TW202342453A - Glp-1r調節化合物 - Google Patents
Glp-1r調節化合物 Download PDFInfo
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- TW202342453A TW202342453A TW112107093A TW112107093A TW202342453A TW 202342453 A TW202342453 A TW 202342453A TW 112107093 A TW112107093 A TW 112107093A TW 112107093 A TW112107093 A TW 112107093A TW 202342453 A TW202342453 A TW 202342453A
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- alkyl
- heterocyclyl
- cycloalkyl
- aryl
- haloalkyl
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- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D401/00—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
- 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
- C07D401/10—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 linked by a carbon chain containing aromatic rings
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Abstract
本發明提供了GLP-1R促效劑及其組合物和方法,並用於治療人體內GLP-1R介導的疾病或病症。
Description
[相關引用]
本發明要求於2022年2月28日提交的美國臨時專利申請號63/268,622,和2022年6月17日提交的美國臨時專利申請號63/366,565號的優先權,這兩份申請案在此藉由引用全部納入本文中。
本發明關於與胰高血糖素樣肽-1受體(GLP-1R)結合並作為其促效劑或調節劑的化合物,以及此類化合物用於治療和/或預防GLP-1R介導的疾病和狀況。
胰高血糖素樣肽-1(GLP-1)是一種肽類激素,由腸道中的腸內分泌細胞對膳食作出反應而分泌。GLP-1被認為在餐後血糖的調節中發揮作用,藉由直接增加膳食誘導的胰腺β細胞分泌胰島素,以及藉由延遲食物通過腸道的運輸來促進飽腹感。GLP-1藉由GLP-1受體(GLP-1R)介導細胞內訊號傳導,GLP-1受體屬於存在於細胞膜上的G蛋白偶聯受體家族,並且可以在活化時導致第二信使環腺苷單磷酸(cAMP)的積累。非酒精性脂肪性肝炎(NASH)可與代謝綜合征的特徵相關,包括肥胖症、2型糖尿病、胰島素抗性和心血管疾病。
GLP-1R促效劑目前正在被廣泛的研究用於與糖尿病、肥胖症和NASH的相關疾病。GLP-1R促效劑包括肽,如艾塞那肽、利拉魯肽和杜拉魯肽,它們已被批准用於治療2型糖尿病。此類肽類藥物主要通過皮下注射給藥。口服GLP-1促效劑也在研究中,用於治療2型糖尿病。一些GLP-1R促效劑,如利拉魯肽、杜拉魯肽和艾塞那肽,對二肽基肽酶4的快速降解具有抵抗力,導致其半衰期比內源性GLP-1更長。
在治療GLP-1R介導的疾病和病症方面,仍然需要具有理想的治療特性、代謝特性和/或易於服用的化合物,例如GLP-1R的促效劑。
在一個實施方案中,本發明的內容提供了一種式(I-A-1)的化合物:
或其藥學上可接受的鹽,其中:
R
1是C
1-6烷基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-S-R
1b,-S(O)R
1b,-S(O)(NH)R
1b,-S(O)
2R
1b,-S(O)
2N(R
1b)(R
1c),-S(O)(NR
1b)R
1c,-C(O)N(R
1b)(R
1c),-C(O)R
1b,或-C(O)OR
1c,其中所述烷基、鹵代烷基、環烷基、芳基、5-10員雜芳基或雜環基各自可選地地被一至四個Z
1取代,任何兩個Z
1可以與它們所連接的原子結合,形成C
3-10環烷基或雜環基或C
6-10芳基或5-10員雜芳基;
環A是C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基,所述C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基各自可選地被1至4個Z
1a取代;
環B是C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基,所述C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基各自可選地被1至4個R
4取代;
環A和環B各自包含0-3個雙鍵;
R
2是H,C
1-6烷基,C
1-6烷基-烷氧基,C
1-6烷基-環烷氧基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-OR
2a,-S-R
2a,-S(O)R
2a,-S(O)(NH)R
2a,-S(O)
2R
2a,-S(O)
2N(R
2a)(R
2b),或-S(O)(NR
2a)R
2b,其中,烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1取代;任何兩個Z
1可以與它們所連接的原子結合,形成C
3-10環烷基或雜環基或C
6-10芳基或5-10員雜芳基。
X各自獨立地為-N=,-C(H)=,或-C(R
8)=;
每個R
3和R
3’獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-NO
2,-OR
3a,-C(O)R
3a,-CH
2C(O)OR
3a,-C(O)OR
3a,-C(O)N(R
3a)(R
3b),-N(R
3a)C(O)R
3b,-N(R
3a)C(O)OR
3b,-N(R
3a)C(O)N(R
3b)
2,-C(O)NHS(O)
2R
3a,-C(O)NR
3aS(O)
2R
3b,-C(O)NR
3aS(O)
2NR
3bR
3c,-C(O)NR
3a-S(O)(=NR
3b)R
3c,-S(O)
2R
3a,-S(O)
2OR
3a,-S(O)
2N(R
3a)(R
3b),-N(R
3a)S(O)
2R
3b,-S(O)
2NHC(O)R
3a,-S(O)(=NR
3a)R
3b,-S(O)(=NR
3a)NR
3b,-S(=NR
3a)(=NR
3b)R
3c,-P(O)(OR
3a)(R
3b),-P(O)(OR
3a)(OR
3b),-B(OR
3a)(OR
3b),或-O-C
1-6烷基-C(O)OR
3a,其中,所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R
3d取代;
每個R
3a,R
3b,和R
3c獨立地是H,C
1-6烷基,C
6-10芳基,5-10員雜芳基,C
1-6鹵代烷基,C
2-8烷氧基烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-N(R
9a)C(O)-O-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,-CH
2CH(N(R
9a)
2)C(O)OR
9b,-P(O)(OR
9c)
2,-OP(O)(OR
9c)
2,-CH
2P(O)(OR
9c)
2,-CH
2OP(O)(OR
9c)
2,-OCH
2P(O)(OR
9c)
2,-C(O)OCH
2P(O)(OR
9c)
2,-P(O)(R
9c)(OR
9d),-OP(O)(R
9c)(OR
9d),-CH
2P(O)(R
9c)(OR
9d),-OCH
2P(O)(R
9c)(OR
9d),-C(O)OCH
2P(O)(R
9c)(OR
9d),-P(O)(N(R
9c)
2)
2,-OP(O)(N(R
9c)
2)
2,-CH
2P(O)(N(R
9c)
2)
2,-OCH
2P(O)(N(R
9c)
2)
2,-C(O)OCH
2P(O)(N(R
9c)
2)
2,-P(O)(N(R
9c)
2)(OR
9d),-OP(O)(N(R
9c)
2)(OR
9d),-CH
2P(O)(N(R
9c)
2)(OR
9d),-OCH
2P(O)(N(R
9c)
2)(OR
9d),-C(O)OCH
2P(O)(N(R
9c)
2)(OR
9d),-P(O)(R
9c)(N(R
9d)
2),-OP(O)(R
9c)(N(R
9d)
2),-CH
2P(O)(R
9c)(N(R
9d)
2),-OCH
2P(O)(R
9c)(N(R
9d)
2),-C(O)OCH
2P(O)(R
9c)(N(R
9d)
2),C
1-6烷基-雜環基,C
1-6烷基-芳基或C
1-6烷基-(5-10員)雜芳基,其中,所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個R
4獨立地是H、-OH、CH
2OH、C
1-9烷基,C
1-8鹵代烷基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
4a,-C(O)R
4a,-C(O)O-R
4a,-C(O)N(R
4a)(R
4b),-N(R
4a)(R
4b),-N(R
4a)
2(R
4b)
+,-N(R
4a)-C(O)R
4b,-N(R
4a)C(O)O(R
4b),-N(R
4a)C(O)N(R
4b)(R
4c),-N(R
4a)S(O)
2(R
4b),-N(R
4a)S(O)
2-N(R
4b)(R
4c),-N(R
4a)S(O)
2O(R
4b),-OC(O)R
4a,-OC(O)OR
4a,-OC(O)-N(R
4a)(R
4b),-S-R
4a,-S(O)R
4a,-S(O)(NH)R
4a,-S(O)
2R
4a,-S(O)
2N(R
4a)(R
4b),-S(O)(NR
4a)R
4b,或-Si(R
4a)
3;其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;或者,兩個連接在相鄰環原子上的R
4基團與它們所連接的原子結合,形成C
5-10環烷基或雜環基,它們各自可選地被1至4個Z
1b取代;
每個R
5a和R
5b獨立地是H,C
1-6烷基,C
1-6烷氧基,C
1-6鹵代烷基,C
2-6烷氧基烷基,鹵素,C
3-10環烷基,雜環基,-C
1-6烷基-N(R
9a)(R
9b),-CN,-OR
5a1,或-N(R
5a1)(R
5a2);
或者,R
5a和R
5b與它們所連接的原子組合成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
5a3取代;
或者,R
5a或R
5b與環A上的任意取代基環合組成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
5a3取代;
每個R
5a1和R
5a2獨立地是H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、雜環基、C
6-10芳基或5-10員雜芳基;其中,所述環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R
5a4取代;
V是-C(O)-,-O-,-N(R
6a)-,或-C(R
6b)(R
6c)-;
R
6a是H,C
1-6烷基,C
3-10環烷基,雜環基,-S(O)
2R
6a1,或-S(O)
2N(R
6a1)(R
6a2),其中,所述環烷基或雜環基各自可選地被C
1-6烷基、F或-CN取代;
每個R
6b和R
6c獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
2-6烷氧基烷基,鹵素,C
3-10環烷基,雜環基,-C
1-6烷基-N(R
9a)(R
9b),-CN,-OR
6c1,或-N(R
6c2)(R
6c3);
其中,所述烷基、環烷基或雜環基各自可選地被1至4個R
6b1取代;或R
6b和R
6c與它們所連接的原子結合,形成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
6b1取代;或R
6a或R
6c與一個R
4基團和它們所連接的原子結合,形成C
5-10環烷基或雜環基,它們各自可選地被1至4個R
10取代;
Y是-N(R
7)-,-O-,-S-,-S(O)-,-S(O)
2-,-S(O)(=NH)-,或-S(O)(=NR
7)-;
每個R
3d,R
5a3,R
5a4,R
6b1,和R
10獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO
2R
3e,-NO
2,或-C(O)N(R
2a)(R
2b),其中所述雜環基或5-10員雜芳基可選地被C
1-6烷基、C
1-6鹵代烷基或C
1-6鹵代烷氧基取代;並且
每個R
6a1,R
6a2,R
6c1,R
6c2,R
6c3和R
7獨立地是H,C
1-6烷基或C
3-10環烷基;
每個R
8獨立地是C
1-9烷基,C
1-8鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2;
每個R
9a和R
9b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
或R
9a和R
9b融合形成一個3-10員雜環基,並可選地被C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3取代;
每個Z
1獨立地是C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-N
3,-CN,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)C(O)-R
12b,-N(R
12a)C(O)O-R
12b,-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1a取代;
每個Z
1a獨立地是H,-OH,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個Z
1b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
2-6烯基),-O(C
2-6炔基),-O(C
3-15環烷基),-O(雜環基),-O(C
6-10芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
2-6烯基),-NH(C
2-6炔基),-NH(C
3-15環烷基),-NH(雜環基),-NH(C
6-10芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2,-N(C
2-6烯基)
2,-N(C
2-6炔基)
2,-N(C
3-15環烷基)
2,-N(雜環基)
2,-N(C
6-10芳基)
2,-N(5-10員雜芳基)
2,-N(C
1-9烷基)(C
1-8鹵代烷基),-N(C
1-9烷基)(C
2-6烯基),-N(C
1-9烷基)(C
2-6炔基),-N(C
1-9烷基)(C
3-15環烷基),-N(C
1-9烷基)(雜環基),-N(C
1-9烷基)(C
6-10芳基),-N(C
1-9烷基)(5-10員雜芳基),-C(O)(C
1-9烷基),-C(O)(C
1-8鹵代烷基),-C(O)(C
2-6烯基),-C(O)(C
2-6炔基),-C(O)(C
3-15環烷基),-C(O)(雜環基),-C(O)(C
6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C
1-9烷基),-C(O)O(C
1-8鹵代烷基),-C(O)O(C
2-6烯基),-C(O)O(C
2-6炔基),-C(O)O(C
3-15環烷基),-C(O)O(雜環基),-C(O)O(C
6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH
2,-C(O)NH(C
1-9烷基),-C(O)NH(C
1-8鹵代烷基),-C(O)NH(C
2-6烯基),-C(O)NH(C
2-6炔基),-C(O)NH(C
3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C
6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C
1-9烷基)
2,-C(O)N(C
1-8鹵代烷基)
2,-C(O)N(C
2-6烯基)
2,-C(O)N(C
2-6炔基)
2,-C(O)N(C
3-15環烷基)
2,-C(O)N(雜環基)
2,-C(O)N(C
6-10芳基)
2,-C(O)N(5-10員雜芳基)
2,-NHC(O)(C
1-9烷基),-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
2-6烯基),-NHC(O)(C
2-6炔基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C
6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6烯基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C
6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基),-NHC(O)NH(C
1-8鹵代烷基),-NHC(O)NH(C
2-6烯基),-NHC(O)NH(C
2-6炔基),-NHC(O)NH(C
3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C
6-10芳基),-NHC(O)NH(5-10員雜芳基),-NHS(O)(C
1-9烷基),-N(C
1-9烷基)(S(O)(C
1-9烷基),-S(C
1-9烷基),-S(C
1-8鹵代烷基),-S(C
2-6烯基),-S(C
2-6炔基),-S(C
3-15環烷基),-S(雜環基),-S(C
6-10芳基),-S(5-10員雜芳基),-S(O)N(C
1-9烷基)
2,-S(O)(C
1-9烷基),-S(O)(C
1-8鹵代烷基),-S(O)(C
2-6烯基),-S(O)(C
2-6炔基),-S(O)(C
3-15環烷基),-S(O)(雜環基),-S(O)(C
6-10芳基),-S(O)(5-10員雜芳基),-S(O)
2(C
1-9烷基),-S(O)
2(C
1-8鹵代烷基),-S(O)
2(C
2-6烯基),-S(O)
2(C
2-6炔基),-S(O)
2(C
3-15環烷基),-S(O)
2(雜環基),-S(O)
2(C
6-10芳基),-S(O)
2(5-10員雜芳基),-S(O)(NH)(C
1-9烷基),-S(O)
2NH(C
1-9烷基),或者-S(O)
2N(C
1-9烷基)
2;
其中所述烷基、環烷基、雜環基、芳基或5-10員雜芳基在每一種情況下都可選地被1至3個C
1-9烷基,C
1-8鹵代烷基,鹵素,-OH,-NH
2,CO
2H-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
3-15環烷基)
2,-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基),S(O)
2(C
1-9烷基),-S(O)
2(C
1-8鹵代烷基),-S(O)
2(C
3-15環烷基),-S(O)
2(雜環基),-S(O)
2(芳基),-S(O)
2(5-10員雜芳基),-S(O)(NH)(C
1-9烷基),-S(O)
2NH(C
1-9烷基),或-S(O)
2N(C
1-9烷基)
2;
每個R
1b,R
1c,R
2a,R
2b,R
4a,R
4b,R
4c,R
9c,R
9d,R
12a,R
12b,和R
12c獨立地是H,-OH,C
1-9烷基,C
2-6烯基,C
2-6炔基,C
3-15環烷基,雜環基,C
6-10芳基,或5-10員雜芳基,其中所述烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個R
3e獨立地是H,C
1-6烷基,C
1-6鹵代烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基,-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-P(O)(OR
9c)
2,-CH
2P(O)(OR
9c)
2,-OCH
2P(O)(OR
9c)
2,-C(O)OCH
2P(O)(OR
9c)
2,-P(O)(R
9c)(OR
9d),-OP(O)(R
9c)(OR
9d),-CH
2P(O)(R
9c)(OR
9d),-C(O)OCH
2P(O)(R
9c)(OR
9d),-P(O)(N(R
9c)
2)
2,-CH
2P(O)(N(R
9c)
2)
2,-C(O)OCH
2P(O)(N(R
9c)
2)
2,-P(O)(N(R
9c)
2)(OR
9d),-CH
2P(O)(N(R
9c)
2)(OR
9d),-C(O)OCH
2P(O)(N(R
9c)
2)(OR
9d),-P(O)(R
9c)(N(R
9d)
2),-CH
2P(O)(R
9c)(N(R
9d)
2),或者-C(O)OCH
2P(O)(R
9c)(N(R
9d)
2);
其中所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
其中,每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;
其中,每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子。
本發明的另一個方面涉及用本發明的化合物治療GLP-1R介導的疾病或狀況的方法。
本發明的另一個方面涉及用於製備本發明化合物的方法。
[I. 定義]
除非另有定義,本文使用的所有技術和科學術語與本領域普通技術人員通常理解的含義相同。在化學基團的前端或末端的破折號是為了方便表示與母體的連接點;化學基團可以用或不用一個或多個破折號來描述,而不會失去其普通含義。首碼如 "C
u-v"或 "C
u-C
v"表示以下基團有u到v個碳原子,其中u和v是整數。例如,"C
1-6烷基 "或 "C
1-C
6烷基 "表示該烷基具有1至6個碳原子。
"烷基 "是一價或二價線性或支鏈飽和烴基。例如,一個烷基可以有1至10個碳原子(即C
1-10烷基)或1至8個碳原子(即C
1-8烷基)或1至6個碳原子(即C
1-6烷基)或1至4個碳原子(即C
1-4烷基)。烷基的例子包括但不限於:甲基(Me,-CH
3)、乙基(Et,-CH
2CH
3)、1-丙基(n-Pr,n-propyl,-CH
2CH
2CH
3)、2-丙基(i-Pr,i-Propyl,-CH(CH
3)
2)、1-丁基(n-Bu,n-butyl,-CH
2CH
2CH
2CH
3)、2-甲基-1-丙基(i-Bu,i-butyl,-CH
2CH(CH
3)
2),2-丁基(s-Bu,s-butyl,-CH(CH
3)CH
2CH
3),2-甲基-2-丙基(t-Bu,t-butyl,-C(CH
3)
3);1-戊基(正戊基,-CH
2CH
2CH
2CH
2CH
3),2-戊基(-CH(CH
3)CH
2CH
2CH
3),3-戊基(-CH(CH
2CH
3)
2),2-甲基-2丁基(-C(CH
3)
2CH
2CH
3)。3-甲基-2-丁基(-CH(CH
3)CH(CH
3)
2),3-甲基-1-丁基(-CH
2CH
2CH(CH
3)
2),2-甲基-1-丁基(-CH
2CH(CH
3)CH
2CH
3);1-己基(-CH
2CH
2CH
2CH
2CH
2CH
3),2-己基(-CH(CH
3)CH
2CH
2CH
2CH
3),3-己基(-CH(CH
2CH
3)(CH
2CH
2CH
3)),2-甲基-2-戊基(-C(CH
3)
2CH
2CH
2CH
3);3-甲基-2-戊基(-CH(CH
3)CH(CH
3)CH
2CH
3),4-甲基-2-戊基(-CH(CH
3)CH
2CH(CH
3)
2),3-甲基-3-戊基(-C(CH
3)(CH
2CH
3)
2);2-甲基-3-戊基(-CH(CH
2CH
3)CH(CH
3)
2),2,3-二甲基-2-丁基(-C(CH
3)
2CH(CH
3)
2),3,3-二甲基-2-丁基(-CH(CH
3)C(CH
3)
3,和辛基(-(CH
2)
7CH
3),烷基可以是未被取代的或被取代的。
"烷氧基 "是指基團-O-烷基,其中烷基如上定義。例如,C
1-4烷氧基是指具有1至4個碳原子的-O-烷基基團。烷氧基可以是未取代的或取代的。
"烷氧基烷基 "是連接到上述定義的烷基的烷氧基,從而使該烷基是二價的。例如,C
2-6烷氧基烷基包括-CH
2-OMe、-CH
2-O-iPr、-CH
2-CH
2-OMe、-CH
2-CH
2-O-CH
2-CH
3、以及-CH
2-CH
2-O-tBu。烷氧基烷基可以是未被取代的或被取代的。
"烯基 "是具有至少一個碳-碳雙鍵的一價或二價線性或支鏈烴基。例如,一個烯基可以有2至8個碳原子(即C
2-8烯基)或2至6個碳原子(即C
2-6烯基)或2至4個碳原子(即C
2-4烯基)。烯基的例子包括但不限於:乙烯基(-CH=CH
2)、烯丙基(-CH
2CH=CH
2)和-CH
2-CH=CH-CH
3。烯基可以是未被取代的或被取代的。
"炔基 "是具有至少一個碳-碳三鍵的一價或二價線性或支鏈烴基。例如,一個炔基可以有2至8個碳原子(即C
2-8炔基)或2至6個碳原子(即C
2-6炔基)或2至4個碳原子(即C
2-4炔基)。炔基的例子包括但不限於乙炔基(-C≡CH)、丙炔基(-CH
2C≡CH)、和-CH
2-C≡C-CH
3。炔基可以是未被取代的或被取代的。
“鹵素”指氟(-F)、氯(-Cl)、溴(-Br)和碘(-I)。
"鹵代烷基 "是本文定義的烷基,其中該烷基的一個或多個氫原子獨立地被一個鹵素取代,該鹵素可以是相同的或不同的,從而該烷基是二價。烷基和鹵素可以是上文所述的任何一種。在一些實施方案中,鹵代烷基確定了烷基部分的碳原子數,例如,C
1-4鹵代烷基包括CF
3、CH
2F、CHF
2、CH
2CF
3、CH
2CH
2CF
3、CCl
2CH
2CH
2CH
3和C(CH
3)
2(CF
2H)。鹵代烴基可以是未取代的或取代的。
"鹵代烷氧基 "是本文定義的烷氧基,其中烷氧基中的一個或多個氫原子獨立地被鹵素取代,鹵素可以是相同或不同的,從而使該烷基是二價的。烷氧基和鹵素可以是上文所述的任何一種。在一些實施方案中,鹵代烷氧基定義了烷基部分的碳原子數,例如,C
1-4鹵代烷氧基包括OCF
3、OCH
2F、OCH
2CF
3、OCH
2CH
2CF
3、OCCl
2CH
2CH
2CH
3和OC(CH
3)
2(CF
2H)。鹵代烷氧基可以是未取代的或取代的。
"環烷基 "是一個一價或二價的單一全碳環或多個縮合全碳環系統,其中每個實例中的環是一個非芳香族飽和或不飽和環。例如,在一些實施方案中,環烷基具有3至12個碳原子、3至10個碳原子、3至8個碳原子、3至6個碳原子、3至5個碳原子,或3至4個碳原子。示例性的單環環烷基包括環丙基、環丁基、環戊基、環己基、環烯基、環庚基、環庚烯基和環辛基。環烷基還包括具有約7至12個碳原子的多個縮合環系統(例如,包括2個環的環系統)。在化合價要求允許的情況下,多個縮合環系統的環可以藉由熔合鍵、螺線鍵或橋接鍵相互連接。示例性的多環環烷基包括八氫戊烯、雙環[2. 2. 1]庚烷、雙環[2. 2. 2]辛烷、雙環[2. 2. 2]辛-2烯和螺[2. 5]辛烷。環烷基基團可以是未取代的或取代的。
“烷基環烷基”是指本文定義的烷基,其中該烷基的一個或多個氫原子獨立地被環烷基取代,該環烷基可以是相同或不同的。烷基和環烷基可以是上述的任何一種。在一些實施方案中,烷基和環烷基部分的碳原子數可以分別指定,例如,C
1-6烷基-C
3-12環烷基。烷基環烷基基團可以是未取代的或取代的。
此處使用的 "芳基 "是指一價或二價單全碳芳香環或多縮合全碳環系統,其中該環是芳香的。例如,在一些實施方案中,一個芳基有6至20個碳原子,6至14個碳原子,6至12個碳原子,或6至10個碳原子。芳基包括一個苯基。芳基還包括具有約9至20個碳原子的多個縮合環系統(例如,由2、3或4個環組成的環系統),其中多個環是芳香族的。在化合價要求允許的情況下,多個縮合環系統的環可以藉由熔合鍵相互連接。還可以理解的是,當提到某個原子範圍的成員芳基(如6-10個成員的芳基)時,該原子範圍是指該芳基的總環原子。例如,6個成員的芳基包括苯基,10個成員的芳基則包括萘基。芳基的非限制性例子包括,但不限於,苯基、萘基、蒽基等。芳基可以是未被取代的或被取代的。
"烷基芳基 "是指本文定義的烷基,其中該烷基的一個或多個氫原子獨立地被一個芳基取代,該芳基可以是相同或不同。烷基和芳基可以是上文所述的任何一種,這樣的烷基是二價的。在一些實施方案中,一個烷基芳基有7至24個碳原子,7至16個碳原子,7至13個碳原子,或7至11個碳原子。由碳原子數定義的烷基芳基是指構成烷基和芳基中存在的碳原子總數。例如,C
7烷基芳基是指苄基,而C
11烷基芳基包括1-甲基萘和正戊基苯基。在一些實施方案中,烷基和芳基部分的碳原子數可以分別指定,例如,C
1-6烷基-C
6-10芳基。烷基芳基的非限制性例子包括但不限於苄基、2,2-二甲基苯基、正戊基苯基、1-甲基萘基、2-乙基萘基等。烷基芳基可以是未被取代的或被取代的。
本文所用的 "雜環 "或 "雜環 "或 "雜環基 "是指單一飽和或部分不飽和的非芳香族環或非芳香族多環系統,該環中至少有一個雜原子(即至少有一個選自氧、氮和硫的環狀(即環形)雜原子)。除非另有規定,雜環基團具有3至約20個環狀原子,例如3至12個環狀原子,例如4至12個環狀原子,4至10個環狀原子,或3至8個環狀原子,或3至6個環狀原子,或3至5個環狀原子,或4至6個環狀原子,或4至5個環狀原子。因此,該術語包括具有約1至6個環狀碳原子和約1至3個環狀雜原子的單一飽和或部分不飽和環(例如3、4、5、6或7-員環),這些環中的雜原子選自氧、氮和硫組成的組。在化合價要求允許的情況下,多個縮合環(如雙環雜環)系統的環可以藉由熔合鍵、螺線鍵和橋接鍵相互連接。雜環包括但不限於氮雜環丁烷、氮雜吡啶、咪唑烷、嗎啉、環氧乙烷、氧雜環、硫雜環、呱嗪、呱啶、吡唑烷、吡咯烷,吡咯烷酮,四氫呋喃,四氫噻吩,二氫吡啶,四氫吡啶,奎寧環,2-氧-6-氮雜螺[3.3]庚烷-6-基,6-氧雜-1-氮雜螺[3. 3]庚烷-1-基,2-硫雜-6-氮雜螺[3. 3]庚烷-6-基,2,6-二氮雜螺[3. 3]庚烷-2-基,2-氮雜雙環[3. 1. 0]己烷-2-基,3-氮雜雙環[3. 1. 0]己基,2-氮雜雙環[2. 1. 1]己基,2-氮雜雙環[2. 2. 1]庚-2-基,4-氮雜螺[2. 4]庚基,5-氮雜螺[2. 4]庚基,以及類似物。雜環基可以是未被取代的或被取代的。
"烷基雜環基 "是指本文定義的烷基,其中該烷基的一個或多個氫原子獨立地被雜環基取代,該雜環基可以是相同的或不同的。烷基和雜環基可以是上述的任何一種,這樣的烷基是二價的。在一些實施方案中,烷基和雜環基部分的原子數可以分別指定,例如,C
1-6烷基-3至12個成員的雜環基具有1至3個雜原子,每個雜原子獨立地是N、O或S。 烷基雜環基可以是未取代的或取代的。
"5-10員雜芳基 "是指在環中具有至少一個碳以外的原子的單一芳環,其中該原子選自氧、氮和硫組成的組;"5-10員雜芳基 "還包括具有至少一個這樣的芳環的多個縮合環系統,該多個縮合環系統將在下文進一步描述。因此,"5-10個成員的雜芳基 "包括約1-6個碳原子的單芳環和約1-4個選自氧、氮和硫組的雜原子。硫和氮原子也可以以氧化的形式存在,只要該環是芳香族的。示例性的5-10員雜芳基環系統包括但不限於吡啶基、嘧啶基、噁唑基或呋喃基。"5-10員雜芳基 "還包括多個縮合環系統(例如由2、3或4個環組成的環系統),其中如上定義的5-10員雜芳基與一個或多個選自5-10員雜芳基(形成例如1,8-萘啶基)和芳基(形成例如苯并咪唑基或吲唑基)的環縮合,形成多個縮合環系統。因此,5-10員雜芳基(單個芳環或多個縮合環系統)可以有大約1-20個碳原子,在5-10員雜芳基環內有大約1-6個雜原子。例如,四唑基在環內有1個碳原子和4個氮雜原子。在化合價要求允許的情況下,多個縮合環系統的環可以藉由熔合鍵相互連接。應該理解的是,多個縮合環系統的各個環可以按任何順序相互連接。應該理解的是,5-10員雜芳基或5-10員雜芳基多重縮合環系統的連接點可以是5-10員雜芳基或5-10員雜芳基多重縮合環系統的任何合適的原子,包括碳原子和雜原子(例如,氮)。還應理解的是,當提及某個原子範圍的成員雜芳基(例如,5至10個成員的雜芳基)時,該原子範圍是針對雜芳基的總環原子,包括碳原子和雜原子。還應理解的是,多個縮合環系統的環可以包括融合到具有飽和或部分不飽和鍵的雜環(例如3、4、5、6或7員環)的芳基環,該環具有約1至6個環狀碳原子和約1至3個選自環中氧、氮和硫的環狀雜原子。例如,5-10員雜芳基包括噻唑基,5-10員雜芳基包括喹啉基。示例性5-10員雜芳基包括但不限於吡啶基、吡咯基、吡嗪基、嘧啶基、噠嗪基、吡唑基、噻吩基、吲哚基、咪唑基、噁唑基、異噁唑基、噻唑基、呋喃基、噁二唑基、噻二唑基、喹啉基、異喹啉基、苯并噻唑基、苯并惡唑基、吲唑基、喹惡唑基、喹唑基、苯并呋喃基、苯并咪唑基、硫代苯基、吡咯并[2,3-b]吡啶基、喹唑啉基-4(3H)-酮、三唑基和四唑基。5-10員雜芳基可以是未被取代的或被取代的。
"烷基-雜芳基 "是指本文定義的烷基,其中該烷基的一個或多個氫原子獨立地被雜芳基取代,該雜芳基可以是相同的或不同的,從而使該烷基是二價。烷基和雜芳基可以是上述的任何一種。在一些實施方案中,烷基和雜芳基部分的原子數被分別指定,例如,C
1-6烷基-5至10個成員的雜芳基,具有1至4個雜原子,每個雜原子獨立地是N、O或S。 烷基-雜芳基可以是未取代的或取代的。
本文中的 "Oxo "是指=O。
此處使用的 "取代的 "是指其中基團的一個或多個氫原子獨立地被如所示的一個或多個取代基(例如,1、2、3或4個或更多)取代。
"本發明的化合物 "包括本文公開的化合物,例如本發明的化合物包括式(I-A-1)的化合物,包括實施例的化合物。在一些實施方案中,"本發明的化合物 "包括式(I-A-1)的化合物。
"藥學上可接受的賦形劑 "包括但不限於任何佐劑、載體、賦形劑、滑潤劑、甜味劑、稀釋劑、防腐劑、染料/著色劑、增味劑、表面活性劑、潤濕劑、分散劑、懸浮劑、穩定劑、等滲劑、溶劑或乳化劑,其已被美國食品和藥物管理局批准為可用於人類或家畜。
本文所用的 "治療有效量 "或 "有效量 "是指能有效地引起所需生物或醫學反應的量,包括當施用於治療疾病的受試者時,足以影響該疾病的治療的化合物的量。有效量將根據化合物、疾病及其嚴重程度以及待治療對象的年齡、體重等因素而變化。有效量可以包括一定範圍的量。正如本領域所理解的,有效量可以是一個或多個劑量,即可能需要一個劑量或多個劑量來實現所需的治療終點。有效量可在施用一種或多種治療劑的情況下考慮,如果與一種或多種其他藥劑一起使用,可能或已經達到了理想的或有益的結果,則可認為單一藥劑是以有效量給予的。由於化合物的聯合作用(例如,相加或協同作用),任何共同施用的化合物的適當劑量可以選擇性地降低。
本文所用的 "共同給藥 "是指在給藥一種或多種額外治療劑的單位劑量之前或之後給藥本發明的化合物的單位劑量,例如,在給藥一種或多種額外治療劑的幾秒鐘、幾分鐘或幾小時內給藥本發明的化合物。例如,在一些實施方案中,首先施用本發明的化合物的單位劑量,然後在幾秒鐘或幾分鐘內施用一種或多種附加治療劑的單位劑量。或者,在其他實施方案中,先施用一個或多個額外治療劑的單位劑量,然後在數秒或數分鐘內施用本發明的化合物的單位劑量。在一些實施方案中,首先施用本發明的化合物的單位劑量,然後在數小時後(例如1-12小時),施用一種或多種額外治療劑的單位劑量。在其他實施方案中,先施用一個或多個額外治療劑的單位劑量,然後在數小時後(例如1-12小時),施用本發明的化合物的單位劑量。本文公開的化合物與一種或多種附加治療劑的共同給藥一般是指同時或相繼給藥本文公開的化合物和一種或多種附加治療劑,從而使每種藥劑的治療有效量存在於受試者的體內。
還提供了本文所述化合物的藥學上可接受的鹽、水合物、溶解物、同分異構體形式、多晶型和前藥。
"藥學上可接受的 "或 "生理上可接受的 "是指化合物、鹽類、組合物、劑型和其他材料,它們在製備適合於獸醫或人類藥物使用的藥物組合物中是有用的。
