 7.92 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.84-7.82 (m, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.75 (s, 2H), 7.62-7.60 (m, 1H), 7.53 (s, 1H), 7.47 (s, 1H), 6.67 (s, 1H), 3.84 (s, 3H), 3.61 (s, 3H). LCMS (M+H)
+357.
表12中的
實例 205-246係使用適當的硼酸或酯以與實例204類似的方式來製備的。羧酸係自相應的腈以與實例203類似的方式來製備的。
表 12 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
205 | 2-[4-(1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.10 (s, 1H), 7.93 (s, 1H), 7.87 (d, J= 6.4 Hz ,1H ),7.78 (t, J= 6.8 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.65 (s, 1H), 7.56 (t, J= 7.2 Hz, 1H), 7.39 (d, J= 6.4 Hz, 1H), 6.58 (s, 1H), 6.51 (s, 1H), 6.21 (d, J= 6.4 Hz, 1H), 3.66 (s, 3H). | 370 | |
206 | 2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.12 (s, 1H), 7.90-7.87 (m, 2H), 7.80 (t, J= 6.8 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.65 (s, 1H), 7.58 (t, J= 7.2 Hz, 1H), 7.50 (s, 1H), 7.37 (d, J= 6.4 Hz, 1H), 6.58 (s, 1H), 6.46 (d, J= 6.4 Hz, 1H), 3.65 (s, 3H). | 370 | |
207 | 2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.47 (s, 1H), 8.01 (s, 1H), 7.95-7.93 (m, 1H), 7.87-7.86 (m, 2H), 7.76 (s, 1H), 7.63-7.59 (m, 1H), 6.19 (s, 1H), 3.60 (s, 3H), 1.99-1.96 (m, 1H), 1.14-1.09 (m, 2H), 0.87-0.83 (m, 2H). | 317 | |
208 | 2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | (DMSO- d 6 , 400 MHz) δ 8.07 (s, 1H), 7.78 (dd, J =6.8 Hz, 1.2 Hz, 1H), 7.73 (s, 1H), 7.66 (td, J =6.4 Hz, J =1.2 Hz, 1H), 7.55-7.52 (m, 4H), 7.48 (s, 1H), 6.57 (s, 1H), 3.75 (s, 3H), 3.45 (s, 3H). | 376 | |
209 | 2-[4-(1,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.12 (s, 1H), 7.92-7.90 (m, 2H), 7.85-7.80 (m, 2H), 7.74 (d, J= 8.0 Hz, 1H), 7.70 (s, 1H), 7.59 (t, J= 6.8 Hz, 1H), 7.31 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 6.61 (s, 1H), 6.48 (d, J= 9.6 Hz, 1H), 3.67 (s, 3H), 3.58 (s, 3H). | 384 | |
210 | 2-[4-(5,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.10 (s, 1H), 7.89 (d, J= 8.4 Hz, 1H), 7.86 (s, 1H), 7.81 (t, J= 8.4 Hz, 1H), 7.69 (d, J= 7.6 Hz, 1H), 7.63 (s, 1H), 7.57 (t, J= 7.6 Hz, 1H), 7.35-7.34 (m, 1H), 7.25 (s, 1H), 6.57 (s, 1H), 3.64(s, 3H), 2.02 (s, 3H). | 384 | |
211 | 2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | (CD 3OD, 400 MHz) δ 8.06 (s, 1H), 7.93-7.90 (m, 1H), 7.83 (s, 1H), 7.71-7.67 (m, 2H), 7.61-7.54 (m, 2H), 6.15 (s, 1H), 3.57 (s, 3H), 1.97-1.93 (m, 1H), 1.09-1.04 (m, 2H), 0.83-0.79 (m, 2H). | 336 | |
212 | 2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (DMSO- d 6, 400 MHz,) δ 8.03 (s, 1H), 7.99-7.97 (m, 2H), 7.85-7.81 (m, 1H), 7.61 (d, J= 8.4 Hz, 1H), 7.55 (t, J= 7.6 Hz, 1H), 7.41-7.39 (m, 3H), 7.32 (s, 1H), 7.27-7.25 (m, 2H), 6.37 (s, 1H), 3.53 (s, 3H). | 353 | |
213 | 2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (CDCl 3, 400 MHz) δ 7.77-7.75 (m, 2H), 7.68-7.65 (m, 2H), 7.43-7.42 (m, 2H), 7.30 (s, 1H), 7.16-7.10 (m, 4H), 6.62 (s, 1H), 3.65 (s, 3H), 2.36 (s, 3H). | 367 | |
214 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | (CDCl 3, 400 MHz) δ 7.78-7.76 (m, 2H), 7.72-7.66 (m, 2H), 7.46-7.42 (m, 2H), 7.34-7.32 (m, 3H), 7.18-7.15 (m, 2H), 6.61 (s, 1H), 3.65 (s, 3H). | 387 | |
215 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | (CD 3OD, 400 MHz) δ 7.91 (d, J= 1.6 Hz, 2H), 7.88 (dd, J= 7.6, 1.6 Hz, 1H), 7.79 (td, J= 7.6, 0.8 Hz, 1H), 7.63 (d, J= 7.6 Hz, 1H), 7.56 (td, J= 7.6, 0.8 Hz, 1H), 7.37 (s, 1H), 7.32-7.29 (m, 2H), 7.14-7.10 (m, 2H), 6.56 (s, 1H), 3.67 (s, 3H). | 371 | |
216 | 2-{4-[4-(3-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | (CD 3OD, 400 MHz) δ 7.93-7.86 (m, 3H), 7.79 (t, J= 8.0 Hz, 1H), 7.61 (d, J= 7.6 Hz, 1H), 7.58 (t, J= 7.6 Hz, 1H), 7.40-7.35 (m, 3H), 7.32 (s, 1H), 7.21 (d, J= 7.2 Hz, 1H), 6.59 (s, 1H), 3.67 (s, 3H). | 387 | |
217 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲酸 | (DMSO- d 6 , 400 MHz) δ 13.04 (br, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.98 (dd, J= 7.6, 1.2 Hz, 1H), 7.93 (d, J= 8.4 Hz, 2H), 7.85-7.81 (m, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.56 (td, J= 7.6, 0.8 Hz, 1H), 7.38 (d, J= 8.4 Hz, 2H), 7.34 (s, 1H), 6.43 (s, 1H), 3.35 (s, 3H). | 397 | |
218 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲醯胺 | (DMSO- d 6, 400 MHz) δ 8.08 (s, 1H), 8.03-7.97 (m, 3H), 7.88-7.80 (m, 3H), 7.64 (d, J= 7.6 Hz, 1H), 7.55 (t, J= 7.6 Hz, 1H), 7.41 (s, 1H), 7.35-7.33 (m, 3H), 6.41 (s, 1H), 3.54 (s, 3H). | 396 | |
219 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-N-甲基-苯甲醯胺 | (DMSO- d 6 , 400 MHz) δ 8.49 (q, J= 4.8, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 7.98 (dd, J= 8.0, 1.2 Hz, 1H), 7.85-7.80 (m, 3H), 7.65 (m, d, J= 8.0 Hz, 1H), 7.55 (td, J= 7.6, 0.8 Hz, 1H), 7.35 (d, J= 8.0 Hz, 2H), 7.32 (s, 1H), 6.41 (s, 1H), 3.54 (s, 3H), 2.78 (d, J= 4.4 Hz, 3H). | 410 | |
220 | 2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 300 MHz) δ 8.12 (d, J =5.1 Hz, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.90-7.78 (m, 2H), 7.67-7.57 (m, 2H), 7.48 (s, 1H), 6.8 (dd, J =5.4 Hz, 1.2 Hz, 1H), 6.75 (s, 1H), 6.58 (s, 1H), 3.91 (s, 3H), 3.68 (s, 3H). | 384 | |
221 | 2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.05 (s, 1H), 7.93 (s, 1H), 7.86 (dd, J= 7.6, 1.2 Hz, 1H), 7.80 (td, J= 8.0, 1.6 Hz, 1H), 7.75-7.71 (m, 2H), 7.59 (d, J= 7.2 Hz, 1H), 7.55 (td, J= 7.6, 1.2 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J= 1.6 Hz, 1H), 6.19 (dd, J= 7.2 , 1.6 Hz, 1H), 3.66 (s, 3H), 3.54 (s, 3H). | 384 | |
222 | 2-[4-(1'-環丙基-1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.04 (s, 1H), 7.93 (s, 1H), 7.87-7.85 (m, 1H), 7.82-7.78 (m, 1H), 7.75-7.72 (m, 2H), 7.57-7.53 (m, 2H), 6.55 (s, 1H), 6.49 (d, J= 2.0 Hz, 1H), 6.15 (dd, J= 7.2, 2.4 Hz, 1H), 3.66 (s. 3H), 3.32-3.30 (m, 1H), 1.11-1.06 (m, 2H), 0.95-0.91 (m, 2H). | 410 | |
223 | 2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | (DMSO- d 6, 400 MHz) δ 7.99 (s, 1H), 7.67 (d, J= 7.2 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J= 7.2 Hz, 1H), 7.45 (t, J= 7.6 Hz, 1H), 7.39-7.38 (m, 4H), 7.26-7.23 (m, 2H), 7.14 (s, 1H), 6.35 (s, 1H), 3.52 (s, 3H). | 372 | |
224 | 2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | (DMSO- d 6, 400 MHz) δ 12.87 (br, 1H), 7.96 (s, 1H), 7.70-7.68 (m, 2H), 7.64-7.60 (m, 1H), 7.49-7.40 (m, 2H), 7.20-7.12 (m, 5H), 6.33 (s, 1H), 3.51 (s, 3H), 2.32 (s, 3H). | 386 | |
225 | 2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸 | (CD 3OD, 400 MHz) δ 7.89 (s, 1H), 7.81 (dd, J= 7.6, J= 1.2, 1H), 7.64 (s, 1H), 7.61 7.57 (m, 1H), 7.52-7.48 (m, 1H), 7.43-7.38 (m, 3H), 7.29- 7.26 (m, 2H), 7.17 (s, 1H), 6.55 (s,1H), 3.66 (s, 3H). | 405 | |
226 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | (CD 3OD, 300 MHz) δ 7.92-7.89 (m, 2H), 7.66-7.63 (m, 1H), 7.57-7.52 (m, 2H), 7.42 (d, J= 7.5 Hz, 1H), 7.34-7.30 (m, 2H), 7.23 (s, 1H), 7.16-7.10 (m, 2H), 6.56 (s, 1H), 3.67 (s, 3H). | 390 | |
227 | 2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | (DMSO- d 6, 400 MHz) δ 8.58 (d, J= 4.8 Hz, 1H), 8.50 (s, 1H), 7.80 (s, 1H), 7.76 (s, 1H), 7.71-7.60 (m, 3H), 7.50-7.37 (m, 3H), 7.20 (s, 1H), 6.47 (s, 1H), 3.53 (s, 3H). | 373 | |
228 | 2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | (CD 3OD, 400 MHz) δ 8.12 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.70 (d, J= 8.7 Hz, 1H), 7.57-7.44 (m, 4H), 7.18 (s, 1H), 6.79 (d, J= 8.8 Hz, 1H), 6.58 (s, 1H), 3.93 (s, 3H), 3.67 (s, 3H). | 403 | |
229 | 2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | (DMSO- d 6, 400 MHz) δ 7.94 (s, 1H), 7.71-7.65 (m, 2H), 7.64-7.60 (m, 1H), 7.50-7.42 (m, 2H), 7.19-7.16 (m, 3H), 6.92 (d, J= 8.8 Hz, 2H), 6.33 (s, 1H), 3.77 (s, 3H), 3.51 (s, 3H). | 401 | |
230 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | (CD 3OD, 400 MHz) δ 8.08 (d, J= 2.0 Hz, 1H), 7.89 (s, 1H ), 7.78 (s, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.55-7.44 (m, 4H), 7.18 (s, 1H), 6.75 (d, J= 8.8 Hz, 1H), 6.57 (s, 1H), 4.33 (q, J= 7.2 Hz, 2H), 3.66 (s, 3H), 3.66 (t, J= 7.2 Hz, 3H). | 417 | |
231 | 2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | (DMSO- d 6, 400 MHz) δ 8.10 (d, J= 2.4 Hz, 1H), 7.94 (s, 1H), 7.83 (s, 1H), 7.72-7.70 (m, 1H), 7.64-7.60 (m, 1H), 7.50-7.42 (m, 3H), 7.24 (s, 1H), 6.68 (d, J= 8.4 Hz, 1H), 6.43 (s, 1H), 5.27-5.22 (m, 1H), 3.51 (s, 3H), 1.28 (d, J= 6.0 Hz, 6H). | 431 | |
232 | 2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | (CD 3OD, 400 MHz) δ 8.07 (d, J= 2.4 Hz, 1H), 7.90 (dd, J= 8.0, 1.6 Hz, 1H ), 7.86 (s, 1H), 7.67-7.63 (m, 2H), 7.56-7.53 (m, 2H), 7.43 (d, J= 7.6 Hz, 1H), 7.27 (s, 1H), 6.77 (d, J= 8.4 Hz, 1H), 6.58 (s, 1H), 4.05 (d, J= 6.8 Hz, 2H), 3.65 (s, 3H), 2.11-2.01 (m, 1H), 1.00 (d, J= 6.4 Hz, 6H). | 445 | |
233 | 2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | (CD 3OD, 400 MHz) δ 7.89-7.87 (m, 3H), 7.81-7.76 (m, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.55 (t, J= 7.6 Hz, 1H), 7.35 (s, 1H), 7.20 (d, J= 8.4 Hz, 2H), 6.93 (d, J= 8.8 Hz, 2H), 6.53 (s, 1H), 3.80 (s, 3H), 3.66 (s, 3H). | 382 | |
234 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (DMSO- d 6, 400 MHz) δ 8.16 (s, 1H), 8.09 (s, 1H), 8.00-7.99 (m, 2H), 7.84-7.82 (m, 1H), 7.70-7.68 (m, 1H), 7.58-7.50 (m, 2H), 7.45 (s, 1H), 6.75 (d, J= 8.4 Hz, 1H), 6.44 (s, 1H), 4.32 (q, J= 7.2 Hz, 2H), 3.52 (s, 3H), 1.30 (t, J= 7.2 Hz, 3H). | 398 | |
235 | 2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.05 (d, J= 2.8 Hz, 1H), 7.99 (s, 1H ), 7.89-7.87 (m, 2H), 7.81-7.77 (m, 1H), 7.67-7.65 (m, 1H), 7.58-7.50 (m, 2H), 7.45 (s, 1H), 6.69 (d, J= 8.8 Hz, 1H), 6.58 (s, 1H), 5.28-5.22 (m, 1H), 3.66 (s, 3H), 1.31 (d, J= 6.4 Hz, 6H). | 412 | |
236 | 2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.05 (d, J= 2.4 Hz, 1H), 7.99 (s, 1H), 7.89-7.86 (m, 2H), 7.81-7.77 (m, 1H), 7.68-7.65 (m, 1H), 7.57-7.52 (m, 2H), 7.45 (s, 1H), 6.77 (d, J= 8.4 Hz, 1H), 6.58 (s, 1H), 4.04 (d, J =6.8 Hz, 2H), 3.66 (s, 3H), 2.09-2.02 (m, 1H), 1.00 (d, J= 6.8 Hz, 6H). | 426 | |
237 | 2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.56 (d, J= 4.0 Hz, 1H), 8.47 (s, 1H), 7.97-7.94 (m, 2H), 7.88-7.77 (m, 3H), 7.64-7.42 (m, 3H), 7.42 (s, 1H), 6.63 (s, 1H), 3.68 (s, 3H). | 354 | |
238 | 2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (CDCl 3, 300 MHz) 8.11 (d, J= 2.1 Hz, 1H), 7.85 (s, 1H), 7.79-7.71 (m, 3H), 7.47-7.37 (m, 4H), 6.72 (d, J= 8.4 Hz, 1H), 6.64 (s, 1H), 3.96 (s, 3H), 3.66 (s, 3H). | 384 | |
239 | 2-(4-(1,1',5-三甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.09 (s, 1H), 7.90-7.87 (m, 2H), 7.81 (dd, J= 7.6, 7.6 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.66-7.62 (m, 2H), 7.57 (dd, J= 7.6, 7.6 Hz, 1H), 7.16 (s, 1H), 6.58 (s, 1H), 3.65 (s, 3H), 3.56 (s, 3H), 2.01 (s, 3H). | 398 | |
240 | 2-(4-(5-氟-1'-甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 400 MHz) δ 8.27 (s, 1H), 8.00 (dd, J= 7.6, 1.2 Hz, 1H), 7.94 (s, 1H), 7.89-7.85 (m, 1H), 7.75-7.71 (m, 2H), 7.59-7.56 (m, 1H), 7.25 (d, J= 1.6 Hz, 1H), 7.16 (dd, J= 11.4, 2.2 Hz, 1H), 6.47 (s, 1H), 3.49 (s, 3H). | 388 | |
241 | 2-{4-[4-(3-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | (CD 3OD, 400 MHz) δ 7.92 (s, 1H), 7.88 (s, 1H), 7.86 (s, 1H), 7.77-7.75 (m, 1H), 7.59-7.75 (m, 2H), 7.36 (s, 1H), 7.30 (t, J= 8.0 Hz, 1H), 6.94 (dd, J= 2.8, 8.8 Hz, 1H), 6.84 (d, J= 8.0 Hz, 1H), 6.79 (s, 1H), 6.55 (s, 1H), 3.72 (s, 3H), 3.67 (s, 3H). | 383 | |
242 | 2-(4-(5-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.25 (d, J =2.8 Hz, 1H), 8.06 (d, J =1.6 Hz, 1H), 7.94 (s, 1H), 7.90 (s, 1H), 7.87-7.76 (m, 2H), 7.67 (s, 1H), 7.57-7.53 (m, 1H), 7.44 (s, 1H), 7.24-7.23 (m, 1H), 6.65 (s, 1H), 3.82 (s, 3H), 3.70 (s, 3H). | 384 | |
243 | 2-(4-(4-(3,4-二甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 7.30 (s, 1H), 7.88-7.87 (m, 2H), 7.81-7.77 (m, 1H),7.62 (d, J =7.6 Hz, 1H), 7.57-7.53 (m, 1H), 7.38 (s, 1H), 6.98 (d, J =8.8 Hz, 1H), 6.91-6.88 (m, 1H), 6.77 (s, 1H), 6.57 (s, 1H), 3.84 (s, 3H), 3.67 (s, 3H), 3.66 (s, 3H). | 413 | |
244 | 2-{4-[4-(2-甲氧基-嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | (CD 3OD + CDCl 3, 400 MHz) δ 8.47 (s, 2H), 8.03 (s, 1H), 7.88 (s, 1H), 7.84 (dd, J =8.0 Hz, J =1.2 Hz, 1H), 7.79 (td, J =8.0 Hz, J =1.2 Hz, 1H), 7.73 (dd, J =8.0 Hz, J =0.8 Hz, 1H), 7.56 (s, 1H), 7.54 (dd, J =7.6 Hz, J =0.8 Hz, 1H), 6.66 (s, 1H), 4.03 (s, 3H), 3.68 (s, 3H). | 385 | |
245 | 2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz,) δ 8.18 (br, 2H), 8.10 (s, 1H), 7.88-7.80 (m, 2H), 7.78 (s, 1H), 7.73 (d, J =7.6 Hz, 1H), 7.57 (s, 1H), 7.54 (dd, J =7.6 Hz, 1.2 Hz, 1H), 6.59 (s, 1H), 3.66 (s, 3H), 2.93 (s, 3H). | 384 | |
246 | 2-{4-[1-甲基-6-側氧-4-(3,4,5-三甲氧基-苯基)-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | (CD 3OD, 400 MHz) δ 7.76 (d, J =4.4 Hz, 2H), 7.76 (d, J =7.6 Hz, 1H), 7.79 (t, J =2.8 Hz, 1H), 7.62 (t, J =7.6 Hz, 1H), 7.56 (t, J =6.8 Hz, 1H), 7.44 (s, 1H), 6.61 (s, 1H), 6.55 (s, 2H) 3.77 (s, 3H), 3.73 (s, 6H), 3.67 (s, 3H). | 443 |
表13中的
實例 247-249係自相應的腈以與實例203類似的方式來製備的。
實例 250:5-(1-(2-氯苯基)-1H-吡唑-4-基)-1-甲基-4-((1-甲基-1H-吡唑-4-基)甲氧基)吡啶-2(1H)-酮
步驟 1:5-溴-1-甲基-4-((1-甲基-1H-吡唑-4-基)甲氧基)吡啶-2(1H)-酮
表 13 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
247 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲酸 | (DMSO- d 6, 400 MHz) δ 8.23 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.73 (d, J =8.8 Hz, 1H), 7.11 (d, J =2.4 Hz, 1H), 7.05 (dd, J =8.8 Hz, 2.8 Hz, 1H), 5.89 (s, 1H), 4.08 (q, J =7.2 Hz, 2H), 3.87 (s, 3H), 3.41 (s, 3H), 1.40 (t, J =6.8 Hz, 3H). | 370 | |
248 | 4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | (CD 3OD+CDCl 3, 400 MHz) δ 8.07 (s, 1H), 7.97-7.95 (m, 2H), 7.82 (s, 1H), 7.20-7.18 (m, 2H), 6.03 (s, 1H), 4.15 (q, J= 7.2 Hz, 2H), 3.90-3.87 (m, 1H), 3.58 (s, 3H), 1.51 (t, J= 7.2 Hz, 3H), 0.88-0.85 (m, 2H), 0.82-0.80 (m, 2H). | 396 | |
249 | 2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸 | (DMSO- d 6 , 400 MHz) δ 12.96 (br s, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.69 (d, J= 7.3 Hz, 1H), 7.67-7.54 (m, 2H), 7.54-7.32 (m, 1H), 5.90 (s, 1H), 4.09 (q, J= 7.0 Hz, 2H), 3.41 (s, 3H), 1.41 (t, J=7.0 Hz, 3H) | 340 |
向5-溴-4-氯-1-甲基吡啶-2(1H)-酮(100 mg, 0.45 mmol)及(1-甲基-1H-吡唑-4-基)甲醇(150 mg, 1.35 mmol)在THF (2 mL)中之溶液添加NaH (90 mg, 2.25 mmol)。在70℃加熱反應經歷2小時。隨後冷卻至室溫,用EtOAc (10 mL)稀釋,並依次用含水HCl (1N)、水及鹽水洗滌。將有機相用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由矽膠管柱層析法(DCM至5% MeOH/DCM)純化殘餘物,得到呈白色固體的標題化合物(80 mg, 60%)。
步驟 2:5-(1-(2-氯苯基)-1H-吡唑-4-基)-1-甲基-4-((1-甲基-1H-吡唑-4-基)甲氧基)吡啶-2(1H)-酮
將(1-(2-氯苯基)-1H-吡唑-4-基)硼酸(50 mg, 0.23 mmol)及5-溴-1-甲基-4-((1-甲基-1H-吡唑-4-基)甲氧基)吡啶-2(1H)-酮(80 mg, 0.27 mmol)、Pd(PPh
3)
4(30 mg, 0.03 mmol)及Na
2CO
3(2M, 0.25 ml)在二噁烷 (1 mL)中之混合物在微波反應器中加熱至120℃經歷10分鐘。將反應冷卻,經由矽藻土過濾,並藉由製備HPLC(10-100% ACN/水)純化,得到呈白色固體的標題化合物(24 mg, 27%)。
1H NMR (DMSO-d
6, 400 MHz) δ 8.24 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.67-7.65 (m, 1H), 7.61-7.59 (m, 1H), 7.50 (d, J = 1.0 Hz, 1H), 7.48-7.45 (m, 2H), 6.06 (s, 1H), 5.02 (s, 2H), 3.82 (s, 3H), 3.42 (s, 3H). LCMS (M+H)
+397.