本文所述的化合物可作為藥學上可接受的鹽或在適當時作為游離鹼製備和/或配製。藥學上可接受的鹽是化合物的游離鹼形式的無毒鹽,它具有游離鹼所需的藥理活性。這些鹽可以從無機或有機酸或鹼中提取。例如,含有鹼性氮的化合物可藉由使該化合物與無機或有機酸接觸來製備成藥學上可接受的鹽。藥學上可接受的鹽的非限制性例子包括硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、磷酸鹽、單氫磷酸鹽、雙氫磷酸鹽、偏磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物、醋酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、丙烯酸鹽、甲酸鹽、異丁酸鹽、己酸鹽、庚酸鹽、丙醇鹽、草酸鹽、丙二酸鹽、亞鐵酸鹽、癸二酸鹽、富馬酸鹽、馬來酸鹽,丁炔-1,4-二酸鹽,己炔-1,6-二酸鹽,苯甲酸鹽,氯苯甲酸鹽,甲基苯甲酸鹽,二硝基苯甲酸鹽,羥基苯甲酸鹽,甲氧基苯甲酸鹽,鄰苯二甲酸鹽,磺酸鹽,甲磺酸鹽,丙磺酸鹽、苯磺酸鹽、二甲苯磺酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽、苯乙酸鹽、苯丙酸鹽、苯丁酸鹽、檸檬酸鹽、乳酸鹽、γ-羥基丁酸鹽、乙醇酸鹽、酒石酸鹽和扁桃酸鹽。 其他合適的藥學上可接受的鹽的清單可在《雷明頓:藥學科學與實踐,第21版,利平科特.威廉姆斯和威爾金斯,費城,賓夕法尼亞州,2006》中找到。
本文公開的化合物的 "藥學上可接受的鹽 "的例子還包括來自適當的鹼的鹽,如鹼金屬(例如鈉、鉀)、鹼土金屬(例如鎂)、銨和N(C
1-C
4烷基)
4 +。還包括鹼加成鹽,如鈉鹽或鉀鹽。
還提供了本文所述的化合物或藥學上可接受的鹽、異構體或其混合物,其中連接到碳原子的1至n個氫原子可選地被氘原子或D取代,其中n是分子中氫原子的數量。如本領域所知,氘原子是氫原子的一種非放射性同位素。這樣的化合物可增加對代謝的抵抗力,因此可用於增加本文所述化合物或藥學上可接受的鹽、異構體或其混合物在給哺乳動物服用時的半衰期。參見“福斯特, “藥物代謝研究中的氘同位素效應”趨勢藥理學,科學 5(12):524-527 (1984)”。此類化合物是藉由本領域眾所周知的方法合成的,例如採用其中一個或多個氫原子被氘取代的起始材料。
可納入所公開的化合物的同位素的例子還包括氫、碳、氮、氧、磷、氟、氯和碘的同位素,如
2H,
3H,
11C,
13C,
14C,
13N,
15N,
15O,
17O,
18O, 31P,
32P,
35S,
18F,
36Cl,
123I和
125I。用正電子發射同位素,如
11C、
18F、
15O和
13N取代,可用於正電子發射拓撲圖(PET)研究,以檢查受質受體的佔用情況。同位素標記的式(I-A-1)化合物一般可藉由本領域技術人員已知的常規技術製備,或藉由類似於下述實施例中所述的工藝,用適當的同位素標記的試劑代替先前使用的非標記試劑。
本文公開的實施方案的化合物或其藥學上可接受的鹽可能含有一個或多個不對稱中心,因此可能產生對映體、非對映體和其他立體異構體形式,這些形式在絕對立體化學方面可定義為(R)-或(S)-,或者,對於氨基酸來說,可定義為(D)-或(L)-。本聲明的意思是包括所有這些可能的異構體,以及它們的外消旋體和光學純形式。光學活性的(+)和(-)、(R)和(S)、或(D)和(L)-異構體可以用手性合成物或手性試劑製備,或用常規技術,例如色譜法和分餾結晶法進行解析。製備/分離單個對映體的常規技術包括從合適的光學純前體進行手性合成,或使用例如手性高壓液相色譜法(HPLC)解析外消旋物(或鹽或衍生物的外消旋物)。當本文所述的化合物含有烯烴雙鍵或其他幾何不對稱中心時,除非另有規定,否則這些化合物打算包括E和Z幾何異構體。同樣,所有的同分異構體形式也被包括在內。當化合物以其手性形式表示時,應理解為該實施方案包括但不限於特定的非對映體或對映體富集形式。如果沒有指定但存在手性,則可以理解為該實施方案是針對特定的非對映體或對映體富集形式;或這種化合物的外消旋或標量混合物。如本文所用,"標量混合物 "是指立體異構體以非1:1的比例的混合物。
此處使用的 "立體異構體 "是指由相同的原子結合但具有不同的三維結構的化合物,它們不能互換。本發明內容考慮了各種立體異構體及其混合物,並包括 "對映體",它指的是其分子是彼此不可疊加的鏡像的兩種立體異構體。
本文所用的“互變異構體”是指質子從一個分子的一個原子轉移到同一分子的另一個原子。在一些實施方案中,本發明包括所述化合物的互變異構體。
本文所用的“溶劑化物”是指溶劑和化合物相互作用的結果。還提供了本文所述化合物的鹽的溶劑化物。還提供了本文所述化合物的水合物。
本文所用的“水合物”是指與一種或多種水分子化學結合的本發明化合物。
“預防(Prevention)”或“防止(preventing)”是指任何治療導致疾病或病症的臨床症狀不發展的疾病或病症。在一些實施方案中,化合物可以給藥於具有疾病或病症風險或家族史的受試者(包括人)。
本文所用的“前體藥物”是指一種藥物的衍生物,其在施用到人體後根據某種化學或酶促途徑轉化為母體藥物。在一些實施方案中,前藥是藥物的生物活性衍生物,其在施用到人體後根據一些化學或酶促途徑轉化為生物活性母體藥物。
這裡使用的“治療(Treatment)”或“處理(treat)”或“醫治(treating)”是指獲得有益或期望結果的方法。出於本發明的目的,有益或期望的結果包括但不限於減輕症狀和/或減輕症狀的程度和/或防止與疾病或狀況相關的症狀惡化。在一個實施例中,“治療”或“醫治”包括以下一個或多個:a)抑制疾病或病症(例如,減少由疾病或病症引起的一種或多種症狀,和/或減少疾病或病症的程度);b)減緩或阻止與疾病或病症相關的一種或多種症狀的發展(例如,穩定疾病或病症,延緩疾病或病症的惡化或進展);和c)緩解疾病或病症,例如,導致臨床症狀消退、改善疾病狀態、延緩疾病進展、提高生活品質和/或延長生存期。本文所用的“有風險的個體”是指有發展為需要治療的疾病的風險的個體。“處於危險中”的個體可能患有或可能不患有可檢測的疾病或病症,並且可能在本文所述的治療方法之前表現出或可能沒有表現出可檢測的疾病。“有風險”表示個體具有一個或多個所謂的風險因素,這些因素是與疾病或狀況的發展相關的可測量參數,並且在本領域中是已知的與沒有這些風險因素的個體相比,具有一個或多個這些風險因素的個體患疾病或病症的概率更高。
[II.化合物]
本發明的一個方面涉及到一些結合GLP-1R並作為GLP-1R促效劑或調節劑的化合物。在一些實施方案中,本發明的化合物是式(I-A-1)的化合物:
或其藥學上可接受的鹽,其中:
R
1是C
1-6烷基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-S-R
1b,-S(O)R
1b,-S(O)(NH)R
1b,-S(O)
2R
1b,-S(O)
2N(R
1b)(R
1c),-S(O)(NR
1b)R
1c,-C(O)N(R
1b)(R
1c),-C(O)R
1b,或-C(O)OR
1c,其中所述烷基、鹵代烷基、環烷基、芳基、5-10員雜芳基或雜環基各自可選地地被一至四個Z
1取代,並且其中任何兩個Z
1可以與它們所連接的原子結合,形成C
3-10環烷基或雜環基或C
6-10芳基或5-10員雜芳基;
環A是C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基,所述C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基各自可選地被1至4個Z
1a取代;
環B是C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基,所述C
3-10環烷基,雜環基,C
6-10芳基或5-10員雜芳基各自可選地被1至4個R
4取代;
環A和環B各自包含0-3個雙鍵;
R
2是H,C
1-6烷基,C
1-6烷基-烷氧基,C
1-6烷基-環烷氧基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-OR
2a,-S-R
2a,-S(O)R
2a,-S(O)(NH)R
2a,-S(O)
2R
2a,-S(O)
2N(R
2a)(R
2b),或-S(O)(NR
2a)R
2b,其中,烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1取代;並且其中任何兩個Z
1可以與它們所連接的原子結合以形成C
3-10環烷基或雜環基或C
6-10芳基或5-10員雜芳基;
X各自獨立地為-N=,-C(H)=,或-C(R
8)=;
每個R
3和R
3’各自獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-NO
2,-OR
3a,-C(O)R
3a,-CH
2C(O)OR
3a,-C(O)OR
3a,-C(O)N(R
3a)(R
3b),-N(R
3a)C(O)R
3b,-N(R
3a)C(O)OR
3b,-N(R
3a)C(O)N(R
3b)
2,-C(O)NHS(O)
2R
3a,-C(O)NR
3aS(O)
2R
3b,-C(O)NR
3aS(O)
2NR
3bR
3c,-C(O)NR
3a-S(O)(=NR
3b)R
3c,-S(O)
2R
3a,-S(O)
2OR
3a,-S(O)
2N(R
3a)(R
3b),-N(R
3a)S(O)
2R
3b,-S(O)
2NHC(O)R
3a,-S(O)(=NR
3a)R
3b,-S(O)(=NR
3a)NR
3b,-S(=NR
3a)(=NR
3b)R
3c,-P(O)(OR
3a)(R
3b),-P(O)(OR
3a)(OR
3b),-B(OR
3a)(OR
3b),或-O-C
1-6烷基-C(O)OR
3a,其中,所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R
3d取代;
每個R
3a,R
3b,和R
3c獨立地是H,C
1-6烷基,C
6-10芳基,5-10員雜芳基,C
1-6鹵代烷基,C
2-8烷氧基烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-N(R
9a)C(O)-O-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,-CH
2CH(N(R
9a)
2)C(O)OR
9b,-P(O)(OR
9c)
2,-OP(O)(OR
9c)
2,-CH
2P(O)(OR
9c)
2,-CH
2OP(O)(OR
9c)
2,-OCH
2P(O)(OR
9c)
2,-C(O)OCH
2P(O)(OR
9c)
2,-P(O)(R
9c)(OR
9d),-OP(O)(R
9c)(OR
9d),-CH
2P(O)(R
9c)(OR
9d),-OCH
2P(O)(R
9c)(OR
9d),-C(O)OCH
2P(O)(R
9c)(OR
9d),-P(O)(N(R
9c)
2)
2,-OP(O)(N(R
9c)
2)
2,-CH
2P(O)(N(R
9c)
2)
2,-OCH
2P(O)(N(R
9c)
2)
2,-C(O)OCH
2P(O)(N(R
9c)
2)
2,-P(O)(N(R
9c)
2)(OR
9d),-OP(O)(N(R
9c)
2)(OR
9d),-CH
2P(O)(N(R
9c)
2)(OR
9d),-OCH
2P(O)(N(R
9c)
2)(OR
9d),-C(O)OCH
2P(O)(N(R
9c)
2)(OR
9d),-P(O)(R
9c)(N(R
9d)
2),-OP(O)(R
9c)(N(R
9d)
2),-CH
2P(O)(R
9c)(N(R
9d)
2),-OCH
2P(O)(R
9c)(N(R
9d)
2),-C(O)OCH
2P(O)(R
9c)(N(R
9d)
2),C
1-6烷基-雜環基,C
1-6烷基-芳基,或C
1-6烷基-(5-10員)雜芳基,其中,所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個R
4獨立地是H、-OH、CH
2OH、C
1-9烷基,C
1-8鹵代烷基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
4a,-C(O)R
4a,-C(O)O-R
4a,-C(O)N(R
4a)(R
4b),-N(R
4a)(R
4b),-N(R
4a)
2(R
4b)
+,-N(R
4a)-C(O)R
4b,-N(R
4a)C(O)O(R
4b),-N(R
4a)C(O)N(R
4b)(R
4c),-N(R
4a)S(O)
2(R
4b),-N(R
4a)S(O)
2-N(R
4b)(R
4c),-N(R
4a)S(O)
2O(R
4b),-OC(O)R
4a,-OC(O)OR
4a,-OC(O)-N(R
4a)(R
4b),-S-R
4a,-S(O)R
4a,-S(O)(NH)R
4a,-S(O)
2R
4a,-S(O)
2N(R
4a)(R
4b),-S(O)(NR
4a)R
4b,或-Si(R
4a)
3;其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;或者,兩個連接在相鄰環原子上的R
4基團與它們所連接的原子結合以形成C
5-10環烷基或雜環基,它們各自可選地被1至4個Z
1b取代;
每個R
5a和R
5b獨立地是H,C
1-6烷基,C
1-6烷氧基,C
1-6鹵代烷基,C
2-6烷氧基烷基,鹵素,C
3-10環烷基,雜環基,-C
1-6烷基-N(R
9a)(R
9b),-CN,-OR
5a1,或-N(R
5a1)(R
5a2);
或者,R
5a和R
5b與它們所連接的原子組合以形成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
5a3取代;
或者,R
5a或R
5b與環A上的任意取代基環合組成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
5a3取代;
每個R
5a1和R
5a2獨立地是H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、雜環基、C
6-10芳基,或5-10員雜芳基;其中,所述環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R
5a4取代;
V是-C(O)-,-O-,-N(R
6a)-,或-C(R
6b)(R
6c)-;
R
6a是H,C
1-6烷基,C
3-10環烷基,雜環基,-S(O)
2R
6a1,或-S(O)
2N(R
6a1)(R
6a2),其中,所述環烷基或雜環基各自可選地被C
1-6烷基、F或-CN取代;
每個R
6b和R
6c獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
2-6烷氧基烷基,鹵素,C
3-10環烷基,雜環基,-C
1-6烷基-N(R
9a)(R
9b),-CN,-OR
6c1,或-N(R
6c2)(R
6c3);
其中,所述烷基、環烷基或雜環基各自可選地被1至4個R
6b1取代;或R
6b和R
6c與它們所連接的原子結合以形成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
6b1取代;或R
6a或R
6c與一個R
4基團和它們所連接的原子結合以形成C
5-10環烷基或雜環基,它們各自可選地被1至4個R
10取代;
Y是-N(R
7)-,-O-,-S-,-S(O)-,-S(O)
2-,-S(O)(=NH)-,或-S(O)(=NR
7)-;
每個R
3d,R
5a3,R
5a4,R
6b1,和R
10獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO
2R
3e,-NO
2,或-C(O)N(R
2a)(R
2b),其中所述雜環基或5-10員雜芳基各自可選地被C
1-6烷基、C
1-6鹵代烷基或C
1-6鹵代烷氧基取代;
每個R
6a1,R
6a2,R
6c1,R
6c2,R
6c3和R
7獨立地是H,C
1-6烷基或C
3-10環烷基;
每個R
8獨立地是C
1-9烷基,C
1-8鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2;
每個R
9a和R
9b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
或R
9a和R
9b融合形成一個3-10員雜環基,並可選地被C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3取代;
每個Z
1獨立地是C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1a取代;
每個Z
1a獨立地是H,-OH,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個Z
1b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
2-6烯基),-O(C
2-6炔基),-O(C
3-15環烷基),-O(雜環基),-O(C
6-10芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
2-6烯基),-NH(C
2-6炔基),-NH(C
3-15環烷基),-NH(雜環基),-NH(C
6-10芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2,-N(C
2-6烯基)
2,-N(C
2-6炔基)
2,-N(C
3-15環烷基)
2,-N(雜環基)
2,-N(C
6-10芳基)
2,-N(5-10員雜芳基)
2,-N(C
1-9烷基)(C
1-8鹵代烷基),-N(C
1-9烷基)(C
2-6烯基),-N(C
1-9烷基)(C
2-6炔基),-N(C
1-9烷基)(C
3-15環烷基),-N(C
1-9烷基)(雜環基),-N(C
1-9烷基)(C
6-10芳基),-N(C
1-9烷基)(5-10員雜芳基),-C(O)(C
1-9烷基),-C(O)(C
1-8鹵代烷基),-C(O)(C
2-6烯基),-C(O)(C
2-6炔基),-C(O)(C
3-15環烷基),-C(O)(雜環基),-C(O)(C
6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C
1-9烷基),-C(O)O(C
1-8鹵代烷基),-C(O)O(C
2-6烯基),-C(O)O(C
2-6炔基),-C(O)O(C
3-15環烷基),-C(O)O(雜環基),-C(O)O(C
6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH
2,-C(O)NH(C
1-9烷基),-C(O)NH(C
1-8鹵代烷基),-C(O)NH(C
2-6烯基),-C(O)NH(C
2-6炔基),-C(O)NH(C
3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C
6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C
1-9烷基)
2,-C(O)N(C
1-8鹵代烷基)
2,-C(O)N(C
2-6烯基)
2,-C(O)N(C
2-6炔基)
2,-C(O)N(C
3-15環烷基)
2,-C(O)N(雜環基)
2,-C(O)N(C
6-10芳基)
2,-C(O)N(5-10員雜芳基)
2,-NHC(O)(C
1-9烷基),-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
2-6烯基),-NHC(O)(C
2-6炔基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C
6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6烯基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C
6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基),-NHC(O)NH(C
1-8鹵代烷基),-NHC(O)NH(C
2-6烯基),-NHC(O)NH(C
2-6炔基),-NHC(O)NH(C
3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C
6-10芳基),-NHC(O)NH(5-10員雜芳基),-NHS(O)(C
1-9烷基),-N(C
1-9烷基)(S(O)(C
1-9烷基),-S(C
1-9烷基),-S(C
1-8鹵代烷基),-S(C
2-6烯基),-S(C
2-6炔基),-S(C
3-15環烷基),-S(雜環基),-S(C
6-10芳基),-S(5-10員雜芳基),-S(O)N(C
1-9烷基)
2,-S(O)(C
1-9烷基),-S(O)(C
1-8鹵代烷基),-S(O)(C
2-6烯基),-S(O)(C
2-6炔基),-S(O)(C
3-15環烷基),-S(O)(雜環基),-S(O)(C
6-10芳基),-S(O)(5-10員雜芳基),-S(O)
2(C
1-9烷基),-S(O)
2(C
1-8鹵代烷基),-S(O)
2(C
2-6烯基),-S(O)
2(C
2-6炔基),-S(O)
2(C
3-15環烷基),-S(O)
2(雜環基),-S(O)
2(C
6-10芳基),-S(O)
2(5-10員雜芳基),-S(O)(NH)(C
1-9烷基),-S(O)
2NH(C
1-9烷基),或者-S(O)
2N(C
1-9烷基)
2;
其中所述烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團取代:C
1-9烷基,C
1-8鹵代烷基,鹵素,-OH,-NH
2,CO
2H-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
3-15環烷基)
2,-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基),S(O)
2(C
1-9烷基),-S(O)
2(C
1-8鹵代烷基),-S(O)
2(C
3-15環烷基),-S(O)
2(雜環基),-S(O)
2(芳基),-S(O)
2(5-10員雜芳基),-S(O)(NH)(C
1-9烷基),-S(O)
2NH(C
1-9烷基),或-S(O)
2N(C
1-9烷基)
2;
每個R
1b,R
1c,R
2a,R
2b,R
4a,R
4b,R
4c,R
9c,R
9d,R
12a,R
12b,和R
12c獨立地是H,-OH,C
1-9烷基,C
2-6烯基,C
2-6炔基,C
3-15環烷基,雜環基,C
6-10芳基,或5-10員雜芳基,其中所述烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;並且
每個R
3e獨立地是H,C
1-6烷基,C
1-6鹵代烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基,-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-P(O)(OR
9c)
2,-CH
2P(O)(OR
9c)
2,-OCH
2P(O)(OR
9c)
2,-C(O)OCH
2P(O)(OR
9c)
2,-P(O)(R
9c)(OR
9d),-OP(O)(R
9c)(OR
9d),-CH
2P(O)(R
9c)(OR
9d),-C(O)OCH
2P(O)(R
9c)(OR
9d),-P(O)(N(R
9c)
2)
2,-CH
2P(O)(N(R
9c)
2)
2,-C(O)OCH
2P(O)(N(R
9c)
2)
2,-P(O)(N(R
9c)
2)(OR
9d),-CH
2P(O)(N(R
9c)
2)(OR
9d),-C(O)OCH
2P(O)(N(R
9c)
2)(OR
9d),-P(O)(R
9c)(N(R
9d)
2),-CH
2P(O)(R
9c)(N(R
9d)
2),或者-C(O)OCH
2P(O)(R
9c)(N(R
9d)
2);
其中所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
其中,每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;
其中,每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子。
在一些實施方案中,式I-A-1中的每個Z
1或其藥學上可接受的鹽獨立地為C
1-9烷基、C
1-8鹵代烷基、C
1-6烷氧基、C
1-6鹵代烷氧基,C
2-6烷氧烷基、C
2-6烯基、C
2-6炔基、鹵素、C
3-15環烷基、雜環基、C
6-10芳基、5-10員雜芳基、氧代、-NO
2、-N
3、-CN、-O-R
12a、-C(O)-R
12a、-C(O)O-R
12a、-C C(O)-N(R
12a)(R
12b)或-N(R
12a)(R
12b)。
在一些實施方案中,式I-A-1中的每個Z
1a或其藥學上可接受的鹽獨立地為H、-OH、C
1-9烷基、C
1-8鹵代烷基、C
1-6烷氧基、C
1-6鹵代烷氧基,C
2-6烷氧烷基或鹵素。
在一些實施方案中,式I-A-1中的每個Z
1b或其藥學上可接受的鹽獨立地為H、C
1-9烷基、C
1-8鹵代烷基、鹵素、氧代、-OH或-CN。
在一些實施方案中,式I-A-1中的每個R
8或其藥學上可接受的鹽獨立地為H、氧代、OH、C
1-9烷基、C
1-8鹵代烷基、鹵素、-O(C
1-3烷基)或-O(C
1-3鹵代烷基)。
在一些實施方案中,化合物具有式(I-A-2)或式(I-A-3)的結構,或其藥學上可接受的鹽:
其中,C環是C
3-10環烷基,雜環基,C
6-10的芳基或5-10員雜芳基,其各自可選地被1-4個Z
1取代;
Y
1-V是N-CH
2,N-CH(CH
3),N-CF
2,CH-CH
2,CH-CF
2,CH-NH,N-S(O),N-S(O)
2,N-C(O),CH-C(O)或環丙烷基;
Y
2是C,CH或N;
R
2是H,C
1-6烷基,-C
1-6烷基-烷氧基,-C
1-6烷基-環烷氧基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-OR
2a,-S-R
2a,-S(O)R
2a,-S(O)(NH)R
2a,-S(O)
2R
2a,-S(O)
2N(R
2a)(R
2b),或-S(O)(NR
2a)R
2b,
其中,所述烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1取代,其中任何兩個Z
1可以與它們所連接的原子結合,形成C
3-10環烷基或雜環基或C
6-10芳基或5-10員雜芳基;
X各自獨立地為-N=,-C(H)=,或-C(R
8)=;
每個R
3和R
3’獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-NO
2,-OR
3a,-C(O)R
3a,-CH
2C(O)OR
3a,-C(O)OR
3a,-C(O)N(R
3a)(R
3b),-N(R
3a)C(O)R
3b,-N(R
3a)C(O)OR
3b,-N(R
3a)C(O)N(R
3b)
2,-C(O)NHS(O)
2R
3a,-C(O)NR
3aS(O)
2R
3b,-C(O)NR
3aS(O)
2NR
3bR
3c,-C(O)NR
3a-S(O)(=NR
3b)R
3c,-S(O)
2R
3a,-S(O)
2OR
3a,-S(O)
2N(R
3a)(R
3b),-N(R
3a)S(O)
2R
3b,-S(O)
2NHC(O)R
3a,-S(O)(=NR
3a)R
3b,-S(O)(=NR
3a)NR
3b,-S(=NR
3a)(=NR
3b)R
3c,-P(O)(OR
3a)(R
3b),-P(O)(OR
3a)(OR
3b),-B(OR
3a)(OR
3b),或-O-C
1-6烷基-C(O)OR
3a,
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R
3d取代;
每個R
3a,R
3b和R
3c獨立地是H,C
1-6烷基,C
6-10芳基,5-10員雜芳基,C
1-6鹵代烷基,C
2-8烷氧基烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-N(R
9a)C(O)-O-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,-CH
2CH(N(R
9a)
2)C(O)OR
9b,C
1-6烷基-雜環基,C
1-6烷基-芳基或C
1-6烷基-(5-10員)雜芳基,
其中所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個R
5a和R
5b獨立地是H,C
1-6烷基,C
1-6烷氧基,C
1-6鹵代烷基,C
2-6烷氧基烷基,鹵素,C
3-10環烷基,雜環基,-C
1-6烷基-N(R
9a)(R
9b),-CN,-OR
5a1,或-N(R
5a1)(R
5a2);
或者,R
5a和R
5b與它們所連接的原子組合成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
5a3地取代;
每個R
5a1和R
5a2獨立地是H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、雜環基、C
6-10芳基或5-10員雜芳基,
其中,環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個鹵素取代;
每個R
3d和R
5a3獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO
2R
3e,-NO
2,或-C(O)N(R
2a)(R
2b),其中,該雜環基或5-10員雜芳基可選地被C
1-6烷基、C
1-6鹵代烷基或C
1-6鹵代烷氧基取代;
每個R
8獨立地是C
1-9烷基,C
1-8鹵代烷基,C
2-6烯烴基,C
2-6炔烴基,鹵素,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2;
每個R
9a和R
9b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
或R
9a和R
9b融合形成一個3-10員雜環基,其可選地被C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3取代;
每個Z
1獨立地是C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1a取代;
每個Z
1a獨立地是H、C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個Z
1b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
2-6烯基),-O(C
2-6炔基),-O(C
3-15環烷基),-O(雜環基),-O(C
6-10芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
2-6烯基),-NH(C
2-6炔基),-NH(C
3-15環烷基),-NH(雜環基),-NH(C
6-10芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2,-N(C
2-6烯基)
2,-N(C
2-6炔基)
2,-N(C
3-15環烷基)
2,-N(雜環基)
2,-N(C
6-10芳基)
2,-N(5-10員雜芳基)
2,-N(C
1-9烷基)(C
1-8鹵代烷基),-N(C
1-9烷基)(C
2-6烯基),-N(C
1-9烷基)(C
2-6炔基),-N(C
1-9烷基)(C
3-15環烷基),-N(C
1-9烷基)(雜環基),-N(C
1-9烷基)(C
6-10芳基),-N(C
1-9烷基)(5-10員雜芳基),-C(O)(C
1-9烷基),-C(O)(C
1-8鹵代烷基),-C(O)(C
2-6烯基),-C(O)(C
2-6炔基),-C(O)(C
3-15環烷基),-C(O)(雜環基),-C(O)(C
6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C
1-9烷基),-C(O)O(C
1-8鹵代烷基),-C(O)O(C
2-6烯基),-C(O)O(C
2-6炔基),-C(O)O(C
3-15環烷基),-C(O)O(雜環基),-C(O)O(C
6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH
2,-C(O)NH(C
1-9烷基),-C(O)NH(C
1-8鹵代烷基),-C(O)NH(C
2-6烯基),-C(O)NH(C
2-6炔基),-C(O)NH(C
3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C
6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C
1-9烷基)
2,-C(O)N(C
1-8鹵代烷基)
2,-C(O)N(C
2-6烯基)
2,-C(O)N(C
2-6炔基)
2,-C(O)N(C
3-15環烷基)
2,-C(O)N(雜環基)
2,-C(O)N(C
6-10芳基)
2,-C(O)N(5-10員雜芳基)
2,-NHC(O)(C
1-9烷基),-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
2-6烯基),-NHC(O)(C
2-6炔基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C
6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6烯基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C
6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基),-NHC(O)NH(C
1-8鹵代烷基),-NHC(O)NH(C
2-6烯基),-NHC(O)NH(C
2-6炔基),-NHC(O)NH(C
3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C
6-10芳基),-NHC(O)NH(5-10員雜芳基);
其中,烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團所取代:C
1-9烷基,C
1-8鹵代烷基,鹵素,-OH,-NH
2,CO
2H-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
3-15環烷基)
2,-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基);
每個R
1b,R
1c,R
2a,R
2b,R
4c,R
9c,R
12a,R
12b和R
12c獨立地是H,OH,C
1-9烷基,C
2-6烯基,C
2-6炔基,C
3-15環烷基,雜環基,C
6-10芳基,或5-10員雜芳基,其中烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個R
3e獨立地是H,C
1-6烷基,C
1-6鹵代烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基,-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基;
其中烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1-4個Z
1b取代;
其中每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;
其中每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子。
在一些實施方案中,化合物具有式(I-A-4)或式(I-A-5)的結構,或其藥學上可接受的鹽:
其中C環是C
3-10環烷基,雜環基,C
6-10的芳基或5-10員雜芳基,其各自可選地被1-4個Z
1取代;
Y
1-V是N-CH
2,N-CH(CH
3),N-CF
2,CH-CH
2,CH-CF
2,CH-NH,N-S(O),N-S(O)
2,N-C(O),CH-C(O) 或者環丙烷基;
Y
2是C,CH或N;
R
2是H,C
1-6烷基,-C
1-6烷基-烷氧基,-C
1-6烷基-環烷氧基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-OR
2a,-S-R
2a,-S(O)R