表14中的
實例 251-253係使用適當的經取代之吡唑及醇類以與實例250類似的多步驟方式來製備的。
表 14 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
251 | 3-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (DMSO- d 6 , 400 MHz) δ 8.67 (s, 1H), 8.30 (s, 1H), 8.18-8.07 (m, 1H), 8.02 (s, 1H), 7.98 (s, 1H), 7.80-7.55 (m, 2H), 5.85 (s, 1H), 4.04 (q, J= 7.0 Hz, 2H), 3.35 (s, 3H), 1.35 (t, J= 7.0 Hz, 3H) | 321 | |
252 | 4-乙氧基-5-(1-(2-氟苯基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | (CD 3OD, 400 MHz) δ 8.39 (d, J= 2.7 Hz, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.83-7.78 (m, 1H), 7.52-7.28 (m, 3H), 6.04 (s, 1H), 4.16 (q, J= 7.0 Hz, 2H), 3.57 (s, 3H), 1.51 (t, J= 7.0 Hz, 3H) | 314 | |
253 | 4-乙氧基-1-甲基-5-(1-(吡啶-2-基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | (DMSO- d 6 , 400 MHz) δ 8.86 (s, 1H), 8.50 (m, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.03-7.92 (m, 2H), 7.36 (ddd, J= 1.2, 4.9, 7.2 Hz), 5.92 (s,1H), 4.12 (q, J= 7.0 Hz, 2H), 3.43 (s, 3H), 1.43 (t, J= 7.0 Hz) | 297 |
表15中的
實例 254-259係藉由使用適當的2-氟苯甲腈衍生物及用相應的3-烷基-5-溴吡啶酮代替5-溴-4-氯-1-甲基-1H-吡啶-2-酮以與實例202步驟2類似的方式來製備的。羧酸係自相應的腈以與實例203類似的方式來製備的。
表 15 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
254 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (DMSO- d 6, 400 MHz) δ 8.70 (s, 1H), 8.19 (s, 1H), 8.04-8.01 (m, 2H), 7.89-7.81 (m, 3H), 7.58 (t, J= 7.6 Hz, 1H), 3.50 (s, 3H), 2.07 (s, 3H). | 291 | |
255 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | (DMSO- d 6, 400 MHz) δ 8.18 (s, 1H), 7.94-7.86 (m, 3H), 7.73-7.66 (m, 2H), 7.57-7.54 (m, 2H), 3.62 (s, 3H), 2.18 (s, 3H). | 310 | |
256 | 2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (CDCl 3, 400 MHz) δ 8.22 (s, 1H), 7.91 (s, 1H), 7.82 (t, J= 8.4Hz, 2H), 7.74 (t, J= 7.8Hz, 1H), 7.46 (t, J= 7.6Hz, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 3.62 (s, 3H), 2.63 (q, J= 7.5 Hz, 2H), 1.24 (t, J= 7.4 Hz, 3H). | 305 | |
257 | 2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | (DMSO-d 6, 400 MHz) δ 12.90 (s, 1H), 8.47 (s, 1H), 8.01 (s, 1H), 7.99 (d, J= 2.4Hz, 1H), 7.73 (dd, J= 7.6Hz, 0.8 Hz, 1H), 7.69-7.60 (m, 3H), 7.50 (td, J= 7.6Hz, 0.8 Hz, 1H), 3.49 (s, 3H), 2.47 (q, J= 7.5 Hz, 2H), 1.15 (t, J= 7.4 Hz, 3H). | 324 | |
258 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈 | (DMSO- d 6, 400 MHz) δ 8.72 (s, 1H), 8.17 (s, 1H), 8.03-7.97 (m, 2H), 7.70 (s, 1H), 7.51-7.49 (m, 3H), 7.42-7.24 (m, 3H), 7.21 (s, 1H), 3.49 (s, 3H), 2.07 (s, 3H). | 383 | |
259 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲酸 | (CD 3OD, 400 MHz) δ 8.12 (s, 1H), 7.96-7.92 (m, 2H), 7.84 (s, 1H), 7.70 (s, 1H), 7.47-7.43 (m, 2H), 7.26-7.22 (m, 1H), 7.15-7.13 (m, 2H), 7.09-7.07 (m, 2H), 3.61 (s, 3H), 2.16 (s, 3H). | 402 |
表16中的
實例 260-280係使用適當的經取代之2-氟苯甲腈及硼酸衍生物以與實例204類似的方式來製備的。羧酸係自相應的腈以與實例203類似的方式來製備的。
實例 281:2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈
表 16 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
260 | 4-甲氧基-2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.12 (s, 1H), 7.87 (s, 1H), 7.78 (d, J= 8.8 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J= 2.4 Hz, 1H), 7.38 (dd, J= 9.6 Hz, 2.8 Hz, 1H), 7.24 (d, J =2.0 Hz, 1H), 7.11 (dd, J =9.6 Hz, 2.8 Hz, 1H), 6.58 (s, 1H), 6.47 (d, J= 9.6 Hz, 1H), 3.93 (s, 3H), 3.64 (s, 3H). | 400 | |
261 | 4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 7.94 (s, 1H), 7.83 (s, 1H), 7.78-7.76 (m, 1H), 7.45-7.39 (m, 3H), 7.35 (s, 1H), 7.33-7.27 (m, 2H), 7.11-7.07 (m, 2H), 7.03-6.54 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H). | 383 | |
262 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | (CD 3OD, 400 MHz) δ 7.92 (s, 2H), 7.77 (d, J= 9.2 Hz, 1H), 7.42-7.37 (m, 3H), 7.28-7.26 (m, 2H), 7.14-7.08 (m, 2H), 6.56 (s, 1H), 3.92 (s, 3H), 3.67 (s, 3H). | 416 | |
263 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | (CD 3OD, 400 MHz) δ 7.91 (d, J= 3.6 Hz, 2H), 7.77 (d, J= 8.8 Hz, 1H), 7.36 (s, 1H), 7.33-7.29 (m, 2H), 7.15-7.08 (m, 4H), 6.56 (s, 1H), 3.92 (s, 3H), 3.67 (s, 3H). | 401 | |
264 | 4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.07 (d, J= 2.4 Hz, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.77 (d, J= 8.8 Hz, 1H), 7.54 (dd, J= 8.4, 2.4 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J= 2.4 Hz, 1H), 7.09 (dd, J= 9.2, 2.8 Hz, 1H), 6.78 (d, J= 8.4 Hz, 1H), 6.58 (s, 1H), 3.92 (s, 3H), 3.91 (s, 3H), 3.66 (s, 3H). | 414 | |
265 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲腈 | (CD 3OD, 400 MHz) δ 8.05 (s, 1H), 7.99 (s, 1H), 7.89 (s, 1H), 7.77 (d, J =8.4 Hz, 1H), 7.53 (d, J =8.4 Hz, 1H), 7.44 (s, 1H), 7.17 (s, 1H), 7.09 (d, J =8.4 Hz, 1H), 6.76 (d, J =8.8 Hz, 1H), 6.58 (s, 1H), 4.33 (q, J =7.2 Hz, 2H), 3.92 (s, 3H), 3.64 (s, 3H), 1.36 (t, J =7.2 Hz, 3H). | 428 | |
266 | 4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.13 (d, J =5.2 Hz, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.76 (d, J =8.8 Hz, 1H), 7.49 (s, 1H), 7.17 (d, J =2.8 Hz, 1H), 7.08 (dd, J =8.8 Hz, J =2.8 Hz, 1H), 6.87 (dd, J =5.2 Hz, J =1.2 Hz, 1H), 6.83 (s, 1H), 6.58 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.67 (s, 3H). | 414 | |
267 | 4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | (DMSO- d 6, 400 MHz) δ 12.63 (br, 1H), 7.98 (s, 1H), 7.69 (d, J= 8.8 Hz, 1H), 7.52 (s, 1H), 7.40-7.38 (m, 3H), 7.26-7.23 (m, 2H), 7.15 (s, 1H), 7.02 (dd, J= 9.2, 2.8 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 6.35 (s, 1H), 3.83 (s, 3H), 3.52 (s, 3H). | 402 | |
268 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸 | (DMSO-d 6, 400 MHz) δ 7.96 (s, 1H), 7.71 (d, J =8.4 Hz, 1H), 7.67 (s, 1H), 7.44 (d, J=8.4Hz, 2H), 7.27-7.25 (m, 2H), 7.17 (s, 1H), 7.04 (dd, J= 8.4Hz, J=6.0 Hz, 1H), 6.89 (d, J=2.8 Hz, 1H), 6.39 (s, 1H), 3.85 (s, 3H), 3.58 (s, 3H). | 435 | |
269 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸 | (CD 3OD, 400 MHz) δ 7.89 (s, 1H), 7.79 (d, J =8.8 Hz, 1H), 7.59 (s, 1H), 7.33-7.29 (m, 2H), 7.14-7.01 (m, 4H), 6.93 (d, J =2.4 Hz, 1H), 6.54 (s, 1H), 3.86 (s, 3H), 3.66 (s, 3H). | 420 | |
270 | 4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | (DMSO- d 6, 400 MHz) δ 8.14 (d, J= 2.0 Hz, 1H), 7.93 (s, 1H), 7.76 (s, 1H), 7.72 (d, J= 8.8 Hz, 1H), 7.46 (dd, J= 8.4, 2.4 Hz, 1H), 7.23 (s, 1H), 7.05 (dd, J= 8.8, 2.8 Hz, 1H), 6.92 (d, J= 2.4 Hz, 1H), 6.77 (d, J= 8.8 Hz, 1H), 6.43 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.51 (s, 3H). | 433 | |
271 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲酸 | (CD 3OD, 400 MHz) δ 8.08 (s, 1H), 7.90-7.87 (m, 2H), 7.62 (s, 1H), 7.53 (dd, J =8.8, 6.4 Hz, 1H), 7.25 (s, 1H), 7.07 (dd, J =8.8, 2.8 Hz, 1H), 6.94 (s, 1H), 6.76 (d, J =8.8 Hz, 1H), 6.57 (s, 1H), 4.36 (q, J =7.2 Hz, 2H), 3.88 (s, 3H), 3.66 (s, 3H), 1.36 (t, J =7.2 Hz, 3H). | 447 | |
272 | 4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲酸 | (DMSO-d 6, 400 MHz) δ 8.12 (d, J =6.4 Hz, 1H), 7.98 (s, 1H), 7.77 (s, 1H), 7.71 (d, J =8.4 Hz, 1H), 7.24 (s, 1H), 7.04 (dd, J =8.8, 1.8 Hz, 1H), 6.89 (d, J =2.4 Hz, 1H), 6.77-6.76 (m, 2H), 6.42 (s, 1H), 3.85 (s, 6H), 3.53 (s, 3H). | 433 | |
273 | 2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-6-氟-苯甲腈 | (CD 3OD, 400 MHz) δ 6.63 (s, 1H), 6.46 (s, 1H), 6.38-6.32 (m, 1H), 6.26 (s, 1H), 6.14 (d, J= 7.6 Hz, 2H), 5.91 (t, J= 8.8 Hz, 1H), 5.10 (s, 1H), 5.03 (d, J= 2.0 Hz, 1H), 4.73 (dd, J= 6.8, 4.8 Hz, 1H), 2.20 (s, 3H), 2.07 (s, 3H). | 401 | |
274 | 2-氟-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.08-8.06 (m, 2H), 7.90 (s, 1H), 7.83-7.80 (m, 1H), 7.56-7.52 (m, 2H), 7.46 (s, 1H), 7.39 (t, J =8.0 Hz, 1H), 6.78 (d, J =8.8 Hz, 1H), 6.58 (s, 1H), 3.92 (s, 3H), 3.67 (s, 3H). | 402 | |
275 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-6-氟-苯甲腈 | (CD 3OD, 300 MHz) δ 8.00 (s, 1H), 7.93 (s, 1H), 7.86-7.80 (m, 1H), 7.50 (d, J =6.3 Hz, 1H), 7.44-7.40 (m, 4H), 7.30-7.26 (m, 2H), 6.57 (s, 1H), 3.68 (s, 3H). | 405 | |
276 | 2-氯-6-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 6.59 (s, 1H), 6.44 (s, 1H), 6.30-6.17 (m, 4H), 6.11 (d, J =6.8 Hz, 1H), 5.08 (s, 1H), 5.02 (s, 1H), 4.70 (d, J =6.8 Hz, 1H), 2.18 (s, 3H), 2.06 (s, 3H). | 418 | |
277 | 2-氯-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CD 3OD, 400 MHz) δ 8.09 (d, J =2.0 Hz, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.77 (t, J =8.4 Hz, 1H), 7.68 (d, J =7.2 Hz, 1H), 7.63 (d, J =8.0 Hz, 1H), 7.54 (dd, J =8.4, 2.4 Hz, 1H), 7.47 (s, 1H), 6.78 (d, J =8.8 Hz, 1H), 6.59 (s, 1H), 3.93 (s, 3H), 3.68 (s, 3H). | 418 | |
278 | 2-氟-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (DMSO, 300 MHz) δ 8.21 (s, 1H), 8.02 (s, 1H), 7.99-7.84 (m, 1H), 7.61-7.48 (m, 2H), 7.37 (s, 1H), 7.15 (d, J= 7.4 Hz, 1H), 6.76 (d, J= 7.4 Hz, 2H), 6.44 (s, 1H), 3.68 (s, 3H), 3.54 (s, 3H), 2.16 (s, 3H). | 415 | |
279 | 2-氯-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 400 MHz) δ 8.16 (s, 1H), 8.00 (s, 1H), 7.86 (t, J = 8.2 Hz, 1H), 7.78 (dd, J = 8.2, 1.0 Hz, 1H), 7.65 (dd, J = 8.2, 1.1 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.82-6.73 (m, 2H), 6.43 (s, 1H), 3.67 (s, 3H), 3.53 (s, 3H), 2.16 (s, 3H). | 431 | |
280 | 2-氯-6-(4-(4-(2-乙基嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.67 (s, 2H), 8.10 (s, 1H), 7.98 (s, 1H), 7.79 (t, J= 8.2 Hz, 1H), 7.74 - 7.66 (m, 2H), 7.63 (s, 1H), 6.71 (s, 1H), 3.71 (s, 3H), 3.00 (q, J= 7.6 Hz, 2H), 1.37 (t, J= 7.6 Hz, 3H). | 417 |
將5-溴-4-乙氧基-1-甲基吡啶-2(1H)-酮(30 mg, 0.13 mmol)及(2-(4-(4,4,5,5- 四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑-1-基)苯甲腈(50 mg, 0.16 mmol)溶於無水二噁烷(1 mL)。向此溶液添加Pd(PPh
3)
4(15 mg, 0.013 mmol)及Na
2CO
3(2 M,0.15 mL)。將反應在微波反應器中於120℃加熱20分鐘。在完成後,在減壓下移除溶劑。將殘餘物重新溶於MeOH (3 mL),經由矽藻土過濾,並藉由製備HPLC(10至100% MeCN/水/0.1%甲酸)純化,得到呈白色固體的標題化合物(8 mg, 19%)。
1H NMR (CD
3OD, 400 MHz) δ 8.55 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.92-7.90 (m, 1H), 7.83-7.80 (m, 2H), 7.59-7.55 (m, 1H), 6.05 (s, 1H), 4.21 (q, J = 6.9 Hz, 2H), 1.54 (t, J = 6.9 Hz, 3H). LCMS (M+H)
+321.
實例 282:2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺
向來自實例281之標題化合物(30 mg, 0.009 mmol)添加TFA (1 mL)。將反應加熱至回流經歷1小時,並隨後冷卻至室溫。移除溶劑。將殘餘物溶於DMF (3 mL),經由矽藻土過濾,並藉由製備HPLC(10至100% MeCN/水/0.1%甲酸)純化,得到呈白色固體的標題化合物(10 mg, 32%)。
1H NMR (DMSO-d
6, 400 MHz) δ 8.27 (s, 1H), 8.09 (s, 1H), 8.03 (s, 1H), 7.86 (s, 1H), 7.66-7.39 (m, 4H), 5.90 (s, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.42 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H). LCMS (M+H)
+339.
實例 283:2-(4-(1-甲基-4-(2-嗎啉基乙氧基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈
藉由用5-溴-1-甲基-4-(2-嗎啉基乙氧基)吡啶-2(1H)-酮替換5-溴-4-乙氧基-1-甲基吡啶-2(1H)-酮以與實例281類似的方式來製備標題化合物。
1H NMR (DMSO-d
6, 400 MHz) δ 8.71 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.17 (s, 1H), 8.05 (dd, J = 1.3, 7.8 Hz, 1H), 7.93-7.82 (m, 1H), 7.83-7.71 (m, 1H), 7.61 (td, J = 1.2, 7.6 Hz, 1H), 5.96 (s, 1H), 4.16 (t, J = 5.4 Hz, 2H), 3.37-3.54 (m, 2H), 3.44 (s, 3H), 2.78 (t, J = 5.4 Hz, 2H), 2.48-2.41 (m, 1H), 2.46-2.32 (m, 3H). LCMS (M+H)
+406.
實例 284:5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮
步驟 1:4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-吡唑-1-甲酸第三丁酯
向4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡唑 (5.0 g, 25.8 mmol)及DMAP (3.8 g, 31.1 mmol)在DMF (30 mL)中之溶液添加0℃的(Boc)
2O (8.4 g, 38.5 mmol)。將混合物在室溫下攪拌隔夜。將反應用NH
4Cl (150 mL)稀釋,並用DCM (200 mL)萃取。將有機層用含水1N HCl洗滌,用Na
2SO
4乾燥,過濾,並在減壓下濃縮,得到呈白色固體的標題化合物(7.4 g, 25.2 mmol, 99%)。
1H NMR (CD
3OD, 400 MHz) δ 8.36 (s, 1H), 7.87 (s, 1H), 1.58 (s, 9H), 1.27 (s, 12H).
步驟 2:4-氯-1-甲基-5-(1H-吡唑-4-基)-1H-吡啶-2-酮
將來自步驟1之標題化合物(2.0 g, 6.8 mmol)、5-溴-4-氯-1-甲基-1H-吡啶-2-酮(1.3 g, 5.9 mmol)、Pd(dppf)Cl
2(500 mg, 0.68 mmol)及K
2CO
3(2.3 g, 16.7 mmol)在二噁烷/水混合物(30 mL/6 mL)中之混合物在N
2下於85℃攪拌隔夜。將反應在減壓下濃縮,並藉由矽膠管柱層析法(DCM/MeOH=20:1)純化,得到呈黃色固體的標題化合物(540 mg, 2.6 mmol)。
步驟 3:4-氯-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮
在N
2下向0℃的來自步驟2之標題化合物(540 mg, 2.58 mmol)在DMF (25 mL)中之溶液添加NaH (60 %, 207 mg, 5.18 mmol)。在30分鐘後,添加1-氟-2-甲磺醯基-苯(674 mg, 3.87 mmol)在DMF (5 mL)中之溶液,並將混合物在室溫下攪拌隔夜。將反應混合物用NH
4Cl (80 mL)中止,並用DCM (120 mL)萃取。將有機相用Na
2SO
4乾燥,過濾,並濃縮。藉由矽膠管柱層析法(100% EtOAc)純化殘餘物,得到呈黃色固體的標題化合物(280 mg, 0.77 mmol)。
1H NMR (CDCl
3, 400 MHz) δ 8.24 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.99 (s, 1H), 7.86 (s, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.56 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.46 (s, 1H), 6.78 (s, 1H), 3.58 (s, 3H), 3.10 (s, 3H).
步驟 4:5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮
將來自步驟3之標題化合物(30 mg, 0.08 mmol)、(1-甲基-2-側氧-1,2-二氫吡啶-4-基)硼酸(20 mg, 0.13 mmol)、Pd(PPh
3)
4(10 mg, 0.009 mmol)及Na
2CO
3(22 mg, 0.21 mmol)在二噁烷/水混合物(10 mL/2 mL)中之混合物在N
2下於90℃攪拌隔夜。將混合物冷卻至室溫,並用DCM (60 mL)萃取。將有機層用Na
2SO
4乾燥,過濾,並濃縮。藉由製備HPLC純化殘餘物,得到呈白色固體的標題化合物(9 mg, 0.02 mmol)。
1H NMR (CD
3OD, 400 MHz) δ 8.17 (dd, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.90 (s, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.77-7.73 (m, 2H), 7.63-7.61 (m, 2H), 7.51 (dd, J = 8.0 Hz, J = 0.8 Hz, 1H), 6.56 (s, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.22 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 3.66 (s, 3H), 3.56 (s, 3H), 3.05 (s, 3H). LCMS (M+H)
+437。
表17中的
實例 285-287係使用步驟4中的適當硼酸或酯以與實例284類似的多步驟方式來製備的。
實例 288:N-氰基-2-(4-(4-(4-氟苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺
表 17 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
285 | 5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-6-甲氧基-1'-甲基-1'H-[3,4']聯吡啶基-2'-酮 | (CD 3OD, 400 MHz) δ 8.09 (dd, J =8.0 Hz, J =1.6 Hz, 1H), 8.01 (d, J =2.8 Hz, 1H), 7.77 (s, 1H), 7.74 (t, J =7.6 Hz, 1H), 7.66 (t, J =7.2 Hz, 1H), 7.63 (s, 1H), 7.45 (dd, J =8.8 Hz, J =2.8 Hz, 1H), 7.40 (d, J =7.6 Hz, 1H), 7.25 (s, 1H), 6.87 (d, J =8.4 Hz, 1H), 6.49 (s, 1H), 3.83 (s, 3H), 3.56 (s, 3H), 3.05 (s, 3H). | 437 | |
286 | 4-(4-氯-苯基)-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 8.18 (d, J =8.0 Hz, 1H), 7.87 (s, 1H), 7.84 (t, J =7.6 Hz, 1H), 7.75 (t, J =8.0 Hz, 1H), 7.66 (s, 1H), 7.46 (d, J =7.6 Hz, 1H), 7.40-7.38 (m, 2H), 7.29-7.27 (m, 3H), 6.56 (s, 1H), 3.66 (s, 3H), 3.15 (s, 3H). | 440 | |
287 | 5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮 | (CD 3OD, 400 MHz) δ 8.18 (dd, J =7.6 Hz, J =1.2 Hz, 1H), 7.87-7.83 (m, 2H), 7.80 (s, 1H), 7.77-7.73 (m, 2H), 7.54-7.52 (m, 2H), 7.36 (dd, J =9.6 Hz, J =2.8 Hz, 1H), 6.58 (s, 1H), 6.48 (d, J =9.2 Hz, 1H), 3.64 (s, 3H), 3.57 (s, 3H), 3.25 (s, 3H). | 437 |
將2-(4-(4-(4-氟苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸(53 mg, 0.14 mmol)、氰胺(12 mg, 2 eq)、HATU (62 mg, 1.2 eq)及TEA (34 mg, 2.5 eq)在DMF (10 mL)中之混合物在室溫下攪拌六小時。將混合物在減壓下濃縮,並藉由製備HPLC純化,得到呈白色固體的標題化合物(26 mg,46%產率)。
1H NMR (DMSO-d
6, 400 MHz) δ 7.97 (s, 1H), 7.87 (s, 1H), 7.63-7.60 (m, 2H), 7.49-7.44 (m, 2H), 7.31-7.28 (m, 2H), 7.22-7.18 (m, 3H), 6.38 (s, 1H), 3.52 (s, 3H). LCMS (M+H)
+414.
表18中的
實例 289-296係使用適當的羧酸以與實例288類似的多步驟方式來製備的。
實例 297:5-(1-(2-(1H-四唑-5-基)苯基)-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基吡啶-2(1H)-酮
表 18 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
289 | N-氰基-2-(4-(1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | (CD 3OD, 400 MHz) δ 7.86 (s, 1H), 7.68-7.66 (m, 3H), 7.53-7.51 (m, 3H), 7.46-7.44 (m, 1H), 7.43 (s, 1H), 6.70 (s, 1H), 3.89 (s, 3H), 3.60 (s, 3H). | 400 | |
290 | N-氰基-2-(4-(4-(4-甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | (DMSO- d 6 , 400 MHz) δ 7.93 (s, 1H), 7.84 (s, 1H), 7.65 (t, J= 8.0 Hz, 1H), 7.60 (d, J= 7.6 Hz, 1H), 7.51 (t, J= 7.6 Hz, 2H), 7.23 (d, J= 8.4 Hz, 2H), 7.12 (s, 1H), 6.99 (d, J= 8.4 Hz, 2H), 6.49 (s, 1H), 3.79 (s, 3H), 3.58 (s, 3H). | 426 | |
291 | 2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-N-氰基苯甲醯胺 | (DMSO- d 6 , 400 MHz) δ 7.99-7.98 (m, 2H), 7.68-7.63 (m, 2H), 7.53-7.47 (m, 2H), 7.44-7.42 (m, 2H), 7.28 (s, 1H), 7.27 (s, 1H), 7.18 (s, 1H), 6.40 (s, 1H), 3.52 (s, 3H). | 430 | |
292 | N-氰基-2-(4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺 | (CD 3OD, 400 MHz) δ 7.92 (d, J= 5.2 Hz, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 7.39 (d, J= 7.6 Hz, 1H), 7.31-7.27 (m, 1H), 7.23-7.19 (m, 2H), 7.00 (s, 1H), 6.62 (dd, J= 5.2 Hz, J= 4.0 Hz, 1H), 6.56 (s, 1H), 6.34 (s, 1H), 3.70 (s, 3H), 3.01 (s, 3H). | 426 | |
293 | N-氰基-2-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺 | (CD 3OD, 400 MHz) δ 7.91 (s, 1H), 7.76 (s, 1H), 7.67-7.60 (m, 2H), 7.52-7.41 (m, 4H), 6.56 (s, 2H), 6.19 (dd, J= 6.8, 1.2 Hz, 1H), 3.66 (s, 3H), 3.58 (s, 3H). | 427 | |
294 | N-氰基-2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺 | (CD 3OD, 400 MHz) δ 8.12 (d, J= 2.4 Hz, 1H), 7.88 (s, 1H), 7.72 (s, 1H), 7.63-7.61 (m, 1H), 7.57-7.54 (m, 2H), 7.51-7.40 (m, 2H), 7.17 (s, 1H), 6.83 (d, J= 8.4 Hz, 1H), 6.57 (s, 1H), 3.92 (s, 3H), 3.66 (s, 3H). | 426 | |
295 | N-氰基-2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | (CD 3OD, 400 MHz) δ 8.21 (s, 2H), 7.86 (s, 1H), 7.82 (s, 1H), 7.62 (dd, J =7.6 Hz, J =0.8 Hz, 1H), 7.53-7.41 (m, 3H), 7.35 (s, 1H), 6.57 (s, 1H), 3.63 (d, J =10.8 Hz, 3H), 2.92 (s, 3H). | 427 | |
296 | N-氰基-2-(4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺 | (CD 3OD, 400 MHz) δ 8.10 (d, J =2.4 Hz, 1H), 7.88 (s, 1H), 7.73 (s, 1H), 7.63-7.61 (m, 1H), 7.56-7.55 (m, 2H), 7.46-7.43 (m, 2H), 7.19 (s, 1H), 6.80 (d, J =8.8 Hz, 1H), 6.57 (s, 1H), 4.33 (q, J =7.2 Hz, 2H), 3.66 (s, 3H) , 1.37 (t, J =7.2 Hz, 3H). | 441 |
將2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈(80 mg, 0.21 mmol)、疊氮化鈉(140 mg, 2.1 mmol)及CuSO
4.5H
2O (10 mg, 0.04 mmol)在DMF (15 mL)中之混合物在130℃攪拌隔夜。添加第二份疊氮化鈉(140 mg, 2.1 mmol)及CuSO
4.5H
2O (10 mg, 0.04 mmol),繼之以在130℃額外攪拌隔夜。將反應用NH
4Cl中止,並用含水NH
4OH將pH調節至9。隨後用DCM洗滌兩次。將水相用HCl(6N, 水溶液)酸化,並用DCM萃取。將有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備HPLC純化殘餘物,得到呈黃色固體的標題化合物(5 mg,6%產率)。
1H NMR (CD
3OD, 400 MHz) δ 7.82 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.56-7.53 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.03 (s, 1H), 6.54 (s, 1H), 3.65 (s, 3H). LCMS (M+H)
+430.
表19中的
實例 298-301係使用適當的苯甲腈以與實例297類似的多步驟方式來製備的。
實例 302:N-{2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苄醯基}-甲磺醯胺
表 19 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
298 | 4-(4-甲氧基-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.79-7.76 (m, 2H), 7.71-7.67 (m, 1H), 7.64-7.60 (m, 1H), 7.55 (d, J =7.6 Hz, 1H), 7.41 (s, 1H), 7.15 (d, J =8.4 Hz, 2H), 7.04 (s, 1H), 6.93 (d, J =8.8 Hz, 2H), 6.51 (s, 1H), 3.83 (s, 3H), 3.64 (s, 3H). | 426 | |
299 | 4-(4-氟-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.64-7.63 (m, 2H), 7.63-7.44 (m, 3H), 7.15-7.12 (m, 3H), 7.01 (t, J= 8.8 Hz, 2H), 6.89 (s, 1H), 6.41 (s, 1H), 3.54 (s, 3H). | 413 | |
300 | 1-甲基-4-(1-甲基-1H-吡唑-4-基)-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | (CD 3OD, 400 MHz) δ 7.77-7.75 (m, 2H), 7.67-7.65 (m, 1H), 7.61-7.56 (m, 3H), 7.51 (d, J =4.4 Hz, 2H), 7.25 (s, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 3.49 (s, 3H). | 400 | |
301 | 4-環丙基-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | (CD 3OD, 300 MHz) δ 7.76-7.64 (m, 3H), 7.62-7.42 (m, 3H), 7.41 (s, 1H), 6.07 (s, 1H), 3.55 (s, 3H), 1.59-1.00 (m, 1H), 0.99-0.96 (m, 2H), 0.72-0.70 (m, 2H). | 360 |
向用冰/水浴冷卻的2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸(50 mg, 0.15 mmol)、甲磺醯胺(18 mg, 0.18 mmol)及DMAP (27 mg, 0.22 mmol)在DCM (8 mL)中之混合物添加EDCI (43 mg, 0.22 mmol)。允許反應混合物緩慢升溫至室溫並攪拌隔夜。隨後用含水HCl (3.0 N)處理,並用DCM (25 mL×3)萃取。將合併的有機層用鹽水(35 mL×5)洗滌,用Na
2SO
4乾燥,並過濾。在減壓下濃縮濾液。藉由製備HPLC純化殘餘物,得到呈白色固體的標題化合物(6 mg, 0.01 mmol)。
1H NMR (CD
3OD+CDCl
3, 400 MHz) δ 8.06 (s, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.63-7.59 (m, 2H), 7.58-7.56 (m, 1H), 7.50-7.48 (m, 1H), 6.15 (s, 1H), 3.56 (s, 3H), 3.19 (s, 3H), 1.96-1.93 (m, 1H), 1.11-1.07 (m, 2H), 0.86-0.83 (m, 2H). LCMS (M+H)
+413.
表20中的
實例 303-304係使用適當的磺醯胺以與實例302類似的多步驟方式來製備的。
實例 305:3-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈.
步驟 1:3-(4-(4-氯-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈
表 20 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
303 | 乙磺酸2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲醯胺 | (DMSO- d 6 , 400 MHz) δ 12.1 (br, 1H), 8.37 (s, 1H), 7.87 (s, 1H), 7.82 (s, 1H), 7.70-7.68 (m, 1H), 7.59-7.42 (m, 3H), 6.00 (s, 1H), 3.42 (s, 3H), 3.31-3.17 (m, 2H), 1.92-1.88 (m, 1H), 1.28-1.24 (m, 3H), 1.01-0.96 (m, 2H), 0.77-0.73 (m, 2H). | 427 | |
304 | N-[(二甲胺基)磺醯基]-{2-[4-(4-環丙基-1-甲基-6-側氧(3-氫吡啶))吡唑基]苯基}羧醯胺 | (DMSO- d 6 , 300 MHz) δ 11.8 (s, 1H), 8.32 (s, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.69-7.65 (m, 2H), 7.57-7.54 (m, 1H), 7.50-7.47 (m, 1H), 6.01 (s, 1H), 3.43 (s, 3H), 2.85 (s, 6H), 1.93-1.85 (m, 1H), 0.99-0.95 (m, 2H), 0.78-0.71 (m, 2H). | 442 |
向4-氯-1-甲基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮(400 mg, 1.9 mmol)及(5-氰基-2-甲氧基苯基)硼酸(677 mg, 3.8 mmol)在DCM (20 mL)中之溶液添加Cu(OAc)
2(760 mg, 3.8 mmol)及吡啶(10 mL)。將混合物在氧氣氛下於室溫攪拌隔夜。將反應用DCM稀釋並用氫氧化銨洗滌。將有機相用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由矽膠管柱層析法純化殘餘物,得到呈白色固體的標題化合物(100 mg,15%產率)。
步驟 2:3-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈
向來自步驟1之標題化合物(30 mg, 0.09 mmol)及(1-甲基-2-側氧-1,2-二氫吡啶-4-基)硼酸(20 mg, 0.132 mmol)在二噁烷/水混合物(10 mL/2 mL)中之溶液添加Pd(PPh
3)
4(10 mg, 0.1 eq)及Na
2CO
3(18 mg, 0.18 mmol)。將混合物在90℃攪拌三小時。隨後冷卻至室溫,用DCM稀釋,並用飽和NH
4Cl水溶液洗滌。將有機相用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備TLC純化殘餘物,得到呈黃色固體的標題化合物(22 mg,60%產率)。
1H NMR (CDCl
3, 400 MHz) δ 8.12 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.59 (dd, J = 8.4, 2.0 Hz, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.59 (s, 1H), 6.55 (d, J = 1.6 Hz, 1H), 5.88 (dd, J = 7.2, 2.0 Hz, 1H), 3.95 (s, 3H), 3.64 (s, 3H), 3.53 (s, 3H). LCMS (M+H)
+414.
表21中的
實例 306-307係使用步驟2中的適當硼酸以與實例305類似的多步驟方式來製備的。
實例 308:6-甲氧基-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮
表 21 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
306 | 4-甲氧基-3-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | (CDCl 3, 400 MHz) δ 8.10-8.09 (m, 2H), 7.62 (s, 1H), 7.57 (dd, J= 8.8, 2.0 Hz, 1H), 7.44 (d, J= 5.6 Hz, 2H), 7.37 (dd, J= 8.8, 2.4 Hz, 1H), 7.06 (d, J= 8.8 Hz, 1H), 6.69 (d, J= 8.8 Hz, 1H), 6.62 (s, 1H), 3.95 (s, 3H), 3.87 (s, 3H), 3.65 (s, 3H). | 414 | |
307 | 3-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | (CDCl 3, 400 MHz) δ 8.09 (d, J= 2.0 Hz, 1H), 7.56 (dd, J= 8.4, 2.0 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J= 5.6 Hz, 2H), 7.35-7.33 (m, 2H), 7.18-7.16 (m, 2H), 7.05 (d, J= 8.8 Hz, 1H), 6.60 (s, 1H), 3.85 (s, 3H), 3.65 (s, 3H). | 417 |
用氮淨化6-甲氧基-3-吡啶基硼酸(38.02 mg, 0.25 mmol)、4-氯-1-甲基-5-[1-(1-苯基乙基)吡唑-4-基]吡啶-2-酮(60 mg, 0.19 mmol)及Pd[(Ph)
3P]
4(22.1 mg, 0.02 mmol)在1,4-二噁烷(1.2748 mL)及2M(水溶液)碳酸鈉(0.29 mL, 0.57 mmol)中之混合物。將小瓶密封並加熱至80℃經歷14小時。將混合物冷卻至室溫,用MeOH (1 mL)稀釋,並經由2A針筒過濾器過濾。藉由製備HPLC(10-100% ACN/0.01%甲酸)純化濾液,得到呈黃褐色固體的標題化合物(47 mg, 0.11 mmol)。
1H NMR (400 MHz, DMSO-d
6) δ 7.98 - 8.09 (m, 1 H), 7.78 - 7.90 (m, 1 H), 7.36 - 7.45 (m, 2 H), 7.22 - 7.35 (m, 3 H), 7.14 - 7.21 (m, 1 H), 7.03 - 7.13 (m, 2 H), 6.67 - 6.76 (m, 1 H), 6.35 - 6.41 (m, 1 H), 5.45 - 5.55 (m, 1 H), 3.83 - 3.89 (m, 3 H), 3.45 - 3.52 (m, 3 H), 1.65 - 1.74 (m, 3 H). LCMS (M+H)
+387.
表22中的
實例 309-313係使用適當的嘧啶或吡啶硼酸衍生物以與實例308類似的方式來製備的。
實例 314:5-(1-(2-氯苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮
步驟 1:4-氯-5-[1-(2-氯苯基)吡唑-4-基]-1-甲基-吡啶-2-酮
表 22 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
309 | 1-甲基-4-(2-(甲胺基)嘧啶-5-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 7.98 - 8.15 (m, 2 H), 7.76 - 7.83 (m, 1 H), 7.57 - 7.64 (m, 1 H), 7.21 - 7.39 (m, 5 H), 7.09 - 7.16 (m, 2 H), 6.35 - 6.44 (m, 1 H), 5.50 - 5.61 (m, 1 H), 3.43 - 3.49 (m, 3 H), 2.78 - 2.85 (m, 3 H), 1.70 - 1.77 (m, 3 H) | 387 | |
310 | 1,1'-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | 1H NMR (400 MHz, DMSO-d6) δ 7.84 - 7.89 (m, 1 H), 7.52 - 7.59 (m, 2 H), 7.23 - 7.36 (m, 4 H), 7.05 - 7.13 (m, 2 H), 6.30 - 6.34 (m, 1 H), 6.23 - 6.27 (m, 1 H), 5.82 - 5.89 (m, 1 H), 5.48 - 5.59 (m, 1 H), 3.45 - 3.50 (m, 3 H), 3.38 - 3.42 (m, 3 H), 1.69 - 1.77 (m, 3 H) | 387 | |
311 | 4-(2-(乙胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 7.99 - 8.15 (m, 2 H), 7.76 - 7.81 (m, 1 H), 7.58 - 7.64 (m, 1 H), 7.38 - 7.44 (m, 1 H), 7.29 - 7.36 (m, 2 H), 7.22 - 7.29 (m, 2 H), 7.09 - 7.17 (m, 2 H), 6.36 - 6.43 (m, 1 H), 5.49 - 5.61 (m, 1 H), 3.41 - 3.52 (m, 3 H), 3.25 - 3.31 (m, 2 H), 1.68 - 1.79 (m, 3 H), 1.06 - 1.19 (m, 3 H) | 401 | |
312 | 4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 8.08 (br s, 2 H), 7.80 (s, 1 H), 7.60 (s, 1 H), 7.23 - 7.42 (m, 5 H), 7.13 (m, 2 H), 6.40 (s, 1 H), 5.55 (m, 1 H), 3.42 - 3.49 (m, 7 H), 3.21 - 3.29 (m, 3 H), 1.73 (m, 3 H) | 431 | |
313 | 6-(3-(二甲胺基)丙氧基)-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 7.97 - 8.04 (m, 1 H), 7.82 - 7.88 (m, 1 H), 7.36 - 7.45 (m, 2 H), 7.22 - 7.34 (m, 3 H), 7.14 - 7.20 (m, 1 H), 7.04 - 7.11 (m, 2 H), 6.66 - 6.73 (m, 1 H), 6.34 - 6.41 (m, 1 H), 5.44 - 5.56 (m, 1 H), 4.23 - 4.32 (m, 2 H), 3.49 (s, 3 H), 2.39 - 2.47 (m, 2 H), 2.21 (s, 6 H), 1.82 - 1.94 (m, 2 H), 1.65 - 1.74 (m, 3 H) | 458 |
將5-溴-4-氯-1-甲基-吡啶-2-酮(100 mg, 0.45 mmol)、[1-(2-氯苯基)吡唑-4-基]硼酸(110 mg, 0.49 mmol)及1,1'-雙(二苯基膦基)二茂鐵二氯鈀(II)二氯甲烷錯合物(26.3 mg, 0.04 mmol)在1,4-二噁烷(2.7 mL)及3.5 M K
3PO
4(0.3 mL, 1.05 mmol)中之混合物用氮起泡5分鐘。將密封小瓶加熱至75℃經歷8小時。在將混合物冷卻至室溫並用EtOAC及水稀釋後,經由短矽藻土插塞過濾。將含水層分離,並用EtOAc (3×15 ml)萃取。將合併的有機層用鹽水洗滌,用硫酸鈉乾燥,並過濾。藉由矽膠管柱層析法使用DCM中的MeOH(0至2%經歷17分鐘,2-10%經歷7分鐘)之梯度純化所得殘餘物。合併適當的餾分,並在減壓下濃縮,得到呈黃褐色固體的標題化合物(60 mg, 0.19 mmol)。 1H NMR (400 MHz, DMSO-d
6) δ ppm 8.34 - 8.39 (s, 1 H), 8.10 - 8.13 (s, 1 H), 7.95 - 7.99 (s, 1 H), 7.68 - 7.73 (m, 1 H), 7.61 - 7.67 (m, 1 H), 7.48 - 7.58 (m, 2 H), 6.67 - 6.72 (s, 1 H), 3.46 - 3.50 (s, 3 H). LCMS (M+H)
+320.