2a,-S(O)(NH)R
2a,-S(O)
2R
2a,-S(O)
2N(R
2a)(R
2b),或-S(O)(NR
2a)R
2b,
其中,烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1取代,任何兩個Z
1可以與它們所連接的原子結合以形成C
3-10環烷基或雜環基或C
6-10芳基或5-10員雜芳基;
X各自獨立地為-N=,-C(H)=,或-C(R
8)=;
每個R
3和R
3’各自獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-NO
2,-OR
3a,-C(O)R
3a,-CH
2C(O)OR
3a,-C(O)OR
3a,-C(O)N(R
3a)(R
3b),-N(R
3a)C(O)R
3b,-N(R
3a)C(O)OR
3b,-N(R
3a)C(O)N(R
3b)
2,-C(O)NHS(O)
2R
3a,-C(O)NR
3aS(O)
2R
3b,-C(O)NR
3aS(O)
2NR
3bR
3c,-C(O)NR
3a-S(O)(=NR
3b)R
3c,-S(O)
2R
3a,-S(O)
2OR
3a,-S(O)
2N(R
3a)(R
3b),-N(R
3a)S(O)
2R
3b,-S(O)
2NHC(O)R
3a,-S(O)(=NR
3a)R
3b,-S(O)(=NR
3a)NR
3b,-S(=NR
3a)(=NR
3b)R
3c,-P(O)(OR
3a)(R
3b),-P(O)(OR
3a)(OR
3b),-B(OR
3a)(OR
3b),或-O-C
1-6烷基-C(O)OR
3a,
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R
3d取代;
每個R
3a,R
3b和R
3c獨立地是H,C
1-6烷基,C
6-10芳基,5-10員雜芳基,C
1-6鹵代烷基,C
2-8烷氧基烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-N(R
9a)C(O)-O-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,-CH
2CH(N(R
9a)
2)C(O)OR
9b,C
1-6烷基-雜環基,C
1-6烷基-芳基orC
1-6烷基-(5-10員)雜芳基;
其中,烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
R
5a各自獨立地選自H,C
1-6烷基,C
1-6烷氧基,C
1-6鹵代烷基,C
2-6烷氧基烷基,鹵素,C
3-10環烷基,雜環基,-C
1-6烷基-N(R
9a)(R
9b),-CN,-OR
5a1,或-N(R
5a1)(R
5a2);
每個R
5a1和R
5a2獨立地是H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、雜環基、C
6-10芳基或5-10員雜芳基,
其中,環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個鹵素取代;
R
3d獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO
2R
3e,-NO
2,或-C(O)N(R
2a)(R
2b),其中,該雜環基或5-10員雜芳基各自可選地被C
1-6烷基、C
1-6鹵代烷基或C
1-6鹵代烷氧基取代;
每個R
8獨立地是C
1-9烷基,C
1-8鹵代烷基,C
2-6烯烴基,C
2-6炔烴基,鹵素,C
3-15環烷基,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2;
每個R
9a和R
9b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
或R
9a和R
9b融合形成一個3-10員雜環基,其可選性地被以下基團取代:C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
每個Z
1獨立地是C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-N
3,-CN,-O-R
12a,
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1a取代;
每個Z
1a獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3,
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個Z
1b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
2-6烯基),-O(C
2-6炔基),-O(C
3-15環烷基),-O(雜環基),-O(C
6-10芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
2-6烯基),-NH(C
2-6炔基),-NH(C
3-15環烷基),-NH(雜環基),-NH(C
6-10芳基),-NH(5-10員雜芳基),-N(環烷基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2,-N(C
2-6烯基)
2,-N(C
2-6炔基)
2,-N(C
3-15環烷基)
2,-N(雜環基)
2,-N(C
6-10芳基)
2,-N(5-10員雜芳基)
2,-N(C
1-9烷基)(C
1-8鹵代烷基),-N(C
1-9烷基)(C
2-6烯基),-N(C
1-9烷基)(C
2-6炔基),-N(C
1-9烷基)(C
3-15環烷基),-N(C
1-9烷基)(雜環基),-N(C
1-9烷基)(C
6-10芳基),-N(C
1-9烷基)(5-10員雜芳基),-C(O)(C
1-9烷基),-C(O)(C
1-8鹵代烷基),-C(O)(C
2-6烯基),-C(O)(C
2-6炔基),-C(O)(C
3-15環烷基),-C(O)(雜環基),-C(O)(C
6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C
1-9烷基),-C(O)O(C
1-8鹵代烷基),-C(O)O(C
2-6烯基),-C(O)O(C
2-6炔基),-C(O)O(C
3-15環烷基),-C(O)O(雜環基),-C(O)O(C
6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH
2,-C(O)NH(C
1-9烷基),-C(O)NH(C
1-8鹵代烷基),-C(O)NH(C
2-6烯基),-C(O)NH(C
2-6炔基),-C(O)NH(C
3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C
6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C
1-9烷基)
2,-C(O)N(C
1-8鹵代烷基)
2,-C(O)N(C
2-6烯基)
2,-C(O)N(C
2-6炔基)
2,-C(O)N(C
3-15環烷基)
2,-C(O)N(雜環基)
2,-C(O)N(C
6-10芳基)
2,-C(O)N(5-10員雜芳基)
2,-NHC(O)(C
1-9烷基),-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
2-6烯基),-NHC(O)(C
2-6炔基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C
6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6烯基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C
6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基),-NHC(O)NH(C
1-8鹵代烷基),-NHC(O)NH(C
2-6烯基),-NHC(O)NH(C
2-6炔基),-NHC(O)NH(C
3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C
6-10芳基),-NHC(O)NH(5-10員雜芳基);
其中,烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團所取代:C
1-9烷基,C
1-8鹵代烷基,鹵素,-OH,-NH
2,CO
2H-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
3-15環烷基)
2,-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基);
每個R
1b,R
1c,R
2a,R
2b,R
4c,R
9c,R
12a,R
12b,和R
12c獨立地是H,OH,C
1-9烷基,C
2-6烯基,C
2-6炔基,C
3-15環烷基,雜環基,C
6-10芳基,或5-10員雜芳基,其中烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;同時
每個R
3e獨立地是H,C
1-6烷基,C
1-6鹵代烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基;
其中烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1-4個Z
1b取代;
其中每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;
其中每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子。
在一些實施方案中,化合物具有式(I-A-6)或式(I-A-7)的結構,或其藥學上可接受的鹽:
其中C環是C
3-10環烷基,雜環基,C
6-10的芳基或5-10員雜芳基,其各自可選地被1-4個Z
1取代;
V是CH
2、CH(CH
3)、NH、C(O)、S(O)、S(O)
2;
n=0,1,2,3,或4;
R
2是H,C
1-6烷基,-C
1-6烷基-烷氧基,-C
1-6烷基-環烷氧基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-OR
2a,-S-R
2a,-S(O)R
2a,-S(O)(NH)R
2a,-S(O)
2R
2a,-S(O)
2N(R
2a)(R
2b),或-S(O)(NR
2a)R
2b,
其中,烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1取代,並且其中任何兩個Z
1可以與它們所連接的原子結合,形成C
3-10環烷基或雜環基或C
6-10芳基或5-10員雜芳基;
X各自獨立地為-N=,-C(H)=,或-C(R
8)=;
每個R
3和R
3’獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CN,-NO
2,-OR
3a,-C(O)R
3a,-CH
2C(O)OR
3a,-C(O)OR
3a,-C(O)N(R
3a)(R
3b),-N(R
3a)C(O)R
3b,-N(R
3a)C(O)OR
3b,-N(R
3a)C(O)N(R
3b)
2,-C(O)NHS(O)
2R
3a,-C(O)NR
3aS(O)
2R
3b,-C(O)NR
3aS(O)
2NR
3bR
3c,-C(O)NR
3a-S(O)(=NR
3b)R
3c,-S(O)
2R
3a,-S(O)
2OR
3a,-S(O)
2N(R
3a)(R
3b),-N(R
3a)S(O)
2R
3b,-S(O)
2NHC(O)R
3a,-S(O)(=NR
3a)R
3b,-S(O)(=NR
3a)NR
3b,-S(=NR
3a)(=NR
3b)R
3c,-P(O)(OR
3a)(R
3b),-P(O)(OR
3a)(OR
3b),-B(OR
3a)(OR
3b),或-O-C
1-6烷基-C(O)OR
3a,
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R
3d取代;
每個R
3a,R
3b,和R
3c獨立地是H,C
1-6烷基,C
6-10芳基,5-10員雜芳基,C
1-6鹵代烷基,C
2-8烷氧基烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-N(R
9a)C(O)-O-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-O-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基-OP(O)(OR
9c)
2,-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CH
2CH(N(R
9a)
2)C(O)OR
9b,C
1-6烷基-雜環基,C
1-6烷基-芳基或C
1-6烷基-(5-10員)雜芳基;
其中,烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個R
4獨立地是H、-OH、CH
2OH、C
1-9烷基,C
1-8鹵代烷基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
4a,-C(O)R
4a,-C(O)O-R
4a,-C(O)N(R
4a)(R
4b),-N(R
4a)(R
4b),-N(R
4a)
2(R
4b)
+,-N(R
4a)-C(O)R
4b,-N(R
4a)C(O)O(R
4b),-N(R
4a)C(O)N(R
4b)(R
4c),-N(R
4a)S(O)
2(R
4b),-N(R
4a)S(O)
2-N(R
4b)(R
4c),-N(R
4a)S(O)
2O(R
4b),-OC(O)R
4a,-OC(O)OR
4a,-OC(O)-N(R
4a)(R
4b),-S-R
4a,-S(O)R
4a,-S(O)(NH)R
4a,-S(O)
2R
4a,-S(O)
2N(R
4a)(R
4b),-S(O)(NR
4a)R
4b,或-Si(R
4a)
3;
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;或者,兩個連接在相鄰環原子上的R
4基團與它們所連接的原子結合以形成C
5-10環烷基或雜環基,它們各自可選地被1至4個Z
1b取代;
每個R
5a和R
5b獨立地是H,C
1-6烷基,C
1-6烷氧基,C
1-6鹵代烷基,C
2-6烷氧基烷基,鹵素,C
3-10環烷基,雜環基,-C
1-6烷基-N(R
9a)(R
9b),-CN,-OR
5a1,或-N(R
5a1)(R
5a2);
或者,R
5a和R
5b與它們所連接的原子組合成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
5a3取代;
或者,R
5a或R
5b與環A上的任意取代基環合組成C
3-10環烷基或雜環基,它們各自可選地被1至4個R
5a3取代;
每個R
5a1和R
5a2獨立地是H、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、雜環基、C
6-10芳基或5-10員雜芳基,
其中,環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個鹵素取代;
每個R
3d和R
5a3獨立地是H,C
1-6烷基,C
1-6鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO
2R
3e,-NO
2,或-C(O)N(R
2a)(R
2b),其中,所述雜環基或5-10員雜芳基各自可選地被C
1-6烷基、C
1-6鹵代烷基或C
1-6鹵代烷氧基取代;
每個R
8獨立地是C
1-9烷基,C
1-8鹵代烷基,C
2-6烯烴基,C
2-6炔烴基,鹵素,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2;
每個R
9a和R
9b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
或R
9a和R
9b融合形成一個3-10員雜環基,其可選地被以下基團所取代:C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
每個Z
1獨立地是C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-N
3,-CN,-O-R
12a,
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1a取代;
每個Z
1a獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-R
12a,-C(O)R
12a,-C(O)O-R
12a,-C(O)N(R
12a)(R
12b),-N(R
12a)(R
12b),-N(R
12a)
2(R
12b)
+,-N(R
12a)-C(O)R
12b,-N(R
12a)C(O)O(R
12b),-N(R
12a)C(O)N(R
12b)(R
12c),-N(R
12a)S(O)
2(R
12b),-N(R
12a)S(O)
2-N(R
12b)(R
12c),-N(R
12a)S(O)
2O(R
12b),-OC(O)R
12a,-OC(O)OR
12a,-OC(O)-N(R
12a)(R
12b),-S-R
12a,-S(O)R
12a,-S(O)(NH)R
12a,-S(O)
2R
12a,-S(O)
2N(R
12a)(R
12b),-S(O)(NR
12a)R
12b,或-Si(R
12a)
3;
其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;
每個Z
1b獨立地是H,C
1-9烷基,C
1-8鹵代烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO
2R
3e,-NO
2,-NH
2,-N
3,-SH,-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
2-6烯基),-O(C
2-6炔基),-O(C
3-15環烷基),-O(雜環基),-O(C
6-10芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
2-6烯基),-NH(C
2-6炔基),-NH(C
3-15環烷基),-NH(雜環基),-NH(C
6-10芳基),-NH(5-10員雜芳基),-N(環烷基),-N(C
1-9烷基)
2,-N(C
1-8鹵代烷基)
2,-N(C
2-6烯基)
2,-N(C
2-6炔基)
2,-N(C
3-15環烷基)
2,-N(雜環基)
2,-N(C
6-10芳基)
2,-N(5-10員雜芳基)
2,-N(C
1-9烷基)(C
1-8鹵代烷基),-N(C
1-9烷基)(C
2-6烯基),-N(C
1-9烷基)(C
2-6炔基),-N(C
1-9烷基)(C
3-15環烷基),-N(C
1-9烷基)(雜環基),-N(C
1-9烷基)(C
6-10芳基),-N(C
1-9烷基)(5-10員雜芳基),-C(O)(C
1-9烷基),-C(O)(C
1-8鹵代烷基),-C(O)(C
2-6烯基),-C(O)(C
2-6炔基),-C(O)(C
3-15環烷基),-C(O)(雜環基),-C(O)(C
6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C
1-9烷基),-C(O)O(C
1-8鹵代烷基),-C(O)O(C
2-6烯基),-C(O)O(C
2-6炔基),-C(O)O(C
3-15環烷基),-C(O)O(雜環基),-C(O)O(C
6-10芳基),-C(O)O(5-10員雜芳基),C(O)O(C
1-9烷基),-C(O)O(C
1-8鹵代烷基),-C(O)O(C
2-6烯基),-C(O)O(C
2-6炔基),-C(O)O(C
3-15環烷基),-C(O)O(雜環),-C(O)O(C
6-10芳基),-C(O)O(5-10員雜環),-C(O)NH
2,-C(O)NH(C
1-9烷基),-C(O)NH(C
1-8鹵代烷基),-C(O)NH(C
2-6烯基),-C(O)NH(C
2-6炔基),-C(O)NH(C
3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C
6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C
1-9烷基)
2,-C(O)N(C
1-8鹵代烷基)
2,-C(O)N(C
2-6烯基)
2,-C(O)N(C
2-6炔基)
2,-C(O)N(C
3-15環烷基)
2,-C(O)N(雜環基)
2,-C(O)N(C
6-10芳基)
2,-C(O)N(5-10員雜芳基)
2,-NHC(O)(C
1-9烷基),-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
2-6烯基),-NHC(O)(C
2-6炔基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C
6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6烯基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C
6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基),-NHC(O)NH(C
1-8鹵代烷基),-NHC(O)NH(C
2-6烯基),-NHC(O)NH(C
2-6炔基),-NHC(O)NH(C
3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C
6-10芳基),-NHC(O)NH(5-10員雜芳基);
其中,烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團所取代:C
1-9烷基,C
1-8鹵代烷基,鹵素,-OH,-NH
2,CO
2H-O(C
1-9烷基),-O(C
1-8鹵代烷基),-O(C
3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C
1-9烷基),-NH(C
1-8鹵代烷基),-NH(C
3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C
1-9烷基)
2,-N(C
3-15環烷基)
2,-NHC(O)(C
1-8鹵代烷基),-NHC(O)(C
3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C
1-9烷基),-NHC(O)O(C
1-8鹵代烷基),-NHC(O)O(C
2-6炔基),-NHC(O)O(C
3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C
1-9烷基);
每個R
1b,R
1c,R
2a,R
2b,R
4a,R
4b,R
4c,R
9c,R
12a,R
12b,和R
12c獨立地是H,OH,C
1-9烷基,C
2-6烯基,C
2-6炔基,C
3-15環烷基,雜環基,C
6-10芳基,或5-10員雜芳基,其中烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z
1b取代;並且
每個R
3e獨立地是H,C
1-6烷基,C
1-6鹵代烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,
其中烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1-4個Z
1b取代;
其中每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;
其中每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;
在一些實施方案中,具有通式(I-A-2),(I-A-3),(I-A-4),(I-A-5),(I-A-6),(I-A-7)的化合物或其藥學上可接受的鹽,每個R
5a和R
5b獨立地是H,C
1-9烷基,C
2-6烷氧基烷基,其中C
1-9烷基或C
2-6烷氧基烷基各自可選擇地被一個或多個鹵素取代;在一些實施方案中,具有通式(I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7)的化合物或其藥學上可接受的鹽,環C是選自以下結構的C
6-10芳基或5-10員雜芳基:
其中每個各自可選擇地被一至四個以下基團所取代:H、OH、氧代、鹵素、C
1-6烷基、C
1-6鹵代烷基、C
1-6烷氧基、C
1-6鹵代烷氧基、C
2-6烷氧基烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、雜環基、-NO
2、-N
3、-CN、-O-C
1-6烷基、-C(O)-C
1-6烷基、-C(O)-N(C
0-6烷基) ( C
0-6烷基),和-N(C
0-6烷基) (C
0-6烷基),其中,這1至4個取代基各自可選擇地被一個或多個鹵素所取代。
在一些實施方案中,具有通式(I-A-1)的化合物或其藥學上可接受的鹽,環A選自以下的一種:
其可選地被1-4個Z
1a取代;
在一些實施方案中,具有通式(I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7) 的化合物或其藥學上可接受的鹽,Z
1a較佳自H,鹵素,C
1-9烷基,C
1-6烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,C
3-15環烷基,或雜環基,它們各自可選地被一個或多個鹵素所取代。
在一些實施方案中,具有通式(I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-A-7) 的化合物或其藥學上可接受的鹽,R
2是C
1-6烷基,-C
1-6烷基-烷氧基,-C
1-6烷基-環烷氧基,C
1-6鹵代烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,它們各自可選地被1至4個Z
1取代。
較佳地,R
2選自以下的一種:
其可選地被1至4個Z
1取代。
在一些實施方案中,具有通式(I-A-1),(I-A-2),(I-A-3),(I-A-4),(I-A-5),(I-A-6),(I-A-7)的化合物或其藥學上可接受的鹽,R
2’是H、C
1-6烷基、C
1-6鹵代烷基、-C
1-6烷基或-環烷氧基;它們各自可選地被一個或多個鹵素取代。
在一些實施方案中,具有通式(I-A-1),(I-A-2),(I-A-3),(I-A-4),(I-A-5),(I-A-6),(I-A-7)的化合物或其藥學上可接受的鹽,每個R
3和R
3’獨立地選自H,C
6-10芳基,5-10員雜芳基,-C(O)R
3a,-CH
2C(O)OR
3a,-C(O)N(R
3a)(R
3b),-N(R
3a)C(O)R
3b,-N(R
3a)C(O)OR
3b,-N(R
3a)C(O)N(R
3b)
2,-C(O)NHS(O)
2R
3a,-C(O)NR
3aS(O)
2R
3b,-C(O)NR
3aS(O)
2NR
3bR
3c,-C(O)NR
3a-S(O)(=NR
3b)R
3c,-S(O)
2N(R
3a)(R
3b),-N(R
3a)S(O)
2R
3b,-S(O)
2NHC(O)R
3a,或者-O-C
1-6烷基-C(O)OR
3a,其中每個這些基團各自可選地被1至4個R
3d取代。
較佳地,每個R
3和R
3’獨立地選自H,C(O)NR
3a(CH
2)
mR
3b,C(O)NR
3a(CH
2)
mC(O)R
3b,NR
3aC(O)(CH
2)
mR
3b,NR
3a(CH
2)
mR
3b,NR
3a(CH
2)
mC(O)R
3b,C(O)NR
3aR
3b,NR
3aC(O)R
3b。這些基團中的每一個各自可選地被1至4個R
3d取代,其中m是0,1,2,3。
較佳地,每個R
3和R
3’獨立地選自H,C(O)NHR
3b,或者NHC(O)R
3b。
在一些實施方案中,具有通式(I-A-1),(I-A-2),(I-A-3),(I-A-4),(I-A-5),(I-A-6),(I-A-7)的化合物或其藥學上可接受的鹽,R
3b獨立地選自H,C
1-6烷基,C
1-6鹵代烷基,C
2-8烷氧基烷基,-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C(O)N(R
9a)(R
9b),-C
1-4烷基-O-C(O)-C
1-4烷基,-C
1-4烷基-O-C(O)-C
1-4烷基-N(R
9a)(R
9b),-C
1-4烷基-C
3-8環烷基,-C
1-4烷基-雜環基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,C
6-10芳基,5-10員雜芳基,-CH
2CH(N(R
9a)
2)C(O)OR
9b,C
1-6烷基-雜環基,或者C
1-6烷基-芳基和C
1-6烷基-5-10員雜芳基。其中,烷基、烯基、環烷基、雜環基、芳基或雜芳基各自可選地被1至4個Z
1b取代。
較佳地,R
3b是取代的C
5-10芳基或取代的5-10員雜芳基:它們各自可選地被1至5個R
3f取代;R
3f選自H,OH,氧代,NH
2,鹵素,-NO
2,-N
3,-CN,C
1-6烷基,C
1-6鹵代烷基,C
1-6烷氧基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,C
3-10環烷基,雜環基,-O-C
1-6烷基,-C(O)-C
1-6烷基,-C(O)-N(R
12a)(R
12b),-N(R
12a)(R
12b),C
6-10芳基,5-10員雜芳基。而R
3f各自可選地被一個或多個鹵素、C
1-6烷基、C
1-6鹵代烷基、C
1-6烷氧基、C
1-6鹵代烷氧基取代。
更佳地,R
3b選自以下的一種:
它們各自可選地被1至5個R
3f取代。
在一些實施方案中,具有通式(I-A-1)或其藥學上可接受的鹽,R
4獨立地選自H,-OH,C
1-9烷基,C
1-8鹵代烷基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基,雜環基,C
6-10芳基,5-10員雜芳基,氧代,-NO
2,-CN,-N
3,-O-C
1-9烷基,或者-C(O)C
1-9烷基,他們各自可選地被1至4個Z
1b取代;或者,連接在相鄰環原子上的兩個R
4基團與它們所連接的原子結合,形成C
5-10環烷基或雜環基,它們各自可選地被1-4個Z
1b取代。
較佳地,R
4獨立地選自H,-OH,C
1-9烷基,C
1-8鹵代烷基,C
1-6鹵代烷氧基,C
2-6烷氧基烷基,C
2-6烯基,C
2-6炔基,鹵素,C
3-15環烷基。
本發明進一步提供藥物組合物、方法和用途,其中包括式(I-A-1)、(I-A-2)、(I-A-3)、(I-A-4)、(I-A-5)、(I-A-6)、(I-A-7)的化合物或其藥學上可接受的鹽。例如,本發明的化合物一般在治療GLP-1R介導的疾病或病症的方法中有用。
在一些實施方案中,式(I-A-1),(I-A-2),(I-A-3),(I-A-4),(I-A-5),(I-A-6),或者(I-A-7)化合物或其藥學上可接受的鹽具有以下式的一種:
[III.藥物組合物]
本發明的另一個方面提供了一種藥物組合物,其包含本發明的化合物。在一些實施方式中,本發明提供了一種藥物組合物,其包含本發明的化合物,以及一種或多種藥學上可接受的賦形劑(輔料,excipient)。
在一些實施方案中,該藥物組合物包含式(I-A-1)化合物或其藥學上可接受的鹽。
在一些實施方案中,該藥物組合物包含式(I-A-2)化合物或其藥學上可接受的鹽。
在一些實施方案中,該藥物組合物包含式(I-A-3)化合物或其藥學上可接受的鹽。
在一些實施方案中,該藥物組合物包含式(I-A-4)化合物或其藥學上可接受的鹽。
在一些實施方案中,該藥物組合物包含式(I-A-5)化合物或其藥學上可接受的鹽。
在一些實施方案中,該藥物組合物包含式(I-A-6)化合物或其藥學上可接受的鹽。
在一些實施方案中,該藥物組合物包含式(I-A-7)化合物或其藥學上可接受的鹽。
在一些實施方案中,本發明的藥物組合物還包含一種或多種其他治療劑。其他治療劑的實例包括但不限於本發明的聯合療法部分中列出的那些治療劑。
本發明的藥物組合物可以是適用於預期給藥方法的任何形式。在一些實施方案中,藥物組合物是片劑、小袋、錠劑、含片、水性或油性懸浮液、可分散粉末或顆粒、乳劑、硬膠囊或軟膠囊、糖漿或口服給藥的藥劑的形式。
在一些實施方案中,本發明的藥物組合物以單位劑型呈現,包括但不限於膠囊、小袋或片劑,每個膠囊、小囊或片劑含有預定量的活性成分。在一個實施方案中,藥物組合物是片劑。
藥物組合物可藉由藥學領域中已知的任何方法製備。這種方法包括使活性成分(例如本發明的化合物或其藥用鹽)與一種或多種藥學上可接受的賦形劑結合的步驟。在一些實施方案中,藥物組合物藉由將活性成分與液體賦形劑或細碎的固體賦形劑或者兩者均勻且緊密地結合,然後如果需要,對產品進行成型來製備。技術和配方通常見於《雷明頓:藥學科學與實踐》,第21版,賓夕法尼亞州費城Lippincott Wiliams和Wilkins,2006年。
一種或多種添加劑的實例包括但不限於填料、黏合劑、膨鬆劑、糖脂、甜味劑、調味劑、著色劑和防腐劑。在一些實施方案中,藥物組合物為片劑形式,並包含一種或多種適於製備片劑的藥學上可接受的賦形劑。這些賦形劑可以是例如惰性稀釋劑,例如碳酸鈣或碳酸鈉、乳糖、乳糖一水合物、交聯羧甲基纖維素鈉、聚維酮、磷酸鈣或磷酸鈉;造粒和崩解劑,如玉米澱粉或褐藻酸;黏合劑,如纖維素、微晶纖維素、澱粉、明膠或阿拉伯膠;以及潤滑劑,例如硬脂酸鎂、硬脂酸或滑石。片劑可以是無塗層的,或者可以藉由已知的技術進行包衣,包括微膠囊化以延遲消化道中的崩解和吸附,從而在更長的時間內提供持續作用。例如,可以單獨或與蠟一起使用諸如單硬脂酸甘油酯或二硬脂酸甘油脂的時間延遲材料。
可以與非活性成分結合以產生劑型的活性成分的量可以根據預期的治療受試者和給藥方式而變化。例如,在一些實施方案中,用於人類口服給藥的劑型可以包含約1至1000 mg的活性物質,該活性物質用適當且方便量的藥學上可接受的賦形劑配製。在一些實施方案中,藥學上可接受的賦形劑占總組合物的約5%至約95%(重量:重量)。
在一些實施方案中,本發明的藥物組合物不包含影響活性成分代謝速率的試劑。因此,應當理解,在一個方面,包含本發明的化合物的組合物不包含會影響(例如,減緩、阻礙或延遲)本發明的化合物或與本發明的化合物分開、順序或同時給藥的任何其它活性成分的代謝的試劑。還應當理解,在一個方面,本文詳述的任何方法、試劑盒、製品等不包含會影響(例如,減緩、阻礙或延遲)本發明的化合物或與本發明的化合物分開、順序或同時施用的任何其它活性成分的代謝的試劑。
[IV. 治療方法]
本發明的另一方面涉及一種使用本發明的化合物預防、治療或改善GLP-1R介導的疾病或病症的症狀的方法。在一些實施方案中,該方法包括向需要這種治療的受試者施用有效量的式I-A-1、I-A-2、I-A-3、I-A-4、I-A-5、I-A-6、I-A-7的化合物、或其藥學上可接受的鹽的步驟。
GLP-1R介導的疾病或病症的實例包括但不限於本發明中的慢性肝內或某些形式的肝外膽汁淤積症、肝纖維化、急性肝內膽汁淤積症,由不當膽汁成分引起的阻塞性或慢性炎症性疾病,胃腸道疾病,飲食脂肪和脂溶性膳食維生素攝入減少,炎症性腸病,脂質和脂蛋白紊亂,II型糖尿病和I型和II型糖尿病的臨床併發症,由於脂質和特別是甘油三酯的積聚以及隨後的促纖維化途徑的激活而導致的器官慢性脂肪和纖維化變性、肥胖和代謝綜合征(血脂異常、糖尿病和異常高的體重指數的綜合病症)、急性心肌梗塞、急性中風,作為慢性阻塞性動脈粥樣硬化、細胞內細菌或寄生原生動物的持續感染、非惡性過度增殖性疾病、惡性過度增殖疾病、結腸腺癌和肝細胞癌(例如肝脂肪變性和相關綜合征)的終點而發生的血栓形成,慢性肝病或外科肝臟切除術、乙型肝炎感染、丙型肝炎感染和/或與酒精誘導的肝硬化或病毒性肝炎、I型糖尿病、糖尿病前期、特發性1型糖尿病、潛伏性自身免疫性糖尿病相關的膽汁淤積和纖維化影響導致的肝衰竭或肝功能衰竭,年輕人的成熟期糖尿病、早發糖尿病、營養不良相關糖尿病、妊娠期糖尿病、高血糖、胰島素抵抗、肝胰島素抵抗、糖耐量受損、糖尿病神經病變、糖尿病腎病、腎病、糖尿病視網膜病變、脂肪細胞功能障礙、內臟脂肪沉積、肥胖、飲食障礙、睡眠呼吸暫停、體重增加、糖渴求、血脂異常、高胰島素血症、充血性心力衰竭、心肌梗死、中風、出血性中風、缺血性中風、創傷性腦損傷、肺動脈高壓、血管成形術後再狹窄、間歇性跛行、餐後脂血症、代謝性酸中毒、酮症、關節炎、左心室肥大、帕金森病、外周動脈疾病、黃斑變性、白內障、腎小球硬化、慢性腎功能衰竭、代謝綜合征、心絞痛、經前綜合征、血栓形成、動脈粥樣硬化、糖代謝受損或血管再狹窄。