步驟 2:5-(1-(2-氯苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮
藉由用來自步驟1之標題化合物代替3-(4-(4-氯-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈以與實例305步驟2類似的方式來製備標題化合物,並在78℃執行反應。
1H NMR (400 MHz, DMSO-d
6) δ ppm 8.00 (s, 1 H), 7.83 (s, 1 H), 7.62 - 7.70 (m, 3 H), 7.43 - 7.58 (m, 3 H), 6.37 (s, 1 H), 6.27 - 6.32 (m, 1 H), 5.95 - 6.01 (m, 1 H), 3.51 (s, 3 H), 3.41 (s, 3 H). LCMS (M+H)
+393.
表23中的
實例 315-320係使用適當的嘧啶或吡啶硼酸衍生物及經取代之吡唑以與實例314類似的多步驟方式來製備的。
實例 321:5-(1-(2-羥基環己基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮
步驟 1:4-氯-5-(1-(2-羥基環己基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮
表 23 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
315 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 8.48 (s, 2 H), 7.99 (s, 1 H), 7.79 (s, 1 H), 7.62 - 7.67 (m, 1 H), 7.58 - 7.60 (m, 1 H), 7.44 - 7.55 (m, 3 H), 6.54 (s, 1 H), 3.92 (s, 3 H), 3.52 (s, 3 H) | 394 | |
316 | 5'-(1-(2-氯苯基)-1H-吡唑-4-基)-6-甲氧基-1',5-二甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 7.97 (s, 1 H), 7.89 - 7.93 (m, 1 H), 7.61 - 7.67 (m, 2 H), 7.42 - 7.55 (m, 4 H), 7.34 - 7.38 (m, 1 H), 6.40 (s, 1 H), 3.88 (s, 3 H), 3.51 (s, 3 H), 2.08 (s, 3 H) | 407 | |
317 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-2'-甲氧基-1-甲基-[4,4'-聯吡啶]-2(1H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 8.09 (m, 1 H), 7.98 (s, 1 H), 7.67 (s, 1 H), 7.64 ( m, 1 H), 7.44 - 7.55 (m, 5 H), 6.81 (m, 1 H), 6.43 (s, 1 H), 3.86 (s, 3 H), 3.52 (s, 3 H) | 393 | |
318 | 5-(1-(2-氟苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | 1H NMR (400 MHz, DMSO- d6) δ 7.96 (s, 1 H), 7.91 (s, 1 H), 7.71 (m, 1 H), 7.60 (m, 1 H), 7.52 (s, 1 H), 7.25 - 7.41 (m, 3 H), 6.30 (s, 1 H), 6.24 (m, 1 H), 5.92 (m, 1 H), 3.44 (s, 3 H), 3.36 (s, 3 H) | 377 | |
319 | 5'-(1-(2-氟苯基)-1H-吡唑-4-基)-6-甲氧基-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 7.24 - 7.31 (m, 1 H), 7.15 - 7.21 (m, 1 H), 6.98 - 7.03 (m, 1 H), 6.89 - 6.97 (m, 1 H), 6.68 - 6.75 (m, 1 H), 6.48 - 6.67 (m, 4 H), 5.95 - 6.02 (m, 1 H), 5.56 - 5.63 (m, 1 H), 3.02 - 3.08 (m, 3 H), 2.66 - 2.73 (m, 3 H) | 377 | |
320 | 5-(1-(2-氟苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮 | 1H NMR (400 MHz, DMSO- d6) δ 8.42 (s, 2 H), 7.94 (s, 1 H), 7.87 ( m, 1 H), 7.69 (m, 1 H), 7.25 - 7.46 (m, 4 H), 6.48 (s, 1 H), 3.86 (s, 3 H), 3.45 (s, 3 H) | 378 |
將4-氯-1-甲基-5-(1H-吡唑-4-基)吡啶-2-酮(209 mg, 1 mmol)、7-氧雜雙環[4.1.0]庚烷(0.2 mL, 2 mmol)及三氟甲烷磺酸鎰(III)(62 mg, 0.10 mmol)之混合物在室溫下攪拌15分鐘,隨後加熱至40℃經歷2小時。將混合物用DCM (2 mL)稀釋,加蓋並於45℃攪拌12小時。LCMS分析展示了所需產物為主峰的證據。將混合物用DCM及水稀釋,並過濾。將有機層分離,用硫酸鈉乾燥,過濾,並在真空中濃縮。藉由矽膠管柱層析法(2.5% MeOH繼之以DCM中的2.5-10% MeOH)純化所得殘餘物。合併適當的餾分,並在減壓下濃縮,得到呈無色固體的標題化合物(250 mg, 0.80 mmol)。LCMS (M+H)
+308.
步驟 2:5-(1-(2-羥基環己基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮
將來自步驟1之標題化合物(65 mg, 0.21 mmol)、苯基硼酸(34 mg, 0.28 mmol)及Pd(PPh
3)
4(25 mg, 0.02 mmol)之混合物合併在具有攪拌棒的8 ml小瓶中;用1,4-二噁烷(1.4 mL)及2M(水溶液)碳酸鈉(0.32 mL, 0.64 mmol)稀釋乾混合物。在將攪拌的懸浮液起泡5分鐘後,將小瓶密封並加熱至80℃經歷14小時。將混合物用MeOH (1 mL)稀釋,並經由2A針筒過濾器過濾。藉由矽膠管柱層析法(10-60%之ACN/0.1%甲酸12分鐘,繼之以60-100%之ACN/0.1%甲酸3分鐘)純化濾液。收集適當的餾分,並在真空中濃縮,得到呈淺粉紅色固體的標題化合物(14 mg, 0.04 mmol)。
1H NMR (400 MHz, DMSO-d
6) δ ppm 6.99 - 7.06 (m, 1 H), 6.49 - 6.58 (m, 3 H), 6.34 - 6.40 (m, 2 H), 6.27 - 6.32 (m, 1 H), 6.10 - 6.17 (m, 1 H), 5.44 - 5.50 (m, 1 H), 3.75 - 3.83 (m, 1 H), 2.79 - 2.91 (m, 1 H), 2.65 - 2.70 (m, 3 H), 0.71 - 1.12 (m, 5 H), 0.34 - 0.49 (m, 3 H). LCMS (M+H)
+350.
實例 322:2-氯-6-[4-[4-[2-(環丙基胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈
步驟 1:2-氯-6-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑-1-基)苯甲腈
在氮氣氛下向0℃的4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑 (5 g, 25.8 mmol)在DMF (10 mL)中之攪拌溶液逐部分地添加NaH (2.58 g, 107.5 mmol)。將所得混合物攪拌20分鐘,繼之以2-氯-6-氟-苯甲腈(4.8 g, 30.9 mmol)。將混合物在室溫下攪拌3小時。藉由添加0℃的水(300 mL)中止反應混合物。隨後用EtOAc (5×500 mL)萃取。將合併的有機層用鹽水洗滌,用Na
2SO
4乾燥,並在減壓下濃縮,得到粗標題化合物之3公克粗品。LCMS (M+H)
+330.
步驟 2:2-氯-6-[4-(4-氯-1-甲基-6-側氧-3-吡啶基)吡唑-1-基]苯甲腈
在氮氣氛下向來自步驟1之標題化合物(1.3 g, 3.9 mmol)、5-溴-4-氯-1-甲基-吡啶-2-酮(1.17 g, 5.3 mmol)、K
3PO
4(2.79 g, 13.1 mmol)在水(18 mL)及1,4-二噁烷(90 mL)中之溶液添加Pd(dppf)Cl
2(769 mg, 1.1 mmol)。將所得混合物於80℃攪拌2.5小時。隨後冷卻至室溫,用水稀釋,並用EtOAc萃取。在真空下濃縮合併的有機層。藉由矽膠管柱層析法用DCM/MeOH混合物(40/1)純化殘餘物,得到呈黃色固體的500 mg之標題化合物(500 mg, 37%)。LCMS (M+H)
+345.
步驟 3:5-溴-N-環丙基-嘧啶-2-胺
向室溫的5-溴-2-氯-嘧啶(2 g, 10.3 mmol)在乙醇(20 mL)中之溶液添加環丙基胺(1.18 g, 20.7 mmol)。將所得混合物於80℃攪拌隔夜。將反應混合物用EtOAc稀釋,並用飽和NaHCO
3水溶液洗滌。將有機層用硫酸鈉乾燥,並在減壓下濃縮。藉由矽膠管柱層析法純化殘餘物,得到呈白色固體的標題化合物(1.9 g,86%產率)。LCMS (M+H)
+214.
步驟 4:N-環丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)嘧啶-2-胺
在密封管中將5-溴-N-環丙基-嘧啶-2-胺(600 mg, 2.8 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1,3,2-二氧硼戊烷(1.1 g, 4.2 mmol)、乙酸鉀(550 mg, 5.6 mmol)及PdCl
2(PPh
3)
2(393 mg, 0.56 mmol)在1,4-二噁烷(20 mL)中之混合物在氮氣氛下於80℃攪拌隔夜。在減壓下移除溶劑,並藉由矽膠管柱層析法純化殘餘物,得到呈黃色固體的標題化合物。LCMS (M+H)
+180 (M-pinacol)。
步驟 5:2-氯-6-[4-[4-[2-(環丙基胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈.
在密封管中將來自步驟2之標題化合物(100 mg, 0.29 mmol)、來自步驟4之標題化合物(227 mg, 0.87 mmol)、Na
2CO
3(92 mg, 0.87 mmol)、Pd(PPh
3)
4(67 mg, 0.06 mmol)在1,4-二噁烷 (15 mL)及水(3 mL)中之混合物除氣,並在氮下於80℃攪拌2.5小時。將反應混合物用水稀釋,用乙酸乙酯萃取,並用鹽水洗滌。將有機層用硫酸鈉乾燥,並在減壓下濃縮。藉由製備HPLC純化殘餘物,得到呈白色固體的標題化合物(29.4 mg, 22%)。
1H NMR (CD
3OD, 400 MHz) δ 88.32 (d, 2H), 8.15 (s, 1H), 7.91 (s, 1H), 7.80-7.67 (m, 4H), 6.65 (S, 1H), 3.66-3.48 (m, 3H), 2.71 (s, 1H), 0.89-0.84 (d, 2H), 0.67-0.63 (d, 2H). LCMS (M+H)
+444.
表24中的
實例 323-338係使用適當的嘧啶硼酸頻那醇酯(pyrimidine bboronic acid pinacol ester)及經取代之苯甲腈以與實例322類似的多步驟方式來製備的。
實例 339:2-氯-6-[4-[4-[6-(異丙基胺基)-3-吡啶基]-1-甲基-6-側氧-3-吡啶基]-吡唑-1-基]苯甲腈
步驟 1:5-溴-N-異丙基-吡啶-2-胺
表 24 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
323 | 2-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | 1H NMR (400 MHz, DMSO- d6) δ 8.27 - 8.31 (m, 1 H), 8.09 - 8.21 (m, 2 H), 7.99 - 8.03 (m, 1 H), 7.92 - 7.96 (m, 1 H), 7.82 - 7.89 (m, 1 H), 7.71 - 7.76 (m, 1 H), 7.54 - 7.62 (m, 2 H), 7.39 - 7.47 (m, 1 H), 6.43 - 6.50 (m, 1 H), 3.47 - 3.53 (m, 3 H), 3.25 - 3.31 (m, 2 H), 1.06 - 1.14 (m, 3 H) | 398 | |
324 | 2-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | 1H NMR (400 MHz, DMSO- d6) δ 7.44 - 7.47 (m, 1 H), 7.27 - 7.37 (m, 2 H), 7.15 - 7.20 (m, 1 H), 7.09 - 7.13 (m, 1 H), 6.99 - 7.06 (m, 1 H), 6.88 - 6.93 (m, 1 H), 6.72 - 6.78 (m, 2 H), 6.56 - 6.62 (m, 1 H), 5.62 - 5.66 (m, 1 H), 2.66 - 2.70 (m, 3 H), 2.58 - 2.63 (m, 4 H), 2.38 - 2.42 (m, 3 H) | 428 | |
325 | 2-氯-6-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 300 MHz) δ 8.31 (s, 2H), 8.18 (s, 1H), 7.92 (s, 1H), 7.87-7.75 (m, 1H), 7.77-7.66 (m, 3H), 6.66 (s, 1H), 3.68 (s, 3H), 3.53-3.39 (m, 2H), 1.26 (t, J= 7.2 Hz, 3H). | 432 | |
326 | 2-氯-6-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 300 MHz) δ 8.30 (s, 2H), 8.17 (d, J = 0.7 Hz, 1H), 7.92 (s, 1H), 7.84-7.76 (m, 1H), 7.74-7.66 (m, 3H), 6.65 (s, 1H), 3.68 (s, 3H), 3.65-3.55 (m, 4H), 3.38 (s, 3H). | 462 | |
327 | 2-氯-6-(4-(4-(2-((環丙基甲基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (DMSO, 300 MHz) δ 8.31 (s, 1H), 8.15 (s, 2H) 7.93 (s, 1H), 7.85 (t, J=8.1Hz, 1H), 7.79 (d, J=8.2Hz, 1H), 7.72 (d, J=8.1Hz, 1H),7.64-7.61(m,2H) 6.47 (s, 1H), 3.50 (s, 3H), 3.16 (d, J=6.7Hz, 2H), 1.09-1.03 (m, 1H), 0.41-0.33 (m, 2H), 0.21-0.17 (m, 2H) | 458 | |
328 | 2-氯-6-(4-(4-(2-(二甲胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 300 MHz) δ 8.33 (s, 2H), 8.16 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.84-7.76 (m, 1H), 7.75-7.68 (m, 3H), 6.65 (s, 1H), 3.68 (s, 3H), 3.25 (s, 6H). | 432 | |
329 | 2-氯-6-(4-(4-(2-(環戊基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 300 MHz) δ 8.32 (s, 2H), 8.18 (s, 1H) 7.93 (s, 1H), 7.83-7.69 (m, 4H), 6.67 (s, 1H), 4.28-4.20 (m, 1H), 3.68 (s, 3H), 2.09-1.97 (m, 2H), 1.82-1.73 (m, 2H), 1.68-1.59 (m, 4H) | 472 | |
330 | 2-氯-6-(4-(1-甲基-6-側氧-4-(2-(吡咯啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.35 (s, 2H), 8.17 (s, 1H), 7.92 (s, 1H), 7.85-7.76 (m, 1H), 7.78-7.67 (m, 3H), 6.67 (s, 1H), 3.68 (s, 3H), 3.67-3.59 (m, 4H), 2.13-2.04 (m, 4H) | 458 | |
331 | 2-氯-6-(4-(4-(2-(異丙基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 300 MHz) δ 8.31 (s, 2H), 8.18 (s, 1H) 7.92 (s, 1H), 7.83-7.66 (m, 4H), 7.61-7.35 (m, 1H), 6.66 (s, 1H), 4.20-4.11 (m, 1H), 3.67 (s, 3H), 1.20-1.14 (m, 6H) | 446 | |
332 | 2-氯-6-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 300 MHz) δ 8.38 (s, 2H), 8.18 (d, J= 0.8 Hz, 1H), 7.94 (s, 1H), 7.92 - 7.61 (m, 5H), 6.68 (s, 1H), 3.68 (s, 3H), 3.03 (s, 3H). | 418 | |
333 | 2-[4-[4-[2-(乙胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | (CD 3OD, 400 MHz) δ 8.33 (s, 2H), 8.19 (d, J= 0.7 Hz, 1H), 7.92 (s, 1H), 7.91-7.80 (m, 1H), 7.75 (s, 1H), 7.68-7.60 (m, 1H), 7.47-7.37 (m, 1H), 6.66 (s, 1H), 3.68 (s, 3H), 3.52-3.42 (m, 2H), 1.31-1.22 (m, 3H). | 416 | |
334 | 2-[4-[4-[2-(二甲胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | (CD 3OD, 400 MHz) δ 8.23 (s, 2H), 8.18 (s, 1H), 7.90-7.79 (m, 2H), 7.61 (d, J= 9.3 Hz, 2H), 7.45-7.36 (m, 1H), 6.60 (s, 1H), 3.67 (s, 3H), 3.19 (s, 6H), 2.05 (s, 0H). | 416 | |
335 | 2-氯-6-(4-(1-甲基-4-(2-嗎啉基嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.27 (s, 2H), 8.15 (s, 1H), 7.87 (s, 1H), 7.79 (dd, J = 9.1, 7.2 Hz, 1H), 7.74-7.66 (m, 2H), 7.63 (s, 1H), 6.62 (s, 1H), 3.82 (dd, J = 5.5, 3.7 Hz, 4H), 3.74 (t, J = 4.7 Hz, 4H), 3.67 (s, 3H). | 474 | |
336 | 2-氟-6-[4-[1-甲基-6-側氧-4-(2-吡咯啶-1-基嘧啶-5-基)-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.21 (d, J= 17.9 Hz, 3H), 7.86 (d, J= 8.6 Hz, 1H), 7.83 (dd, J= 8.4, 6.1 Hz, 1H), 7.63 (d, J= 4.5 Hz, 1H), 7.61 (d, J= 1.0 Hz, 0H), 7.45-7.36 (m, 1H), 6.61 (s, 1H), 3.67 (s, 3H), 3.61-3.53 (m, 4H), 2.07-1.98 (m, 4H). | 442 | |
337 | 2-氯-6-(4-(1-甲基-4-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 400 MHz) δ 9.97 (s, 1H), 8.34 (s, 3H), 7.97 (s, 1H), 7.88 (t, J = 8.2 Hz, 1H), 7.83-7.71 (m, 2H), 7.61 (s, 1H), 6.50 (s, 1H), 4.72 (d, J = 14.4 Hz, 2H), 3.52 (s, 5H), 3.34 (s, 2H), 3.26 (s, 2H), 3.06 (s, 2H), 2.84 (s, 3H). | 487 | |
338 | 2-氯-6-(4-(1-甲基-6-側氧-4-(2-(哌啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.26 (s, 2H), 8.16 (d, J = 0.7 Hz, 1H), 7.88 (s, 1H), 7.84-7.75 (m, 1H), 7.76-7.59 (m, 3H), 6.63 (s, 1H), 3.87-3.79 (m, 4H), 3.67 (s, 3H), 1.74 (d, J = 5.1 Hz, 2H), 1.74-1.59 (m, 4H). | 472 |
在室溫下向5-溴-2-氟-吡啶(1 g, 5.7 mmol)在DMSO (10 mL)中之攪拌溶液添加丙醯-2-胺(2 g, 33.8 mmol)及DIEA (2.7 mL, 15.5 mmol)。將反應於120℃攪拌2小時。將所得溶液冷卻至室溫,並藉由逆相管柱層析法純化,得到呈黃色固體的標題化合物(900 mg, 74%產率)。LCMS (M+H)
+215.
步驟 2:N-異丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-2-胺
在N
2下向來自步驟1之標題化合物(500 mg, 2.3 mmol)在1,4-二噁烷(10 mL)中之溶液添加聯硼酸頻那醇酯(1.18 g, 4.7 mmol)、Pd(dppf)Cl
2(50 mg, 0.07 mmol)及乙酸鉀(684 mg, 6.9 mmol)。將反應於80℃攪拌2小時。將反應混合物冷卻至室溫,並在減壓下濃縮。藉由逆相管柱層析法純化殘餘物,得到呈白色固體的標題化合物。LCMS (M+H)
+263.
步驟 3:2-氯-6-[4-[4-[6-(異丙基胺基)-3-吡啶基]-1-甲基-6-側氧-3-吡啶基]-吡唑-1-基]苯甲腈
在N
2下向2-氯-6-[4-(4-氯-1-甲基-6-側氧-3-吡啶基)吡唑-1-基]苯甲腈(120 mg, 0.35 mmol)在1,4-二噁烷(5 mL)及水(1 mL)中之溶液添加來自步驟2之標題化合物 (365 mg, 1.39 mmol)、Pd(PPh
3)
4(40 mg, 0.03 mmol)及Na
2CO
3(111 mg, 1.04 mmol)。將混合物於80℃攪拌2小時。將反應冷卻至室溫,並在減壓下濃縮。將殘餘物用水處理,並用EtOAc萃取。將合併的有機層用硫酸鈉乾燥,過濾,濃縮,並藉由製備TLC純化,得到呈白色固體的標題化合物(6.6 mg, 4.2%產率)。
1H NMR (CD
3OD, 400 MHz) δ 8.11 (s, 1H), 7.93 (s, 1H), 7.83 - 7.73 (m, 5H), 7.64 (m, 1H), 6.92 (m, 1H), 6.65 (s, 1H), 3.95 - 3.88 (m, 1H), 3.69 (s, 3H), 1.34 (d, 6H). LCMS (M+H)
+445.
表25中的
實例 340-351係使用適當的吡啶硼酸衍生物及經取代之苯甲腈以與實例339類似的多步驟方式來製備的。
實例 352:2-氯-6-[4-[4-[6-(環戊氧基)-3-吡啶基]-1-甲基-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈
步驟 1:5-溴-2-(環戊氧基)吡啶
表 25 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
340 | 2-氯-6-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | 1H-NMR (DMSO, 300 MHz) δ 8.18 (s, 1H), 7.92-7.72 (m, 4H), 7.65 (d, J= 8.2 Hz, 1H), 7.47 (s, 1H), 7.13 (d, J= 8.8 Hz, 1H), 6.73 (d, J= 6.8 Hz, 1H), 6.34 (d, J= 10.1 Hz, 2H), 4.06 (d, J= 8.8 Hz, 1H), 3.46 (s, 3H), 2.04 (s, 1H), 1.73 (d, J= 67.8 Hz, 4H), 1.43 (d, J= 33.1 Hz, 4H). | 471 | |
341 | 2-氯-6-(4-(1'-甲基-6-(甲胺基)-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | 1H-NMR (CD 3OD, 300 MHz) 8.10 (d, J= 0.7 Hz, 1H), 7.96 (s, 1H), 7.86- 7.65 (m, 6H), 6.99 (d, J= 9.3 Hz, 1H), 6.66 (s, 1H), 3.69 (s, 3H), 3.05 (s, 3H). | 417 | |
342 | 2-氯-6-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | 1H-NMR (CD 3OD, 400 MHz) 8.09 (s, 1H), 7.93 (s, 1H), 7.93-7.76 (m, J= 8.0, 3.7 Hz, 3H), 7.76-7.62 (m, 3H), 6.96 (d, J= 9.3 Hz, 1H), 6.64 (s, 1H), 3.67 (s, 3H), 3.43-3.34 (q, J= 7.3 Hz, 2H), 1.34 (t, J= 7.2 Hz, 3H). | 431 | |
343 | 2-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | (CD 3OD, 400 MHz) δ 8.15 (s, 1H), 7.96 (s, 1H), 7.94-7.79 (m, 3H), 7.75-7.62 (m, 2H), 7.48-7.38 (m, 1H), 6.99 (d, J= 9.4 Hz, 1H), 6.66 (s, 1H), 4.09-3.99 (m, 1H), 3.69 (s, 3H), 2.17-2.06 (m, 2H), 1.91-1.81 (m, 2H), 1.81-1.64 (m, 4H). | 455 | |
344 | 2-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | (DMSO, 400 MHz) δ 8.74 (s, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.97-7.86 (m, 2H), 7.72 (s, 1H), 7.65 (d, J= 8.3 Hz, 1H), 7.60-7.50 (m, 2H), 6.90 (d, J= 9.3 Hz, 1H), 6.52 (s, 1H), 3.53 (s, 3H), 3.35 (q, J= 7.2 Hz, 2H), 1.22 (t, J= 7.2 Hz, 3H). | 415 | |
345 | 2-氯-6-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}苯甲腈 | (CD 3OD, 400 MHz) δ 8.06 (s, 1H), 7.97 (s, 1H), 7.88 (m, 1H), 7.87–7.78 (m, 3H), 7.76 (m, 2H), 7.21 (d, 1H), 6.66 (s, 1H), 3.69 (s, 3H), 3.33 (s, 6H) | 431 | |
346 | 2-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)-6-氟苯甲腈 | (CD 3OD, 400 MHz) δ 8.12 (s, 1H), 7.95 (s, 1H), 7.89-7.78 (m, 3H), 7.70-7.65 (m, 2H), 7.43 (t, 1H), 7.00 (d, 1H), 6.65 (s, 1H), 3.69 (s, 3H), 3.23 (d, 2H), 1.22-1.14 (m, 1H), 0.71–0.66 (m, 2H), 0.39-0.35 (m, 2H). | 441 | |
347 | 2-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}-6-氟苯甲腈 | (CD 3OD, 400 MHz) δ 8.06 (s, 1H), 7.93 (s, 1H), 7.87–7.74 (m, 4H), 7.65 (m, 1H), 7.42 (m, 1H), 7.18 (d, 1H), 6.64 (s, 1H), 3.67 (s, 3H), 3.30 (s, 6H) | 415 | |
348 | 2-氯-6-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.10 (s, 1H), 7.94 (s, 1H), 7.85-7.64 (m, 6H), 7.02 (d, 1H), 6.65 (s, 1H), 3.69 (s, 3H), 3.23 (d, 2H), 1.21 (m, 1H), 0.74–0.64 (m, 2H), 0.38-0.37 (m, 2H) | 457 | |
349 | 2-氯-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.08 (d, J= 0.7 Hz, 1H), 7.96 (s, 1H), 7.86 (dd, J= 2.2, 0.7 Hz, 1H), 7.86 – 7.71 (m, 4H), 7.72 (dd, J= 7.9, 1.3 Hz, 1H), 7.07 (dd, J= 9.4, 0.8 Hz, 1H), 6.67 (s, 1H), 3.69 (s, 3H), 3.62 (s, 5H), 2.19 (s, 4H), 2.19 (d, J= 13.5 Hz, 1H). | 457 | |
350 | 2-氟-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.10 (d, J= 0.7 Hz, 1H), 7.97 (s, 1H), 7.92 – 7.79 (m, 3H), 7.77 (dd, J= 9.5, 2.2 Hz, 1H), 7.67 (dd, J= 8.3, 1.0 Hz, 1H), 7.48 – 7.38 (m, 1H), 7.07 (d, J= 9.5 Hz, 1H), 6.67 (s, 1H), 3.70 (s, 3H), 3.62 (s, 1H), 2.19 (d, J= 6.6 Hz, 1H). | 441 | |
351 | 2-氟-6-(4-(6-(異丙基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.14 (s, 1H), 7.95 (s, 1H), 7.93-7.76 (m, 3H), 7.75-7.62 (m, 2H), 7.48-7.38 (m, 1H), 6.96 (d, J = 9.4 Hz, 1H), 6.66 (s, 1H), 3.90 (t, J = 6.4 Hz, 1H), 3.69 (s, 3H), 1.35 (d, J = 6.4 Hz, 6H). | 429 |
在100 mL圓底燒瓶中於0℃向環戊醇(587.3 mg, 6.8 mmol)在THF (20 mL)中之溶液添加NaH (205 mg, 8.5 mmol)。將所得混合物攪拌20分鐘。隨後添加5-溴-2-氟-吡啶(1 g, 5.7 mmol)。將所得混合物於50℃攪拌2小時。將反應混合物用水稀釋,並用乙酸乙酯萃取。將有機層用水洗滌,用硫酸鈉乾燥,並在減壓下濃縮。藉由矽膠管柱層析法純化殘餘物,得到呈黃色固體的1.3 g之標題化合物。LCMS (M+H)
+242.
步驟 2:2-(環戊氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶
將來自步驟1之標題化合物(1.3 g, 5.4 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1,3,2-二氧硼戊烷(2.7 g, 10.7 mmol)、乙酸鉀(1.05 g, 10.7 mmol)、Pd(dppf)Cl
2(785.8 mg, 1.07 mmol)及1,4-二噁烷(15 mL)之混合物在氮氣氛下於80℃攪拌2小時。在減壓下移除溶劑,並藉由矽膠管柱層析法純化殘餘物,得到呈白色固體的2 g之標題化合物。LCMS (M+H)
+290.
步驟 3:2-氯-6-[4-[4-[6-(環戊氧基)-3-吡啶基]-1-甲基-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈
將2-氯-6-[4-(4-氯-1-甲基-6-側氧-3-吡啶基)吡唑-1-基]苯甲腈(120 mg, 0.35 mmol)、來自步驟2之標題化合物(302 mg, 1.04 mmol)、Na
2CO
3(110.6 mg, 1.04 mmol)、Pd(PPh
3)
4(80.3 mg, 0.07 mmol)、水(3 mL)及1,4-二噁烷(15 mL)之混合物在N
2下於80℃攪拌2小時。將反應混合物用水稀釋,並用乙酸乙酯萃取。將有機層用鹽水洗滌,用硫酸鈉乾燥,並在減壓下濃縮。藉由製備HPLC純化粗產物,得到呈白色固體的標題化合物(30 mg, 18%)。
1H NMR (CD
3OD, 300 MHz) δ 9.14 (s, 1H), 8.05 (s, 1H), 7.75 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 5.36 (s, 1H), 3.70-3.66 (m, 3H), 2.02-1.96 (d, 2H), 1.79-1.78 (m, 3H), 1.64-1.28 (d, 2H). LCMS (M+H)
+472.
表26中的
實例 353-365係使用適當的吡啶硼酸頻那醇酯及經取代之苯甲腈以與實例352類似的多步驟方式來製備的。
實例 366:2-氯-6-[4-[4-(6-環丙基-3-吡啶基)-1-甲基-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈
步驟 1:2-環丙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶
表 26 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
353 | 2-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | (CD 3OD, 300 MHz) δ 8.23 – 8.15 (m, 1H), 8.05 (d, J= 0.7 Hz, 1H), 7.95 (s, 1H), 7.88 – 7.52 (m, 5H), 7.49 – 7.35 (m, 1H), 7.04 – 6.94 (m, 1H), 6.63 (s, 1H), 3.70 (s, 3H) | 438 | |
354 | 2-氯-6-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 400 MHz) 8.24-8.15 (m, 2H), 8.04 (s, 1H), 7.90-7.83 (m, 1H), 7.82-7.73 (m, 2H), 7.72-7.52 (m, 3H), 7.08 (d, J = 8.5 Hz, 1H), 6.51 (s, 1H), 3.54 (s, 3H). | 454 | |
355 | 2-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | 1H NMR (400 MHz, DMSO- d6) δ 8.16 (s, 2 H), 8.07 - 8.10 (m, 1 H), 7.96 - 8.01 (m, 1 H), 7.67 - 7.88 (m, 2 H), 7.53 - 7.60 (m, 1 H), 7.48 - 7.54 (m, 1 H), 7.42 - 7.46 (m, 1 H), 6.73 - 6.80 (m, 1 H), 6.42 - 6.45 (m, 1 H), 4.25 - 4.30 (m, 2 H), 3.49 - 3.54 (m, 3 H), 2.39 - 2.45 (m, 2 H), 2.19 (s, 6 H), 1.81 - 1.90 (m, 2 H) | 455 | |
356 | 2-氯-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | 1H NMR (DMSO, 400 MHz) 8.18 (s, 1H), 8.08 (d, J= 2.5 Hz, 1H), 7.98 (s, 1H), 7.85 (t, J= 8.1 Hz, 1H), 7.77 (d, J= 8.1 Hz, 1H), 7.66 (d, J= 8.2 Hz, 1H), 7.51 (d, J= 8.3 Hz, 2H), 6.75 (d, J= 8.6 Hz, 1H), 6.44 (s, 1H), 4.27 (t, J= 6.6 Hz, 2H), 3.51 (s, 3H), 2.31 (t, J= 7.1 Hz, 2H), 2.11 (s, 6H), 1.87-1.76 (m, J= 6.9 Hz, 2H). | 489 | |
357 | 2-氯-6-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.10 – 8.02 (m, 2H), 7.91 (s, 1H), 7.78 (t, J= 8.2 Hz, 1H), 7.67 (ddd, J= 23.2, 8.2, 1.1 Hz, 2H), 7.56 (dd, J= 8.6, 2.5 Hz, 1H), 7.49 (d, J= 0.7 Hz, 1H), 6.79 (dd, J= 8.6, 0.8 Hz, 1H), 6.61 (s, 1H), 4.14 (d, J= 7.1 Hz, 2H), 3.69 (s, 3H), 1.29 (t, J= 7.6 Hz, 0H), 0.65 – 0.55 (m, 2H), 0.35 (q, J= 4.7 Hz, 2H). | 458 | |
358 | 2-氟-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.14–8.04 (m, 2H), 7.94 (s, 1H), 7.83 (d, 1H), 7.64 (d, 1H), 7.60–7.51 (m, 2H), 7.40 (d, 1H), 6.85 (d, 1H), 6.62 (s, 1H), 5.25 (m, 1H), 3.69 (s, 3H), 1.36 (d, 6H). | 430 | |
359 | 2-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | (CD 3OD, 400 MHz) δ 8.11 (d, J= 2.5 Hz, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.85-7.78 (m, 1H), 7.69-7.63 (m, 1H), 7.58-7.50 (m, 2H), 7.42- 7.34 (m, 1H), 6.89 (d, J= 8.7 Hz, 1H), 6.61 (s, 1H), 4.41-4.33 (m, 2H), 3.67 (s, 3H), 1.40 (t, J= 7.0 Hz, 3H). | 416 | |
360 | 2-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | (CD 3OD, 400 MHz) δ 8.12 – 8.03 (m, 2H), 7.92 (s, 1H), 7.88 – 7.73 (m, 1H), 7.62 (dd, J= 8.7, 2.5 Hz, 1H), 7.61 – 7.50 (m, 2H), 7.41 (t, J= 8.6 Hz, 1H), 6.89 – 6.79 (m, 1H), 6.62 (s, 1H), 4.16 (d, J= 7.1 Hz, 2H), 3.69 (s, 3H), 1.34 – 1.24 (m, 0H), 0.66 – 0.56 (m, 2H), 0.41 – 0.32 (m, 2H). | 442 | |
361 | 2-[4-[4-[6-(環戊氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | (CD 3OD, 400 MHz) δ 8.08 (dd, J= 18.3, 1.5 Hz, 2H), 7.94 (s, 1H), 7.83 (td, J= 8.4, 6.1 Hz, 1H), 7.63 (dd, J= 8.7, 2.5 Hz, 1H), 7.60 – 7.52 (m, 2H), 7.41 (td, J= 8.7, 0.9 Hz, 1H), 6.84 (d, J= 8.7 Hz, 1H), 6.62 (s, 1H), 5.41 – 5.32 (m, 1H), 3.69 (s, 3H), 2.03 – 1.95 (m, 3H), 1.84 (d, J= 11.0 Hz, 5H), 1.68 (s, 3H). | 456 | |
362 | 2-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | (CD 3OD, 400 MHz) δ 8.15 – 8.05 (m, 2H), 7.93 (s, 1H), 7.84 (td, J= 8.5, 6.2 Hz, 1H), 7.65 (dd, J= 8.6, 2.5 Hz, 1H), 7.60 – 7.50 (m, 2H), 7.46 – 7.37 (m, 1H), 6.96 (dd, J= 8.7, 0.7 Hz, 1H), 6.62 (s, 1H), 4.22 – 4.12 (m, 1H), 3.69 (s, 3H), 0.86 – 0.73 (m, 4H). | 428 | |
363 | 2-氯-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 300 MHz) δ 8.13 (d, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.78 (t, 1H), 7.74–7.60 (m, 3H), 7.55 (s, 1H), 6.90 (d, 1H), 6.63 (s, 1H), 5.24 (p, 1H), 3.69 (s, 3H), 1.38 (d, 6H) | 446 | |
364 | 2-氯-6-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.13 (dd, J= 2.5, 0.7 Hz, 1H), 8.05 (d, J= 0.8 Hz, 1H), 7.93 (s, 1H), 7.79 (t, J= 8.2 Hz, 1H), 7.74 – 7.62 (m, 3H), 7.53 (d, J= 0.6 Hz, 1H), 6.99 (dd, J= 8.7, 0.8 Hz, 1H), 6.63 (s, 1H), 4.23 – 4.13 (m, 1H), 3.69 (s, 3H), 2.05 (s, 0H), 0.89 – 0.72 (m, 4H). | 444 | |
365 | 2-氯-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO, 400 MHz) δ 8.19 (s, 1H), 8.09 (d, J= 2.5 Hz, 1H), 7.98 (s, 1H), 7.85 (t, J= 8.2 Hz, 1H), 7.77 (d, J= 8.2, 1H), 7.67 (d, J= 8.2, 1H), 7.55-7.47 (m, 2H), 6.75 (d, J= 8.6 Hz, 1H), 6.45 (s, 1H), 4.31 (q, J= 7.0 Hz, 2H), 3.53 (s, 3H), 1.31 (t, J= 7.0 Hz, 3H). | 432 |
在氮下向5-溴-2-環丙基-吡啶(1 g)在1,4-二噁烷(20 mL)中之攪拌溶液添加4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1,3,2-二氧硼戊烷(2.5 g)、Pd(dppf)Cl
2(27 mg)及乙酸鉀(1.3 g)。隨後將所得混合物除氣三次,並於80℃攪拌2小時。在減壓下蒸發溶劑。將粗標題化合物(800 mg, 65 %)用於下一步驟而無需進一步純化。LCMS (M+H)
+246.
步驟 2:2-氯-6-[4-[4-(6-環丙基-3-吡啶基)-1-甲基-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈
在氮下向2-氯-6-[4-(4-氯-1-甲基-6-側氧-3-吡啶基)吡唑-1-基]苯甲腈 (120 mg, 0.35 mmol)在1,4-二噁烷(10 mL)中之攪拌溶液添加來自步驟1之標題化合物(128 mg, 0.52 mmol)及飽和Na
2CO
3水溶液 (2 mL)。隨後將Pd(PPh
3)
4(80 mg, 0.07 mmol)添加至上述混合物。隨後將所得混合物除氣三次,並於80℃攪拌2小時。將反應混合物用水稀釋,並用乙酸乙酯萃取。將合併的有機層用鹽水洗滌,用硫酸鈉乾燥,並在減壓下濃縮。藉由製備HPLC純化粗產物,得到呈黃色固體的標題化合物(24 mg, 16 %產率)。
1H NMR (300 MHz, DMSO-D6) δ 8.37 (s, 1H), 8.16 (s, 1H) 8.01 (s, 1H), 7.88-7.76 (m, 2H), 7.63 (t, J = 9.0 Hz, 2H), 7.49 (s, 1H), 7.33 (d, J = 4.2 Hz, 1H), 6.48 (s, 1H), 3.53 (s, 3H), 2.20-2.12 (m, 1H), 1.07-0.94 (m, 4H). LCMS (M+H)
+428.
表27中的
實例 367-379係使用適當的吡啶硼酸頻那醇酯及經取代之苯甲腈以與實例366類似的多步驟方式來製備的。
實例 380:2-環丙基-6-[4-[1-甲基-4-(1-甲基-2-側氧-4-吡啶基)-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈
步驟 1:2-環丙基-6-氟苯甲腈
表 27 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
367 | 2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | (DMSO, 300 MHz) δ 8.40 (s, 1H), 8.25 (s, 1H), 8.05 (s, 1H), 7.99-7.84 (m, 1H), 7.73-7.38 (m, 5H), 7.32 (d, J= 7.8 Hz, 1H), 6.48 (s, 1H), 3.53 (d, J= 6.9 Hz, 4H) | 386 | |
368 | 2-氟-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 300 MHz) δ 8.69 – 8.61 (m, 1H), 8.26 – 8.04 (m, 1H), 8.04 – 7.88 (m, 2H), 7.88 – 7.75 (m, 2H), 7.73 – 7.57 (m, 1H), 7.58 – 7.46 (m, 2H), 7.46 – 7.35 (m, 1H), 6.76 (d, J= 38.0 Hz, 1H), 3.70 (d, J= 7.4 Hz, 3H) | 440 | |
369 | 2-氯-6-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 300 MHz) 8.36 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.2, 1.2 Hz, 1H), 7.67 (dd, J = 8.1, 1.2 Hz, 1H), 7.56 (dd, J = 8.0, 2.4 Hz, 1H), 7.46 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.47 (s, 1H), 3.54 (s, 3H), 2.49 (s, 4H). | 402 | |
370 | 2-氯-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO- d 6, 400 MHz) 8.68 (d, J= 2.0 Hz, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.96 (dd, J= 8.1, 2.1 Hz, 1H), 7.92-7.82 (m, 2H), 7.78 (dd, J= 8.2, 1.1 Hz, 1H), 7.65 (dd, J= 8.1, 1.1 Hz, 1H), 7.58 (s, 1H), 6.60 (s, 1H), 3.56 (s, 3H). | 456 | |
371 | 2-氯-6-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 400 MHz) 8.59 (d, J = 2.1 Hz, 1H), 8.15 (s, 1H), 8.08 (s, 1H), 7.92-7.82 (m, 2H), 7.82-7.75 (m, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.62-7.52 (m, 2H), 6.56 (s, 1H), 3.56 (s, 3H), 2.94-2.83 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). | 416 | |
372 | 2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | (DMSO, 400 MHz) δ 8.64 (d, J= 2.1 Hz, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 8.00 – 7.86 (m, 2H), 7.66 – 7.50 (m, 4H), 6.58 (s, 1H), 3.56 (s, 3H), 2.97 – 2.86 (m, 2H), 1.28 (t, J= 7.6 Hz, 3H) | 400 | |
373 | 2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 400 MHz) δ 8.61 (s, 1H), 8.10 (d, J = 15.4 Hz, 2H), 7.99 (dd, J = 7.8, 1.4 Hz, 1H), 7.96 – 7.80 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.62 – 7.54 (m, 3H), 6.57 (s, 1H), 2.90 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). | 382 | |
374 | 2-[4-[4-(6-環丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | (DMSO, 300 MHz) δ 8.40 (d, J =1.8 Hz, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.94-7.86 (m, 1H), 7.67-7.63 (m, 1H), 7.58-7.49 (m, 3H), 7.35 (d, J =8.1 Hz, 1H), 6.49 (s, 1H), 3.53 (s, 3H), 2.22-2.13 (m, 1H), 1.08-1.00 (m, 4H), | 412 | |
375 | 2-氟-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (DMSO, 300 MHz) δ 8.70 (s, 1H), 8.50 (d, J =1.8 Hz, 2H), 8.45 (s, 1H), 7.92-7.85 (m, 1H), 7.77 (d, J =3.2 Hz, 1H), 7.56-7.45 (m, 4H), 6.53 (s, 1H), 3.54 (s, 3H), 1.26 (d, J =6.9 Hz, 6H) | 414 | |
376 | 2-氯-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (DMSO, 300 MHz) δ 8.50 (d, J =1.8 Hz, 1H), 8.06 (d, J =8.1 Hz, 2H), 7.86-7.75 (m, 3H), 7.62-7.55 (m, 2H), 7.46 (d, J =8.4 Hz, 1H), 6.55 (s, 1H), 3.54 (s, 3H), 3.16-3.06 (m, 1H), 1.26 (d, J =6.9 Hz, 6H), | 430 | |
377 | 2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO-d6, 400 MHz) δ 8.66 (d, J = 2.2 Hz, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.99 (ddd, J = 8.0, 6.0, 1.9 Hz, 2H), 7.86 (td, J = 8.0, 7.6, 1.5 Hz, 1H), 7.71 (dd, J = 8.4, 1.1 Hz, 1H), 7.67 – 7.54 (m, 3H), 6.58 (s, 1H), 2.67 (d, J = 12.4 Hz, 0H), 2.63 (s, 3H). | 368 | |
378 | 2-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | (DMSO- d 6,300 MHz,) δ 8.35 (d, J= 2.3 Hz, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.86 (td, J= 8.4, 6.4 Hz, 1H), 7.58 – 7.41 (m, 4H), 7.25 (d, J= 8.1 Hz, 1H), 6.44 (s, 1H), 3.51 (s, 3H), 3.16 (t, J= 7.8 Hz, 1H), 2.05 (s, 0H), 1.97 (d, J= 7.7 Hz, 2H), 1.80 – 1.55 (m, 6H). | 440 | |
379 | 2-氯-6-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO- d 6,400 MHz) δ 8.51 (d, J= 2.2 Hz, 1H), 8.07 (d, J= 15.8 Hz, 2H), 7.84 (t, J= 8.1 Hz, 1H), 7.80 – 7.73 (m, 2H), 7.62 (dd, J= 8.2, 1.2 Hz, 1H), 7.56 (s, 1H), 7.48 (d, J= 8.2 Hz, 1H), 6.53 (s, 1H), 3.55 (s, 3H), 3.26 (p, J= 8.1 Hz, 1H), 2.04 (t, J= 9.4 Hz, 2H), 1.84 – 1.48 (m, 6H). | 456 |
在N
2下向2-溴-6-氟-苯甲腈(5 g, 25 mmol)在1,4-二噁烷(150 mL)中之攪拌溶液依次添加2-環丙基-4,4,5,5-四甲基-1,3,2-二氧硼戊烷(6.3 g, 37.5 mmol)、作為在水(40 mL)中的溶液之Na
2CO
3(7.95 g, 75 mmol)及Pd(dppf)Cl
2.DCM (2.04 g, 2.5 mmol)。將反應在80℃攪拌隔夜。在減壓下移除1,4-二噁烷。所得混合物用水稀釋,並用EtOAc萃取。將合併的有機層用鹽水洗滌,濃縮,並藉由矽膠管柱層析法(PE/EA=20/1)純化,得到呈灰白色固體的標題化合物(3.06 g, 76%)。
步驟 2:2-環丙基-6-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑-1-基)苯甲腈
在N
2下向0℃的4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡唑 (1 g, 5.15 mmol) 在DMF (10 mL)中之攪拌溶液部分地添加NaH (310 mg, 12.9 mmol)。將所得混合物攪拌20分鐘。添加來自步驟1之標題化合物(1 g, 6.2 mmol)在DMF中之溶液。將所得混合物在0℃攪拌30分鐘及在30℃攪拌3小時。藉由添加水中止反應,並用EtOAc萃取。將合併的有機層用鹽水洗滌,用硫酸鈉乾燥,過濾,並在減壓下濃縮,得到呈黃色油的標題化合物(1.3 g),此標題化合物用於後續步驟中而無需進一步純化。LCMS (M+H)
+336.