在一些實施方案中,GLP-1R介導的疾病或病症選自I型糖尿病(T1D)、II型糖尿病(T2DM)、糖尿病前期、特發性T1D、成人遲發性自身免疫性糖尿病(LADA)、早發性T2DM(EOD)、青年發病型非典型糖尿病(YOAD)、青年成熟型糖尿病(MODY)、營養不良相關糖尿病、妊娠期糖尿病、高血糖、胰島素抵抗、肝胰島素抵抗、糖耐量受損、糖尿病神經病變、糖尿病腎病、腎病、糖尿病視網膜病變、脂肪細胞功能障礙、內臟脂肪沉積、睡眠呼吸暫停、肥胖、飲食失調、使用其他藥物導致的體重增加、過度嗜糖、血脂異常、高胰島素血症、NAFLD、NASH、纖維化、肝硬化、肝細胞癌、心血管疾病、動脈粥樣硬化、冠狀動脈疾病、外周血管疾病、高血壓、內皮功能障礙、血管順應性受損、充血性心力衰竭、心肌梗死、中風、出血性中風、缺血性中風、創傷性腦損傷、肺動脈高壓、血管成形術後再狹窄、間歇性跛行、餐後脂血症、代謝性酸中毒、酮症、關節炎、骨質疏鬆症、帕金森病、左心室肥大、外周動脈疾病、黃斑變性、白內障、腎小球硬化、慢性腎功能衰竭、代謝綜合征、綜合征X、經前綜合征、心絞痛、血栓形成、動脈粥樣硬化、短暫性缺血發作、血管再狹窄、糖代謝受損、空腹血糖受損、高尿酸血症、痛風、勃起功能障礙、皮膚和結締組織疾病、銀屑病、足部潰瘍、潰瘍性結腸炎、高載脂蛋白B脂蛋白血症、阿爾茨海默病、精神分裂症、認知受損、炎症性腸病、短腸綜合征、克羅恩病、結腸炎、腸易激綜合征、多囊卵巢綜合征的預防或治療以及成癮的治療。
在一些實施方案中,GLP-1R介導的疾病或病症是肝病,例如肝纖維化、非酒精性脂肪性肝病(NAFLD)、非酒精脂肪性肝炎(NASH)、肝硬化、代償性肝纖維化、失代償性肝肝纖維化、肝細胞癌、原發性膽汁性肝硬化(PBC)或原發性硬化性膽管炎(PSC)。
在一些實施方案中,GLP-1R介導的疾病或病症是代謝性疾病。
在一些實施方案中,本發明涉及一種治療和/或預防NAFLD的方法,包括向有需要的受試者施用有效量的式I-A-1化合物、或其藥學上可接受的鹽。
在一些實施方案中,本發明涉及一種治療和/或預防NASH的方法。在一些實施方案中,該方法包括向有需要的受試者施用有效量的式I-A-1化合物。
在一些實施方案中,本發明涉及心血管疾病的預防和創傷後治療,如急性心肌梗死、急性中風或血栓形成,其作為慢性阻塞性動脈粥樣硬化的終點發生。在一些實施方案中,該方法包括向有需要的受試者施用有效量的式I-A-1化合物。
在一些實施方案中,本發明涉及一種治療和/或預防肥胖和相關疾病的方法,如代謝綜合征(血脂異常、糖尿病和異常高體重指數的綜合病症),其可藉由GLP1R介導的血清甘油三酯降低來克服,血糖和胰島素敏感性增加以及GLP1R介導的體重減輕。在一些實施方案中,該方法包括向有需要的受試者施用有效量的式I-A-1化合物。
在一些實施方案中,本發明涉及預防和/或治療I型和II型糖尿病臨床併發症的方法。此類併發症的例子包括糖尿病腎病、糖尿病視網膜病變、糖尿病神經病或外周動脈閉塞性疾病(PAOD)。本發明還包括糖尿病的其他臨床併發症。在一些實施方案中,該方法包括向有需要的受試者施用有效量的式I-A-1化合物。
此外,還可以藉由施用本發明的化合物或藥物組合物來預防和/或治療由於脂質和/或甘油三酯的累積以及隨後的促纖維化途徑的激活而導致的器官慢性脂肪和纖維化變性所導致的病症和疾病。此類病症和疾病包括但不限於NASH和肝臟慢性膽汁淤積症、腎臟腎小球硬化症和糖尿病腎病、眼睛黃斑變性和糖尿病視網膜病變以及神經退行性疾病,如大腦中的阿爾茨海默病或周圍神經系統中的糖尿病神經病。
在一些實施方案中,本發明涉及一種用於治療和/或預防由於脂質和/或甘油三酯的積聚以及隨後的促纖維化途徑的激活而導致的器官慢性脂肪和纖維化變性所導致的病症和疾病的方法。在一些實施方案中,該方法包括向有需要的受試者施用有效量的式I-A-1化合物。
在一些實施方案中,本發明的化合物以在體內釋放活性成分的前藥或其他適當修飾形式使用。
本發明的化合物(在此也被稱為活性成分)或藥物組合物,可以藉由適合於待治療的條件的任何途徑給藥。合適的途徑包括口服、直腸、鼻腔、局部(包括口腔和舌下)、透皮、陰道和腸外(包括皮下、肌肉注射、靜脈注射、皮內、瘤內、鞘內和硬膜外)等。可以理解的是,較佳的途徑可能隨著例如接受者的狀況而變化。本文所公開的某些化合物的優點是它們是口服生物可利用的,並且可以口服給藥。
本發明的化合物可以按照有效的給藥方案在所需的時間段或持續時間內給予個體,例如至少約1個月、至少約2個月、至少約3個月、至少約6個月、或至少約12個月或更長。在一個變體中,該化合物在個體生命的持續時間內以每日或間歇的方式給藥。
本發明的化合物的劑量或給藥頻率可以基於給藥醫生的判斷在治療的過程中進行調節。
該化合物可以有效量給予個體(例如人)。在一些實施方案中,該化合物每天給藥一次。
該化合物可以藉由任何有用的途徑和手段給藥,例如藉由口服或腸外(例如靜脈)給藥。該化合物的治療有效量可包括從每天約0.00001毫克/千克體重到每天約10毫克/千克體重,例如從每天約0.0001毫克/千克體重到每天約10毫克/千克體重,或如從每天約0.001毫克/千克體重到每天約1毫克/千克體重,或如從每天約0. 01毫克/公斤體重到每天約1毫克/公斤體重,或如從每天約0.05毫克/公斤體重到每天約0.5毫克/公斤體重,或如從每天約0.3毫克到每天約30毫克,或如從每天約30毫克到每天約300毫克。
本發明的化合物可與一種或多種額外的治療劑以本發明的化合物的任何劑量(例如,從1毫克到1000毫克的化合物)組合。治療有效量可包括從每劑約1毫克到每劑約1000毫克,例如從每劑約50毫克到每劑約500毫克,或如從每劑約100毫克到每劑約400毫克,或如從每劑約150毫克到每劑約350毫克,或如從每劑約200毫克到每劑約300毫克。本發明的化合物的其他治療有效量為每劑約100、125、150、175、200、225、250、275、300、325、350、375、400、425、450、475、或約500毫克。本發明的化合物的其他治療有效量為每劑約100毫克,或每劑約125、150、175、200、225、250、275、300、350、400、450或約500毫克。單一劑量可以每小時、每天或每週給藥。例如,單劑量可以每1小時、2、3、4、6、8、12、16或每24小時給藥一次。單一劑量也可以每1天、2、3、4、5、6或每7天給藥一次。單一劑量也可以每1周、2、3或每4周給藥一次。在一些實施方案中,單次劑量可以每週給藥一次。單一劑量也可以每月給藥一次。
包含本發明的化合物,或其藥學上可接受的鹽的試劑盒也包括在本發明中。在一個實施方案中,一個試劑盒進一步在治療本文所述的適應症,如疾病或病症中使用該化合物的標籤和/或說明。在一個實施方案中,提供了包含本發明的化合物或其藥學上可接受的鹽與一種或多種(例如一種、兩種、三種、四種、一種或兩種,或一至三種,或一至四種)附加治療劑的試劑盒。
[V.聯合療法]
本文還提供了本發明的化合物與一種或多種與本發明的化合物具有協同作用的其他治療劑組合的用途。
在一些實施方案中,一種或多種附加治療劑包括凋亡訊號調節激酶(ASK-1)抑制劑、法尼醇X受體(FXR)促效劑、過氧化物酶體增殖體激活受體α(PPARα)促效劑、魚油、乙醯輔酶(ACC)抑制劑、或TGFβ拮抗劑,或其組合。
在一些實施方案中,一種或多種附加治療劑選自由以下組成的組:ACE抑制劑、2-醯基甘油O-醯基轉移酶2(DGAT2)抑制劑、乙醛脫氫酶抑制劑、乙醯輔酶a羧化酶抑制劑、腎上腺素能受體促效劑、Alstrom綜合征蛋白1(ALMS1)/PKCα-蛋白相互作用抑制劑,Apelin受體促效劑、二醯甘油O醯基轉移酶2抑制劑、腺苷A3受體促效劑、腺苷A3受體拮抗劑、脂聯素受體促效劑、乙醛脫氫酶2刺激劑、AKT蛋白激酶抑制劑、AMP活化蛋白激酶(AMPK)、AMP激酶活化劑、ATP檸檬酸裂解酶抑制劑、AMP活化蛋白激酶促效劑、內皮型一氧化氮合酶促效劑、NAD依賴性去乙醯化酶sirtuin-1促效劑、腎上腺素能受體拮抗劑、雄激素受體促效劑、胰澱素受體促效劑、血管緊張素II AT-1受體拮抗劑、自噬蛋白調節劑、自噬蛋白抑制劑、Axl酪氨酸激酶受體抑制劑、Bax蛋白刺激劑、β-連環蛋白抑制劑、生物活性脂質、降鈣素促效劑、大麻素受體調節劑、半胱天冬酶抑制劑、半胱天冬酶-3刺激劑、組織蛋白酶抑制劑、小窩蛋白1抑制劑、CCK受體拮抗劑、CCL26基因抑制劑、CCR2趨化因子拮抗劑、CCR2趨化因子拮抗劑、血管緊張素II AT-1受體拮抗劑,CCR3趨化因子拮抗劑,CCR5趨化因子拮抗劑,CD3拮抗劑,CDGSH鐵硫結構域蛋白調節劑,幾丁質酶抑制劑,氯通道刺激劑,幾丁質酶1抑制劑,CNR1抑制劑,結締組織生長因子配體抑制劑,細胞週期蛋白D1抑制劑,細胞色素P4507A1抑制劑、DGAT1/2抑制劑、二醯甘油O醯基轉移酶1抑制劑(DGAT1)、細胞色素P4502E1抑制劑(CYP2E1)、CXCR4趨化因子拮抗劑、二氫神經醯胺δ4去飽和酶抑制劑、二氫乳糖酸脫氫酶抑制劑、二肽基肽酶IV抑制劑、內皮素調節劑、Eotaxin配體抑制劑、細胞外基質蛋白調節劑、法尼類X受體促效劑、脂肪酸合成酶抑制劑、FGF1受體促效劑、成纖維細胞生長因子(FGF-15、FGF-19、FGF-21)配體、成纖維細胞活化蛋白抑制劑、游離脂肪酸受體1促效劑、半乳糖凝集素-3抑制劑、GDNF家族受體α樣促效劑、胰高血糖素受體促效劑、胰高血糖素樣肽1促效劑、糖皮質激素受體拮抗劑、葡萄糖6-磷酸1-脫氫酶抑制劑、G-蛋白偶聯膽汁酸受體1促效劑、G-蛋白偶聯受體119促效劑、G-蛋白偶聯受體84拮抗劑、刺蝟(Hh)調節劑、丙型肝炎病毒NS3蛋白酶抑制劑、肝細胞核因子4α調節劑(HNF4A)、肝細胞生長因子調節劑、組蛋白去乙醯化酶抑制劑、STAT-3調節劑、HMG-CoA還原酶抑制劑、HSD17B13基因抑制劑、5-HT 2a受體拮抗劑、水解酶抑制劑、缺氧誘導因子-2α抑制劑、IL-10促效劑、IL-17拮抗劑、IL-22促效劑、回腸鈉-膽汁酸協同轉運抑制劑、胰島素增敏劑、胰島素配體促效劑、胰島素受體促效劑、整合素調節劑、整合素拮抗劑、整合素α-V/β-1拮抗劑、整合素α-V/β-6拮抗劑、Eukin-1受體相關激酶4(IRAK4)抑制劑、IL-6受體促效劑、白細胞介素17配體抑制劑、Jak2酪氨酸激酶抑制劑,Jun N末端激酶-1抑制劑,Kelch樣ECH相關蛋白1調節劑,酮己激酶(KHK)抑制劑,Klothoβ刺激劑,白三烯A4水解酶抑制劑,5-脂氧合酶抑制劑,脂蛋白脂肪酶抑制劑,肝X受體,LPL基因刺激劑,溶血磷脂酸-1受體拮抗劑,賴氨醯氧化酶同系物2抑制劑、LXR反向促效劑、巨噬細胞甘露糖受體1調節劑、基質金屬蛋白酶(MMPs)抑制劑、MEKK-5蛋白激酶抑制劑、MCH受體1拮抗劑、膜銅胺氧化酶(VAP-1)抑制劑、蛋氨酸氨肽酶-2抑制劑、甲基CpG結合蛋白2調節劑、MicroRNA-132(miR-132)拮抗劑、MicroRNA-21(miR-21)抑制劑、線粒體解偶聯劑、混合譜系激酶-3抑制劑、活動精子域蛋白2抑制劑、髓鞘鹼性蛋白刺激劑、NACHT LRR PYD域蛋白3(NLRP3)抑制劑、NAD依賴性脫乙醯基酶sirtuin刺激劑、NADPH氧化酶抑制劑(NOX)、NFE2L2基因抑制劑、煙酸受體1促效劑、阿片受體mu拮抗劑、P2Y13嘌呤受體促效劑、核紅系2相關因子2促效劑、核受體調節劑、P2X7嘌呤受體調節劑、PACAP I型受體促效劑、PDE 3抑制劑、PDE 4抑制劑、PDE 5抑制劑、PDGF受體β調節劑、苯丙氨酸羥化酶刺激劑、磷脂酶C抑制劑、磷酸二酯水解酶抑制劑、PPARα促效劑、PPARδ促效劑、PPARγ促效劑、肽基脯氨醯順反異構酶A抑制劑、PNPLA3基因抑制劑、PPARγ調節劑、蛋白酶激活受體-2拮抗劑、蛋白激酶調節劑、蛋白質NOV同源調節劑、PTGS2基因抑制劑、腎素抑制劑、抵抗素/CAP1(腺苷酸環化酶相關蛋白1)相互作用抑制劑、Rho相關蛋白激酶抑制劑、三硫代麩胱甘肽還原酶(GSNOR)酶抑制劑、鈉葡萄糖轉運蛋白-2抑制劑、鞘脂δ4去飽和酶DES1抑制劑、SREBP轉錄因子抑制劑、STAT-1抑制劑、硬脂醯輔酶A去飽和酶-1抑制劑、STK25抑制劑、細胞因子訊號抑制因子-1刺激因子、細胞因子訊號抑制因子-3刺激因子、端粒酶刺激因子、TERT基因調節劑、TGF-β(TGFB1)配體抑制劑、TNF拮抗劑、轉化生長因子β(TGF-β),轉化生長因子β活化激酶1(TAK1)、甲狀腺激素受體β促效劑、TLR-4拮抗劑、轉穀氨醯胺酶抑制劑、酪氨酸激酶受體調節劑、GPCR調節劑、核激素受體調節劑、TLR-9拮抗劑、VDR促效劑、WNT調節劑或YAP/TAZ調節劑和Zonulin抑制劑。
一種或多種附加治療劑的非限制性示例包括:
-ACE抑制劑,如依那普利;
-乙醛脫氫酶抑制劑,如ADX-629;
-乙醯輔酶A羧化酶(ACC)抑制劑,如NDI-010976(firsocostat)、DRM-01、gemcabene、GS-834356、PF-05175157、QLT-091382、PF-05221304;
-乙醯輔酶A羧化酶/二醯甘油O醯基轉移酶2抑制劑,如PF-07055341;
-腺苷受體促效劑,如CF-102(納莫代森)、CF-101、CF-502、CGS21680;
-腺苷A3受體拮抗劑,如FM-101;
-脂聯素受體促效劑,如ADP-355、ADP-399;
-腎上腺素能受體拮抗劑,如溴隱亭、芬特明、VI-0521;
-乙醛脫氫酶2刺激劑,如FP-045;
-α-葡萄糖苷酶抑制劑(如伏格列糖、阿卡波糖或米格列醇);
-胰澱素/降鈣素受體促效劑,如KBP-042、KBP-089;
-AMP活化蛋白激酶刺激物,如C-455、PXL-770、O-304;
-AMP激酶活化劑/ATP檸檬酸裂解酶抑制劑,如苯丙烯二酸(ETC-1002,ESP-55016);
-AMP活化蛋白激酶/內皮型一氧化氮合酶/NAD依賴性脫乙醯基酶sirtuin-1刺激劑,如NS-0200(亮氨酸+二甲雙胍+西地那非);-雄激素受體促效劑,如LPCN-1144、LPCN-1148、睾酮前藥;-血管緊張素ⅡAT-1受體拮抗劑,如厄貝沙坦;血管生成素相關蛋白-3抑制劑,如vupanorsen(IONI-ANGPTL3-LRx);
-Apelin受體促效劑,如CB-5064、MBT-2;
-自噬蛋白調節劑,如A-2906;
-自噬毒素(外核苷酸焦磷酸酶/磷酸二酯酶2(NPP2或ENPP2))抑制劑,如FP10.47、PAT-505、PAT-048、GLPG-1690、X-165、PF-8380、TJC-0265、TJC-0316、AM-063、BBT-877;
-Axl酪氨酸激酶受體抑制劑,如貝莫替尼(BGB-324,R-428);
-Bax蛋白刺激劑,如CBL-514;
-生物活性脂質,如DS-102;
-大麻素受體調節劑,如納馬昔單抗(尼莫昔單抗),GWP-42004,REV-200,CRB-4001,INV-101,SCN-002;
-半胱氨酸天冬氨酸蛋白酶抑制劑,如emricasan;
-泛組織蛋白酶B抑制劑,如VBY-376;
-泛組織蛋白酶抑制劑,如VBY-825;
-CCK受體拮抗劑,如丙穀胺;
-CCL26基因抑制劑,如mosedipimod、KDDF-201410-10;
-CCR2/CCR5趨化因子拮抗劑,如BMS-687681、cenicriviroc、maraviroc、CCX-872、leronlimab、WXSH-0213;
-CCR2/CCR5趨化因子拮抗劑和FXR促效劑,如LJC-242(托匹非索+塞尼維羅);
-CCR2趨化因子拮抗劑,如丙鍺;
-CCR2趨化因子/血管緊張素II AT-1受體拮抗劑,如DMX-200、DMX-250;
-CCR3趨化因子拮抗劑,如bertilimumab;
-CD3拮抗劑,如NI-0401(福魯單抗);
-CDGSH鐵硫結構域蛋白調節劑,如EYP-002;
-幾丁質酶抑制劑,如OATD-01;
-殼三糖苷酶1抑制劑,如OAT-2068;
-氯通道刺激器,如鈷前列酮和盧比前列酮;
-酪蛋白激酶-1(CK1)δ/ε抑制劑,如PF-05006739;
-結締組織生長因子配體抑制劑,如PBI-4050;
-CXCR4趨化因子拮抗劑,如AD-214;
-二甘油三酯醯基轉移酶2(DGAT2)抑制劑,如電離-DGAT2Rx,PF-06865571;
-二甘油三酯醯基轉移酶1(DGAT1)抑制劑,如GSK-3008356;
-二醯甘油O醯基轉移酶1(DGAT1)/細胞色素P4502E1抑制劑(CYP2E1),如SNP-610;
-二氫乳清酸脫氫酶抑制劑,如維多夫魯定;
-二肽基肽酶IV抑制劑,如利格列汀、依格列汀;
-Eotaxin配體抑制劑,如bertilimumab、CM-101;
-細胞外基質蛋白調節劑,如CNX-024;
-法尼醇X受體(FXR)促效劑,如AGN-242266、AGN-242256、ASC-42、EDP-297(EP-024297)、RDX-023、BWL-200、AKN-083、EDP-305、GNF-5120、西洛非克索氨丁三醇(GS-9674)、HPG-1860、IOT-022、LMB-763、苯膽酸、Px-102、Px-103、M790、M780、M450、M-480、MET-409、MET-642、PX20606、SYHA-1805、EYP-001、TERN-101、TC-100、INT-2228、TQA-3526、ZG-5266;
-法尼類醇受體(FXR)/G蛋白偶聯膽汁酸受體1(TGR5)促效劑,如INT-767;
-脂肪酸合成酶抑制劑,如TVB-2640、FT-8225;
-成纖維細胞生長因子19(rhFGF19)/細胞色素P450(CYP)7A1抑制劑,如阿爾達費明(NGM-282);
-成纖維細胞生長因子21(FGF-21)配體調節劑,如AP-025、BMS-986171、B-1654、BIO89-100、BOS-580,
-Pegbelfermin(BMS-986036),B-1344;
-成纖維細胞生長因子21(FGF-21)/胰高血糖素樣肽1(GLP-1)促效劑,如YH-25723(YH-25724;YH-22241)、Efraxifermin(AKR-001);
-FGF受體促效劑/Klothoβ刺激劑,如BFKB-8488A(RG-7992);
-游離脂肪酸受體1促效劑,如SCO-267;
-半乳糖凝集素-3抑制劑,如貝拉果膠(GR-MD-02)、GB-1107(Gal-300)、GB-1211(Gal-400);
-GDNF家族受體α樣促效劑,如NGM-395;
-胰高血糖素樣肽1(GLP-1R)促效劑,如ALT-801、AC-3174、利拉魯肽、考他肽(MEDI-0382)、SAR-425899、LY-3305677、HM-15211、YH-25723、YH-GLP1、RPC-8844、PB-718、PF-06882961、塞馬魯肽;
-胰高血糖素樣肽1受體促效劑;氧調節蛋白配體;胰高血糖素受體促效劑,如efinopegduide;
-胃抑制多肽/胰高血糖素樣肽-1(GIP/GLP-1)受體輔促效劑,如替瑞帕肽(LY-3298176);
-聚乙二醇化長效胰高血糖素樣肽-1/胰高血糖素(GLP-1R/GCGR)受體雙促效劑,如DD-01;
-胰高血糖素/GLP1受體促效劑,如BI-456906;
-糖皮質激素受體拮抗劑,如CORT-118335(米利克林);
-葡萄糖6-磷酸1-脫氫酶抑制劑,如ST001;
-葡萄糖激酶刺激劑,如多沙格列汀、華格列汀(RO-5305552);
-G蛋白偶聯膽汁酸受體1(TGR5)促效劑,如RDX-009、INT-777、HY-209;
-G蛋白偶聯受體84拮抗劑,如PBI-4547;
-G蛋白偶聯受體119促效劑,如DA-1241;
-熱休克蛋白47(HSP47)抑制劑,如ND-L02-s0201;
-刺蝟蛋白和/或TGF-β配體抑制劑,如Oxy-210;
-組蛋白去乙醯化酶抑制劑/STAT-3調節劑,如SFX-01;
-HMG-CoA還原酶抑制劑,如阿托伐他汀、氟伐他汀、匹他伐他汀、普伐他汀、瑞舒伐他汀、辛伐他汀;
-HSD17B13基因抑制劑,如ALN-HSD、ARO-HSD;
-水解酶抑制劑,如ABD-X;
-缺氧誘導因子-2α抑制劑,如PT-2567;
-IL-10促效劑,如聚乙二醇-伊洛替卡金;
-回腸鈉-膽汁酸協同轉運抑制劑,如奧德維西巴特(A-4250)、沃利昔巴特水合乙醇酸鉀(SHP-262)、GSK2330672、CJ-14199、埃洛昔巴特(A-3309);-胰島素增敏劑,如KBP-042、氮雜咪唑鉀(MSDC-0602K)、離子-224、MSDC-5514、Px-102、RG-125(AZD4076)、托利米酮、VVP-100X、CB-4211、ETI-101、吡格列酮;
-胰島素配體/胰島素受體促效劑,如ORMD-0801;
-整合素拮抗劑,如IDL-2965;
-IL-6受體促效劑,如KM-2702;
-整合素α-V/β-6和α-V/β-1雙重抑制劑;如PLN-74809;
-白細胞介素17配體抑制劑,如netakimab;
-Jak1/2酪氨酸激酶抑制劑,如巴瑞西替尼;
-Jun N末端激酶-1抑制劑,如CC-90001;
-Kelch樣ECH相關蛋白1調節劑,如α-環糊精穩定的萊菔硫烷;
-酮己激酶(KHK)抑制劑,如PF-06835919、LY-3478045;
-β-Klotho(KLB)-FGF1c促效劑,如MK-3655(NGM-313);
-白三烯A4水解酶抑制劑,如LYS-006;
-5-脂氧合酶抑制劑,如替呱魯司特(MN-001)、依泊魯通(DS-102,(AF-102);
-脂蛋白脂肪酶抑制劑,如CAT-2003;
-LPL基因刺激劑,如alipogene tiparvovec;
-肝X受體(LXR)抑制劑,如PX-665、PX-L603、PX-L493、BMS-852927、T-0901317、GW-3965、SR-9238;
-溶血磷脂酸-1受體拮抗劑,如BMT-053011、UD-009(CP-2090)、AR-479、ITMN-10534、BMS-986020、KI-16198;
-賴氨醯氧化酶同系物2抑制劑,如simtuzumab、PXS-5382A(PXS-5338);
-巨噬細胞甘露糖受體1調節劑,如替馬諾西普-Cy3(鍀Tc 99m替馬諾西普);
-基質金屬蛋白酶抑制劑,如ALS-L1023;
-膜銅胺氧化酶(VAP-1)抑制劑,如TERN-201、TT-01025;
-MEKK-5蛋白激酶(ASK-1)抑制劑,如CJ-16871、CS-17919、selonsertib(GS-4997)、SRT-015、GS-444217、GST-HG-151、TERN-301;
-MCH受體-1拮抗劑,如CSTI-100(ALB-127158);
-氨基脲敏感胺氧化酶/血管黏附蛋白-1(SSAO/VAP-1)抑制劑,如PXS-4728A(BI-1467335);
-甲硫氨酸氨基肽酶-2抑制劑,如ZGN-1061、ZGN-839、ZN-1345;
-甲基CpG結合蛋白2調節劑,如硫醇;
-鹽皮質激素受體拮抗劑(MCRA),如MT-3995(阿帕雷酮);
-線粒體解偶聯物,如2,4-二硝基苯酚、HU6、Mito-99-0053;
-混合譜系激酶-3抑制劑,如URMC-099-C;
-活動精子結構域蛋白2抑制劑,如VB-601;
-髓鞘鹼性蛋白刺激劑,如油磺肟;
-髓過氧化物酶抑制劑,如PF-06667272、AZM-198;
-NADPH氧化酶抑制劑,如GKT-831、GenKyoTex、APX-311、司他那昔布;
-煙酸受體1促效劑,如ARI-3037MO;
-NACHT LRR PYD結構域蛋白3(NLRP3)抑制劑,如KDDF-201406-03、NBC-6、IFM-514、JT-194(JT-349);
-NFE2L2基因抑制劑,如GeRP-amiR-144;
-核受體調節劑,如DUR-928(DV-928);
-阿片受體mu拮抗劑,如甲基納曲酮;
-P2X7嘌呤受體調節劑,如SGM-1019;
-P2Y13嘌呤受體促效劑,如CER-209;
-PDE 3/4抑制劑,如替呱魯司特(MN-001);
-PDE 5抑制劑,如西地那非、MSTM-102;
-PDGF受體β調節劑,如BOT-191、BOT-509;
-肽基脯氨醯順反異構酶抑制劑,如CRV-431(CPI-432-32)、NVP-018、NV-556(NVP-025);
-苯丙氨酸羥化酶刺激劑,如肝素;
-磷酸二酯水解酶抑制劑,如ZSP-1601;
-PNPLA3基因抑制劑,如AZD-2693;
-PPAR促效劑,如奇格列他唑、依拉貝諾(GFT-505)、塞拉地帕賴氨酸(MBX-8025)、氘化吡格列酮R-對映體、吡格列酮、PXL-065(DRX-065),
saroglitazar、lanifibranor(IVA-337)、CHS-131、pemafibrate(K-877)、ZG-0588、ZSP-0678;ZSYM-008;
-蛋白酶激活的受體-2拮抗劑,如PZ-235;
-蛋白激酶調節劑,如CNX-014;
-蛋白質NOV同源調節劑,如BLR-200;
-PTGS2基因抑制劑,如STP-705、STP-707;
-腎素抑制劑,如PRO-20;
-抵抗素/CAP1(腺苷酸環化酶相關蛋白1)相互作用抑制劑,如DWJ-211;
-Rev蛋白調節劑,如ABX-464;
-Rho相關蛋白激酶(ROCK)抑制劑,如REDX-10178(REDX-10325)、KD-025、RXC-007、TDI-01;
-麩胱甘肽還原酶抑制劑,如SL-891;
-鈉葡萄糖轉運體-2(SGLT2)抑制劑,如依普拉格列嗪、依他波酸瑞格利嗪、厄特格列嗪、達帕格列嗪、託福格列嗪、索他格列嗪;
-鈉-葡萄糖轉運蛋白-1/2(SGLT 1/2)抑制劑,如利格列酮雙(脯氨酸)(LIK-066);
-SREBP轉錄因子抑制劑,如CAT-2003、HPN-01、MDV-4463;
-硬脂醯輔酶A去飽和酶-1抑制劑,如芳樟醇;
-甲狀腺激素受體β促效劑,如ALG-009、ASC-41、CNPT-101101;CNPT-101207、CS-27186、KY-41111、resmetirom(MGL-3196)、MGL-3745、TERN-501、VK-2809;
-TLR-2/TLR-4拮抗劑,如VB-201(CI-201);
-TLR-4拮抗劑,如JKB-121、JKB-122、納曲酮;
-酪氨酸激酶受體調節劑,如CNX-025、GFE-2137(重新利用硝唑沙尼);
-TLR-9拮抗劑,如GNKS-356;
-TNF拮抗劑,如ALF-421;
-GPCR調節劑,如CNX-023;
-核激素受體調節劑,如Px-102;
-VDR促效劑,如CK-15;
-黃嘌呤氧化酶抑制劑,如ACQT-1127;
-黃嘌呤氧化酶/尿酸鹽陰離子交換劑1(URAT1)抑制劑,如RLBN-1001、RLBN-1127;和
-Zonulin抑制劑,如醋酸蘿拉唑肽(INN-202)。
在一些實施方案中,一種或多種附加治療劑選自A-4250、AC-3174、乙醯水楊酸、AK-20、alipogene tiparvovec、AMX-342、AN-3015、抗TAGE抗體、aramchol、ARI-3037MO、ASP-8232、AZD-2693、bertilimumab、無水甜菜鹼、BI-1467335、BMS-986036,BMS-986171, BMT-053011, BOT-191, BTT-1023, budesonide, BX-003, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dabigatran etexilate mesylate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R-enantiomer, 2,4-dinitrophenol, DRX-065, DS-102, DUR-928, EDP-305, elafibranor (GFT-505), emricasan, enalapril, ertugliflozin, evogliptin, F-351, fluasterone(ST-002), FT-4101, gdd-3898, gh-509, gkt-831, gnf-5120, gri-0621, gr-md-02, gs-300, gs-4997, gs-9674, hec-96719, htd-1801, hs-10356, hsg-4112, hst-202, hst-201, hu-6, hydrochlorothiazide, icosabutate (PRC-4016), icosapent ethyl ester, IMM-124-E, INT-767, INV-240, IONIS-DGAT2Rx, ipragliflozin, Irbesarta, propagermanium, IVA-337, J2H-1702, JKB-121, KB-GE-001, KBLP-004, KBLP-009, KBP-042, KD-025, M790, M780, M450, metformin, sildenafil, LB-700, LC-280126, linagliptin, liraglutide, (LJN-452) (tropifexor), LM-011, LM-002 (CVI-LM-002), LMB-763, LYN-100, MB-N-008, MBX-8025, MDV-4463, mercaptamine, MGL-3196, MGL-3745,MP-301, MSDC-0602K, namacizumab, NC-101, NDI-010976, ND-L02-s0201 (BMS-986263), NGM-282, NGM-313, NGM-386, NGM-395, NP-011, NP-135, NP-160, norursodeoxycholic acid, NV-422, NVP-022, O-304, obeticholic acid(OCA), 25HC3S, olesoxime, PAT-505, PAT-048, PBI-4547, peg-ilodecakin, pioglitazone, pirfenidone, PRI-724, PX20606, Px-102, PX-L603, PX-L493, PXS-4728A, PZ-235, PZH-2109, RCYM-001, RDX-009, remogliflozin etabonate, RG-125(AZD4076),RPI-500, S-723595, saroglitazar, SBP-301, semaglutide, SH-2442, SHC-028, SHC-023, simtuzumab, solithromycin, sotagliflozin, statins (atorvastatin, 氟伐他汀、匹伐他汀、普伐他汀、羅伐他汀、辛伐他汀)、共生素、TCM-606F、TEV-45478、TQA-3526、TQA-3563、tipelukast(MN-001)、TLY-012,TRX-318, TVB-2640, TXR-612, TS-20004, UD-009, UN-03, 熊去氧膽酸, VBY-376, VBY-825, VK-2809, vismodegib, volixibat乙醇酸鉀水合物(SHP-626),VVP-100X, WAV-301, WNT-974, WXSH-0038, WXSH-0078, XEN-103, XRx-117, XTYW-003, XW-003, XW-004, ZGN-839, ZG-5216, ZSYM-008, ZYSM-007。
在一些實施方案中,本發明的化合物與一種或多種選自由以下組成的組的治療劑組合:抗肥胖劑、肽YY及其類似物、神經肽Y受體2型(NPYR2)促效劑、NPYR1促效劑、NPYR5拮抗劑、 大麻素受體1型(CB1 R)拮抗劑、脂肪酶抑制劑(例如orlistat)、人胰島素肽(HIP)、黑皮素受體4促效劑(如Setmelanotide),黑色素濃縮激素受體1的拮抗劑,法尼醇X受體(FXR)促效劑(如obeticholic acid),凋亡訊號調節激酶(ASK-1)抑制劑,zonisamide,phentermine(單獨或與topiramate聯合),去甲腎上腺素/多巴胺再攝取抑制劑(如buproprion),阿片類受體拮抗劑(如納曲酮),去甲腎上腺素/多巴胺再攝取抑制劑和阿片類受體拮抗劑的組合(例如GDF-15類似物、西布曲明、膽囊收縮素促效劑、澱粉酶及其類似物(如普蘭林特)、瘦素及其類似物(如甲狀腺素)、血清素能劑(如lorcaserin)、蛋氨酸氨肽酶2(MetAP2)抑制劑(如beloranib或ZGN-1061)、phendimetrazine、diethylpropion、benzhetamine、SGLT2抑制劑(如:empagliflozin, canagliflozin, dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozin etabonate, 或 ertugliflozin),一種SGLTL1抑制劑,一種SGLTL2/SGLT1雙重抑制劑。一種成纖維細胞生長因子受體(FGFR)調節劑、一種AMP激活蛋白激酶(AMPK)活化劑、生物素、一種MAS受體調節劑或一種胰高血糖素受體促效劑(單獨使用或與另一種GLP-1R促效劑聯合使用,例如liraglutide, exenatide, dulaglutide, albiglutide, lixisenatide, 或 semaglutide,胰島素增敏劑,如噻唑烷二酮類(TZDs),過氧化物酶體增殖激活受體α(PPARα)促效劑,魚油,乙醯輔酶(ACC)抑制劑。轉化生長因子β(TGFβ)拮抗劑、GDNF家族α受體(GFRAL)促效劑、黑皮素-4受體(MC4R)促效劑,包括具體命名的藥劑的藥學上可接受的鹽以及所述藥劑和鹽的藥學上可接受的溶解物。
[實施例]
合成
本發明的化合物可以用本文公開的方法及其常規修改來製備,鑒於本文公開的方法和本領域眾所周知的方法,這些修改是顯而易見的。除了本文的教導之外,還可以使用常規的和眾所周知的合成方法。
式(I-A-1)的典型化合物或其藥學上可接受的鹽的合成,例如具有式(I-A-1)中一個或多個描述的結構的化合物,或本文公開的其他公式或化合物,可按以下例子所述完成。
一般合成方法
根據本發明的化合物的典型實施方案可使用下文描述的一般反應方案和/或實例進行合成。鑒於本文的描述,顯然可以藉由用具有類似結構的其他材料替代起始材料來改變一般方案,從而產生相應不同的產品。後面的合成描述提供了許多例子,說明起始材料如何變化以提供相應的產品。起始材料通常從商業來源獲得,或使用已公佈的合成化合物的方法合成,這些化合物是本發明的實施方案,檢查要合成的化合物的結構將提供每個取代基的身份,鑒於這裡的例子,最終產品的身份通常會藉由簡單的檢查過程使必要的起始材料的身份變得明顯。本文反應方案中使用的基團標籤(如R
1,R
2)僅用於說明目的,除非另有說明,否則在名稱或功能上不一定與其他地方用於描述式(I-A-1)化合物或其方面或片段的標籤一致。
合成反應參數
本發明的化合物可以使用例如以下的一般方法和程式,從容易獲得的起始材料製備。可以理解的是,凡是給出典型或較佳的工藝條件(即反應溫度、時間、反應物的摩爾比、溶劑、壓力等);除非另有說明,否則也可以使用其他工藝條件。最佳的反應條件可能隨特定的反應物或溶劑的使用而變化,但這種條件可以由本領域的技術人員藉由常規優化程式來確定。
此外,對於本領域的技術人員來說,傳統的保護基可能是必要的,以防止某些官能團進行不希望的反應。用於各種官能團的保護基團以及保護和脫保護特定官能團的合適條件,在本領域是眾所周知的。例如,在T.W.Greene和G.M.Wuts(1999)《有機合成中的保護基團》,第三版,Wiley,紐約,以及其中引用的文獻中描述了許多保護基團。
此外,本發明的化合物可以包含一個或多個手性中心。因此,如果需要,可以將此類化合物製備或分離為純立體異構體,即作為單獨的對映體或非對映體或作為立體異構體富集的混合物來製備或分離。除非另有說明,所有這些立體異構體(和富集的混合物)都包括在本聲明的範圍內。純粹的立體異構體(或富集的混合物)可以用例如本領域中眾所周知的光學活性起始材料或立體選擇性試劑來製備。另外,這種化合物的外消旋混合物可以用例如手性柱色譜法、手性分解劑等進行分離。
以下反應的起始材料一般是已知的化合物,或者可以藉由已知程式或其明顯的修改來製備。例如,許多起始材料可從商業供應商處獲得,如Aldrich Chemical Co. (Milwaukee, Wisconsin, USA)。其他的可以藉由標準參考文獻中描述的程式或其明顯的修改來製備,如Fieser的《有機合成試劑》:第1-15卷(John Wiley, and Sons, 1991);Rodd的《碳化合物化學》:第1-5卷, 和補編版本(Elsevier科學出版社,1989年);《有機反應》第1-40卷(John Wiley, and Sons, 1991年),March的《高級有機化學》(John Wiley, and Sons, 5
thEdition, 2001年),以及Larock的《綜合有機轉化》(VCH出版公司, 1989).