步驟 3:2-(4-(4-氯-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-6-環丙基苯甲腈
在N
2下向來自步驟2之標題化合物(3 g, 8.95 mmol)在1,4-二噁烷(60 mL)中之攪拌溶液添加5-溴-4-氯-1-甲基-吡啶-2-酮(1.99 g, 8.95 mmol)、K
3PO
4(4.74 g, 22.37 mmol)在水(12 mL)中之溶液及Pd(dppf)Cl
2(1.3 g, 1.79 mmol)。將反應升溫至80℃經歷3小時。將混合物冷卻至室溫,用水中止,並用EtOAc萃取。將合併的有機層用鹽水洗滌,濃縮,並藉由矽膠管柱層析法(EtOAc)純化,得到呈黃色固體的標題化合物(1.5 g)。LCMS (M+H)
+351.
步驟 4:2-環丙基-6-[4-[1-甲基-4-(1-甲基-2-側氧-4-吡啶基)-6-側氧-3-吡啶基]吡唑-1-基]苯甲腈
藉由用來自步驟3之標題化合物代替3-(4-(4-氯-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈以與實例305步驟2類似的方式來製備標題化合物。
1H NMR (CD
3OD, 400 MHz) δ 8.02 (d, J = 0.7 Hz, 1H), 7.94 (s, 1H), 7.74-7.59 (m, 2H), 7.47 (dd, J = 8.1, 1.1 Hz, 1H), 7.18-7.11 (m, 1H), 6.62-6.52 (m, 2H), 6.22 (dd, J = 6.9, 1.9 Hz, 1H), 3.69 (s, 3H), 3.57 (s, 3H), 2.39-2.27 (m, 1H), 1.27-1.17 (m, 2H), 0.95-0.86 (m, 2H). LCMS (M+H)
+424.
表28中的
實例 381-391係使用步驟4中的適當硼酸衍生物以與實例380類似的多步驟方式來製備的。
實例 392:4-乙氧基-5-(5-甲磺醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-1-甲基-1H-吡啶-2-酮
步驟 1:2-[苄基-(2H-吡唑-3-基甲基)-胺基]-乙醇
表 28 | ||||
實例 | 結構 | IUPAC 名稱 | 1H NMR (ppm) | MS (M+H) |
381 | 2-環丙基-6-[4-[4-[1-(環丙基甲基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.00 (d, J= 0.7 Hz, 1H), 7.94 (s, 1H), 7.72-7.62 (m, 3H), 7.44 (dd, J= 8.1, 1.0 Hz, 1H), 7.14 (d, J= 8.0 Hz, 1H), 6.63-6.53 (m, 2H), 6.21 (dd, J= 6.9, 2.0 Hz, 1H), 3.85 (d, J= 7.2 Hz, 2H), 3.69 (s, 3H), 2.39-2.27 (m, 1H), 1.22-0.89 (m, 3H), 0.61-0.50 (m, 2H), 0.50-0.37 (m, 2H). | 464 | |
382 | 2-環丙基-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO, 400 MHz) δ 8.05-7.99 (m, 2H), 7.90 (s, 1H), 7.66 (t, J= 8.0 Hz, 1H), 7.57-7.50 (m, 1H), 7.36 (t, J= 11.5 Hz, 2H), 7.09 (d, J= 8.0 Hz, 1H), 6.78 (d, J= 8.6 Hz, 1H), 6.46 (s, 1H), 4.29 (t, J= 6.1 Hz, 2H), 3.52 (s, 3H), 3.22-3.13 (m, 2H), 2.77 (s, 6H), 2.24-2.14 (m, 1H), 2.13-2.02 (m, 2H), 1.19-1.07 (m, 2H), 0.87-0.80 (m, 2H) | 495 | |
383 | 2-環丙基-6-(4-(6-甲氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (DMSO, 400 MHz) δ 8.13 (2, J= 2.6, 1H), 8.07 (d, J= 0.7 Hz, 1H), 7.99 (s, 1H), 7.70 (t, J= 8.0 Hz, 1H), 7.55-7.49 (m, 1H), 7.46 (d, J= 0.7 Hz, 1H), 7.41 (d, J= 8.1, 1H), 7.14 (d, J= 8.0 Hz, 1H), 6.79 (d, J= 8.6, 1H), 6.45 (s, 1H), 3.87 (s, 3H), 3.53 (s, 3H), 2.32-2.20 (m, 1H), 1.27-1.13 (m, 2H), 0.94-0.85 (m, 2H). | 424 | |
384 | 2-環丙基-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.10 (d, J= 2.5 Hz, 1H), 7.94 (d, 2H), 7.68- 7.58 (m, 2H), 7.46 (d, J= 0.7 Hz, 1H), 7.40-7.36 (m, 1H), 7.14-7.10 (m, 1H), 6.87-6.81 (m, 1H), 6.59 (s, 1H), 4.38-4.31 (m, 2H), 3.66 (s, 3H), 2.35-2.26 (m, 1H), 1.38 (t, J= 7.0 Hz, 3H), 1.23-1.16 (m, 2H), 0.91-0.85 (m, 2H). | 438 | |
385 | 2-環丙基-6-[4-[1-甲基-6-側氧-4-(2-側氧-1-丙基-4-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.00 (s, 1H), 7.94 (s, 1H), 7.71-7.62 (m, 2H), 7.60 (d, J= 7.0 Hz, 1H), 7.47-7.40 (m, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.60 (s, 1H), 6.55 (d, J= 1.9 Hz, 1H), 6.25-6.18 (m, 1H), 4.01-3.92 (m, 2H), 3.69 (s, 3H), 2.39-2.27 (m, 1H), 1.85-1.71 (m, 2H), 1.27-1.17 (m, 2H), 0.99-0.86 (m, 5H). | 452 | |
386 | 2-環丙基-6-[4-[4-(1-乙基-2-側氧-4-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.02 (s, 1H), 7.93 (s, 1H), 7.71-7.60 (m, 3H), 7.52-7.41 (m, 1H), 7.15 (d, J= 8.0 Hz, 1H), 6.62-6.52 (m, 2H), 6.27-6.19 (m, 1H), 4.09-3.99 (m, 2H), 3.69 (s, 3H), 2.39-2.27 (m, 1H), 1.40-1.31 (m, 3H), 1.27-1.17 (m, 2H), 0.98-0.86 (m, 2H). | 438 | |
387 | 2-環丙基-6-[4-[4-[6-(2-氟乙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 8.12 (d, J= 2.5 Hz, 1H), 7.98 – 7.90 (m, 2H), 7.67 (t, J= 8.1 Hz, 1H), 7.59 (dd, J= 8.6, 2.5 Hz, 1H), 7.47 (d, J= 0.7 Hz, 1H), 7.40 (dd, J= 8.0, 1.0 Hz, 1H), 7.16 (d, J= 7.8 Hz, 1H), 6.85 (d, J= 8.6 Hz, 1H), 6.62 (s, 1H), 4.83 – 4.76 (m, 1H), 4.71 – 4.64 (m, 1H), 4.64 – 4.57 (m, 1H), 4.57 – 4.50 (m, 1H), 3.69 (s, 3H), 2.41 – 2.29 (m, 1H), 1.28 – 1.18 (m, 2H), 0.92 (dt, J= 6.8, 4.7 Hz, 2H). | 456 | |
388 | 2-環丙基-6-(4-(1'-環丙基-1-甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲腈 | (CD 3OD, 400 MHz) δ 8.00 (s, 1H), 7.93 (s, 1H), 7.74-7.62 (m, 2H), 7.58 (d, J = 7.1 Hz, 1H), 7.46 (dd, J = 8.1, 1.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.58 (s, 1H), 6.53 (d, J = 1.9 Hz, 1H), 6.18 (dd, J = 7.1, 2.0 Hz, 1H), 3.68 (s, 3H), 3.40-3.29 (m, 1H), 2.38-2.26 (m, 1H), 1.28-1.17 (m, 2H), 1.20-1.05 (m, 2H), 1.01-0.86 (m, 4H). | 450 | |
389 | 2-環丙基-6-[4-[4-[1-(2-氟乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (CD 3OD, 400 MHz) δ 7.99 (d, J= 0.7 Hz, 1H), 7.95 (s, 1H), 7.72 (d, J= 0.7 Hz, 1H), 7.70-7.61 (m, 1H), 7.59 (d, J= 7.0 Hz, 1H), 7.46-7.39 (m, 1H), 7.15 (d, J= 7.9 Hz, 1H), 6.61 (s, 1H), 6.57 (d, J= 1.9 Hz, 1H), 6.24-6.17 (m, 1H), 4.77 (s, 0H), 4.70-4.63 (m, 1H), 4.38-4.30 (m, 1H), 4.28 (t, J= 4.8 Hz, 1H), 3.69 (s, 3H), 2.39-2.27 (m, 1H), 1.27-1.17 (m, 2H), 0.95-0.86 (m, 2H). | 456 | |
390 | 2-環丙基-6-[4-[4-[1-(2-羥基乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | (DMSO- d 6, 300 MHz) δ 8.07 (s, 1H), 8.00 (s, 1H), 7.66 (s, 2H), 7.66 (d, J= 16.2 Hz, 1H), 7.52 (d, J= 6.9 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 7.11 (d, J= 8.0 Hz, 1H), 6.40-6.27 (m, 2H), 5.98-5.89 (m, 1H), 3.90 (t, J= 5.5 Hz, 2H), 3.61 (d, J= 5.6 Hz, 2H), 3.50 (s, 3H), 2.24 (s, 0H), 1.15 (d, J= 7.7 Hz, 2H), 0.86 (d, J= 5.6 Hz, 2H). | 454 | |
391 | 2-環丙基-6-(4-(6-(環丙基甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | (400 MHz, CD 3OD ) δ 8.06 (d, J = 2.5 Hz, 1H), 7.93 (s, 1H), 7.89 (s, 1 H), 7.67 (t, J = 8.0 Hz, 1H), 7.57 (dd, J = 8.6, 2.5 Hz, 1H), 7.47 (s, 1H), 7.44 – 7.37 (m, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 6.61 (s, 1H), 4.15 (d, J = 7.1 Hz, 2H), 3.69 (s, 3H), 2.40 – 2.29 (m, 1H), 1.34 – 1.18 (m, 3H), 0.96 – 0.87 (m, 2H), 0.64 – 0.55 (m, 2H), 0.40 – 0.31 (m, 2H). | 464 |
將2H-吡唑-3-甲醛(1.6 g, 10.6 mmol)及2-苄基胺基-乙醇(1.0 g, 10.4)在MeOH (40 mL)中之溶液在室溫下攪拌1小時。添加NaBH(OAc)
3(6.6 g, 31.1 mmol)及AcOH (1 mL),並將混合物攪拌4小時。將混合物用NaHCO
3(50 mL)中止,並用DCM (40 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮。標題化合物(2.4 g, 10.4 mmol)用於後續步驟而無需進一步純化。LCMS (M+H)
+232.
步驟 2:5-苄基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪
向0℃的來自步驟1之標題化合物(2.4 g, 10.4 mmol)在DCM (40 mL)中之溶液添加SOCl
2(10 mL)。將混合物升溫至室溫,並攪拌隔夜。在減壓下移除溶劑。將殘餘物溶於DMF (30 mL)中,繼之以添加NaH (2.2 g, 55 mmol),並攪拌3小時。將混合物用H
2O (30 mL)中止,並用DCM (40 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由矽膠管柱層析法用PE/EtOAc (1:1)溶離來純化殘餘物,得到標題化合物(460 mg, 2.2 mmol)。
1H NMR (300 MHz, CDCl
3) δ 7.46 (s, 1H), 7.38-7.31 (m, 5H), 5.96 (s, 1H), 4.21 (t, J = 5.4 Hz, 2H), 3.73 (s, 2H), 3.70 (s, 2H), 2.96 (t, J = 5.4 Hz, 2H). LCMS (M+H)
+214.
步驟 3:6,7-二氫-4H-吡唑并[1,5-a]吡嗪-5-甲酸第三丁酯
向室溫下的來自步驟2之標題化合物(460 mg, 2.2 mmol)在MeOH (20 mL)中之溶液添加Pd(OH)
2/C (60 mg)及(Boc)
2O (1.2 g, 5.4 mmol)。將反應在H
2氣氛下攪拌隔夜。過濾混合物,並在減壓下濃縮濾液。藉由矽膠管柱層析法用PE/EtOAc (1:1)溶離來純化殘餘物,得到呈無色油的標題化合物(400 mg, 1.8 mmol)。LCMS (M+H)
+224.
步驟 4:3-溴-6,7-二氫-4H-吡唑并[1,5-a]吡嗪-5-甲酸第三丁酯
將室溫下的來自步驟3之標題化合物(400 mg, 1.8 mmol)及NBS (318 mg, 1.8 mmol)在DCM (200 mL)中之溶液在室內攪拌隔夜。將混合物用NH
4Cl水溶液(50 mL)稀釋,並用DCM (30 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮,得到標題化合物(450 mg, 1.5 mmol),此標題化合物用於下一步驟中而無需進一步純化。LCMS (M+H)
+302.
步驟 5:3-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-6,7-二氫-4H-吡唑并[1,5-a]吡嗪-5-甲酸第三丁酯
將來自步驟4之標題化合物(210 mg, 0.70 mmol)、4-乙氧基-1-甲基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼戊烷-2-基)-1H-吡啶-2-酮(190 mg, 0.69 mmol)、Pd(dppf)Cl
2(50 mg, 0.07 mmol)及Na
2CO
3(288 mg, 2.7 mmol)在二噁烷/H
2O混合物(15 mL/3 mL)中之混合物在N
2下於110℃攪拌4小時。將混合物冷卻至室溫,並用DCM (30 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備TLC用DCM/MeOH (30:1)溶離來純化殘餘物,得到標題化合物(103 mg, 0.28 mmol)。LCMS (M+H)
+375.
步驟 6:4-乙氧基-1-甲基-5-(4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-1H-吡啶-2-酮
將來自步驟5之標題化合物(100 mg, 0.27 mmol)在DCM/TFA (5 mL/5 mL)混合物中之溶液在室溫下攪拌4小時。在減壓下移除溶劑。將殘餘物溶於DCM (20 mL),並用H
2O (40 mL)洗滌。將有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮,得到呈黃色油的標題化合物(40 mg, 0.15 mmol),此標題化合物用於後續步驟中而無需進一步純化。LCMS (M+H)
+275.
步驟 7:4-乙氧基-5-(5-甲磺醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-1-甲基-1H-吡啶-2-酮
將來自步驟6之標題化合物(30 mg, 0.11 mmol)、MsCl (25 mg, 0.22 mmol)及Et
3N (33 mg, 0.33 mmol)在DCM (10 mL)中之混合物在室溫下攪拌2小時。隨後用H
2O (50 mL)稀釋,並用DCM (20 mL×3)萃取。將合併的有機層用Na
2SO
4乾燥,過濾,並在減壓下濃縮。藉由製備TLC用DCM/MeOH (25:1)溶離來純化殘餘物,得到呈白色固體的標題化合物(17 mg, 0.05 mmol)。
1H NMR (400 MHz, CD
3OD) δ 7.57 (s, 1H), 7.55 (s, 1H), 6.01 (s, 1H), 4.52 (s, 2H), 4.27 (t, J = 5.2 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.81 (t, J = 5.4 Hz, 2H), 3.52 (s, 3H), 2.98 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). LCMS (M+H)
+353.
實例 393:5-(5-乙醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-4-乙氧基-1-甲基-1H-吡啶-2-酮
藉由用乙醯基氯化物代替步驟7中的甲磺醯基氯化物以與實例392類似的方式來製備標題化合物。
1H NMR (CD
3OD, 400 MHz) 7.56-7.54 (m, 2H), 6.02 (s, 1H), 4.77 (d, J = 6.0 Hz, 2H), 4.29-4.01 (m, 6H), 3.52 (s, 3H), 2.23 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). LCMS (M+H)
+317.
實例 394:1-甲基-4-苯基-5-(5-苯基噁唑-2-基)吡啶-2(1H)-酮
步驟 1:5-溴-2-甲氧基-4-苯基吡啶
將溴苯(4.1 g, 25.9 mmol)、(5-溴-2-甲氧基-4-吡啶基)硼酸(3 g, 12.9 mmol)、Pd(PPh
3)
4(2.99 g, 2.6 mmol)、Na
2CO
3(4.11 g, 38.8 mmol)在1,4-二噁烷(20 mL)及水(3 mL)中之溶液在氮氣氛下於60℃攪拌3小時。將反應混合物用水(100 mL)中止,並用EtOAc (2×100 mL)萃取。將有機層用Na
2SO
4乾燥,過濾,並濃縮。藉由矽膠管柱層析法(石油醚中0至25% EtOAc)純化粗產物,得到呈白色固體的標題化合物(1.2 g, 35%)。(M+H)
+263/265.
步驟 2:2-甲氧基-4-苯基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶
將5-溴-2-甲氧基-4-苯基-吡啶e (500 mg, 1.9 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1,3,2-二氧硼戊烷(961 mg, 3.79 mmol)、Pd(dppf)Cl
2(277 mg, 0.38 mmol)、KOAc (557 mg, 5.68 mmol)及DMSO (5 mL)之混合物在氮氣氛下於80℃攪拌隔夜。將反應混合物用水稀釋,並用EtOAc萃取。將有機層用硫酸鈉乾燥,在減壓下濃縮,並藉由矽膠管柱層析法(PE/EA=50/1)純化,得到呈白色固體的標題化合物(300 mg)。LCMS (M+H)
+312.
步驟 3:2-(6-甲氧基-4-苯基吡啶-3-基)-5-苯基噁唑
在氮氣氛下向2-溴-5-苯基-噁唑(200 mg, 0.89 mmol)、2-甲氧基-4-苯基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶(305 mg, 0.98 mmol)、Xphos Pd G3 (151 mg, 0.18 mmol)在1,4-二噁烷(5 mL)中之混合物添加Cs
2CO
3(872 mg, 2.68 mmol)在水(0.5 mL)中之溶液。將反應在60℃攪拌隔夜。隨後冷卻至室溫,用水稀釋,並用EtOAc萃取。將有機層用硫酸鈉乾燥,並在減壓下濃縮。藉由矽膠管柱層析法(EA/PE=1/50)純化殘餘物,得到標題化合物(100 mg, 34%)。LCMS (M+H)
+329.
步驟 4:4-苯基-5-(5-苯基噁唑-2-基)吡啶-2-醇
將2-(6-甲氧基-4-苯基-3-吡啶基)-5-苯基-噁唑(100 mg, 0.3 mmol)及HBr(水溶液)(10 mL, 40 mmol)在乙醇(10 mL)中之混合物於80℃攪拌隔夜。將混合物冷卻至室溫,用水稀釋,用EtOAc萃取。將有機層用鹽水洗滌,在減壓下濃縮,並藉由管柱層析法(DCM/MeOH=30/1)純化,得到呈黃色固體的所需產物(80 mg, 84%)。LCMS (M+H)
+315.