術語 "溶劑"、"惰性有機溶劑 "或 "惰性溶劑 "是指在與之相關的反應條件下的惰性溶劑(例如包括苯、甲苯、乙腈、四氫呋喃("THF")、N,N-二甲基甲醯胺("DMF")、氯仿、二氯甲烷(或二氯甲烷)、二乙醚、甲醇、吡啶等)。除非有相反的規定,本發明的反應中使用的溶劑是惰性有機溶劑,反應是在惰性氣體,最好是氮氣下進行的。
術語 "q.s. "是指加入足以實現所述功能的數量,例如,使溶液達到所需體積(即100%)。
本文提供的化合物可根據下文提供的一般方案進行合成。在下面的方案中,應該理解其中所示的每個化合物都可以在任何步驟中按要求存在保護基。標準的保護基團在本領域技術人員的範圍內。
實施例1:式(I-A-1)化合物的合成
在另一個方面,本發明提供了一種製備式(I-A-1)化合物、其藥學上可接受的鹽、酯或立體異構體的方法,該方法包括六條常規路線(路線1、路線2、路線3、路線4、路線5和路線6)。
路線1:
路線2:
路線3:
路線4:
路線5:
路線6:
中間體的製備
該中間體可藉由以下5個路線製備:
路線4
路線5
3,7-二甲基-1H-吲唑-5-胺(Int A)的製備
向5-溴-7-甲基-1H-吲唑(25.0 g)的二氯乙烷溶液(200 mL)中加入NIS(29.0 g,1.1 eq.),在80 ℃下攪拌12 小時。冷卻至室溫後,用THF稀釋反應混合液,用Na
2S
2SO
3飽和水溶液清洗。用無水Na
2SO
4乾燥並濃縮後,經石油醚打漿制得
Int A-2(黃色固體),35.0 g,收率:87.7%。
在0 ℃條件下,將
Int A-2(40.0 g)和SEMCl(40.0 g,2.1 eq.)加入至THF(250 mL)溶液中,再加入NaH(11.5 g,2.5 eq.),在25 ℃下攪拌2 小時, 加水(300 mL)淬滅反應混合物,EA(100 mL×2)萃取,合併有機相,經無水硫酸鈉乾燥減壓濃縮得
Int A-3,45.4 g,收率:81.9%。
在25 ℃條件下,將
Int A-3(9.0 g)加入到二氧六環溶液中,加入Pd
2(dppf)Cl
2(0.9 g)、K
3PO
4(11.04 g,2.7 eq.)、CH
3B(OH)
2(1.96 g,1.7eq.),氮氣保護條件下將混合物在95 ℃攪拌反應3 小時。冷卻至室溫,濾出固體,濾液經減壓濃縮後再經柱層析純化制得
Int A-4,5.4g,收率:78.9%。
在室溫條件下,向溶於二氧六環(100 mL)的
Int A-4(4.0 g)溶液中加入NH
2Boc(5.2 g,4 eq.)、Cs
2CO
3(14.4g,4 eq.)、Pd
2(dba)
3(1.2 g,0.15 eq)和X-phos(1.8 g,0.3 eq),並在100 ℃、氮氣條件下,攪拌反應4小時。冷卻至室溫,加入水(100 mL),並用EA(100 mL×2)萃取。有機相經減壓濃縮後,經矽膠柱層析(EA/PE = 1/40-1/10)純化,得
Int A-5,3.6 g,收率:81.7%。
向溶於MeOH(5 mL)的
Int A-5(3.6 g)溶液中加入HCl/EA(2 M,10 mL),在40 ℃條件下攪拌混合物4 小時,沉澱析出出白色固體,過濾得到
Int A,1.4 g,收率:94.5%。1H NMR(500 MHz,氯仿-d)δ11.40(s,1H)、6.85(d,J = 2.2 Hz,1H)、6.68(d,J = 2.0 Hz,1H)、4.35(d,J = 5.1 Hz,1H)、4.33(d,J = 5.1 Hz,1H)、2.95(s,3H)、2.65(s,3H)。
7-氟-3-甲基-1H-吲唑-5-胺(Int B)的製備
將
Int B-1(5.0 g)和水合肼溶液(98%、2.7 g、2.5 eq)加入至NMP(15 mL)。在150 ℃、氮氣條件下攪拌反應4小時,冷卻至室溫,沉澱析出固體,過濾,濾餅用水洗滌得
Int B-2,3.8 g,78.0%。
接下來的一系列反應可以參考
Int A的製備,制得7-氟-3-甲基-1H-吲唑-5-胺。
3,7-二甲基-1H-吲唑-5-羧酸(Int C)的製備
將
Int C-1(2.0 g)、三甲胺(2.24 g,2.5 eq)、2,2'-雙(二苯基膦)-1,10-聯萘基(0.55 g,0.1 eq)和Pd(dppf)Cl
2(0.31 g,0.2 eq)加入至甲醇(20 mL)和乙腈(20 mL)的混合溶液中,將混合物置於一氧化碳(40 bar)環境下,100 ℃條件下劇烈攪拌混合物18小時。冷卻反應混合物至室溫,向大氣中打開反應混合物,藉由矽藻土過濾反應混合物,濾液減壓濃縮除去溶劑,加入NaOH溶液(4 M,5 mL),攪拌30 min。向混合物中加入HCl(2 M)調節pH值為6,沉澱析出白色固體,過濾得到
Int C,0.7g,收率:41.4%。
1H NMR (500 MHz, 三氯甲烷-
d) δ 8.44 (d,
J= 2.2 Hz,1H),7.84 (d,
J= 2.0 Hz,1H),2.97 (s,3H),2.66 (s,3H)。
3-環丙基-7-甲基-1H-吲唑-5-胺(Int D)的製備
在0 ℃條件下,向三氯化硼(20 mL,0.02 mol,1 M,溶於甲苯)的二氯甲烷溶液中加入2-異丙基苯胺(
Int D-1,2.14 g,0.02 mol)的1,2-二氯乙烷(10 mL)溶液。向混合物中加入氯化鋁(2.96 g,0.022 mol)和環丙腈(2.01 g,0.03 mol),反應混合液在80 ℃下回流20 h,冷卻反應混合液至0 ℃,然後加入2 N HCl(10 mL),再將反應混合物加熱至80 ℃,攪拌30 分鐘,將反應混合物冷卻至室溫,用二氯甲烷萃取,1 N NaOH(10 mL)和飽和食鹽水清洗有機層,無水MgSO
4乾燥,減壓濃縮除去溶劑,柱層析對殘留物進行純化,得到標題化合物
Int D-2(2.1 g,60%),為黃色固體。
在0 ℃條件下,將
Int D-2(2.0 g,11.4 mmol) 加入至H
2SO
4(98%,8 mL)溶液中,再緩慢加入KNO
3(1.38 g,13.7 mmol),並攪拌2小時,將混合物溶液緩慢加入至冰水(50 mL)中,再加入乙酸乙酯(50 mL x 2)提取,合併有機層,無水硫酸鈉乾燥,減壓濃縮除去有機層,得到
Int D-3(1.9 g,76%)黃色固體。
在0 ℃條件下向溶有
Int D-3(1.9 g,8.6 mmol)和鹽酸羥胺(1.8 g,25.8 mmol)的水溶液(2 mL)和乙醇(8 mL)中加入氫氧化鈉(2.7 g,68.8 mmol),將混合物在80 ℃下回流1小時,減壓濃縮反應液,加入水(14 mL),並用乙酸乙酯(20 mL×2)提取,得到有機層,無水硫酸鈉乾燥,減壓濃縮,濃縮物溶於二氯甲烷(10 mL)中,緩慢加入三乙胺(1.74 g,17.2 mmol),室溫條件下攪拌15分鐘,然後在冰/水浴中冷卻至0–5 ℃;向30 mL二氯甲烷中加入甲磺醯氯(1.25g,10.9 mmol),並將所得溶液冷卻至0-5 ℃,向混合物中逐滴加入冷的甲磺醯氯溶液,0-5 ℃條件下攪拌1.5小時,加入矽膠,旋轉蒸發濃縮綠色/棕色溶液,藉由快速柱層析對殘留物進行純化,得到標題化合物
Int D-4(1.65g,88%),為黃色固體。
在50 mL單頸圓底燒瓶中,加入
Int D-4(1.65 g,7.6 mmol)和Pd/C(0.16 g,10%w/w,30%水)以及甲醇(10 mL),向單口瓶上載入氫氣球囊,攪拌4小時,直至黃色消失。過濾後,將濾液減壓濃縮,得到
Int D(1.25 g,88%),為棕色油狀物。LCMS(ESI): C
11H
13N
3;[M + H]+:計算值:188.1,實測值:188.1.
1H NMR (500 MHz,三氯甲烷-
d) δ 7.15 (d,
J= 2.2 Hz,1H),6.84 (d,
J= 2.2 Hz,1H),4.42-4.32 (m,2H),2.66 (s,3H), 2.24-2.19 (m,1H),1.03 – 0.87 (m,4H)。
7-氟-3-甲基-1H-吲唑-5-羧酸(Int E)的製備
在0 ℃條件下,將三氯化硼(20 mL,20 mmol,1M甲苯溶液)加入到二氯甲烷溶液中,攪拌條件下加入4-氨基-3-氟苯羧酸甲酯(
Int E-1,3.38 g,0.20 mol)的1,2-二氯乙烷(10 mL)溶液,氯化鋁(2.94 g,22 mol)和乙腈(1.2 g,30 mmol),反應混合物在80 ℃下回流20 小時,冷卻至室溫,加入2 N HCl(10 mL),然後將反應混合物加熱至80 ℃,再攪拌30 分鐘,然後將反應混合物冷卻至室溫,並用二氯甲烷萃取,1N NaOH(10 mL)和鹽水清洗有機層,用無水Na
2SO
4乾燥,減壓濃縮除去溶劑,藉由快速柱層析對殘留物進行純化,得到
Int E-2(2.98 g,70.65%),為黃色固體。
在0 ℃條件下向溶有
Int E-2(2.0 g,9.5 mmol)和鹽酸羥胺(1.97 g,28.5 mmol)的水 (2 mL)和乙醇(8 mL)混合溶液中加入氫氧化鈉(2.3 g,57.6 mmol),將反應液在80 ℃下回流1 小時,冷卻至室溫,減壓濃縮,向濃縮物加入水(14 mL)並用乙酸乙酯(20 mL×2)萃取,分出有機層,經減壓濃縮後再溶於二氯甲烷(10 mL)中,緩慢加入三乙胺(1.6 g,14.8 mmol),在室溫條件下攪拌15 分鐘,然後在冰/水浴中冷卻至0-5 ℃,向30 mL二氯甲烷中加入甲磺醯氯(1.08 g,9.5 mmol),並將所得溶液冷卻至0-5 ℃,向混合溶液中逐滴加入冷的甲磺醯氯溶液。所得溶液在0-5 ℃攪拌1.5小時,加入矽膠,旋轉蒸發濃縮綠色/棕色溶液。藉由快速柱層析純化,制得
Int E-3(1.43 g,73%),為黃色固體。
將
Int E-3(1.43 g,6.87 mmol)和NaOH(1.1 g,27.5 mmol)加入至甲醇(10 mL)和水(5 mL)的混合溶液中,在60 ℃下攪拌1小時,冷卻至室溫,減壓濃縮反應液,濃縮物溶於水(10 mL)中,加入1N HCl調節pH值至7,然後加入乙酸乙酯(20 mL×2)提取,得到有機層,經減壓濃縮制得白色固體
Int E(1.25 g,94%)。LCMS (ESI): C
9H
7FN
2O
2; [M+H]
+: 計算值:195.0,實測值: 195.0.
1H NMR (500 MHz,三氯甲烷-
d) δ 11.22 (s,1H),8.36 (d,
J= 2.2 Hz,1H),7.705 (dd,
J= 7.9,2.0 Hz,1H),2.95 (s,3H)。
叔丁基( 2- (氯甲基) -1- (( 1- 乙基 -1H- 咪唑 -5- 基)甲基) -1H- 苯并 [d] 咪唑 -5- 基)氨基甲酸酯的製備( Int F )
將二碳酸二叔丁酯 (30.88 g,141.66 mmol) 分批加入Int F-1(17.0 g,108.97 mmol) 的叔丁醇溶液 (250 mL) 中,將反應液在55℃下攪拌8小時,所得混合物減壓濃縮,粗品用石油醚 (300 mL) 在0℃下打漿,得到
Int F-2,為淺白色固體 (26 g 93.2%),LCMS m/z 257.2[M + H]
+。
向中間體
Int F-2(2.56 g,10 mmol) 的 四氫呋喃溶液 (30 mL) 中加入1-(1-乙基-1H-咪唑-5-基)甲胺二鹽酸鹽 (2.18 g,11 mmol) 和K
2CO
3(6.95 g,50 mmol)。將反應混合物在70℃下攪拌16 小時,冷卻至室溫,將反應混合物倒入水中 (300 mL),然後用 EtOAc(2 x 400 mL) 提取,飽和鹽水 (2 x 200 mL) 清洗合併的有機液,用 Na
2SO
4乾燥,過濾並減壓濃縮,藉由快速色譜法 (0-5%MeOH/DCM) 純化粗品,得到
Int F-3(2.2 g,61%) 淡紅色固體,LCMS m/z 362.40[M + H]
+。
將IntF-3 (181 mg,0.501 mmol) 混懸於MeOH(150 mL) 中,加入10%鈀碳 (20 mg),並在室溫、50 psi H
2條件下攪拌混合物1 小時。藉由矽藻土過濾混合物,減壓濃縮濾液,得到
Int F-4(154 mg,93%),為淺棕色固體,直接用於下一步。LCMS m/z 332.20[M + H]
+。
向溶於
Int F-4(123 mg,0.37 mmol) 的 MeCN(5 mL)溶液中加入2-氯-1,1,1-三甲氧基乙烷 (143 mg,0.93 mmol) 和吡啶-1-甲基苯磺酸銨 (23.2 mg,0.093 mmol),將混合物加熱至70℃反應1小時,反應冷卻至室溫,減壓濃縮,在 50%EtOAc/庚烷中研磨所得到棕色固體
Int F(102 mg,70%)。LCMS m/z 390.10[M + H]
+。
2-溴-6-((4-氯-2-氟苄基)氧基)吡啶 (Int G) 的製備
向溶於THF(150 mL) 的中間體Int G-1(20.0 g,124.6 mmol) 溶液中加入t-BuOK(21.0g,187 mmol),將反應混合物在10 ~ 15℃下攪拌45 分鐘,然後向混合物中加入Int G-2(20 g,104 mmol),並在室溫下攪拌過夜,加入 H2O(500 mL) 並過濾,得到Int G(22.0 g,收率:79.7%)。
叔丁基(2-(5-氟-2-(羥甲基)-4-(4,4,5-三甲基-1,3,2-二氧硼雜環戊烷-2-基)苄基)-1-((S)-氧雜環戊烷-2-基)甲基)-1H-苯并 [d] 咪唑-5-基)氨基甲酸酯 (Int H) 的製備
將
Int H-1(1.0 g,2.88 mmol)、
Int H-2(0.93 g,3.17 mmol) 和
HATU(1.44 g,3.45 mmol) 溶於N,N-二甲基甲醯胺 (10.0 mL) 中,並加入N,N-二異丙基乙胺 (2.5 mL,14.4 mmol),將混合物在室溫下攪拌1小時,然後用飽和 NH
4CI 水溶液 (10 mL) 稀釋,並用 EtOAc(3x10 mL) 提取,無水 MgSO
4上乾燥合併的有機物,減壓濃縮,將所得殘留物溶於乙酸 (25 mL) 中,並加熱至100℃ 1小時。此後,將混合物冷卻至室溫,真空濃縮,並藉由正相柱層析(洗脫劑:EtOAc/PE)純化材料,得到產物
Int H-3(1.2 g,yileld:66.9%)。
在 氮氣條件 下,將
Int H-3(1.0 g,1.92 mmol)、雙聯頻哪醇基二硼 (512.4 mg,2.02 mmol)、AcOK(282.3 mg,2.88 mmol)、Pd(dppf)Cl
2(139 mg,0.2 mmol) 加入二氧六環 (10 mL) 中,在90 ~ 95℃下攪拌2小時,冷卻至室溫,加入水 (10 mL) 並用EtOAc(3 × 10 mL) 萃取,無水 MgSO
4上乾燥合併的有機物,並在真空中濃縮,所得殘渣用 EtOH(3 mL) 結晶純化,得到
Int H(0.85g,收率:78%)。LCMS(ESI): C
30H
39BFN
3O
6; [M + H]
+:計算值:568.3,實測值:568.3。
(S)-(2-(氯甲基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并 [d] 咪唑-5-基)氨基甲酸酯 (Int I) 的製備
在25℃條件下,向溶有4-氟-3-硝基苯胺 (15.0 g,96.0 mmol) 的 叔丁醇(150 mL) 溶液中加入 (Boc)
2O(42.0 g,192 mmol),將反應混合物升溫至40℃,攪拌12 小時,反應液減壓濃縮,粗品經石油醚打漿,得到(4-氟-3-硝基苯基)氨基甲酸叔丁酯(21.6 g,收率88%)黃色固體。LCMS(ESI):C
11H
13FN
2O
4; [M + H]
+:計算值:256.2,實測值:256.2。
在25℃條件下,向攪拌的 [(2S)-氧雜環庚烷-2-基] 甲胺 (9.3 g,106.5 mmol) 和化合物2(21.0 g,81.9 mmol) 的 THF(150 mL) 溶液中加入 N-乙基-N-異丙基-丙烷-2-胺 (26.5 g,205.1 mmol),將反應混合物在60℃下攪拌12 小時,用 EtOAc(100 mL) 和 H
2O(200 mL) 稀釋混合物,分離各層,用 EtOAc(2 x 100 mL) 提取水層,鹽水 (200 mL) 清洗合併的有機相,並在無水 Na
2SO
4上乾燥,過濾,減壓濃縮的粗品,粗品經甲基叔丁基醚打漿,得到 (S)-(3-硝基-4-((氧烷-2-基甲基)氨基)苯基)氨基甲酸叔丁酯(23.6g,收率89.1%)黃色固體。LCMS(ESI): C
15H
21N
3O
5; [M + H]
+:計算值:323.3,實測值:323.3。
在25℃條件下下,向溶有化合物Int I-3(23.0 g,71.1 mmol) 的EtOAc:MeOH = 1:1(200 mL) 溶液中加入10%Pd/C(4.6 g),反應混合物在氫氣條件下25℃攪拌12 小時,過濾混合物,用 EtOAc(2 x 100 mL) 洗滌濾餅,合併有機相在真空中濃縮得到 (S)-(3-氨基-4-((氧烷-2-基甲基)氨基)苯基)氨基甲酸酯叔丁酯(18.8 g,收率90%),為棕色固體。LCMS(ESI): C
15H
23N
3O
3; [M + H]
+:計算值:293.4,實測值:293.4。
在室溫下,向 溶有(150 mL) 叔丁基 (S)-(3-氨基-4-((氧烷-2-基甲基)氨基)苯基)氨基甲酸酯 (18.0 g,61.4 mmol) 的 CH
3CN 溶液中加入2-氯-1,1,1-三甲氧基乙烷 (11.4 g,73.6 mmol) 和對甲苯磺酸吡啶 (1.23 g,4.9 mmol),將反應混合物升溫至70℃,攪拌2 小時,反應冷卻至室溫,向混合物中加入 EtOAc(100 mL) 和H
2O(200 mL),分離有機層,用 EtOAc(2 x 100 mL) 提取水層,用鹽水 (200 mL) 清洗合併的有機相,並在無水 Na
2SO
4上乾燥,過濾並在真空中濃縮得粗品,粗品經快速柱層析(石油醚/乙酸乙酯3:1)純化,得到Int I:叔丁基 (S)-(2-(氯甲基)-1-(氧雜環乙烷-2-基甲基)-1H-苯并 [d] 咪唑-5-基)氨基甲酸酯(18.0g,收率83%)為黃色固體。LCMS(ESI): C
17H
22ClN
3O
3; [M + H]
+:計算值:352.1,實測值: 352.1。
(S)-2-(氯甲基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并 [d] 咪唑-5-羧酸甲酯 (Int J) 的製備
向溶有 [(2S)-氧雜環庚烷-2-基] 甲胺 (10.9 g,125.5 mmol) 和4-氟-3-硝基苯甲酸甲酯 (20.0 g,100.5 mmol) 的 四氫呋喃(100 mL) 溶液中加入 N-乙基-N-異丙基-丙胺 (25.9 g,200.8 mmol),將反應混合物升溫至60℃,攪拌4 小時,用 EtOAc(100 mL) 和 H
2O(200 mL) 稀釋混合物,分離各層,用 EtOAc(2 x 100 mL) 提取水層,用鹽水 (200 mL) 清洗合併的有機相,並在無水 Na
2SO
4上乾燥,過濾並在真空中濃縮得粗品,粗品經甲基叔丁基醚打漿,得到化合物
Int J-3: 甲基 (S)-3-硝基-4-((氧烷-2-基甲基)氨基)苯甲酸酯(24.6g,收率92.3%)為黃色固體。LCMS(ESI): C
12H
14N
2O
5; [M + H]
+:計算值:266.2,實測值:267.2。
在25℃條件下,向溶有化合物
Int J-3(24.0 g,90.1 mmol) 的EtOAc:MeOH = 1:1(200 mL) 溶液中加入10%Pd/C(5.0 g),將反應混合物在氫氣下25℃攪拌12 小時,過濾混合物,用 EtOAc(2 x 100 mL) 清洗濾餅,合併有機相在真空中濃縮得到化合物 Int J-4 甲基 (S)-3-氨基-4-((氧烷-2-基甲基)氨基)苯甲酸酯(18.8 g,收率88.1%,純度93%),為棕色固體。LCMS(ESI): C
12H
16N
2O
3;[M + H]
+:計算值:236.2,實測值:237.2。
在室溫條件下,向溶有化合物 Int J-4 甲基 (S)-3-氨基-4-((氧烷-2-基甲基)氨基)苯甲酸酯 (18.0 g,76.2 mmol) 的 CH
3CN 溶液 (150 mL) 中加入2-氯-1,1,1-三甲氧基乙烷 (14.1 g,91.4 mmol) 和4-甲基苯磺酸 (1.3 g,7.62 mmol),將反應混合物升溫至70℃,攪拌2 小時,向混合物中加入 EtOAc(100 mL) 和H
2O(200 mL),分離有機層,用 EtOAc(2 x 100 mL) 提取水層,用鹽水 (200 mL) 清洗合併的有機相,並用無水 Na
2SO
4乾燥,過濾並在真空中濃縮得粗品,粗品經快速柱層析(石油醚/乙酸乙酯3:1)純化,得到化合物
Int J:甲基 (S)-2-(氯甲基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并 [d] 咪唑-5-羧酸酯(18.0 g,收率80%)為黃色固體,LCMS(ESI): C
14H
15ClN
2O
3; [M + H]
+:計算值:294.7,實測值: 295.7。
6-
((
4-
氯
-2-
氟苄基)氧基)
-1'
,
2'
,
3'
,
6'-
四氫
-2
,
4'-
聯吡啶
(Int K)
和
2-
((
4-
氯
-2-
氟苄基)氧基)
-6-
(呱啶
-4-
基)吡啶
(Int L)
的製備
向 500 mL 圓底燒瓶中加入化合物Int G(20.0 g,73.5 mmol,1.0 eq) 至二氧六環(200 mL,10 V) 中,加入叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-羧酸鹽 (27.3 g,88.2 mmol,1.2 eq)、K
2CO
3(20.3 g,147 mmol,2.0 eq)、Pd(dppf)Cl
2·DCM(5.7 g,6.3 mmol,0.085 eq)、H
2O(40 mL)、在氮氣環境下將混合物升溫至90℃,攪拌3.5 小時,然後將反應混合物冷卻至室溫並過濾,用 EA(100 mL) 清洗濾餅,向濾液中加入鹽水 (200 mL) 並分離,用 EA(100 mL x 2) 提取水相,真空濃縮合併的有機相,濃縮物經PE:EA = 1:1重結晶純化得到化合物粗品,然後用活性炭在室溫下脫色2 小時,混合物經矽藻土過濾,濾餅用 EA 洗滌後,真空濃縮得到化合物粗品,EtOH/H
2O = 6/1重結晶純化化合物 Int K-2 粗品,得到所需產物6-((4-氯-2-氟苄基)氧基)-3’,6’-二氫-[2,4’-聯吡啶]-1’ (2'H)-羧酸叔丁酯(20.1g,收率65%),為淡黃色固體。LCMS(ESI): C
22H
24ClFN
2O
3; [M + H]
+:計算值:418.8,實測值: 419.1。
向 500 mL 圓底燒瓶中的DCM(100.0 mL) 中加入化合物Int K-2(20.0 g,47.8 mmol),然後加入TFA(20 mL),在25℃下攪拌反應混合物2小時,加入 DCM 稀釋反應混合物,依次用碳酸氫鈉水溶液、水和飽和氯化鈉水溶液清洗反應混合物,用硫酸鈉乾燥,過濾,真空濃縮,濃縮物用 CH
3CN 重結晶純化化合物2-12粗品,得到所需產物Int K:6-(((4-氯-2-氟苄基)氧基)-1’,2’,3’,6’-四氫-2,4’-聯吡啶(13.5 g,收率88%),為白色固體。LCMS(ESI): C
17H
16ClFN
2O ; [M + H]
+:計算值:318.8,實測值: 319.1。
向在 25 ℃ 條件下,向溶有化合物Int K(13.0 g,40.8 mmol) 的EtOAc:MeOH = 1:1(100 mL) 溶液中加入10%Pd/C(3.9 g),反應混合物在氫氣下25℃攪拌6 小時,過濾混合物,用 EtOAc(2 x 100 mL) 清洗濾餅,合併有機相在真空中濃縮得到化合物Int L:2-((4-氯-2-氟苄基)氧基)-6-(呱啶-4-基)吡啶(12.0 g,收率91%),為白色固體。LCMS(ESI): C
17H
18ClFN
2O ; [M + H]
+:計算值:320.8,實測值: 321.1。
4-
(
2-
(
4-
氯
-2-
氟苯基)
-2-
甲基苯并
[d][1
,
3]
二氧雜環戊
-4-
基)
-1
,
2
,
3
,
6-
四氫吡啶
(Int M)
的製備
在氮氣環境下,將5-氯-2-乙炔基吡啶 (1.8 g,13.1 mmol)、3-溴代苯-1,2-二醇 (2.47 g,13.1 mmol) 和十二羰基三釕 (167 mg,0.261 mmol) 加入到甲苯 (25 mL) 溶液中,並在100℃下加熱16小時,加入乙酸乙酯 (30mL) 稀釋反應混合物,並藉由矽藻土墊過濾;濾液在真空中濃縮,並使用矽膠色譜法(梯度:0%-1%乙酸乙酯的石油醚溶液)進行純化,制得油狀物 Int M-2 (1.5g,37.5%)。
向 50 mL 圓底燒瓶中加入化合物Int M-2(2.0 g,5.84 mmol,1.0 eq) 至二氧六環 (20 mL,10 V) 中,加入叔丁基4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)-3,6-二氫吡啶-1(2H)-羧酸鹽 (2.2 g,8.8 mmol,1.2 eq)、K
2CO
3(1.6 g,11.7 mmol,2.0 eq)、Pd(dppf)Cl
2·DCM(0.4 g,0.50 mmol,0.085 eq)、H
2O(4 mL)、在氮氣環境下,將混合物,升溫至90℃,攪拌3.5 小時,然後將反應混合物冷卻至室溫並過濾,用 EA(20 mL) 清洗濾餅,向濾液中加入鹽水 (20 mL) 並分離,用 EA(20 mL x 2) 提取水相,真空濃縮合併的有機相,濃縮物經PE:EA = 1:1重結晶純化,得到化合物Int M-3(2.1 g,80.9%) 為淡黃色固體。LCMS(ESI): C
24H
25ClFNO
4; [M + H] +:計算值:446.15,實測值:446.15。
向 50 mL 圓底燒瓶中的DCM(10.0 mL) 中加入化合物Int M-3(2.0 g,4.5 mmol),然後加入TFA(2 mL),在25℃下攪拌反應混合物2小時,加入 DCM 稀釋反應混合物,依次用碳酸氫鈉水溶液、水和飽和氯化鈉水溶液清洗反應混合物,用硫酸鈉乾燥,過濾,真空濃縮,用 CH
3CN 重結晶純化化合物粗品,得到所需產物Int M(1.3g,收率83.8%)為白色固體。LCMS(ESI): C
19H
17ClFNO
2; [M + H]
+:計算值:346.1,實測值:346.1。
實施例化合物製備
製備
1 2-
(
4-
(
6-
(((
4-
氰基
-2-
氟苄基)氧基)吡啶
-2-
基)苄基)
-N-
(
4-
羥基苯乙基)
-1-
(
2-
甲氧基乙基)
-1H-
苯并
[d]
咪唑
-5-
甲醯胺
(1)
的製備
參考以下反應方程式(路線1):將叔丁醇鉀(14.7 g,0.13 mol,2.4 eq.)加入至THF(200 mL)中,攪拌5 min,然後分兩份加入3-氟-4-(羥甲基)苯甲腈(14 g,0.092 mol,1.7eq.),並在15 ℃下攪拌45 min,然後分兩份加入2,6-二氯吡啶(8.07 g,0.055 mol,1.0eq.),在15 ℃下攪拌18h。加入飽和氯化銨水溶液(18 eq)和EA(100 mL)處理反應。過濾,用EA(2 x 200 mL)萃取,用鹽水(200 mL)清洗合併的有機相,用無水硫酸鈉乾燥,過濾,真空濃縮濾液。濃縮物經PE/EA = 8/1重結晶純化得到化合物
1-3粗品,化合物
1-3粗品經EtOH/H
2O = 1/1重結晶純化得到所需產物(10.3g,收率70%)為淡黃色固體。LCMS(ESI):C
13H
8ClFN
2O ;[M + H]
+:計算值:262.6,實測值:263.6。
向250 mL圓底燒瓶中加入化合物
1-3(10.0 g,0.038 mol,1.0 eq)和二氧六環(100 mL,10 V),再加入2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊烷-2-基)苯基)乙酸乙酯(14.4 g,0.050 mol,1.3 eq)、K
2CO
3(10.8 g,0.760 mol,2.0 eq)、Pd(dppf)Cl
2·DCM(2.5 g,0.003 mmol,0.085 eq)、H
2O(20 mL)、在氮氣環境下,90 ℃下攪拌3.5h。將反應混合物冷卻至室溫並過濾,用EA(100 mL)清洗濾餅。向濾液中加入鹽水(100 mL)並分離,用EA(100 mL x2)提取水相,真空濃縮合併的有機相。濃縮物經PE:EA = 1:1重結晶純化,得到粗品
1-5 ,再用活性炭室溫脫色2h,經矽藻土墊過濾,濾液經濃縮後,經EtOH/H
2O = 6/1重結晶知得
1-5(8.8 g,收率65%),為淡黃色固體。LCMS(ESI): C
23H
19FN
2O
3;[M + H]
+:計算值:390.4,實測值:391.4。
在25 ℃下,向250 mL圓底燒瓶中加入化合物
1-5(8.0 g,20.49 mmol)、THF(20.0 mL)、CH
3CN(20.0 mL)、水(20.0 mL)和氫氧化鋰(982 mg,41 mmol)。在25 ℃下攪拌反應混合物12小時。然後濃縮除去有機溶劑,加入1m鹽酸將水性殘渣調節至pH 6。用EA(3 x 60 mL)提取所得混合物,用硫酸鎂乾燥合併的有機層,過濾,真空濃縮得到粗品。再經EtOH重結晶制得
1-6(6.5g,收率87%),為淡黃色固體。LCMS(ESI): C
21H
15FN
2O
3;[M + H]
+:計算值:362.3,實測值:363.3。
將化合物
1-6(6.0 g,16.56 mmol)、化合物
1-7(3.71 g,16.56 mmol)和O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲基六氟磷酸鹽(HATU;9.45 g,33.12 mmol)加入至N,N-二甲基甲醯胺(60 mL)溶液,在25 ℃下攪拌30 min,然後加入三乙胺(6.7 g,66.23 mmol),並在25 ℃下繼續攪拌12小時。然後將反應混合物倒入水中(300 mL),並用乙酸乙酯(3 × 200 mL)萃取。用飽和氯化鈉水溶液(3 x 200 mL)清洗合併的有機層,用硫酸鈉乾燥,過濾,並在真空中濃縮。矽膠色譜純化(洗脫液:1:1石油醚/乙酸乙酯)得到化合物
1-8,為棕色固體(7.8 g,收率83%)。LCMS(ESI):C
32H
29FN
4O
5;[M + H]
+:計算值:568.6,實測值:569.6。
將化合物1-8(7.5 g,13.19 mmol)溶於乙酸(50 mL)溶液,在75 ℃下攪拌12小時,再經減壓濃縮後,得到棕色固體粗品。經CH
3CN重結晶,得到所需產物化合物
1-9(6.1g,收率85%),為黃色固體。LCMS(ESI): C
32H
27FN
4O
4;[M + H]
+:計算值:550.6,實測值:551.6。
在0 ℃下,向250 mL圓底燒瓶中加入化合物1-9(6.0 g,10.9 mmol)、THF(20.0 mL)、CH
3CN(20.0 mL)、水(20.0 mL)和氫氧化鋰(522 mg,21.8 mmol)中,在25 ℃下攪拌反應混合物12小時。然後濃縮除去有機溶劑,用1N鹽酸調節pH為 6。用EA(3 x 60 mL)萃取,用硫酸鎂乾燥合併的有機層,過濾,真空濃縮得到粗品。用CH
3CN重結晶制得
1-10(5.1g,收率87%)為黃色固體。LCMS(ESI):計算C
31H
25FN
4O
4;[M + H]
+:計算值:536.5,結果:537.6。
將化合物
1-10(100 mg,1.86 mmol)、N-羥基苯并三唑(HOBT;37.78 mg,2.79 mmol)和N-(3-二甲基氨基丙基)-N''-乙基碳二亞胺鹽酸鹽(EDCI;9.45 g,33.12 mmol)加入至N,N-二甲基甲醯胺(2 mL)中,在25 ℃下攪拌30 min,然後加入N,N-二異丙基乙胺(48.18 mg,3.73 mmol)和4-(2-氨基乙基)苯酚(37.8 mg,1.86 mmol),25 ℃繼續攪拌12小時。然後將反應混合物倒入水中(10 mL),並用乙酸乙酯(3 × 10 mL)提取。用飽和氯化鈉水溶液(3 x 10 mL)清洗合併的有機層,用硫酸鈉乾燥,過濾,並在真空中濃縮。粗品經製備液相色譜法純化,得到化合物
1,67 mg,收率:54.9%。LCMS (ESI): C
39H
34FN
5O
4; [M+H]
+: 計算值:655.73, 實測值:656.2。
製備
2
:
(2S,4R)-1-
((
2-
((
4-
(
6-
((
4-
氯
-2-
氟苄基)氧基)吡啶
-2-
基)呱啶
-1-
基)甲基)
-1-
(
(S)-
氧代
-2-
基)甲基)
-1H-
苯并
[d]
咪唑
-5-
羰基)甘氨醯)
-4-
羥基吡咯烷
-2-
羧酸
(2)
的製備
參考以下反應方程式(路線2):
向化合物
Int L(12.0 g,37.4 mmol)的乙腈(120 mL)溶液中加入化合物
Int J(12.2 g,41.2 mmol),然後加入碳酸鉀(15.5 g,112 mmol),並將反應液在75 ℃下攪拌3小時。過濾反應液並用EA(100 mL)清洗,濾液經減壓濃縮,濃縮物經石油醚和乙酸乙酯混合溶液打漿(PE:EA = 5:1),得到化合物
2-14,甲基(S)-2-((4-(6-(((4-氯-2-氟苄基)氧基)吡啶-2-基)呱啶-1-基)甲基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-5-羧酸酯(17.5 g,收率82%)。LCMS(ESI): C
31H
32ClFN
4O
4;[M + H]
+:計算值:579.1,實測值:579.2。
在0 ℃下,將
2-14(16.0 g,10.9 mmol)加入250 mL圓底燒瓶中,再依次加入MeOH(80.0 mL)、水(80.0 mL)和氫氧化鈉(5.5 g,138.0 mmol),在50 ℃下攪拌反應2小時。然後濃縮除去有機溶劑,用1M鹽酸將水性殘留物調節pH至 6。用EA(3 x 100 mL)萃取,用硫酸鎂乾燥合併的有機層,過濾,經減壓濃縮後。再經CH
3CN打漿純化制得
2-15,(S)-2-((4-(6-(((4-氯-2-氟苄基)氧基)吡啶-2-基)呱啶-1-基)甲基)-1-(氧雜環庚烷-2-基甲基)-1H-苯并[d]咪唑-5-羧酸(13.5 g,收率84%)。LCMS(ESI):C
30H
30ClFN
4O
4;[M + H]
+:計算值:565.1,實測值:565.2。
將化合物
2-15(100 mg,0.177 mmol)、N-羥基苯并三唑(HOBT;35.8 mg,0.265 mmol)和N-(3-二甲基氨基丙基)-N''-乙基碳二亞胺鹽酸鹽(EDCI;50.9 mg,0.265 mmol)加入至N,N-二甲基甲醯胺(2 mL)中。在25 ℃下攪拌30 min,然後加入N,N-二異丙基乙胺(58.0 mg,0.442 mmol)和化合物
2-16(40.0 mg,0.195 mmol),並在25 ℃下繼續攪拌12小時。將反應液倒入水中(10 mL),並用乙酸乙酯(3 × 10 mL)提取。用飽和氯化鈉水溶液(2 x 10 mL)清洗合併的有機層,用硫酸鈉乾燥,過濾,減壓濃縮後,濃縮物經製備液相色譜純化,得到化合物
2-17,甲基(2S,4R)-1-(2-((4-(6-(((4-氯-2-氟苄基)氧基)吡啶-2-基)呱啶-1-基)甲基)-1-((S)-氧雜環庚烷-2-基)甲基)-1H-苯并[d]咪唑-5-羰基)甘氨醯)-4-羥基吡咯烷-2-羧酸酯,67 mg,收率:51%。LCMS(ESI): C
38H
42ClFN
6O
7;[M + H]
+:計算值:749.2,實測值:749.2。
在0 ℃下,向25 mL圓底燒瓶中加入化合物
2-17(60.0 mg,0.08 mmol)、MeOH(1.0 mL)、水(1.0 mL)和氫氧化鈉(16 mg,0.40 mmol),在50 ℃下攪拌反應1.5小時。然後濃縮除去有機溶劑,用1M鹽酸將水性殘渣調節pH至 6。用EA(3 x 10 mL)萃取,硫酸鎂乾燥合併的有機層,過濾,減壓濃縮得到粗品。再經製備液相色譜純化,制得
2,(2S,4R)-1-((2-((4-(6-(((4-氯-2-氟苄基)氧基)吡啶-2-基)呱啶-1-基)甲基)-1-(((S)-氧雜環庚烷-2-基)甲基)-1H-苯并[d]咪唑-5-羰基)甘氨酸)-4-羥基吡咯烷-2-羧酸(35 mg,收率60%)。LCMS(ESI): C
37H
40ClFN
6O
7;[M + H]
+:計算值:735.2,實測值:735.2。
1H NMR (400 MHz, DMSO-
d
6 )。
製備 3 : (S)-2- (( 6- ((( 4- 氯 -2- 氟苄基)氧基) -3',6'- 二氫 -[2,4'- 聯吡啶 ]-1'(2'H)- 基)甲基) -N- ( 3- 甲基 -1H- 吲哚 -5- 基) -1- (氧雜環丁烷 -2- 基甲基) -1H- 苯并 [d] 咪唑 -5- 甲醯胺 (3) 的製備 參考以下反應方程式(路線3):向化合物
Int K(10.0 g,31.3 mmol)的乙腈(100 mL)溶液中加入化合物
Int J(10.2 g,34mmol),然後加入碳酸鉀(10.8 g,78.4 mmol),並將反應混合物在室溫75 ℃下攪拌3小時。過濾反應混合液,用EA(100 mL)洗滌,濾液真空濃縮,粗品經漿液純化(PE:EA = 5:1),得化合物
3-1 ,甲基(S)-2-((6-(((4-氯-2-氟苄基)氧基)-3’,6’-二氫-[2,4’-聯吡啶]-1’(2'H)-基)甲基)-1-(氧雜烷-2-基甲基)-1H-苯并[d]咪唑-5-羧酸酯(14.5g,收率80%)為黃色固體。LCMS(ESI): C
31H
30ClFN
4O
4;[M + H]
+:計算值577.1,實測值:577.1。
在0 ℃下,向250 mL圓底燒瓶中加入化合物
3-1(14.0 g,24.3 mmol)、MeOH(70.0 mL)、水(70.0 mL)和氫氧化鈉(4.85 g,121.3 mmol)中,在50 ℃下攪拌反應混合物2小時。然後濃縮除去有機溶劑,用1M鹽酸調節pH 至6。用EA(3 x 100 mL)萃取,用硫酸鎂乾燥合併的有機層,過濾,減壓濃縮後,經乙腈打漿制得化合物
3-2,(S)-2-((6-(((4-氯-2-氟苄基)氧基)-3’,6’-二氫-[2,4’-聯吡啶]-1’(2'H)-基)甲基)-1-(氧雜環戊烷-2-基甲基)-1H-苯并[d]咪唑-5-羧酸(11.7g,收率86%)為黃色固體。LCMS(ESI): C
30H
28ClFN
4O
4;[M + H]
+:計算值:563.0,實測值:563.1。
將化合物
3-2(100 mg,0.177 mmol)、N-羥基苯并三唑(HOBT;35.8 mg,0.265 mmol)和N-(3-二甲基氨基丙基)-N''-乙基碳二亞胺鹽酸鹽(EDCI;50.9 mg,0.265 mmol)加入至N,N-二甲基甲醯胺(2 mL)中,在25 ℃下攪拌30 min。再加入N,N-二異丙基乙胺(58.0 mg,0.442 mmol)和3-甲基-1H-吲哚-5-胺(28.8 mg,0.195 mmol),並在25 ℃下繼續攪拌12小時。然後將反應混合物倒入水中(10 mL),並用乙酸乙酯(3 × 10 mL)提取。用飽和氯化鈉水溶液(2 x 10 mL)清洗合併的有機層,用硫酸鈉乾燥,過濾,經減壓濃縮後,粗品經製備液相色譜純化,得到化合物
3,(S)-2-((6-(((4-氯-2-氟苄基)氧基)-3’,6’-二氫-[2,4’-聯吡啶]-1’(2'H)-基)甲基)-N-(3-甲基-1H-吲哚-5-基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-5-甲醯胺,64 mg,收率:52%為白色固體。LCMS(ESI): C
38H
35ClFN
7O
3;[M + H]
+:計算值:692.1,實測值:692.2。
1H NMR (400 MHz, DMSO-d6)。
製備
4
:
(S)-N-
(
2-
((
6-
((
4-
氯
-2-
氟苄基)氧基)
-3',6'-
二氫
-[2,4'-
聯吡啶
]-1'(2'H)-
基)甲基)
-1-
(氧雜環庚烷
-2-
基甲基)
-1H-
苯并
[d]
咪唑
-5-
基)
-3-
甲基
-1H-
咪唑
-5-
甲醯胺
(4)
的製備
參考以下反應方程式(路線4):
向化合物
Int I(14.0 g,43.9 mmol)的乙腈(100 mL)溶液中加入化合物
Int K(17.0 g,48.3 mmol),然後加入碳酸鉀(15.2 g,109.8 mmol),並將反應混合物在75 ℃下攪拌3小時。待冷卻後至室溫,過濾反應液,用EA(100 mL)洗滌濾餅,濾液減壓濃縮,所得油狀物經石油醚和乙酸乙酯混合溶液打漿(PE:EA = 6:1),制得化合物
4-6,叔丁基(S)-(2-((6-(((4-氯-2-氟苄基)氧基)-3’,6’-二氫-[2,4’-聯吡啶]-1’(2'H)-基)甲基)-1-(氧雜烷-2-基甲基)-1H-苯并[d]咪唑-5-基)氨基甲酸酯(22.5g,收率80.6%)為類白色固體。LCMS (ESI): C
34H
37ClFN
5O
4;[M+H]
+: 計算值634.1,實測值: 634.2.
向500 mL圓底燒瓶中,加入化合物
4-6(20.0 g,31.5 mmol) 的DCM(100.0 mL)溶液,然後加入TFA(20 mL),反應混合物在25 ℃下攪拌2小時。反應液加壓濃縮後,加入二氯甲烷(100mL),再依次加入碳酸氫鈉水溶液、水和飽和氯化鈉水溶液洗滌,有機相經硫酸鈉乾燥,過濾,減壓濃縮。所得濃縮物經PE:EA = 5:1結晶,得到化合物
4-7,(S)-2-((6-(((4-氯-2-氟苄基)氧基)-3’,6’-二氫-[2,4’-聯吡啶]-1’(2'H)-基)甲基)-1-(氧烷-2-基甲基)-1H-苯并[d]咪唑-5-胺(13.5g,收率80%),為類白色固體。LCMS (ESI): C
29H
29ClFN
5O
2;[M+H]
+: 計算值:534.1,實測值:534.2.
將化合物
4-8(40 mg,0.227 mmol)、N-羥基苯并三唑(HOBT;46.0 mg,0.340 mmol)和N-(3-二甲基氨基丙基)-N''-乙基碳二亞胺鹽酸鹽(EDCI;65.1 mg,0.340 mmol)加入至N,N-二甲基甲醯胺(2 mL)溶液中,在25 ℃下攪拌30 mins,然後加入N,N-二異丙基乙胺(58.0 mg,0.442 mmol)和化合物
4-7(121.1 mg,0.227 mmol),並在25 ℃下繼續攪拌12小時。將反應混合物倒入水中(10 mL),並用乙酸乙酯(3 × 10 mL)萃取。合併有機層經飽和氯化鈉水溶液(2 x 10 mL)清洗,再經硫酸鈉乾燥,過濾,經減壓濃縮後再經製備液相色譜純化,得到化合物
4,(S)-N-(2-((6-(((4-氯-2-氟苄基)氧基)-3’,6’-二氫-[2,4’-聯吡啶]-1’(2'H)-基)甲基)-1-(氧雜環丁烷-2-基甲基)-1H-苯并[d]咪唑-5-基)-3-甲基-1H-吲唑-5-甲醯胺,81 mg,收率:51.9%,為白色固體。LCMS (ESI): C
38H
35ClFN
7O
3;[M+H]
+:計算值692.1,實測值: 692.2。
製備
5
:
2-
((
4-
(
(S)-2-
(
4-
氯
-2-
氟苯基)
-2-
甲基苯并
[d][1,3]
二氧雜環
-4-
基)
-3,6-
二氫吡啶
-1(2H)-
基)甲基)
-N-
(
3-
甲基
-1H-
吲唑
-5-
基)
-1-
((
(S)-
氧雜環丁烷
-2-
基)甲基)
-1H-
苯并
[d]
咪唑
-5-
甲醯胺
(5)
的製備
2-
((
4-
(
(R)-2-
(
4-
氯
-2-
氟苯基)
-2-
甲基苯并
[d][1,3]
二氧雜環
-4-
基)
-3
,
6-
二氫吡啶
-1(2H)-
基)甲基)
-N-
(
3-
甲基
-1H-
吲唑
-5-
基)
-1-
(
(S)-
氧雜環丁烷
-2-
基)甲基)
-1H-
苯并
[d]
咪唑
-5-
甲醯胺
(5’)
的製備
參考以下反應方程式(路線5):
在攪拌下將化合物
Int J(1.0g,3.48mmol)加入化合物
Int M(1.0g、2.9mmol)的乙腈(10ml)溶液中,然後加入碳酸鉀(10.5g,7.25mmol),並且將反應混合物在75 ℃下攪拌3小時。過濾該反應混合物並用EA(20ml)洗滌,濾液真空濃縮,粗品經漿液純化(PE:EA = 5:1),得到黃色固體化合物
5-5(1.5 g,產率85.8%)。LCMS (ESI): C
33H
31ClFN
3O
5;[M+H]
+:計算值604.2,實測值: 604.2。將化合物
5-5(1.4g,2.3mmol)、MeOH(7.0ml)、水(7.0ml)和氫氧化鈉(0.46g,11.5mmol)在0℃下加入25ml圓底燒瓶中,將反應混合物在50℃下攪拌2小時,然後濃縮以除去有機溶劑。藉由加入1M鹽酸將含水殘渣調節至pH 6。所得混合物用EA(10ml x 3)萃取,並將合併的有機層用硫酸鎂乾燥,過濾,真空濃縮,得到粗品。粗化合物5-6藉由用CH
3CN打漿純化,得到所需黃色固體產物(1.2 g, 產率87.8%)。LCMS (ESI): C
32H
29ClFN
3O
5; [M+H]
+: 計算值:590.2,實測值: 590.2。
將化合物5-6(100mg,0.17mmol)、N-羥基苯并三唑(HOBT;35.8mg,0.265mmol)和N-(3-二甲基氨基丙基)-N’’-乙基碳二醯胺鹽酸鹽(EDCI;50.9mg,0.265 mmol)在
N,N-二甲基甲醯胺(2ml)的溶液在25℃下攪拌30分鐘,然後加入N,N-雙異丙基乙胺(58.0mg,0.442mmol)以及3-甲基-1H-吲唑-5-胺(28.8 mg,0.195mmol),並在25℃下繼續攪拌12 h。然後將該反應混合物倒入水(10ml)中並用乙酸乙酯(10ml x 3)萃取。合併的有機層用飽和氯化鈉水溶液(10ml x 2)洗滌,用無水硫酸鈉乾燥,過濾並真空濃縮。藉由製備液相色譜純化粗品以產生非對映體產物5-7的混合物。藉由 SFC (超臨界流體色譜法)[柱:手性技術ChiralCel OD,5 pm;流動相:55:45二氧化碳/(含0.1%氫氧化銨的甲醇)]拆分得到兩種手性化合物:手性化合物
5,23mg, LCMS (ESI): C
40H
36ClFN
6O
4; [M+H]
+: 計算值:719.3, 實測值:719.3;以及化合物
5’, 19mg, LCMS (ESI): C
40H
36ClFN
6O
4; [M+H]
+: 計算值:719.3, 實測值:719.3。
製備
6
:
2-
(
6-
(
6-
(((
4-
氰基
-2-
氟苄基)氧基)吡啶
-2-
基)
-6-
氮雜螺
[2.5]
辛烷
-1-
基)
-1-
(
2-
甲氧基乙基)
-N-
(
3-
甲基
-1H-
吲唑
-5-
基)
-1H-
苯并
[d]
咪唑
-5-
甲醯胺
(6)
的製備
在N
2氣氛下,將化合物
1-3(2.0 g,7.61 mmol)、6-氮雜螺[2.5]辛烷-1-羧酸甲酯(1.42g,8.38 mmol)、Cs
2CO
3(4.97g,15.2 mmol)、Pd
2(dba)
3(696 mg,0.77 mmol)和X-Phose(734 mg,1.54 mmol)的混合物加入至二氧六環(20mL)中,在100 ℃下加熱4小時。用乙酸乙酯(30ml)稀釋反應混合物,並藉由矽藻土墊過濾;將濾液減壓濃縮後經矽膠層析(梯度:0%~5%甲醇二氯甲烷)純化,得到黃色油狀化合物
6-2(1.5g,49%)。
接下來的一系列反應可以按照製備
1進行。經過水解、縮合反應、環化、水解以及縮合得到化合物
6。
根據本文描述的程式(以及表1中程式項下的說明),使用適當的起始材料和必要的 適當的保護基化學方法,製備以下化合物。
表1 化合物列表
編號 | 結構式 | 質譜 (m/z, M+H +) | 核磁氫譜 | 製備方法 |
1 | 656.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.19 (t, J= 4.9 Hz, 1H), 8.13 – 8.06 (m, 2H), 8.04 – 8.02 (m, 1H), 7.75-7.73 (m, 1H), 7.66 – 7.63 (m, 1H), 7.48 – 7.43 (m, 3H), 7.40 – 7.34 (m, 2H), 7.28 – 7.21 (m, 2H), 7.02 – 6.96 (m, 2H), 6.79 – 6.74 (m, 1H), 6.74 – 6.70 (m, 2H), 6.14 (s, 1H), 5.31 (s, 2H), 4.38-4.22 (m, 4H), 3.75-3.45 (m, 4H), 3.35 (s, 3H), 2.87 – 2.83 (m, 2H). | 1 | |
2 | 735.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.14 -8.04(m, 2H), 7.74 – 7.72 (m, 1H), 7.46-7.35 (m, 3H), 7.21 – 7.18 (m, 1H), 7.18 – 7.13 (m, 2H), 6.80 – 6.77 (m, 1H), 5.35 (s, 2H), 4.51 – 4.32 (m, 3H), 4.32 – 4.24 (m, 1H), 4.23 – 4.15(m, 1H), 4.01 – 3.83 (m, 3H), 3.78 – 3.65 (m, 4H), 3.61 – 3.54 (m, 1H), 3.35-2.99 (m, 2H), 2.83 – 2.74 (m, 2H), 2.69 – 2.60 (m, 2H), 2.42 – 2.30 (m, 2H), 2.25 – 2.09 (m, 7H). | 2 | |
3 | 692.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.31 (s, 1H), 10.54 (s, 1H), 8.05-8.02 (m, 1H), 7.88-7.87 (m, 1H), 7.86 – 7.84 (m, 1H), 7.68 – 7.66 (m, 1H), 7.49 – 7.34 (m, 4H), 7.21 – 7.13 (m, 2H), 6.89 – 6.84 (m, 1H), 6.58 – 6.53 (m, 1H), 5.35 – 5.24 (m, 2H), 4.39 – 4.24 (m, 2H), 4.23 – 4.15(m, 1H), 4.00-3.82 (m, 4H), 3.78 – 3.70 (m, 2H), 3.36 – 2.97 (m, 4H), 2.90-2.84 (m, 5H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H). | 3 | |
4 | 692.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.01 (s, 1H), 10.64 (s, 1H), 8.07-7.89(m, 2H), 7.82– 7.78 (m, 1H), 7.66 – 7.63 (m, 1H), 7.47 – 7.33 (m, 4H), 7.21 – 7.16 (m, 2H), 6.89 – 6.87 (m, 1H), 6.58 – 6.54 (m, 1H), 5.35 – 5.24 (m, 2H), 4.39 – 4.13 (m, 3H), 4.00-3.70 (m, 6H), 3.36 – 3.28 (m, 2H), 3.08 – 2.90 (m, 5H), 2.93 – 2.84 (m, 2H), 2.39 – 2.09 (m, 2H). | 4 | |
5 | 719.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.01-7.98 (m, 1H), 7.83 – 7.81 (m, 1H), 7.68 – 7.57 (m, 2H), 7.41-7.27 (m, 3H), 7.21 – 7.07 (m, 2H), 7.01 – 6.93 (m, 2H), 6.10 – 6.07 (m, 1H), 4.39 – 4.13 (m, 3H), 3.97 – 3.70 (m, 4H), 3.37 – 3.29 (m, 5H), 2.89-2.71 (m, 4H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H), 1.82 (s, 3H). | 5 | |
6 | 719.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.01-7.98 (m, 1H), 7.83 – 7.81 (m, 1H), 7.68 – 7.57 (m, 2H), 7.41-7.27 (m, 3H), 7.21 – 7.07 (m, 2H), 7.01 – 6.93 (m, 2H), 6.10 – 6.07 (m, 1H), 4.39 – 4.13 (m, 3H), 3.97 – 3.70 (m, 4H), 3.37 – 3.29 (m, 5H), 2.89-2.71 (m, 4H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H), 1.82 (s, 3H). | 5 | |
7 | 685.4 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.93 (s, 1H), 10.41 (s, 1H), 8.11-8.10 (m, 1H), 7.88 (d, J= 2.1 Hz, 1H), 7.86 – 7.81 (m, 1H), 7.68 – 7.66 (m, 1H), 7.50 – 7.44 (m, 3H), 7.44 – 7.39 (m, 1H), 7.39 – 7.33 (m, 1H), 7.33 – 7.26 (m, 1H), 6.57 – 6.23 (m, 2H), 5.31 (s, 2H), 4.40-3.51 (m, 8H), 3.35 -3.20(m, 4H), 2.90 (s, 3H), 2.12 – 1.75 (m, 6H). | 6 | |
8 | 685.4 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.31 (s, 1H), 10.83 (s, 1H), 8.13-8.11 (m, 1H), 7.83 – 7.79 (m, 2H), 7.68 – 7.66 (m, 1H), 7.50 – 7.44 (m, 3H), 7.44 – 7.39 (m, 1H), 7.39 – 7.26 (m, 2H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.31 (s, 2H), 4.40-3.75 (m, 4H), 3.64 – 3.51 (m, 4H), 3.35-3.20 (m, 4H), 2.90 (s, 3H), 2.12 – 1.75 (m, 6H). | 6 | |
9 | 655.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.33 (s, 1H), 8.13-8.02 (m, 4H), 7.77 – 7.64 (m, 2H), 7.48 – 7.33 (m, 5H), 7.28 – 7.21 (m, 2H), 7.02 – 6.96 (m, 2H), 6.79 –6.70 (m, 3H), 6.01-5.31 (m, 4H), 4.38-3.75 (m, 6H), 3.51 – 3.35 (m, 5H), 2.87 – 2.83 (m, 2H). | 1 | |
10 | 831.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22 (s, 1H), 8.15-8.12 (m, 1H), 8.11 – 8.07 (m, 3H), 7.89 – 7.73 (m, 6H), 7.66 – 7.64 (m, 1H), 7.48 – 7.33 (m, 5H), 7.27 – 7.15 (m, 6H), 6.79 – 6.74 (m, 1H), 5.31 (s, 2H), 4.41-4.38 (m, 2H), 4.22 (t, J= 1.0 Hz, 2H), 3.75 (t, J= 4.4 Hz, 2H), 3.51 – 3.35 (m, 7H), 2.93 – 2.87 (m, 4H). | 1 | |
11 | 672.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.18-8.15 (m, 1H), 8.13 – 8.06 (m, 2H), 8.04 – 8.02 (m, 1H), 7.77 – 7.64 (m, 2H), 7.48 – 7.35 (m, 5H), 7.28 – 7.21 (m, 2H), 7.02 – 6.96 (m, 2H), 6.79 – 6.70 (m, 3H), 6.14 (s, 1H), 5.31 (s, 2H), 4.41-4.38 (m, 2H), 4.27 (s, 2H), 3.75 (t, J= 4.4 Hz, 2H), 3.51 – 3.44 (m, 2H), 3.36 (s, 3H), 2.87 – 2.83 (m, 2H). | 1 | |
12 | 684.4 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.91 (s, 1H), 8.22 (s, 1H), 8.18-8.14 (m, 1H), 8.11 – 8.07 (m, 3H), 7.77 – 7.64 (m, 2H), 7.48 – 7.35 (m, 5H), 7.28 – 7.21 (m, 2H), 7.02 – 6.96 (m, 2H), 6.79 – 6,69 (m, 3H), 5.31 (s, 2H), 4.41-4.38 (m, 2H), 4.27 (s, 2H), 3.75 (t, J= 4.4 Hz, 2H), 3.51 – 3.44 (m, 2H), 3.32 (s, 3H), 2.87 – 2.83 (m, 2H). | 1 | |
13 | 656.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.32 (t, J= 4.9 Hz, 1H), 8.11 – 8.07 (m, 3H), 7.77 – 7.64 (m, 2H), 7.48 – 7.43 (m, 3H), 7.40 – 7.34 (m, 2H), 7.28 – 7.21 (m, 2H), 7.02 – 6.96 (m, 5H), 6.11 (s, 1H), 5.31 (s, 2H), 4.41-4.38 (m, 2H), 4.27 (s, 2H), 3.75 (t, J= 4.4 Hz, 2H), 3.51 – 3.44 (m, 2H), 3.34 (s, 3H), 2.87 – 2.83 (m, 2H). | 1 | |
14 | 704.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.12 (s, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.79 – 7.73 (m, 1H), 7.47 – 7.37 (m, 2H), 7.22 – 7.16 (m, 3H), 6.82 – 6.73 (m, 1H), 6.02-6.01(m, 1H), 5.96 (d, J=6.8 Hz, 1H), 5.28 (d, J = 1.2 Hz, 2H), 4.38-4.36 (m, 2H), 4.13 – 4.03 (m, 1H), 3.80 – 3.71 (m, 4H), 3.36 (s, 3H), 3.07 – 2.91 (m, 2H), 2.85 – 2.78 (m, 5H), 2.69 – 2.60 (m, 2H), 2.12 – 1.94 (m, 5H), 1.80 – 1.77 (m, 1H). | 2 | |
15 | 684.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.19-8.16 (m, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.82 – 7.78(m, 1H), 7.42 – 7.34 (m, 3H),7.22 – 7.14 (m, 3H), 7.02 – 6.96 (m, 2H), 6.82 – 6.70 (m, 3H), 6.14 (s, 1H), 5.35 (s, 2H), 4.39 – 4.28 (m, 2H), 4.23 – 4.15(m, 1H), 3.89 – 3.73 (m, 2H), 3.71 (s, 3H), 3.55 – 3.48 (m, 2H), 3.03 – 3.01 (m, 1H), 2.88 – 2.74 (m, 4H), 2.65 – 2.61 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
16 | 660.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.10 (t, J= 4.2 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.77 – 7.67 (m, 2H), 7.46 – 7.39 (m, 3H), 7.21 – 7.13 (m, 4H), 6.92 – 6.87 (m, 1H), 6.80 – 6.76 (m, 1H), 5.31-5.30 (m, 2H), 4.37-4.33 (m, 2H), 4.05 (t, J= 6.4 Hz, 2H), 3.84 – 3.75 (m, 4H), 3.40 – 3.34 (m, 5H), 3.03 – 3.01 (m, 1H), 2.85– 2.75 (m, 2H), 2.66 – 2.61 (m, 2H), 2.09 – 1.94 (m, 6H). | 2 | |
17 | 711.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.17 (d, J=6.8 Hz, 1H), 8.44 (s, 1H),8.10 – 8.01 (m, 2H), 7.82 – 7.78(m, 1H), 7.46 – 7.39 (m, 3H), 7.21 – 7.13 (m, 4H), 7.08 – 7.02 (m, 2H), 6.82 – 6.75 (m, 2H), 5.29 (d, J= 1.2 Hz, 2H), 4.32-4.30 (m, 2H), 3.82 – 3.75 (m, 4H), 3.67-3.60 (m, 2H), 3.43 – 3.35 (m, 1H), 3.31 (s, 3H), 3.03 – 3.01 (m, 1H), 2.97-2.91 (m, 1H), 2.84– 2.75 (m, 2H), 2.69 – 2.65 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
18 | 672.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.40 (s, 1H), 8.12 (t, J= 4.9 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.81 – 7.73 (m, 1H), 7.47 – 7.37 (m, 2H), 7.25 – 7.17 (m, 3H), 7.08 – 7.01 (m, 2H), 6.88 – 6.77 (m, 3H), 5.26 (d, J = 1.2 Hz, 2H), 4.38-4.36 (m, 2H), 3.79 – 3.71 (m, 4H), 3.59 (m, J = 5.1 Hz, 2H), 3.31 (s, 3H), 3.07 – 2.95 (m, 3H), 2.84– 2.74 (m, 2H), 2.68 – 2.60 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
19 | 672.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.53 (s, 1H), 8.08 (t, J= 4.9 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.81 – 7.73 (m, 1H), 7.46 – 7.39 (m, 2H), 7.24 – 7.15 (m, 3H), 7.08 – 7.00 (m, 2H), 6.88 – 6.74 (m, 3H), 5.25 (d, J= 1.2 Hz, 2H), 4.36 (t, J = 4.4 Hz, 2H), 3.79 – 3.73 (m, 4H), 3.57 (m, J = 5.1 Hz, 2H), 3.32 (s, 3H), 3.07 – 2.95 (m, 3H), 2.83 – 2.75 (m, 2H), 2.69 – 2.65 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
20 | 700.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23(t, J= 4.9 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.83 – 7.71 (m, 1H), 7.42 – 7.33 (m, 2H), 7.21 – 7.15 (m, 3H), 7.05 – 6.99 (m, 2H), 6.87 – 6.82 (m, 2H), 6.81 – 6.73 (m, 1H), 5.27 (d, J = 1.2 Hz, 2H), 4.33 (t, J = 4.4 Hz, 2H), 3.80 – 3.75 (m, 6H), 3.44 – 3.37 (m, 2H), 3.30 (s, 3H), 3.03 – 3.01 (m, 1H), 2.85 – 2.75 (m, 2H), 2.68 – 2.60 (m, 4H), 2.09 – 1.86 (m, 6H). | 2 | |
21 | 681.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.96 – 8.90 (m, 2H), 8.08 (d, J= 2.0 Hz, 1H), 7.80 – 7.73 (m, 1H), 7.63 (t, J= 2.2 Hz, 1H), 7.47 – 7.37 (m, 2H), 7.33 (d, J= 7.3 Hz, 1H), 7.29 – 7.23 (m, 1H), 7.22 – 7.13 (m, 4H), 6.83 – 6.75 (m, 1H), 6.45 – 6.40 (m, 1H), 5.29-5.28 (m, 2H), 4.53 (d, J= 6.3 Hz, 2H), 4.37-4.33 (m, 2H), 3.78 – 3.73 (m, 4H), 3.31 (s, 3H), 3.03 – 3.01 (m, 1H), 2.85 – 2.76 (m, 2H), 2.68 – 2.61 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
22 | 696.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.49 (s, 1H), 8.09-8.08 (m, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.85 – 7.78 (m, 1H), 7.48 – 7.39 (m, 2H), 7.21 – 7.13 (m, 4H), 7.08 – 7.02 (m, 2H), 6.82 – 6.75 (m, 2H), 5.28 (d, J = 1.2 Hz, 2H), 4.32-4.30 (m, 2H), 3.78 – 3.70 (m, 4H), 3.67-3.60 (m, 2H), 3.43 – 3.35 (m, 4H), 3.07 – 2.99 (m, 2H), 2.85 – 2.77 (m, 2H), 2.69 – 2.61 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
23 | 724.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.14-8.12 (m, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.82 – 7.73 (m, 1H), 7.48 – 7.35 (m, 2H), 7.21 – 7.13 (m, 3H), 7.05 – 6.98 (m, 2H), 6.88 – 6.72 (m, 3H), , 5.29 (d, J = 1.2 Hz, 2H), 4.34 (t, J= 4.4 Hz, 2H), 3.79 – 3.70 (m, 4H), 3.65-3.62 (m, 2H), 3.34 (s, 3H), 3.07 – 2.97 (m, 3H), 2.86 – 2.77 (m, 2H), 2.69 – 2.59 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
24 | 670.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.15-8.12 (m, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.80 – 7.72 (m, 1H), 7.42 – 7.36 (m, 3H),7.22 – 7.14 (m, 3H), 7.02 – 6.96 (m, 2H), 6.81 – 6.70 (m, 1H), 6.75 – 6.70 (m, 2H), 6.14 (s, 1H), 5.35 (s, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 2H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.88 – 2.79 (m, 4H), 2.68 – 2.59 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
25 | 686.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23(t, J= 4.9 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.81 – 7.73(m, 1H), 7.45 – 7.35 (m, 2H), 7.22 – 7.15 (m, 3H), 7.05 – 6.99 (m, 2H), 6.85 – 6.76 (m, 3H), 5.31 (d, J = 1.2 Hz, 2H), 4.33 (t, J = 4.4 Hz, 2H), 3.80 – 3.75 (m, 3H), 3.44 – 3.37 (m, 2H), 3.32 (s, 3H), 3.03 – 3.01 (m, 1H), 2.84 – 2.74 (m, 2H), 2.68 – 2.60 (m, 4H), 2.09 – 1.86 (m, 6H). | 2 | |
26 | 659.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 7.84 – 7.80 (m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.34 (m, 3H), 7.25 – 7.17 (m, 3H), 6.86 – 6.77 (m, 1H), 5.68 (s, 2H), 5.31 (d, J = 1.2 Hz, 2H), 4.70 (d, J= 12.0 Hz, 1H), 4.64 (d, J= 12.1 Hz, 1H), 4.48 (s, 2H), 4.37-4.33 (m, 2H), 3.79 – 3.71 (m, 4H), 3.36 (s, 3H), 3.03 – 3.01 (m, 1H), 2.85– 2.74 (m, 2H), 2.69 – 2.62 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
27 | 699.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.25 (s, 1H), 8.86 (t, J= 6.3 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.79 – 7.72(m, 1H), 7.57 – 7.51 (m, 2H), 7.46 – 7.39 (m, 2H), 7.34 – 7.28 (m, 2H), 7.25 – 7.12 (m, 3H), 6.88 – 6.73 (m, 1H), 5.35 (s, 2H), 4.54 – 4.49 (m, 2H), 4.36 – 4.31 (m, 2H), 3.81 – 3.73 (m, 4H), 3.35 (s, 3H), 3.03 – 3.01 (m, 1H), 2.85– 2.75 (m, 2H), 2.65 – 2.60 (m, 2H), 2.16 (s, 3H), 2.09 – 1.94 (m, 4H). | 2 | |
28 | 688.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.05 (s, 1H), 8.86 (t, J= 6.3 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.79 – 7.73(m, 1H), 7.57 – 7.51 (m, 2H), 7.47 – 7.37 (m, 2H), 7.34 – 7.28 (m, 2H), 7.21 – 7.12 (m, 3H), 6.86 – 6.74 (m, 1H), 5.35 (s, 2H), 4.54 – 4.49 (m, 2H), 4.36 – 4.31 (m, 2H), 4.16 (s, 3H), 3.80 – 3.73 (m, 4H), 3.31 (s, 3H), 3.03 – 3.01 (m, 1H), 2.86 – 2.77 (m, 2H), 2.69 – 2.65 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
29 | 799.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.19 (t, J= 4.9 Hz, 1H), 8.04 (d, J= 2.2 Hz, 1H), 7.80 (d, J= 2.1 Hz, 1H), 7.79 – 7.73 (m, 4H), 7.70 – 7.66 (m, 1H), 7.50 – 7.33 (m, 8H), 7.28 – 7.23 (m, 2H), 7.06 (s, 2H), 6.80 – 6.75 (m, 1H), 5.31 (s, 2H), 4.41 – 4.36 (m, 2H), 4.35 – 4.29 (m, 1H), 4.28 – 4.22 (m, 1H), 3.88 (s, 2H), 3.75 (t, J= 4.4 Hz, 2H), 3.51 – 3.44 (m, 2H), 3.34 (s, 3H), 2.92 – 2.86 (m, 2H). | 1 | |
30 | 667.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.86 (t, J= 6.3 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.80 – 7.74(m, 1H), 7.62 – 7.59 (m, 2H), 7.50 – 7.36 (m, 5H), 7.21 – 7.14 (m, 3H), 6.85 – 6.74 (m, 1H), 5.35 (s, 2H), 4.56 – 4.51 (m, 2H), 4.31 (t, J = 4.4 Hz, 2H), 3.80 – 3.73 (m, 4H), 3.32 (s, 3H), 3.03 – 3.01 (m, 1H), 2.86 – 2.73 (m, 2H), 2.66 – 2.61 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
31 | 676.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.82 (t, J= 6.3 Hz, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.77 – 7.70 (m, 1H), 7.62 – 7.59 (m, 2H), 7.50 – 7.36 (m, 5H), 7.25 – 7.14 (m, 3H), 6.85 – 6.78 (m, 1H), 5.35 (s, 2H), 4.56 – 4.51 (m, 2H), 4.34 (t, J = 4.4 Hz, 2H), 3.80 – 3.74 (m, 4H), 3.35 (s, 3H), 3.03 – 3.01 (m, 1H), 2.90 – 2.87 (m, 2H), 2.67 – 2.61 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
32 | 658.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.79 (t, J= 6.3 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.81 – 7.73(m, 1H), 7.48 – 7.37 (m, 2H), 7.21 – 7.10 (m, 4H), 7.02 – 6.97 (m, 1H), 6.95 (s, 1H), 6.86 – 6.81 (m, 2H), , 6.73 – 6.67 (m, 1H), 5.35 (s, 2H), 4.47 – 4.42 (m, 2H), 4.38-4.36 (m, 2H), 3.81 – 3.74 (m, 4H), 3.31 (s, 3H), 3.03 – 3.01 (m, 1H), 2.83 – 2.74 (m, 2H), 2.68 – 2.61 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
33 | 674.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.72 (t, J= 6.3 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.49 – 7.37 (m, 2H), 7.21 – 7.10 (m, 4H), 7.02 – 6.97 (m, 2H), 6.83 – 6.73 (m, 3H), 5.35 (s, 2H), 4.47 – 4.42 (m, 2H), 4.38-4.36 (m, 2H), 3.82 – 3.75 (m, 4H), 3.36 (s, 3H), 3.03 – 3.01 (m, 1H), 2.83 – 2.75 (m, 2H), 2.68 – 2.59 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
34 | 659.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.91 (t, J= 6.3 Hz, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.77 – 7.70 (m, 1H), 7.62 – 7.59 (m, 2H), 7.50 – 7.36 (m, 5H), 7.25 – 7.18 (m, 3H), 6.84 – 6.78 (m, 1H), 5.35 (s, 2H), 4.56 – 4.51 (m, 2H), 4.33 (t, J = 4.4 Hz, 2H), 3.83 – 3.75 (m, 4H), 3.37 (s, 3H), 3.03 – 3.01 (m, 1H), 2.84 – 2.75 (m, 2H), 2.67 – 2.59 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
35 | 658.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.79 (t, J= 6.3 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.82 – 7.74(m, 1H), 7.47 – 7.37 (m, 2H), 7.21 – 7.10 (m, 4H), 7.02 – 6.97 (m, 1H), 6.86 – 6.79 (m, 2H), 6.73 – 6.63 (m, 2H), 5.35 (s, 2H), 4.47 – 4.42 (m, 2H), 4.37-4.33 (m, 2H), 3.81 – 3.76 (m, 4H), 3.30 (s, 3H), 3.03 – 3.01 (m, 1H), 2.84 – 2.74 (m, 2H), 2.67 – 2.58 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
36 | 716.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.88 (t, J= 5.8 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.82 – 7.80 (m, 1H), 7.83 – 7.74(m, 1H), 7.46 (d, J= 15.4 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.27 – 7.13 (m, 4H), 6.90 (d, J= 8.0 Hz, 1H), 6.84 – 6.75 (m, 1H), 5.35 (s, 2H), 4.57 – 4.52 (m, 2H), 4.34 (t, J = 4.4 Hz, 2H), 3.86 (s, 3H), 3.81 – 3.73 (m, 4H), 3.32 (s, 3H), 3.03 – 3.01 (m, 1H), 2.83 – 2.74 (m, 2H), 2.67 – 2.58 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
37 | 702.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.89 (t, J= 5.8 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.82 – 7.80 (m, 1H), 7.78 – 7.72(m, 1H), 7.42 – 7.38 (m, 3H), 7.27 – 7.13 (m, 4H), 6.90 (d, J= 8.0 Hz, 1H), 6.81 – 6.75 (m, 1H), 5.35 (s, 2H), 4.57 – 4.52 (m, 2H), 4.32-4.30 (m, 2H), 3.81 – 3.74 (m, 4H), 3.31 (s, 3H), 3.03 – 3.01 (m, 1H), 2.83 – 2.75 (m, 2H), 2.67 – 2.59 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
38 | 698.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.75 (s, 1H), 9.49 (s, 1H), 8.80 (t, J= 6.3 Hz, 1H), 8.04 – 7.99 (m, 2H), 7.82 – 7.72(m, 1H), 7.46 – 7.37 (m, 2H), 7.21 – 7.16 (m, 1H), 7.18 – 7.13 (m, 2H), 7.13 – 7.05 (m, 2H), 6.81 – 6.73 (m, 1H), 5.35 (s, 2H), 4.50 (d, J= 6.3 Hz, 2H), 4.38-4.36 (m, 2H), 3.81 – 3.76 (m, 4H), 3.35 (s, 3H), 3.03 – 3.01 (m, 1H), 2.85 – 2.75 (m, 2H), 2.65 – 2.59 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
39 | 802.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.20 (d, J= 7.1 Hz, 1H), 8.03 (t, J = 4.9 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.84 – 7.76(m, 1H), 7.55 (d, J= 2.4 Hz, 1H), 7.45 – 7.37 (m, 2H), 7.32 (d, J= 7.1 Hz, 1H), 7.21 – 7.16 (m, 4H), 7.09 (d, J= 7.1 Hz, 1H), 6.89 – 6.79 (m, 1H), 5.86 – 5.79 (m, 1H), 5.35 (s, 2H), 4.36 – 4.31 (m, 4H), 3.82 – 3.76 (m, 4H), 3.63 – 3.57 (m, 2H), 3.43 – 3.35 (m, 1H), 3.37 (s, 3H), 3.07 – 3.00 (m, 2H), 2.84 – 2.75 (m, 2H), 2.65 – 2.58 (m, 2H), 2.57 (d, J= 6.3 Hz, 3H), 2.09 – 1.94 (m, 4H). | 2 | |