步驟 5:1-甲基-4-苯基-5-(5-苯基噁唑-2-基)吡啶-2(1H)-酮
在0℃向4-苯基-5-(5-苯基噁唑-2-基)吡啶-2-醇(80 mg, 0.32 mmol)在DMF (2 mL)中之攪拌溶液逐部分地添加NaH (31.8 mg, 0.80 mmol)。將所得混合物於0℃攪拌30分鐘。添加CH
3I (54.2 mg, 0.38 mmol)。將所得混合物在室溫下攪拌2小時。將反應混合物用水稀釋,並用EtOAc萃取。將有機層用硫酸鈉乾燥,過濾,濃縮,並藉由製備HPLC純化,得到呈白色固體的標題化合物(37.4 mg, 45%)。
1H NMR (DMSO-d
6, 300 MHz) δ 8.56 (s, 1H), 7.64 (s, 1H), 7.49-7.39 (m, 3H), 7.39-7.21 (m, 7H), 6.41 (s, 1H), 3.61 (s, 3H). LCMS (M+H)
+329.
實例 395:1-甲基-5-(1-甲基-5-苯基-1H-吡唑-3-基)-4-苯基吡啶-2(1H)-酮
步驟 1:4-溴-5-氯吡啶-2-醇
向4-溴-5-氯-吡啶-2-胺(1 g, 4.8 mmol)在水(2 mL)中之攪拌溶液逐滴添加H
2SO
4(2.5 mL)。隨後用NaNO
2(399 mg, 5.8 mmol)在水(2 mL)中之溶液逐滴處理混合物。在將反應在N
2下於20℃攪拌30分鐘後,過濾混合物。在真空下乾燥濾餅,得到呈黃色固體的標題化合物(950 mg, 95 %),此標題化合物在後續步驟中直接使用。
步驟 2:4-溴-5-氯-1-甲基吡啶-2(1H)-酮
在氮下於0℃向4-溴-5-氯-吡啶-2-醇(950 mg, 4.56 mmol)在DMF (10mL)中之攪拌溶液添加K
2CO
3(966 mg, 9.12 mmol)及碘甲烷(970 mg, 6.84 mmol)。將所得溶液於0℃攪拌一小時。將反應混合物用水(10 mL)中止,並用EtOAc (2×50 mL)萃取。將有機層用Na
2SO
4乾燥,過濾,並濃縮。藉由矽膠管柱層析法(石油醚中0至25% EtOAc)純化殘餘物,得到呈黃色固體的標題化合物(950 mg, 94%)。LCMS (M+H)
+222.
步驟 3:5-氯-1-甲基-4-苯基吡啶-2(1H)-酮
向4-溴-5-氯-1-甲基-吡啶-2-酮(500 mg, 2.25 mmol)在1,4-二噁烷(5mL)及水(1mL)中之攪拌溶液添加苯基硼酸(329 mg, 2.7 mmol)、Na
2CO
3(715 mg, 6.74 mmol)及Pd(PPh
3)
4(519 mg, 0.45 mmol)。將混合物在N
2下於80℃攪拌12小時。將反應混合物冷卻至室溫,用水(10 mL)中止,並用EtOAc (2×50 mL)萃取。將有機層用Na
2SO
4乾燥,過濾,並濃縮。藉由矽膠管柱層析法(石油醚中0至25% EtOAc)純化殘餘物,得到呈黃色固體的標題化合物(250 mg, 51%)。
步驟 4:1-甲基-4-苯基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-2(1H)-酮
在氮下於室溫下向4,4,5,5-四甲基-2- 5-氯-1-甲基-4-苯基-吡啶-2-酮(1 g, 4.55 mmol)在1,4-二噁烷(20 mL)中之攪拌溶液添加(4,4,5,5-四甲基-1, 3, 2-二氧硼戊烷-2-基)-1,3,2-二氧硼戊烷(2.3 g, 9.1 mmol)、K
3PO
4(2.9 g, 13.66 mmol)、SPhos (374 mg, 0.91 mmol)及Pd(OAc)
2(102 mg, 0.46 mmol)。將所得溶液於25℃攪拌12小時。將反應混合物冷卻至室溫,用水(10 mL)中止,並用EtOAc (2×50 mL)萃取。將有機層用Na
2SO
4乾燥,過濾,並蒸發。藉由矽膠管柱層析法(石油醚中0至25% EtOAc)純化殘餘物,得到呈黃色油的標題化合物(500 mg, 35%)。LCMS (M+H)
+312.
步驟 5:1-甲基-5-(1-甲基-5-苯基-1H-吡唑-3-基)-4-苯基吡啶-2(1H)-酮
在氮氣下於25℃向1-甲基-4-苯基-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)吡啶-2-酮(394 mg, 1.27 mmol)在1,4-二噁烷(10 mL)及水(1 mL)中之攪拌溶液添加3-溴-1-甲基-5-苯基-吡唑(200 mg, 0.84 mmol)、Na
2CO
3(268 mg, 2.53 mmol)及Pd(PPh
3)
4(195 mg, 0.17 mmol)。將所得溶液於60℃攪拌12小時。將反應混合物冷卻至室溫,用水(10 mL)中止,並用EtOAc (2×50 mL)萃取。將有機層用Na
2SO
4乾燥,過濾,並蒸發。藉由製備HPLC(45至75% ACN/水/0.05% TFA)純化粗產物,得到呈白色固體的標題化合物(26.6 mg)。
1H NMR (DMSO, 400 MHz) δ 8.05 (s, 1H), 7.47-7.37 (m, 6H) 7.33-7.30 (m, 2H), 7.28-7.24 (m, 2H), 6.35 (s, 1H), 5.42 (s, 1H), 3.81 (s, 3H), 3.53 (s, 3H). LCMS (M+H)
+342.
實例 396:1-甲基-4-苯基-5-(2-苯基噁唑-4-基)吡啶-2(1H)-酮
藉由用4-溴-2-苯基-噁唑代替步驟5中的3-溴-1-甲基-5-苯基-吡唑以與實例395類似的方式來製備標題化合物。
1H NMR (DMSO, 400 MHz) δ = 8.26 (s, 1H), 7.93-7.91 (m, 2H), 7.91-7.51 (m, 3 H), 7.47-7.43 (m, 3H), 7.34-7.30 (m, 2H), 6.85(s, 1H), 6.34 (s, 1H), 3.59 (s, 3H). LCMS (M+H)
+329.
實例 397:1-甲基-4-苯基-5-(2-苯基噁唑-5-基)吡啶-2(1H)-酮
藉由用5-溴-2-苯基-噁唑代替步驟5中的3-溴-1-甲基-5-苯基-吡唑以與實例395類似的方式來製備標題化合物。
1H NMR (DMSO, 400 MHz) δ = 8.36 (s, 1H), 7.78-7.75 (m, 2H), 7.48-7.44 (m, 6H), 7.33-7.31 (m, 2H), 6.47 (s, 1H), 6.39 (s, 1H), 3.58 (s, 3H). LCMS (M+H)
+329.
II. 生物評估 實例 1:活體外CBP抑制
藉由計算IC 50決定本文所描述化合物之CBP抑制活性。更具體而言,CBP抑制劑活性如下檢定:CBP在大腸桿菌中經選殖並表現為His-標籤蛋白,並藉由鎳親和層析及凝膠過濾層析純化。藉由SDS-PAGE將蛋白質進一步表徵為具有正確分子量的單一條帶。使用AlphaScreen技術(Perkin Elmer)經由監測生物素化的H4-四乙醯胜肽(AnaSpec,H4K5/8/12/16 (Ac),生物素標記的)與靶的相互作用來評估CBP結合與抑制。在384孔ProxiPlate中,在DMSO(最終0.4%DMSO)或DMSO中的化合物稀釋系列之任一者存在下,將CBP(最終濃度50nM)與50mM HEPES (pH 7.3)中的胜肽(最終濃度20nM)、10mM NaCl、0.25mM TCEP、0.1% (w/v) BSA及0.005% (w/v) Brij-35化合。在室溫下培養20分鐘後,加入α-抗生蛋白鏈菌素供體珠及鎳螯合物受體珠以達到5 μg/ mL的最終濃度。在平衡2小時後,在Envision儀器上讀板,並使用四參數非線性曲線擬合計算IC
50。
量化本文揭示的化合物抑制CBP活性的能力並決定各別的IC
50值。各種化合物之CBP IC
50值示於表29中,其中IC
50數據指定在以下範圍內:A:≤0.5 μM;B:>0.5 μM至≤5.0 μM;C:>5.0 μM。
實例 2:活體外酶抑制檢定-BRD4抑制
表 29 | |||
實例 | 結構 | 名稱 | CBP IC 50(μM) |
1 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | B | |
2 | 5-(1-(環丙基(苯基)甲基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | B | |
3 | 2-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈 | B | |
4 | 3-((4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲腈 | B | |
5 | 1-甲基-5-(1-(吡啶-2-基甲基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
6 | 5-(1-(4-氟苄基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | B | |
7 | 5-(1-苄基-1H-吡唑-4-基)-1,4-二甲基吡啶-2(1H)-酮 | A | |
8 | 4-(1-苄基-1H-吡唑-4-基)-2-甲基異喹啉-1(2H)-酮 | A | |
9 | 4-(1-苄基-1H-吡唑-4-基)-2-甲基-2,6-口奈啶基-1(2H)-酮 | A | |
10 | 5-(1-苄基-1H-吡唑-4-基)-1-乙基吡啶-2(1H)-酮 | B | |
11 | 5-(1-(1-(3-(二氟甲基)苯基)乙基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮 | A | |
12 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
13 | 5-(1-苄基-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮 | A | |
14 | (S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
15 | (R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
16 | 3-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈 | B | |
17 | 1,3-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
18 | 5-(1-(環丙基(苯基)甲基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮 | A | |
19 | 5-(1-(1-(2-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | A | |
20 | 1-甲基-5-(1-(1-(間甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
21 | 4-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
22 | 1-甲基-5-(1-(1-(鄰甲苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
23 | 5-(1-(1-(3-氯苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | A | |
24 | 1-甲基-5-(1-(1-(吡啶-3-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
25 | 4-(1-(4-(1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙基)苯甲腈 | B | |
26 | 3-氟-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
27 | 5-(1-(1-(2-甲氧基苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)‑酮 | A | |
28 | 5-(1-(1-(3-甲氧基苯基)乙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | A | |
29 | 1-甲基-5-(1-(1-(吡啶-4-基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
30 | 1,3,4-三甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
31 | 3-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
32 | 3-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
33 | 2-甲基-4-(1-(1-苯基乙基)-1H-吡唑-4-基)-2,5,6,7-四氫-1H-環戊[c]吡啶-1-酮 | A | |
34 | 1,3-二甲基-5-(5-甲基-1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
35 | 5-(1-苄基-1H-吡唑-4-基)-1-(二氟甲基)-4-苯基吡啶-2(1H)-酮 | B | |
36 | 4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
37 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-甲磺醯基-吡咯啶-1-基)-1-甲基-1H-吡啶-2-酮 | A | |
38 | 4-氯-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
39 | 4-乙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
40 | 4-(吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
41 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | A | |
42 | 1-甲基-4-(甲胺基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
43 | 1-甲基-4-嗎啉基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
44 | 1-甲基-4-((1-甲基-1H-吡唑-3-基)甲氧基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
45 | (R)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
46 | (S)-4-異丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
47 | (S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | A | |
48 | 4-異丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
49 | 4-環丁氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
50 | 4-((1-乙醯基吖丁啶-3-基)氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
51 | 4-(環戊氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
52 | 4-(環己氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
53 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | A | |
54 | 1-甲基-4-(3-甲基吖丁啶-1-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
55 | (R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | A | |
56 | 4-(苄氧基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
57 | 1-甲基-4-苯氧基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
58 | 4-(3-甲氧基吖丁啶-1-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
59 | 4-環丙氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
60 | (S)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | A | |
61 | (R)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | A | |
62 | 4-乙氧基-1-甲基-5-(1-(1-(對甲苯基) 乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
63 | 5-(1-(1-([1,1'-聯苯基]-4-基)乙基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
64 | 5-(1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
65 | 4-乙氧基-1-甲基-5-(1-(4-甲苄基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
66 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-1-基)吡啶-2(1H)-酮 | B | |
67 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-嗎啉基吡啶-2(1H)-酮 | A | |
68 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡咯-1-基)吡啶-2(1H)-酮 | A | |
69 | 4-乙氧基-1-甲基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
70 | 甲基2-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯 | A | |
71 | 甲基3-((4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)甲基)苯甲酸酯 | A | |
72 | (R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-基)乙醯胺 | B | |
73 | (S)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)吡咯啶-3-基)乙醯胺 | B | |
74 | (R)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-甲酸 | A | |
75 | (S)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-甲酸 | A | |
76 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺 | A | |
77 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基)-1H-吡咯-3-甲酸甲酯 | A | |
78 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N,N-二甲基-1H-吡咯-3-甲醯胺 | A | |
79 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | A | |
80 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-腈 | A | |
81 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-乙基-1H-吡咯-3-甲醯胺 | A | |
82 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-異丙基-1H-吡咯-3-甲醯胺 | A | |
83 | 1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-(1H-吡咯-1-基)吡啶-2(1H)-酮 | A | |
84 | 1-(1-甲基-5-(1-甲基-1H-吡唑-4-基)-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | A | |
85 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲醯胺 | A | |
86 | 1-(5-(1-(環丙基甲基)-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡咯-3-甲酸 | A | |
87 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-吡咯啶-1-基-1H-吡啶‑2-酮 | A | |
88 | (R)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-甲基吡咯啶-3-甲醯胺 | A | |
89 | (S)-N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基甲基}-乙醯胺 | A | |
90 | (R)-N-{1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-基甲基}-乙醯胺 | B | |
91 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2,2,2-三氟-乙氧基)吡啶-2(1H)-酮 | A | |
92 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3,3,3-三氟-丙氧基)吡啶-2(1H)-酮 | A | |
93 | (S)-1-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-吡咯啶-3-甲酸甲基乙醯胺 | A | |
94 | 5-(1-苄基-1H-吡唑-4-基)-4-(1H-咪唑-1-基)-1-甲基吡啶-2(1H)-酮 | A | |
95 | 5-(5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
96 | 4-乙氧基-1-甲基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
97 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
98 | 5-(1-(2,6-二氯苯基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
99 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(2-甲基肼基)吡啶-2(1H)-酮 | B | |
100 | 4-乙氧基-1-甲基-5-(1-{1-[4-(1-甲基-1H-吡唑-4-基)-苯基]-乙基}-1H-吡唑-4-基)-1H-吡啶-2-酮 | A | |
101 | 4-乙氧基-5-[1-(4-異丙基-苄基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | A | |
102 | 4-乙氧基-1-甲基-5-(1-(4-(1-甲基-1H-吡唑-4-基)苄基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
103 | 5-(1-(4-(1H-吡唑-4-基)苄基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
104 | 4-乙氧基-1-甲基-5-(1-(1-(3-(1-甲基-1H-吡唑-4-基)苯基)乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
105 | 5-(1-(3-溴苄基)-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
106 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(鄰甲苯基)吡啶-2(1H)-酮 | B | |
107 | 1-甲基-5-(1-甲基-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | A | |
108 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
109 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-3-基)吡啶-2(1H)-酮 | B | |
110 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮 | B | |
111 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(間甲苯基)吡啶-2(1H)-酮 | A | |
112 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(對甲苯基)吡啶-2(1H)-酮 | A | |
113 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-甲氧基苯基)-1-甲基吡啶-2(1H)-酮 | A | |
114 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-5-基)吡啶-2(1H)-酮 | A | |
115 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮 | A | |
116 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-2-基)吡啶-2(1H)-酮 | A | |
117 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(噻吩-3-基)吡啶-2(1H)-酮 | A | |
118 | 5-(1-苄基-1H-吡唑-4-基)-4-(3-氯苯基)-1-甲基吡啶-2(1H)-酮 | A | |
119 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基吡啶-2(1H)-酮 | A | |
120 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-甲氧基苯基)-1-甲基吡啶-2(1H)-酮 | A | |
121 | 5-(1-苄基-1H-吡唑-4-基)-4-(異噁唑-3-基)-1-甲基吡啶-2(1H)-酮 | A | |
122 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | A | |
123 | 5-(1-苄基-1H-吡唑-4-基)-4-(2-氯苯基)-1-甲基吡啶-2(1H)-酮 | B | |
124 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-[4,4'-聯吡啶]-2(1H)-酮 | A | |
125 | 5-(1-環己基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
126 | 1-甲基-4-苯基-5-(1-(四氫-2H-哌喃-4-基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
127 | 1-甲基-5-(1-(1-(甲磺醯基) 哌啶-4-基)-1H-吡唑-4-基)-4-苯基-吡啶-2(1H)-酮 | A | |
128 | 1-甲基-4-苯基-5-(1-苯基-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
129 | 1-甲基-5-(1-((甲磺醯基)甲基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | A | |
130 | 1-甲基-5-(1-(2-嗎啉基乙基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | A | |
131 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-[2,4'-聯吡啶]-2'(1'H)-酮 | B | |
132 | 5-(1-乙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
133 | 1-甲基-4-苯基-5-(1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
134 | N-甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙醯胺 | A | |
135 | N,N-二甲基-2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙醯胺 | A | |
136 | 5-(1,3-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
137 | 5-(1-異丁基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
138 | 5-(1-異丙基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
139 | 1-甲基-4-苯基-5-(1-丙基-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
140 | 甲基2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)乙酸酯 | A | |
141 | 2-(4-(1-甲基-6-側氧-4-苯基-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-N-丙基乙醯胺 | A | |
142 | 4-環戊基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
143 | 4-環己基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
144 | 4-環丙基-1-甲基-5-(1-甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
145 | 1-甲基-4-苯基-5-(1,3,5-三甲基-1H-吡唑-4-基)吡啶-2(1H)-酮 | B | |
146 | 5-(1-(環丙基甲基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
147 | 5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-4-(4-三氟甲基-苯基)-1H-吡啶-2-酮 | A | |
148 | 4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-N-甲基苯甲醯胺 | A | |
149 | 5-(1-苄基-1H-吡唑-4-基)-4-(4-氟苯基)-1-甲基吡啶-2(1H)-酮 | A | |
150 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)苯甲腈 | A | |
151 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)苯甲醯胺 | A | |
152 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
153 | 4-(4-氯-苯基)-5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-1H-吡啶-2-酮 | A | |
154 | 4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲酸 | A | |
155 | 4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)苯甲酸 | A | |
156 | 4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲腈 | B | |
157 | 5-(1-(環己基甲基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)‑酮 | A | |
158 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙醯胺 | A | |
159 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙酸 | A | |
160 | 5-(1-苄基-1H-吡唑-4-基)-4-(1-(二氟甲基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | A | |
161 | 5-(1-苄基-1H-吡唑-4-基)-4-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | A | |
162 | 5-(5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
163 | 2-(4-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-1H-吡唑-1-基)乙腈 | A | |
164 | 5-(1,5-二甲基-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | B | |
165 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-丙氧基-1H-吡啶-2-酮 | A | |
166 | 3-[5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-丙酸 | A | |
167 | [5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基氧基]-乙腈 | A | |
168 | 5-(1-苄基-1H-吡唑-4-基)-4-乙基硫基-1-甲基-1H-吡啶-2-酮 | A | |
169 | [5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基硫基]-乙酸 | A | |
170 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-((甲胺基)氧基)吡啶-2(1H)-酮 | A | |
171 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-乙氧基-1-甲基-1H-吡啶-2-酮 | A | |
172 | 1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)-N-甲基吡咯啶-3-磺醯胺 | A | |
173 | (R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)-1,1,1-三氟甲磺醯胺 | B | |
174 | (R)-N-(1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-基)甲磺醯胺 | B | |
175 | 4-甲氧基-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
176 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-異丙基-苯甲腈 | A | |
177 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲氧基-苯甲腈 | A | |
178 | 2-氯-6-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
179 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-6-甲基-苯甲腈 | A | |
180 | 4-乙氧基-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | A | |
181 | 4-乙氧基-1-甲基-5-(1-(1-(甲磺醯基)哌啶-3-基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
182 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲腈 | A | |
183 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈 | A | |
184 | 4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
185 | 5-(1-苄基-3-硝基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
186 | 5-(3-胺基-1-苄基-1H-吡唑-4-基)-4-乙氧基-1-甲基吡啶-2(1H)-酮 | A | |
187 | N-[1-苄基-4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-基]-乙醯胺 | B | |
188 | 5-(1-苄基-1H-吡唑-4-基)-4-(2-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮 | C | |
189 | 5-(1-苄基-1H-吡唑-4-基)-4-(2,6-二甲基-苯基)-1-甲基-1H-吡啶-2-酮 | C | |
190 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-苯基-1H-吡啶-2-酮 | A | |
191 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-4-(4-甲氧基-苯基)-1-甲基-1H-吡啶-2-酮 | A | |
192 | 5-[1-(2,2-二氟-環丙基甲基)-1H-吡唑-4-基]-1-甲基-4-(1-甲基-1H-吡唑-4-基)-1H-吡啶-2-酮 | A | |
193 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮 | A | |
194 | 5'-(1-苄基-1H-吡唑-4-基)-1'-甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮 | A | |
195 | 5-(1-苄基-1H-吡唑-4-基)-1,6-二甲基-1H-吡啶-2-酮 | C | |
196 | 3-二甲胺基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮 | B | |
197 | 3-環丙基-1-甲基-5-[1-(1-苯基-乙基)-1H-吡唑-4-基]-1H-吡啶-2-酮 | C | |
198 | 1-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-1H-吡唑-3-甲酸乙酯 | A | |
199 | 2-苄基-4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-2H-吡唑-3-甲酸乙酯 | A | |
200 | 4-胺基-5-(1-苄基-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | B | |
201 | 3-((5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)胺基)丙酸 | A | |
202 | 2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
203 | 2-[4-(4-異丙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | |
204 | 2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | A | |
205 | 2-[4-(1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | A | |
206 | 2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
207 | 2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
208 | 2-{4-[1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | A | |
209 | 2-[4-(1,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
210 | 2-[4-(5,1'-二甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
211 | 2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | |
212 | 2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
213 | 2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
214 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | A | |
215 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | A | |
216 | 2-{4-[4-(3-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | A | |
217 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲酸 | A | |
218 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-苯甲醯胺 | A | |
219 | 4-{5-[1-(2-氰基-苯基)-1H-吡唑-4-基]-1-甲基-2-側氧-1,2-二氫-吡啶-4-基}-N-甲基-苯甲醯胺 | A | |
220 | 2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | A | |
221 | 2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | A | |
222 | 2-[4-(1'-環丙基-1-甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | A | |
223 | 2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | |
224 | 2-[4-(1-甲基-6-側氧-4-對甲苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | |
225 | 2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸 | A | |
226 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | A | |
227 | 2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | A | |
228 | 2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | A | |
229 | 2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲酸 | A | |
230 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | A | |
231 | 2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | A | |
232 | 2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | A | |
233 | 2-{4-[4-(4-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | A | |
234 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
235 | 2-[4-(6-異丙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
236 | 2-[4-(6-異丁氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
237 | 2-[4-(1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
238 | 2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
239 | 2-(4-(1,1',5-三甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
240 | 2-(4-(5-氟-1'-甲基-6,6'-二側氧-1,1',6,6'-四氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
241 | 2-{4-[4-(3-甲氧基-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | A | |
242 | 2-(4-(5-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
243 | 2-(4-(4-(3,4-二甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
244 | 2-{4-[4-(2-甲氧基-嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | A | |
245 | 2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
246 | 2-{4-[1-甲基-6-側氧-4-(3,4,5-三甲氧基-苯基)-1,6-二氫-吡啶-3-基]-吡唑-1-基}-苯甲腈 | B | |
247 | 2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-甲氧基-苯甲酸 | A | |
248 | 4-環丙氧基-2-[4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | |
249 | 2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲酸 | A | |
250 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-1-甲基-4-((1-甲基-1H-吡唑-4-基)甲氧基)吡啶-2(1H)-酮 | A | |
251 | 3-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
252 | 4-乙氧基-5-(1-(2-氟苯基)-1H-吡唑-4-基)-1-甲基吡啶-2(1H)-酮 | A | |
253 | 4-乙氧基-1-甲基-5-(1-(吡啶-2-基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
254 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
255 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | |
256 | 2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
257 | 2-[4-(5-乙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | B | |
258 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲腈 | A | |
259 | 2-[4-(1,5-二甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-4-苯氧基-苯甲酸 | C | |
260 | 4-甲氧基-2-[4-(1'-甲基-6,6'-二側氧-1,6,1',6'-四氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
261 | 4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲腈 | A | |
262 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | A | |
263 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | A | |
264 | 4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
265 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲腈 | A | |
266 | 4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | A | |
267 | 4-甲氧基-2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | |
268 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸 | A | |
269 | 2-{4-[4-(4-氟-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲酸 | A | |
270 | 4-甲氧基-2-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲酸 | A | |
271 | 2-[4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-4-甲氧基-苯甲酸 | A | |
272 | 4-甲氧基-2-[4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲酸 | A | |
273 | 2-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-6-氟-苯甲腈 | A | |
274 | 2-氟-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
275 | 2-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-6-氟-苯甲腈 | A | |
276 | 2-氯-6-[4-(1,1'-二甲基-6,2'-二側氧-1,6,1',2'-四氫-[4,4']聯吡啶基-3-基)-吡唑-1-基]-苯甲腈 | A | |
277 | 2-氯-6-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
278 | 2-氟-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
279 | 2-氯-6-(4-(4-(3-甲氧基-4-甲基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
280 | 2-氯-6-(4-(4-(2-乙基嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
281 | 2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
282 | 2-(4-(4-乙氧基-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
283 | 2-(4-(1-甲基-4-(2-嗎啉基乙氧基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
284 | 5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[4,4']聯吡啶基-2,2'-二酮 | A | |
285 | 5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-6-甲氧基-1'-甲基-1'H-[3,4']聯吡啶基-2'-酮 | A | |
286 | 4-(4-氯-苯基)-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | A | |
287 | 5'-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1,1'-二甲基-1H,1'H-[3,4']聯吡啶基-6,2'-二酮 | B | |
288 | N-氰基-2-(4-(4-(4-氟苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
289 | N-氰基-2-(4-(1-甲基-4-(1-甲基-1H-吡唑-4-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
290 | N-氰基-2-(4-(4-(4-甲氧基苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
291 | 2-(4-(4-(4-氯苯基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)-N-氰基苯甲醯胺 | A | |
292 | N-氰基-2-(4-(2'-甲氧基-1-甲基-6-側氧-1,6-二氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
293 | N-氰基-2-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
294 | N-氰基-2-(4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
295 | N-氰基-2-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
296 | N-氰基-2-(4-(6-乙氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲醯胺 | A | |
297 | 5-(1-(2-(1H-四唑-5-基)苯基)-1H-吡唑-4-基)-4-(4-氯苯基)-1-甲基吡啶-2(1H)-酮 | A | |
298 | 4-(4-甲氧基-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | A | |
299 | 4-(4-氟-苯基)-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | A | |
300 | 1-甲基-4-(1-甲基-1H-吡唑-4-基)-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | A | |
301 | 4-環丙基-1-甲基-5-{1-[2-(1H-四唑-5-基)-苯基]-1H-吡唑-4-基}-1H-吡啶-2-酮 | A | |
302 | N-{2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苄醯基}-甲磺醯胺 | A | |
303 | 乙磺酸2-[4-(4-環丙基-1-甲基-6-側氧-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲醯胺 | A | |
304 | N-[(二甲胺基)磺醯基]-{2-[4-(4-環丙基-1-甲基-6-側氧(3-氫吡啶))吡唑基]苯基}羧醯胺 | A | |
305 | 3-(4-(1,1'-二甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)-4-甲氧基苯甲腈 | A | |
306 | 4-甲氧基-3-[4-(6-甲氧基-1'-甲基-6'-側氧-1',6'-二氫-[3,4']聯吡啶基-3'-基)-吡唑-1-基]-苯甲腈 | A | |
307 | 3-{4-[4-(4-氯-苯基)-1-甲基-6-側氧-1,6-二氫-吡啶-3-基]-吡唑-1-基}-4-甲氧基-苯甲腈 | A | |
308 | 6-甲氧基-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮. | A | |
309 | 1-甲基-4-(2-(甲胺基)嘧啶-5-基)-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
310 | 1,1'-二甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | A | |
311 | 4-(2-(乙胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
312 | 4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | |
313 | 6-(3-(二甲胺基)丙氧基)-1'-甲基-5'-(1-(1-苯基乙基)-1H-吡唑-4-基)-[3,4'-聯吡啶]-2'(1'H)-酮 | A | |
314 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | A | |
315 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮 | A | |
316 | 5'-(1-(2-氯苯基)-1H-吡唑-4-基)-6-甲氧基-1',5-二甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | A | |
317 | 5-(1-(2-氯苯基)-1H-吡唑-4-基)-2'-甲氧基-1-甲基-[4,4'-聯吡啶]-2(1H)-酮 | A | |
318 | 5-(1-(2-氟苯基)-1H-吡唑-4-基)-1,1'-二甲基-[4,4'-聯吡啶]-2,2'(1H,1'H)-二酮 | A | |
319 | 5'-(1-(2-氟苯基)-1H-吡唑-4-基)-6-甲氧基-1'-甲基-[3,4'-聯吡啶]-2'(1'H)-酮 | A | |
320 | 5-(1-(2-氟苯基)-1H-吡唑-4-基)-4-(2-甲氧基嘧啶-5-基)-1-甲基吡啶-2(1H)-酮 | A | |
321 | 5-(1-(2-羥基環己基)-1H-吡唑-4-基)-1-甲基-4-苯基吡啶-2(1H)-酮 | A | |
322 | 2-氯-6-[4-[4-[2-(環丙基胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
323 | 2-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
324 | 2-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
325 | 2-氯-6-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
326 | 2-氯-6-(4-(4-(2-((2-甲氧基乙基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
327 | 2-氯-6-(4-(4-(2-((環丙基甲基)胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
328 | 2-氯-6-(4-(4-(2-(二甲胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
329 | 2-氯-6-(4-(4-(2-(環戊基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
330 | 2-氯-6-(4-(1-甲基-6-側氧-4-(2-(吡咯啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
331 | 2-氯-6-(4-(4-(2-(異丙基胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
332 | 2-氯-6-(4-(1-甲基-4-(2-(甲胺基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
333 | 2-[4-[4-[2-(乙胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | A | |
334 | 2-[4-[4-[2-(二甲胺基)嘧啶-5-基]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | A | |
335 | 2-氯-6-(4-(1-甲基-4-(2-嗎啉基嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
336 | 2-氟-6-[4-[1-甲基-6-側氧-4-(2-吡咯啶-1-基嘧啶-5-基)-3-吡啶]吡唑-1-基]苯甲腈 | A | |
337 | 2-氯-6-(4-(1-甲基-4-(2-(4-甲基哌嗪-1-基)嘧啶-5-基)-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
338 | 2-氯-6-(4-(1-甲基-6-側氧-4-(2-(哌啶-1-基)嘧啶-5-基)-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
339 | 2-氯-6-[4-[4-[6-(異丙基胺基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]-吡唑-1-基]苯甲腈 | A | |
340 | 2-氯-6-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
341 | 2-氯-6-(4-(1'-甲基-6-(甲胺基)-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
342 | 2-氯-6-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
343 | 2-(4-(6-(環戊基胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
344 | 2-(4-(6-(乙胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
345 | 2-氯-6-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1', 6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}苯甲腈 | A | |
346 | 2-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
347 | 2-{4-[6-(二甲胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基]-1H-吡唑-1-基}-6-氟苯甲腈 | A | |
348 | 2-氯-6-(4-{6-[(環丙基甲基)胺基]-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基}-1H-吡唑-1-基)苯甲腈 | A | |
349 | 2-氯-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | A | |
350 | 2-氟-6-[4-[1-甲基-6-側氧-4-(6-吡咯啶-1-基-3-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | A | |
351 | 2-氟-6-(4-(6-(異丙基胺基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
352 | 2-氯-6-[4-[4-[6-(環戊氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
353 | 2-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
354 | 2-氯-6-(4-(6-(二氟甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
355 | 2-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
356 | 2-氯-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
357 | 2-氯-6-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
358 | 2-氟-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
359 | 2-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
360 | 2-[4-[4-[6-(環丙基甲氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | A | |
361 | 2-[4-[4-[6-(環戊氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | A | |
362 | 2-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | A | |
363 | 2-氯-6-[4-[4-(6-異丙氧基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
364 | 2-氯-6-[4-[4-[6-(環丙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
365 | 2-氯-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
366 | 2-氯-6-[4-[4-(6-環丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
367 | 2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
368 | 2-氟-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
369 | 2-氯-6-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
370 | 2-氯-6-(4-(1'-甲基-6'-側氧-6-(三氟甲基)-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
371 | 2-氯-6-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
372 | 2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
373 | 2-(4-(6-乙基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
374 | 2-[4-[4-(6-環丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]-6-氟-苯甲腈 | A | |
375 | 2-氟-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
376 | 2-氯-6-[4-[4-(6-異丙基-3-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
377 | 2-(4-(1',6-二甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
378 | 2-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)-6-氟苯甲腈 | A | |
379 | 2-氯-6-(4-(6-環戊基-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
380 | 2-環丙基-6-[4-[1-甲基-4-(1-甲基-2-側氧-4-吡啶)-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
381 | 2-環丙基-6-[4-[4-[1-(環丙基甲基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
382 | 2-環丙基-6-(4-(6-(3-(二甲胺基)丙氧基)-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
383 | 2-環丙基-6-(4-(6-甲氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
384 | 2-環丙基-6-(4-(6-乙氧基-1'-甲基-6'-側氧-1', 6'-二氫-[3, 4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
385 | 2-環丙基-6-[4-[1-甲基-6-側氧-4-(2-側氧-1-丙基-4-吡啶)-3-吡啶]吡唑-1-基]苯甲腈 | A | |
386 | 2-環丙基-6-[4-[4-(1-乙基-2-側氧-4-吡啶)-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
387 | 2-環丙基-6-[4-[4-[6-(2-氟乙氧基)-3-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
388 | 2-環丙基-6-(4-(1'-環丙基-1-甲基-2',6-二側氧-1,1',2',6-四氫-[4,4'-聯吡啶]-3-基)-1H-吡唑-1-基)苯甲腈 | A | |
389 | 2-環丙基-6-[4-[4-[1-(2-氟乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
390 | 2-環丙基-6-[4-[4-[1-(2-羥基乙基)-2-側氧-4-吡啶]-1-甲基-6-側氧-3-吡啶]吡唑-1-基]苯甲腈 | A | |
391 | 2-環丙基-6-(4-(6-(環丙基甲氧基)-1'-甲基-6'-側氧-1',6'-二氫-[3,4'-聯吡啶]-3'-基)-1H-吡唑-1-基)苯甲腈 | A | |
392 | 4-乙氧基-5-(5-甲磺醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-1-甲基-1H-吡啶-2-酮 | A | |
393 | 5-(5-乙醯基-4,5,6,7-四氫-吡唑并[1,5-a]吡嗪-3-基)-4-乙氧基-1-甲基-1H-吡啶-2-酮 | B | |
394 | 1-甲基-4-苯基-5-(5-苯基噁唑-2-基)吡啶-2(1H)-酮 | B | |
395 | 1-甲基-5-(1-甲基-5-苯基-1H-吡唑-3-基)-4-苯基吡啶-2(1H)-酮 | A | |
396 | 1-甲基-4-苯基-5-(2-苯基噁唑-4-基)吡啶-2(1H)-酮 | A | |
397 | 1-甲基-4-苯基-5-(2-苯基噁唑-5-基)吡啶-2(1H)-酮 | B |
如前所述檢定BRD4的抑制。參見例如美國專利第9,034,900號。表30中提供了本文揭示的化合物對CRREBBP和BRD4的抑制以及本領域已知的兩種的IC
50值。CBP及BRD4之IC
50數據指定在以下範圍內:A:≤0.5 μM;B:>0.5 μM至≤ 5.0 μM;及C:>5.0 μM。
實例 3:基於活體外細胞的檢定-Th17分化-IL-17A分泌
表 30 | ||||
實例 | 結構 | 名稱 | CRREBBP IC 50(μM) | BRD4 BD1 IC 50(μM) |
18 | 5-(1-(環丙基 (苯基) 甲基)-1H-吡唑-4-基)-1,3-二甲基吡啶-2(1H)-酮 | A | B | |
41 | 1-甲基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)-4-(吡咯啶-1-基)吡啶-2(1H)-酮 | A | B | |
43 | 1-甲基-4-嗎啉基-5-(1-(1-苯基乙基)-1H-吡唑-4-基)吡啶-2(1H)-酮 | A | B | |
74 | ( R)-1-(5-(1-苄基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫吡啶-4-基)吡咯啶-3-甲酸 | A | C | |
94 | 5-(1-苄基-1H-吡唑-4-基)-4-(1H-咪唑-1-基)-1-甲基吡啶-2(1H)-酮 | A | C | |
115 | 5-(1-苄基-1H-吡唑-4-基)-1-甲基-4-(3-甲基-1H-吡唑-5-基)吡啶-2(1H)-酮 | A | C | |
121 | 5-(1-苄基-1H-吡唑-4-基)-4-(異噁唑-3-基)-1-甲基吡啶-2(1H)-酮 | A | C | |
129 | 1-甲基-5-(1-((甲磺醯基) 甲基)-1H-吡唑-4-基)-4-苯基吡啶-2(1H)-酮 | A | C | |
154 | 4-[5-(1-環丙基甲基-1H-吡唑-4-基)-1-甲基-2-側氧-1,2-二氫-吡啶-4-基]-苯甲酸 | A | C | |
223 | 2-[4-(1-甲基-6-側氧-4-苯基-1,6-二氫-吡啶-3-基)-吡唑-1-基]-苯甲酸 | A | C | |
286 | 4-(4-氯-苯基)-5-[1-(2-甲磺醯基-苯基)-1H-吡唑-4-基]-1-甲基-1H-吡啶-2-酮 | A | C | |
323 | 2-(4-(4-(2-(乙胺基)嘧啶-5-基)-1-甲基-6-側氧-1,6-二氫吡啶-3-基)-1H-吡唑-1-基)苯甲腈 | A | B | |
N-(5-(2,4-二氟苯氧基)-4-(1,5-二甲基-6-側氧-1,6-二氫吡啶-3-基)嘧啶-2-基)甲磺醯胺 | C | A | ||
JQ-1 | 第三丁基(S)-2-(4-(4-氯-苯基)-2,3,9-三甲基-6H-噻吩并[3,2-f][1,2,4]三唑[4,3-a][1,4]二氮呯-6-基)乙酸酯 | C | A |
將每孔100K CD4 +細胞以1X Th17分化混合物(0.05 μg/ml IL6,0.02 μg/ml IL23,10 μg/ml抗IFNγ,10 μg/ml抗IL4,0.01 μg/ml IL1β,0.003 μg/ml TGFβ及1個珠/細胞抗CD3/CD28)塗在96孔板上,總體積為100 μL/孔。將板在5% CO
2中於37℃培養96小時。將分化的Th17細胞匯聚,洗滌,並懸浮於完全培養基中。將100K Th17細胞/孔在IL-23存在下塗在96孔板中,最終濃度為25 ng/mL。向細胞中加入適當濃度的CBP抑制劑,總體積為100 μL/孔(包括DMSO及培養基對照)。將板在5% CO
2中於37℃培養96小時。使用製造商協定(Meso Scale Discovery#K151ATB-2)決定細胞上清液中的IL-17A位準。自標準曲線內插分泌的IL-17A位準且藉由%DMSO對照繪圖。
實例 4:基於活體外細胞的檢定-Treg分化與免疫查核點
將每孔100K原始CD4+細胞塗在96孔板中,並將適當濃度之CBP抑制劑加入細胞中。包括DMSO及培養基對照。將細胞在5% CO
2中於37℃培養1小時及添加Treg分化混合物(最終濃度:0.010 μg/mlTGFβ,10 U/ml IL 2及1:1珠:細胞比例的抗CD3/CD28),總體積為100 μL/孔。將板在5% CO
2中於37℃培養96小時。針對CD4 (562424; BD Biosciences)、CTLA4 (563931; BD Biosciences)、CD25 (562660; BD Biosciences)、LAG-3 (11-2239-42; eBioscience)、PD-1 (17-9969-42; eBioscience)、Tim3 (eBioscience; #25-3109-42)及FOXP3 (BD Biosciences; #560046)染色Treg。對於FOXP3及CTLA4細胞內染色,使用BD Cytofix/Cytoperm溶液(BD Biosciences;#554722)固定並透化細胞。使用iQue Screener PLUS流式細胞術分析儀 (IntelliCyt)量化標記,並使用FCS Express 5軟體(DeNovo軟體)分析數據。
實例 III. 醫藥劑型之製備 實例 1:口服片劑
藉由混合48重量%的式I之化合物或其醫藥學上可接受的鹽,45重量%的微晶纖維素,5重量%的低取代羥丙基纖維素及2重量%的硬脂酸鎂來製備片劑。片劑藉由直接壓製來製備。經壓製之片劑的總重量保持在250-500 mg。
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國內寄存資訊(請依寄存機構、日期、號碼順序註記)
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國外寄存資訊(請依寄存國家、機構、日期、號碼順序註記)
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Claims (1)
- 一種具有式I之結構之化合物: 式I 其中一式I之化合物包括其醫藥學上可接受的鹽,且其中 X6為N或CR 7,其中R 7為氫、鹵素、烷基或烷氧基; R 2為氫、烷基、芳基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基; R 5為氫、鹵素、-CN、-N(R 22) 2、-NH(R 22)、-N(R 22)SO 2R 21、-N(R 22)SO 2N(R 22) 2、-N(R 22)CO(R 22)、-N(R 22)CO 2R 21、-N(R 22)CON(R 22) 2、-OC(O)N(R 22) 2、-C(O)N(R 22) 2、-OW、-NW、-SW、-SO 2W,或視情況經取代之烷基、芳基、芳烷基、雜芳基、雜芳基烷基、環烷基、環烷基烷基、雜環基或雜環基烷基,其中 W為至少一個氫、-N(R 22) 2,或視情況經取代之烷基、芳基、芳烷基、環烷基、環烷基烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基; R 6為氫、鹵素、-CN、烷基、環烷基、環烷基烷基、芳基、芳烷基、雜芳基、雜芳基烷基、雜環基、雜環基烷基、-OR 22或-N(R 22) 2; 或R 5及R 6共同形成一視情況經取代之5員或6員環; R A為視情況經取代之含N雜芳基; 其中每個R 22獨立地選自氫、烷基、環烷基、環烷基烷基、芳基、芳烷基、雜環基、雜環基烷基、雜芳基或雜芳基烷基。
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2018
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- 2018-04-18 JP JP2019556274A patent/JP2020516672A/ja active Pending
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TWI788343B (zh) | 2023-01-01 |
WO2018195155A1 (en) | 2018-10-25 |
JP2020516672A (ja) | 2020-06-11 |
EP3612522A1 (en) | 2020-02-26 |
TW201841900A (zh) | 2018-12-01 |
US20200163946A1 (en) | 2020-05-28 |
JP2023088901A (ja) | 2023-06-27 |
US10617680B2 (en) | 2020-04-14 |
US20180296543A1 (en) | 2018-10-18 |
US20210205284A1 (en) | 2021-07-08 |
US11890275B2 (en) | 2024-02-06 |
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