40 | 672.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.39-8.37 (m, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.84 – 7.78 (m, 1H), 7.45 – 7.37 (m, 2H), 7.31 (s, 1H), 7.24 – 7.13 (m, 5H), 6.89 – 6.81 (m, 1H), 6.74 – 6.68 (m, 2H), 5.35 (s, 2H), 5.17 – 5.07 (m, 1H), 4.36 (t, J = 4.4 Hz, 2H), 3.83 – 3.76 (m, 4H), 3.34 (s, 3H), 3.03 – 3.01 (m, 1H), 2.84 – 2.76 (m, 2H), 2.66 – 2.58 (m, 2H), 2.09 – 1.94 (m, 4H), 1.52 (s, 3H). | 2 | |
41 | 714.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.12 (s, 1H), 7.95 – 7.88 (m, 1H), 7.83 – 7.75(m, 1H), 7.46 – 7.39 (m, 3H), 7.29 – 7.13 (m, 8H), 6.86 – 6.78 (m, 1H), 5.35 (s, 2H), 4.33 (t, J = 4.4 Hz, 2H), 3.83 – 3.75 (m, 4H), 3.59 – 3.49 (m, 3H), 3.36 (s, 3H), 3.03 – 3.01 (m, 1H), 2.90 – 2.87 (m, 2H), 2.75 – 2.65 (m, 2H), 2.68 – 2.60 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
42 | 702.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.55 (s, 1H), 8.38 (t, J= 5.9 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.85 – 7.77(m, 1H), 7.54 – 7.47 (m, 2H), 7.42 – 7.34 (m, 3H), 7.22 – 7.15 (m, 3H), 6.86 (d, J= 9.3 Hz, 1H), 6.86 – 6.74 (m, 1H), 5.35 (s, 2H), 4.93 (d, J= 6.0 Hz, 2H), 4.38-4.36 (m, 2H), 3.82 – 3.75 (m, 4H), 3.35 (s, 3H), 3.03 – 3.01 (m, 1H), 2.85 – 2.76 (m, 2H), 2.63 – 2.58 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
43 | 698.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 7.99-7.96 (m, 1H), 7.79 – 7.73 (m, 1H), 7.67 (d, J= 7.5 Hz, 1H), 7.45 – 7.35 (m, 2H), 7.22 – 7.13 (m, 3H), 6.93 (d, J= 1.1 Hz, 1H), 6.84 – 6.74 (m, 1H), 6.52 (t, J= 1.0 Hz, 1H), 5.31-5.30 (m, 2H), 5.24 (s, 1H), 4.38 – 4.29 (m, 3H), 3.82 – 3.73 (m, 4H), 3.31 (s, 3H), 3.11 – 3.00 (m, 3H), 3.00 – 2.93 (m, 2H), 2.87 – 2.79 (m, 2H), 2.63 – 2.55 (m, 2H), 2.16 (s, 3H), 2.09 – 1.94 (m, 4H). | 2 | |
44 | 728.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.83 – 7.77(m, 1H), 7.50 – 7.42 (m, 3H), 7.39 – 7.32 (m, 1H), 7.15-7.01 (m, 2H), 6.85 – 6.74 (m, 1H), 5.35 (s, 2H), 4.94 – 4.89 (m, 1H), 4.49 – 4.43 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.79 – 3.76 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 3H), 3.67 – 3.55 (m, 1H), 3.03 – 3.01 (m, 1H), 2.90 – 2.87 (m, 2H), 2.65 – 2.55 (m, 2H), 2.53 – 2.47 (m, 1H), 2.33 – 2.18 (m, 3H), 2.09 – 1.94 (m, 4H). | 2 | |
45 | 735.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.81 – 7.70(m, 1H), 7.50 – 7.42 (m, 3H), 7.37 – 7.34(m, 1H), 7.15-7.01 (m, 2H), 6.86 – 6.72 (m, 1H), 5.35 (s, 2H), 4.94 – 4.89 (m, 1H), 4.49 – 4.43 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.79 – 3.76 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 3H), 3.67 – 3.55 (m, 1H), 3.03 – 3.01 (m, 1H), 2.83 – 2.74 (m, 2H), 2.65 – 2.56 (m, 2H), 2.53 – 2.47 (m, 1H), 2.33 – 2.18 (m, 3H), 2.09 – 1.94 (m, 4H). | 2 | |
46 | 735.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.20-8.17 (m, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.82 – 7.78(m, 1H), 7.50 – 7.42 (m, 3H), 7.39 – 7.32 (m, 1H), 7.15-7.01 (m, 2H), 6.88 – 6.76 (m, 1H), 5.35 (s, 2H), 4.94 – 4.89 (m, 1H), 4.49 – 4.43 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.79 – 3.76 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 3H), 3.67 – 3.55 (m, 1H), 3.03 – 3.01 (m, 1H), 2.85 – 2.74 (m, 2H), 2.65 – 2.57 (m, 2H), 2.53 – 2.47 (m, 1H), 2.33 – 2.18 (m, 3H), 2.08 – 1.94 (m, 4H). | 2 | |
47 | 740.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.83 – 7.80(m, 1H), 7.50 – 7.42 (m, 3H), 7.39 – 7.32 (m, 1H), 7.15-7.01 (m, 2H), 6.86 – 6.78 (m, 1H), 5.35 (s, 2H), 4.94 – 4.89 (m, 1H), 4.49 – 4.43 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.79 – 3.76 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 3H), 3.67 – 3.55 (m, 1H), 3.25 (s, 3H), 3.03 – 3.01 (m, 1H), 2.85 – 2.72 (m, 2H), 2.65 – 2.58 (m, 2H), 2.53 – 2.47 (m, 1H), 2.33 – 2.18 (m, 3H), 2.09 – 1.94 (m, 4H). | 2 | |
48 | 720.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.14 (t, J= 5.9 Hz, 1H), 8.02 (d, J= 2.4 Hz, 1H), 7.70-7.59 (m, 2H), 7.51 -7.47 (m, 2H), 7.34 (s, 1H), 7.18 – 7.15 (m, 1H), 6.83-6.81 (m, 1H), 5.32 (s, 2H), 4.95 - 4.80 (m, 3H), 4.44 –4.38 (m, 2H), 4.32-4.30 (m, 1H), 4.19-4.16 (m, 1H), 4.01 – 3.82 (m, 6H), 3.72 (s, 2H), 3.01-2.78 (m, 3H), 2.69-2.61 (m, 2H), 2.42– 2.31 (m, 3H), 2.01 – 1.90 (m, 6H). | 2 | |
49 | 709.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.24-8.21 (m, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.90 (d, J= 9.3 Hz, 1H), 7.81 – 7.75(m, 1H), 7.48 – 7.40 (m, 2H), 7.35 (d, J= 8.8 Hz, 1H), 7.21 – 7.12 (m, 4H), 6.86 – 6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.39 – 4.30 (m, 2H), 4.24 – 4.13 (m, 2H), 4.01 (t, J= 5.6 Hz, 1H), 3.92 – 3.88 (m, 1H), 3.90 – 3.78 (m, 2H), 3.80 – 3.75 (m, 1H), 3.71 (s, 2H), 3.70 – 3.62 (m, 1H), 3.03 – 3.01 (m, 1H), 2.84 – 2.74 (m, 2H), 2.64 – 2.56 (m, 2H), 2.36 – 2.31 (m, 1H), 2.09 – 1.94 (m, 5H). | 2 | |
50 | 622.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.24 (t, J= 6.7 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.82 – 7.74(m, 1H), 7.46 – 7.32 (m, 3H), 7.21 – 7.13 (m, 3H), 6.86 – 6.78 (m, 1H), 5.35 (s, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.90 (s, 1H), 3.87 – 3.85 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.83– 2.74 (m, 2H), 2.64 – 2.54 (m, 2H), 2.36 – 2.31 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
51 | 728.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.49-8.46 (m, 1H), 7.99-7.96 (m, 1H), 7.81 – 7.77(m, 1H), 7.42 – 7.33 (m, 3H), 7.21 – 7.12 (m, 3H), 6.98 – 6.92 (m, 2H), 6.82 – 6.71 (m, 3H), 6.14 (s, 1H), 5.31-5.30 (m, 2H), 4.59 – 4.50 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.91 – 3.83 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 2H), 3.08 – 3.03 (m, 1H), 3.06 – 2.99 (m, 2H), 2.83– 2.73 (m, 2H), 2.65 – 2.54 (m, 2H), 2.36 – 2.31 (m, 1H), 2.09 – 1.94 (m, 5H). | 2 | |
52 | 679.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.71 (d, J= 9.2 Hz, 1H), 7.99-7.96 (m, 1H), 7.83 – 7.80(m, 1H), 7.42 – 7.33 (m, 3H), 7.21 – 7.12 (m, 4H), 6.85 – 6.78 (m, 1H), 5.35 (s, 2H), 4.69 – 4.60 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.91 – 3.83 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.83 – 2.73 (m, 3H), 2.73 – 2.63 (m, 2H), 2.69 – 2.65 (m, 1H), 2.36 – 2.31 (m, 1H), 2.09 – 1.94 (m, 5H). | 2 | |
53 | 702.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.82 (d, J= 8.8 Hz, 1H), 7.99-7.96 (m, 1H), 7.82 – 7.77(m, 1H), 7.42 – 7.38 (m, 2H), 7.40 – 7.33 (m, 2H), 7.21 – 7.11 (m, 3H), 6.86 – 6.78 (m, 1H), 6.58 (d, J= 1.8 Hz, 1H), 5.27 (d, J = 1.2 Hz, 2H), 4.72 – 4.63 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.91 – 3.83 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 2H), 3.12 – 2.95 (m, 3H), 2.84– 2.73 (m, 2H), 2.65 – 2.55 (m, 2H), 2.36 – 2.31 (m, 1H), 2.11 – 1.95 (m, 5H). | 2 | |
54 | 719.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23(t, J= 5.6 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.83 – 7.76(m, 1H), 7.42 – 7.32 (m, 3H), 7.22 – 7.11 (m, 3H), 6.86 – 6.76 (m, 1H), 5.31-5.30 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 – 3.61 (m, 3H), 3.63 – 3.54 (m, 2H), 3.49 – 3.40 (m, 1H), 3.03 – 3.01 (m, 1H), 2.86 – 2.82 (m, 1H), 2.84– 2.74 (m, 2H), 2.63 – 2.55 (m, 2H), 2.30 – 2.22 (m, 2H), 2.15 – 1.85 (m, 6H). | 2 | |
55 | 759.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.35-8.31 (m, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.81 – 7.74(m, 1H), 7.42 – 7.32 (m, 3H), 7.22 – 7.12 (m, 3H), 6.80 – 6.77 (m, 1H), 5.26 (d, J= 1.2 Hz, 2H), 4.51 – 4.46 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.85– 2.74 (m, 2H), 2.63 – 2.55 (m, 2H), 2.30 – 2.22 (m, 2H), 2.16 – 2.11 (m, 1H), 2.09 – 1.94 (m, 4H), 1.90 –1.79 (m, 2H), 1.51 – 1.48 (m, 1H), 1.35 (s, 3H), 1.01 (s, 3H). | 2 | |
56 | 725.7 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23(t, J= 5.6 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.82 – 7.73(m, 1H), 7.42 – 7.32 (m, 3H), 7.25 – 7.14 (m, 3H), 6.84 – 6.78 (m, 1H), 5.31-5.30 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 – 3.61 (m, 3H), 3.63 – 3.54 (m, 2H), 3.49 – 3.40 (m, 1H), 3.03 – 3.01 (m, 1H), 2.86 – 2.82 (m, 1H), 2.85– 2.73 (m, 2H), 2.66 – 2.55 (m, 2H), 2.30 – 2.22 (m, 2H), 2.15 – 1.85 (m, 6H). | 2 | |
57 | 749.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.04-8.02 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.80 – 7.73(m, 1H), 7.42 – 7.32 (m, 3H), 7.22 – 7.18 (m, 3H), 6.83 – 6.77 (m, 1H), 5.31-5.30 (m, 2H), 4.63 – 4.58 (m, 1H), 4.51 – 4.40 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.51 – 3.48 (m, 2H), 3.35 (d, J= 5.5 Hz, 1H), 3.03 – 3.01 (m, 1H), 2.83– 2.73 (m, 2H), 2.66 – 2.58 (m, 2H), 2.49 – 2.46 (m, 1H), 2.30 – 2.13 (m, 3H), 2.09 – 1.94 (m, 4H), 1.37 (d, J= 6.2 Hz, 3H). | 2 | |
58 | 747.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.80 – 7.77(m, 1H), 7.42 – 7.33 (m, 3H),7.22 – 7.15 (m, 3H), 6.80 – 6.77 (m, 1H), 5.28 (d, J= 1.2 Hz, 2H), 4.43 – 4.39 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.01 – 3.91 (m, 2H), 3.88 – 3.81 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.55-3.51 (m, 1H), 3.39 (d, J= 12.4 Hz, 1H), 3.03 – 3.01 (m, 1H), 2.83– 2.74 (m, 2H), 2.66 – 2.59 (m, 2H), 2.30 – 2.22 (m, 2H), 2.15 – 2.09 (m, 1H), 2.09 – 1.94 (m, 4H), 1.87 – 1.81 (m, 1H), 1.04 (s, 3H), 0.99 (s, 3H). | 2 | |
59 | 745.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.42 (t, J= 6.1 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.80 – 7.74(m, 1H), 7.42 – 7.33 (m, 3H),7.22 – 7.13 (m, 3H), 6.84 – 6.74 (m, 1H), 5.35 (s, 2H), 4.39 – 4.32 (m, 2H), 4.32 – 4.23 (m, 2H), 4.23 – 4.15(m, 1H), 4.05 – 3.97 (m, 1H), 3.96 – 3.92 (m, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.83– 2.75 (m, 2H), 2.66 – 2.57 (m, 2H), 2.46 – 2.38 (m, 1H), 2.30 – 2.22 (m, 2H), 2.09 – 1.86 (m, 7H), 1.85 – 1.71 (m, 3H). | 2 | |
60 | 719.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23(t, J= 5.6 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.81 – 7.74(m, 1H), 7.42 – 7.35 (m, 3H),7.25 – 7.13 (m, 3H), 6.83 – 6.74 (m, 1H), 5.31-5.30 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 – 3.61 (m, 3H), 3.63 – 3.54 (m, 2H), 3.49 – 3.40 (m, 1H), 3.03 – 3.01 (m, 1H), 2.86 – 2.82 (m, 1H), 2.83– 2.73 (m, 2H), 2.65 – 2.57 (m, 2H), 2.35 – 2.23 (m, 2H), 2.15 – 1.95 (m, 6H). | 2 | |
61 | 705.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.83 – 7.75(m, 1H), 7.42 – 7.38 (m, 3H), 7.21 – 7.12 (m, 3H), 6.83 – 6.76 (m, 1H), 5.31-5.30 (m, 2H), 4.51 – 4.45 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.03 – 3.89 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.66 (m, 2H), 3.71 (s, 2H), 3.63 – 3.53 (m, 1H), 3.03 – 3.01 (m, 1H), 2.84– 2.73 (m, 2H), 2.65 – 2.57 (m, 2H), 2.38 – 2.28 (m, 1H), 2.31 – 2.23 (m, 1H), 2.26 – 2.19 (m, 1H), 2.20– 2.14 (m, 1H), 2.09 – 1.94 (m, 4H). | 2 | |
62 | 755.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.81 – 7.75(m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.36 – 7.32 (m, 1H), 7.21 – 7.12 (m, 3H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.62 – 4.56 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.04 – 3.96 (m, 1H), 3.98 – 3.83 (m, 3H), 3.86 – 3.81 (m, 1H), 3.83 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.84– 2.75 (m, 2H), 2.74 – 2.52 (m, 4H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
63 | 749.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.83 – 7.80(m, 1H), 7.45 – 7.41 (m, 3H),7.25 – 7.17 (m, 3H), 6.81 – 6.74 (m, 1H), 5.31-5.30 (m, 2H), 4.49 – 4.43 (m, 1H), 4.39 – 4.32 (m, 1H), 4.32 – 4.24 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.73 – 3.58 (m, 8H), 3.03 – 3.01 (m, 1H), 2.84– 2.77 (m, 2H), 2.65 – 2.58 (m, 2H), 2.36 – 2.17 (m, 3H), 2.09 – 1.94 (m, 5H). | 2 | |
64 | 769.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.82 – 7.78(m, 1H), 7.47 – 7.36 (m, 3H),7.25 – 7.18 (m, 3H), 6.80 – 6.73 (m, 1H), 5.31-5.30 (m, 2H), 4.49 – 4.43 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.73 – 3.58 (m, 7H), 3.03 – 3.01 (m, 1H), 2.85– 2.77 (m, 2H), 2.65 – 2.59 (m, 2H), 2.36 – 2.17 (m, 3H), 2.09 – 1.94 (m, 5H). | 2 | |
65 | 749.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.04-8.02 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.83 – 7.80(m, 1H), 7.47 – 7.34 (m, 3H),7.25 – 7.18 (m, 3H), 6.83 – 6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.63 – 4.58 (m, 1H), 4.51 – 4.40 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.51 – 3.48 (m, 2H), 3.35 (d, J= 5.5 Hz, 1H), 3.03 – 3.01 (m, 1H), 2.85– 2.74 (m, 2H), 2.65 – 2.55 (m, 2H), 2.49 – 2.46 (m, 1H), 2.30 – 2.13 (m, 3H), 2.09 – 1.94 (m, 4H), 1.37 (d, J= 6.2 Hz, 3H). | 2 | |
66 | 769.2 | H NMR (500 MHz,三氯甲烷- d) δ 8.04-8.02 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.81 – 7.75(m, 1H), 7.45 – 7.34 3(m, 3H),7.24 – 7.16 (m, 3H), 6.83 – 6.77 (m, 1H), 5.31-5.30 (m, 2H), 4.63 – 4.58 (m, 1H), 4.51 – 4.40 (m, 2H), 4.39 – 4.30 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.51 – 3.48 (m, 2H), 3.03 – 3.01 (m, 1H), 2.86– 2.76 (m, 2H), 2.65 – 2.56 (m, 2H), 2.49 – 2.46 (m, 1H), 2.30 – 2.13 (m, 3H), 2.09 – 1.94 (m, 4H), 1.37 (d, J= 6.2 Hz, 3H). | 2 | |
67 | 707.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.16 (t, J= 5.6 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.82 – 7.78(m, 1H), 7.36 – 7.32 (m, 3H), 7.24 – 7.17 (m, 3H), 6.80 – 6.77 (m, 1H), 5.31-5.30 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.12 – 4.03 (m, 2H), 4.01 – 3.96 (m, 1H), 3.94 – 3.81 (m, 2H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.57 – 3.48 (m, 4H), 3.45 – 3.38 (m, 2H), 3.03 – 3.01 (m, 1H), 2.86– 2.75 (m, 2H), 2.67 – 2.56 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
68 | 783.3 | H NMR (500 MHz,三氯甲烷- d) δ 8.04-8.02 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.82 – 7.76(m, 1H), 7.45 – 7.35 (m, 3H),7.24 – 7.15 (m, 3H), 6.82 – 6.80 (m, 1H), 5.31-5.30 (m, 2H), 4.63 – 4.58 (m, 1H), 4.51 – 4.40 (m, 2H), 4.39 – 4.30 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.51 – 3.48 (m, 2H), 3.25 (s, 3H),3.07 – 2.99 (m, 1H), 2.86– 2.77 (m, 2H), 2.67 – 2.57 (m, 2H), 2.49 – 2.46 (m, 1H), 2.30 – 2.13 (m, 3H), 2.09 – 1.94 (m, 4H), 1.37 (d, J= 6.2 Hz, 3H). | 2 | |
69 | 767.3 | H NMR (500 MHz,三氯甲烷- d) δ 8.04-8.02 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.83 – 7.80(m, 1H), 7.45 – 7.34 (m, 3H),7.22 – 7.15 (m, 3H), 6.87 – 6.79 (m, 1H), 5.31-5.30 (m, 2H), 4.63 – 4.58 (m, 1H), 4.51 – 4.40 (m, 2H), 4.39 – 4.32 (m, 1H), 4.32 – 4.24 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.51 – 3.48 (m, 2H), 3.25 (s, 3H),3.07 – 2.99 (m, 1H), 2.86– 2.78(m, 2H), 2.67 – 2.58 (m, 2H), 2.49 – 2.46 (m, 1H), 2.30 – 2.13 (m, 3H), 2.09 – 1.94 (m, 4H). | 2 | |
70 | 691.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23(t, J= 5.6 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.80 – 7.77(m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.22 – 7.17 (m, 3H), 6.86 – 6.79 (m, 1H), 5.31-5.30 (m, 2H), 4.40 – 4.32 (m, 2H), 4.32 – 4.24 (m, 1H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.64 – 3.50 (m, 3H), 3.41 (d, J= 5.5 Hz, 1H), 3.36 – 3.27 (m, 1H), 3.03 – 3.01 (m, 1H), 2.86– 2.76 (m, 2H), 2.67 – 2.59 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 5H), 1.86 – 1.77 (m, 1H). | 2 | |
71 | 781.3 | H NMR (500 MHz,三氯甲烷- d) δ 8.04-8.02 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.80 – 7.74(m, 1H), 7.42 – 7.34 (m, 3H),7.25 – 7.17 (m, 3H), 6.86 – 6.78 (m, 1H), 5.31-5.30 (m, 2H), 4.63 – 4.58 (m, 1H), 4.51 – 4.40 (m, 2H), 4.39 – 4.30 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.70 (s, 2H), 3.51 – 3.48 (m, 2H), 3.25 (s, 3H),3.07 – 2.99 (m, 1H), 2.85– 2.76 (m, 2H), 2.66 – 2.59 (m, 2H), 2.49 – 2.46 (m, 1H), 2.30 – 2.13 (m, 3H), 2.09 – 1.94 (m, 4H), 1.37 (d, J= 6.2 Hz, 3H). | 3 | |
72 | 753.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.22-8.19 (m, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.83 – 7.78(m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.33 (m, 2H), 7.21 – 7.12 (m, 3H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.62 – 4.56 (m, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 4.04 – 3.96 (m, 1H), 3.98 – 3.83 (m, 3H), 3.86 – 3.81 (m, 1H), 3.83 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.85– 2.75 (m, 2H), 2.74 – 2.52 (m, 4H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 3 | |
73 | 767.3 | H NMR (500 MHz,三氯甲烷- d) δ 8.04-8.02 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.83 – 7.77(m, 1H), 7.42 – 7.34 (m, 3H),7.27 – 7.18 (m, 3H), 6.83 – 6.73 (m, 1H), 5.31-5.30 (m, 2H), 4.63 – 4.58 (m, 1H), 4.51 – 4.40 (m, 2H), 4.39 – 4.30 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.51 – 3.48 (m, 2H), 3.03 – 3.01 (m, 1H), 2.85– 2.76 (m, 2H), 2.66 – 2.57 (m, 2H), 2.49 – 2.46 (m, 1H), 2.30 – 2.13 (m, 3H), 2.09 – 1.94 (m, 4H), 1.37 (d, J= 6.2 Hz, 3H). | 3 | |
74 | 790.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 7.99-7.96 (m, 1H), 7.95 (d, J= 8.4 Hz, 1H), 7.83 – 7.76(m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.21 – 7.12 (m, 3H), 6.81 – 6.71 (m, 1H), 5.28 (d, J = 1.2 Hz, 2H), 4.62 – 4.53 (m, 1H), 4.46 (t, J= 5.8 Hz, 1H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.91 – 3.83 (m, 1H), 3.78 – 3.71 (m, 1H), 3.68 (d, J= 3.8 Hz, 5H), 3.63 – 3.51 (m, 2H), 3.38 – 3.29 (m, 1H), 3.03 – 3.01 (m, 1H), 2.86– 2.76 (m, 2H), 2.68 – 2.57 (m, 2H), 2.36 – 2.31 (m, 2H), 2.25 (s, 6H), 2.14 – 1.94 (m, 6H), 1.37 (d, J= 6.2 Hz, 3H). | 2 | |
75 | 644.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.91 (s, 1H), 8.41 (s, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.86 – 7.81 (m, 1H), 7.49 – 7.37 (m, 2H), 7.33 – 7.28 (m, 2H), 7.25 – 7.13 (m, 3H), 6.82 – 6.72 (m, 1H), 6.79 – 6.73 (m, 2H), 5.31-5.30 (m, 2H), 4.41-4.38 (m, 2H), 3.80 – 3.73 (m, 4H), 3.32 (s, 3H), 3.03 – 3.01 (m, 1H), 2.86– 2.78 (m, 2H), 2.68 – 2.59 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
76 | 710.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.92 (t, J= 6.3 Hz, 1H), 8.08 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.80 – 7.76(m, 1H), 7.45 – 7.41 (m, 4H), 7.24 – 7.17 (m, 4H), 6.83 – 6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.56 (d, J= 6.3 Hz, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.87– 2.78 (m, 2H), 2.68 – 2.58 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
77 | 691.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23(t, J= 5.6 Hz, 1H), 8.08 (d, J= 2.4 Hz, 1H), 7.82 – 7.78(m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.34 (m, 2H), 7.21 – 7.13 (m, 3H), 6.85 – 6.77 (m, 1H), 5.31-5.30 (m, 2H), 4.40 – 4.32 (m, 2H), 4.32 – 4.24 (m, 1H), 4.23 – 4.15(m, 1H), 4.06 – 3.93 (m, 2H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.64 – 3.50 (m, 3H), 3.41 (d, J= 5.5 Hz, 1H), 3.36 – 3.27 (m, 1H), 3.03 – 3.01 (m, 1H), 2.87– 2.76 (m, 2H), 2.66 – 2.58 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 5H), 1.86 – 1.77 (m, 1H). | 2 | |
78 | 682.1 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.02 (s, 1H), 8.39 (s, 1H), 8.13 (d, J= 2.1 Hz, 1H), 7.82 – 7.80 (m, 1H), 7.48 – 7.37 (m, 3H), 7.21 – 7.11 (m, 3H), 6.86 – 6.79 (m, 1H), 6.48 (d, J= 8.1 Hz, 1H), 6.40 (d, J= 7.9 Hz, 1H), 5.31-5.30 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.91 – 3.83 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.85– 2.76 (m, 2H), 2.66 – 2.59 (m, 2H), 2.36 – 2.31 (m, 1H), 2.09 – 1.94 (m, 5H). | 2 | |
79 | 695.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.74 (d, J= 1.6 Hz, 1H), 8.67 (d, J= 2.0Hz, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.86 – 7.81 (m, 1H), 7.49 – 7.39 (m, 2H), 7.21 – 7.14 (m, 3H), 6.86 – 6.74 (m, 1H), 5.28 (d, J = 1.2 Hz, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.94 (s, 3H), 2.85– 2.75 (m, 2H), 2.65 – 2.59 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.95 (m, 4H). | 2 | |
80 | 694.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.05 (d, J= 2.4 Hz, 1H), 7.86 – 7.80 (m, 2H), 7.52 (d, J= 2.1 Hz, 1H), 7.45 – 7.39 (m, 2H), 7.21 – 7.12 (m, 3H), 6.83 – 6.73 (m, 1H), 5.31-5.30 (m, 2H), 4.39 – 4.30 (m, 2H), 4.23 – 4.15(m, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.85– 2.76 (m, 2H), 2.68 (s, 3H), 2.65 – 2.60 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
81 | 710.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.66 (s, 1H), 10.49 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.12 (d, J= 2.1 Hz, 1H), 7.96-7.92 (m, 1H), 7.70 – 7.62 (m, 2H), 7.53 – 7.47 (m, 2H), 7.30 – 7.17(m, 3H) , 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.33 – 4.28 (m, 2H), 4.13 (s, 3H), 4.06-4.01 (m, 1H), 3.87 – 3.79 (m, 1H), 3.78 – 3.74 (m, 1H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
82 | 705.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.21 (d, J= 2.1 Hz, 1H), 8.05 (d, J= 2.4 Hz, 1H), 7.83 (dd, J= 8.7, 2.1 Hz, 1H), 7.70-7.67 (m, 1H), 7.60 (d, J= 7.9 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.21 – 7.13 (m, 3H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.35-4.17 (m, 3H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.83 – 2.74 (m, 2H), 2.69 – 2.60 (m, 2H), 2.30 – 2.22 (m, 2H), 2.09 – 1.94 (m, 4H). | 2 | |
83 | 722.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.76 (s, 1H), 10.09 (s, 1H), 8.04 (dd, J= 10.5, 2.1 Hz, 2H), 7.83 – 7.54 (m, 3H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.21 – 7.13 (m, 3H), 6.81-6.75 (m, 1H), 5.29 (d, J= 1.2 Hz, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.24 (m, 1H), 4.17 (dd, J= 15.6, 5.3 Hz, 1H), 3.89 – 3.84 (m, 1H), 3.80 – 3.73 (m, 1H), 3.71 (s, 2H), 3.11 – 3.03 (m, 1H), 3.06 – 2.60 (m, 5H), 2.32 –1.92 (m, 6H), 1.66 (d, J= 6.6 Hz, 3H), 1.60 (s, 1H). | 2 | |
84 | 708.2 | 1H NMR (500 MHz, DMSO- d 6) δ 11.78 (s, 1H), 10.88 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.14 (s, 1H), 7.96-7.92 (m, 1H), 7.76 (d, J= 2.1 Hz, 1H), 7.62 (dd, J= 7.8, 2.0 Hz, 1H), 7.53 – 7.51 (m, 1H), 7.46 – 7.40 (m, 3H), 7.30 – 7.17(m, 3H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.43 – 4.04 (m, 3H), 3.87 – 3.79 (m, 1H), 3.78 – 3.74 (m, 1H), 3.69 (s, 2H), 3.11 –2.78 (m, 5H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
85 | 696.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.33 (s, 1H), 10.12 (s, 1H), 10.32 (s, 1H), 8.27 (d, J= 2.0 Hz, 1H), 7.90 (d, J= 2.4 Hz, 1H), 7.79-7.77 (m, 1H), 7.55 – 7.44 (m, 4H), 7.42 – 7.36 (m, 1H), 7.21 – 7.13 (m, 3H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.02 (m, 2H), 3.89 –3.73 (m, 2H), 3.69 (s, 2H), 3.03 – 3.01 (m, 1H), 2.83 –2.60 (m, 4H), 2.30 – 2.22 (m, 2H), 2.03 – 1.94 (m, 4H). | 2 | |
86 | 721.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.64 (s, 1H), 10.54 (s, 1H), 9.09 (s, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.83 (dd, J= 8.7, 2.1 Hz, 1H), 7.68 (d, J= 1.8 Hz, 1H), 7.60 (dd, J= 7.8, 2.1 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.21 – 7.13 (m, 3H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.17 (m, 2H), 3.89 –3.73 (m, 2H), 3.71 (s, 2H), 3.07 – 2.74 (m, 3H), 2.69 – 2.60 (m, 2H), 2.32 –2.11 (m, 4H), 2.09 – 1.94 (m, 4H), 1.70 – 1.65 (m, 2H). | 2 | |
87 | 680.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.21 (d, J= 1.8 Hz, 2H), 8.04 (t, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.69-7.67 (m, 1H), 7.55 – 7.40 (m, 4H), 7.30 – 7.17(m, 3H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.46 – 4.21 (m, 2H), 4.06-4.01 (m, 1H), 3.90 – 3.68 (m, 4H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.33 –1.92 (m, 6H). | 2 | |
88 | 694.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.32 (s, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.88 (d, J= 2.2 Hz, 1H), 7.83 (dd, J= 8.7, 2.1 Hz, 1H), 7.65 (dd, J= 7.8, 2.1 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.44 – 7.36 (m, 2H), 7.21 – 7.13 (m, 3H), 6.81-6.75 (m, 1H), 5.29 (d, J= 1.2 Hz, 2H), 4.35– 4.24 (m, 2H), 4.17 – 3.70 (m, 3H), 3.71 (s, 2H), 3.03 – 3.01 (m, 1H), 2.90 (s, 2H), 2.83– 2.60 (m, 4H), 2.39– 1.94 (m, 6H). | 2 | |
89 | 682.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.2 2 (s, 1H), 8.95 (s, 1H), 8.41 (d, J= 8.1 Hz, 1H), 8.05 (d, J= 2.2 Hz, 1H), 7.85 (dd, J= 8.7, 2.1 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.19 (dd, J= 8.0, 2.2 Hz, 1H), 7.18 – 7.13 (m, 2H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.33 – 4.19 (m, 3H), 3.91 – 3.83 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 2H), 3.07–2.60 (m, 5H), 2.39 –1.92 (m, 6H). | 2 | |
90 | 696.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.39 (s, 1H), 8.05 (d, J= 2.0 Hz, 1H), 7.83 (dd, J= 8.7, 2.1 Hz, 1H), 7.58 (dd, J= 8.1, 1.8 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.34 (d, J= 2.0 Hz, 1H), 7.21 – 7.13 (m, 3H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.35 – 4.17 (m, 3H), 3.91 – 3.83 (m, 1H), 3.78 – 3.74 (m, 1H), 3.71 (s, 1H), 3.07 –2.60 (m, 5H), 2.39 – 1.94 (m, 6H). | 2 | |
91 | 710.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.11 (s, 1H), 9.46 (s, 1H), 8.07 – 8.03 (m, 1H), 7.83 (dd, J= 8.7, 2.1 Hz, 1H), 7.59 (dd, J= 8.2, 2.1 Hz, 1H), 7.49 (t, J= 7.9 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.32 (d, J= 2.1 Hz, 1H), 7.27 (d, J= 8.0 Hz, 1H), 7.20-7.17 (m, 1H), 7.18 – 7.13 (m, 2H), 6.79 (dd, J= 7.8, 1.1 Hz, 1H), 5.31-5.30 (m, 2H), 4.35 – 4.17(m, 3H), 3.91– 3.70 (m, 2H), 3.71 (s, 2H), 3.46 (s, 2H), 3.07 – 2.99– 2.60 (m, 5H), 2.39 –1.92 (m, 6H). | 2 | |
92 | 714.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.73 (s, 1H), 10.64 (s, 1H), 10.15 (s, 1H), 8.45 (d, J= 5.0 Hz, 1H), 8.23 (d, J= 1.8 Hz, 1H), 7.93 (dd, J= 8.7, 1.8 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.50– 7.40 (m, 3H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35 (dd, J= 15.5, 5.3 Hz, 1H), 4.30 – 3.92 (m, 3H), 3.75 – 3.69(m, 1H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.33 – 1.90 (m, 7H). | 2 | |
93 | 697.2 | 1H NMR (500 MHz, DMSO- d 6) δ 11.15 (s, 1H), 10.96 (s, 1H), 10.74 (s, 1H), 8.23 – 8.16 (m, 1H), 7.93 (dd, J= 8.8, 2.1 Hz, 1H), 7.54 (d, J= 7.9 Hz, 1H), 7.50– 7.40 (m, 3H), 7.35 – 7.28 (m, 2H), 7.21 (dd, J= 7.9, 2.2 Hz, 1H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35– 3.73 (m, 5H), 3.69 (s, 2H), 3.11 –2.78 (m, 5H), 2.30 – 1.90 (m, 7H). | 2 | |
94 | 694.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.53 (s, 1H), 8.23 (d, J= 1.8 Hz, 1H), 8.08 (d, J= 1.8 Hz, 1H), 7.98 (d, J= 8.7 Hz, 1H), 7.97-7.94 (m, 1H), 7.55 (dd, J= 8.6, 2.1 Hz, 1H), 7.50– 7.40 (m, 3H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35– 4.26 (m, 2H), 4.04 – 3.67 (m, 3H), 3.69 (s, 2H), 3.11 –2.78 (m, 5H), 2.34–1.90 (m, 6H). | 2 | |
95 | 711.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.11 (s, 1H), 8.46 – 8.42 (m, 1H), 8.23 (d, J= 1.8 Hz, 1H), 7.97-7.94 (m, 1H), 7.83 – 7.80 (m, 1H), 7.75-7.74 (m, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.26 (m, 2H), 4.04 – 3.67 (m, 3H), 3.69 (s, 2H), 3.11 – 2.82 (m, 5H), 2.36 – 1.90 (m, 7H). | 2 | |
96 | 680.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.24 (s, 1H), 8.44 (d, J= 6.9 Hz, 1H), 8.28 – 8.23 (m, 1H), 8.23 (d, J= 1.8 Hz, 1H), 8.06 – 8.02 (m, 1H), 7.93 (dd, J= 8.7, 1.8 Hz, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.80 – 6.77 (m, 2H), 5.35-5.34 (m, 2H), 4.35 – 4.04 (m, 3H), 3.88 – 3.70 (m, 2H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.32 – 1.90 (m, 6H). | 2 | |
97 | 714.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.78 (s, 1H), 8.49 (d, J= 6.9 Hz, 1H), 8.21-8.19 (m, 2H), 8.04 (s, 1H), 7.93 (dd, J= 8.7, 1.8 Hz, 1H), 7.62-7.60 (m, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.41-4.37 (m, 1H), 4.25 – 4.18 (m, 1H), 4.04 (dd, J= 15.6, 3.9 Hz, 1H), 3.88 – 3.80 (m, 1H), 3.77 – 3.70 (m, 1H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.32 – 1.90 (m, 6H). | 2 | |
98 | 697.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.09 (s, 1H), 9.35 (s, 1H), 8.42 – 8.38 (m, 1H), 8.23 (d, J= 1.8 Hz, 1H), 7.97-7.94 (m, 1H), 7.81 – 7.76 (m, 1H), 7.71 (dd, J= 7.8, 2.1 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.26 (m, 2H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.11 –2.78 (m, 5H), 2.33 – 1.90 (m, 6H). | 2 | |
99 | 694.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.18 (s, 1H), 8.22 – 8.17 (m, 2H), 8.11-8.10 (m, 1H), 7.97-7.94 (m, 1H), 7.71 (dd, J= 7.8, 2.1 Hz, 1H), 7.65 (d, J= 7.6 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35– 4.26 (m, 2H), 4.09-4.02 (m, 1H), 3.92 (s, 3H), 3.87 – 3.74 (m, 2H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.30 – 1.90 (m, 6H). | 2 | |
100 | 708.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.13 (d, J= 1.8 Hz, 1H), 7.97-7.94 (m, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.53 – 7.45 (m, 2H), 7.49 – 7.40 (m, 2H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35– 4.26 (m, 2H), 4.09-4.02 (m, 1H), 3.90 – 3.82 (m, 1H), 3.75 – 3.69(m, 1H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.73 (s, 2H), 2.33 –1.92 (m, 6H). | 2 | |
101 | 704.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.19 (s, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.83-7.82 (m, 1H), 7.66 (d, J= 1.8 Hz, 1H), 7.61-7.58 (m, 1H), 7.49 (t, J= 7.7 Hz, 1H), 7.42 – 7.38 (m, 2H), 7.21 – 7.13 (m, 3H), 6.81-6.75 (m, 1H), 5.31-5.30 (m, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.17 (m, 2H), 3.89 –3.73 (m, 2H), 3.71 (s, 2H), 3.07 – 2.74 (m, 3H), 2.69 – 2.60 (m, 2H), 2.32 –2.11 (m, 4H), 2.09 – 1.94 (m, 4H), 1.70 – 1.65 (m, 2H). | 2 | |
102 | 698.2 | 1H NMR (500 MHz, DMSO- d 6) δ8.21 (dd, J= 12.0, 2.0 Hz, 2H), 7.92 (t, J= 2.0 Hz, 1H), 7.93 (dd, J= 8.7, 2.1 Hz, 1H), 7.65 (dd, J= 8.0, 2.1 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35– 4.04 (m, 3H), 3.87– 3.70 (m, 2H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.30– 1.90 (m, 6H). | 2 | |
103 | 712.1 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 1.8 Hz, 1H), 7.97-7.94 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.55 (dd, J= 8.0, 2.1 Hz, 1H), 7.53 – 7.40 (m, 3H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35– 4.26 (m, 2H), 4.04 – 3.67 (m, 3H), 3.69 (s, 2H), 3.11 – 2.82 (m, 5H), 2.36 – 1.90 (m, 7H). | 2 | |
104 | 739.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.17 (s, 1H), 9.97 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.93 (dd, J= 8.7, 2.1 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35– 4.26 (m, 2H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.30 – 2.18 (m, 2H), 2.21 – 1.90 (m, 6H), 1.73 – 1.66 (m, 1H), 1.69 – 1.62 (m, 1H). | 2 | |
105 | 735.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.01 (s, 1H), 9.93 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.93 (dd, J= 8.7, 2.1 Hz, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.26 (m, 2H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.11 –2.78 (m, 5H), 2.30 – 2.20 (m, 5H), 2.17 – 1.90 (m, 6H), 1.72 – 1.61 (m, 2H). | 2 | |
106 | 762.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 1.8 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.97-7.94 (m, 1H), 7.86 (d, J= 2.1 Hz, 1H), 7.50– 7.40 (m, 3H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.26 (m, 2H), 4.01– 3.77 (m, 3H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.36 – 1.90 (m, 6H). | 2 | |
107 | 789.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.02 (s, 1H), 9.94 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.11 (d, J= 2.1 Hz, 1H), 7.93 (dd, J= 8.7, 2.1 Hz, 1H), 7.62 (d, J= 2.1 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.7 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81-6.78 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.26 (m, 2H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.30 – 1.90 (m, 8H), 1.72 – 1.61 (m, 2H). | 2 | |
108 | 748.2 | 1H NMR (500 MHz, DMSO- d 6) δ8.19 (dd, J= 12.0, 2.1 Hz, 2H), 8.04 (d, J= 2.2 Hz, 1H), 7.99 (t, J= 2.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.8 Hz, 1H), 7.30 – 7.17(m, 3H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.28 (m, 1H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.30 – 1.90 (m, 6H). | 2 | |
109 | 708.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.11 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.97 – 7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.62 (dd, J= 8.4, 2.1 Hz, 1H), 7.56 – 7.40 (m, 4H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.04 (m, 3H), 3.90 (s, 3H), 3.87 – 3.74 (m, 2H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.30 – 1.90 (m, 6H). | 2 | |
110 | 728.2 | 1H NMR (500 MHz, DMSO- d 6) δ 11.30 (s, 1H), 10.68 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.87 – 7.82 (m, 2H), 7.53 – 7.40 (m, 3H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.42-4.38 (m, 1H), 4.34 – 4.04 (m, 2H), 3.90 – 3.70 (m, 2H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.38 – 2.33 (m, 1H), 2.09 – 1.90 (m, 6H). | 2 | |
111 | 748.2 | 1H NMR (500 MHz, DMSO- d 6) δ8.23 (d, J= 2.1 Hz, 1H), 8.12 (d, J= 2.2 Hz, 1H), 7.91-7.88 (m, 1H), 7.69-7.67 (m, 1H), 7.60 (d, J= 7.9 Hz, 1H), 7.53 – 7.40 (m, 3H), 7.30 – 7.17(m, 3H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.04 (m, 3H), 3.90 – 3.67 (m, 2H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.38 – 2.33 (m, 1H), 2.09 – 1.92 (m, 6H). | 2 | |
112 | 720.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.64 (s, 1H), 10.83 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.15 – 8.11 (m, 1H), 7.91-7.88 (m, 1H), 7.67 (dd, J= 7.8, 2.2 Hz, 1H), 7.58 (d, J= 7.9 Hz, 1H), 7.53 – 7.42 (m, 2H), 7.42 (d, J= 8.8 Hz, 1H), 7.30 – 7.17(m, 3H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.26 (m, 2H), 4.04 – 3.67 (m, 3H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.38 – 2.33 (m, 2H), 2.09 – 1.93 (m, 5H), 0.99 – 0.82 (m, 4H). | 2 | |
113 | 788.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.71 (s, 1H), 11.23 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.08 – 8.02 (m, 2H), 7.91-7.88 (m, 1H), 7.53 – 7.40 (m, 3H), 7.30 – 7.17(m, 3H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.35 – 4.04 (m, 2H), 3.90 – 3.71(m, 2H), 3.69 (s, 2H), 3.11 –2.78 (m, 5H), 2.36 – 1.90 (m, 7H), 0.96-0.81 (m, 4H). | 2 | |
114 | 734.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.53 (s, 1H), 11.00 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.90 (d, J= 2.2 Hz, 1H), 7.91-7.88 (m, 1H), 7.53 – 7.45 (m, 2H), 7.49 – 7.40 (m, 2H), 7.30 – 7.17(m, 3H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.28 (m, 1H), 4.06-4.01 (m, 1H), 3.90 – 3.82 (m, 1H), 3.75 – 3.69(m, 1H), 3.69 (s, 2H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.36 – 1.90 (m, 7H), 0.96-0.81 (m, 4H). | 2 | |
115 | 730.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23-8.18 (m, 2H), 7.91-7.88 (m, 1H), 7.68-7.66 (m, 1H), 7.62 – 7.59 (m, 1H), 7.52 – 7.40 (m, 3H), 7.29 – 7.26 (m, 2H), 1H), 7.19 – 7.15 (m, 1H), 7.01 (d, J= 57.1 Hz, 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.46 – 4.21 (m, 2H), 4.04 – 3.69 (m, 3H), 3.69 (s, 2H), 3.15 – 2.76 (m, 5H), 2.42 – 2.22 (m, 1H), 2.14 – 1.88 (m, 5H). | 2 | |
116 | 744.3 | 1H NMR (500 MHz, DMSO- d 6) δ 11.97 (s, 1H), 11.05 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.06 (d, J= 2.2 Hz, 1H), 7.91-7.88 (m, 1H), 7.54 – 7.37 (m, 4H), 7.32-7.31 (m, 1H), 7.25 – 7.14 (m, 2H), 7.05 – 6.83 (m, 2H), 5.35-5.34 (m, 2H), 4.41 – 4.26 (m, 2H), 4.04 – 3.82 (m, 2H), 3.75 – 3.69 (m, 1H), 3.69 (s, 2H), 3.16 – 2.77 (m, 5H), 2.41 – 2.26 (m, 1H), 2.09 – 1.87 (m, 5H). | 2 | |
117 | 722.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.78 (d, J= 2.2 Hz, 1H), 7.53 – 7.44 (m, 4H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.40 –3.82 (m, 2H), 3.76 – 3.68 (m, 3H), 3.11 – 2.99 (m, 3H), 2.87 – 2.69 (m, 4H), 2.33 –1.92 (m, 6H), 1.28 (t, J= 7.6 Hz, 3H). | 2 | |
118 | 734.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.43 (s, 1H), 10.90 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.83 (d, J= 2.2 Hz, 1H), 7.57 (d, J= 2.2 Hz, 1H), 7.53 – 7.40 (m, 3H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.38 – 4.27 (m, 2H), 4.04 – 3.68 (m, 5H), 3.51 – 3.48 (m, 1H), 3.11 – 2.78 (m, 5H), 2.38 – 2.33 (m, 1H), 2.09 – 1.90 (m, 5H), 1.13 – 0.99 (m, 4H). | 2 | |
119 | 744.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.95 (s, 1H), 10.87 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.86 (d, J= 2.0 Hz, 1H), 7.62 (dd, J= 2.2, 0.7 Hz, 2H), 7.53 – 7.40 (m, 3H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.40 – 4.26 (m, 2H), 4.04 – 3.73 (m, 3H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.33 –1.92 (m, 6H). | 2 | |
120 | 722.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.49 – 7.45(m, 1H), 7.46 – 7.39 (m, 2H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.28 (m, 1H), 4.04 – 3.67 (m, 3H), 3.69 (s, 2H), 3.11– 2.78 (m, 5H), 2.73 (s, 3H), 2.36 – 1.90 (m, 6H). | 2 | |
121 | 726.6 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.61 (d, J= 4.9 Hz, 1H), 7.53 – 7.40 (m, 3H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.39 – 4.24 (m, 2H), 4.04 – 3.82 (m, 2H), 3.77 – 3.69 (m, 1H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.74 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 1.90 (m, 5H). | 2 | |
122 | 712.1 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.77-7.75 (m, 1H), 7.53 – 7.51 (m, 1H), 7.46 – 7.44 (m, 1H), 7.43 (dd, J= 8.9, 5.2 Hz, 2H), 7.32 – 7.24 (m, 2H), 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.39 – 4.25 (m, 2H), 4.04 – 3.68 (m, 5H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.36 – 1.90 (m, 6H). | 2 | |
123 | 712.1 | 1H NMR (500 MHz, DMSO- d 6) δ 8.36 (d, J= 2.1 Hz, 1H), 8.01 (d, J= 5.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.53 – 7.40 (m, 3H), 7.36 – 7.28 (m, 2H), 7.25 – 7,19 (m, 2H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.39 – 4.23 (m, 2H), 4.04 – 3.69 (m, 3H), 3.69 (s, 2H), 3.11 –2.78 (m, 7H), 2.36 – 1.90 (m, 6H). | 2 | |
124 | 725.3 | 1H NMR (500 MHz, DMSO- d 6) δ 9.98 (s, 1H), 9.87 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.65 – 7.46 (m, 4H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.42 – 4.27 (m, 2H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.15 – 2.82 (m, 5H), 2.32 – 2.22 (m, 2H), 2.22 (s, 3H), 2.18 – 2.09 (m, 2H), 2.08 – 1.58 (m, 6H). | 2 | |
125 | 730.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.17 (s, 1H), 9.97 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.63 – 7.44 (m, 6H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.43 – 4.20 (m, 2H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.11– 2.78 (m, 5H), 2.23 – 1.90 (m, 8H), 1.75 – 1.58 (m, 2H). | 2 | |
126 | 703.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.63-7.61 (m, 1H), 7.55– 7.47 (m, 4H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.33 – 4.28 (m, 2H), 4.04 – 3.68 (m, 6H), 3.11 – 2.78 (m, 5H), 2.36 – 1.90 (m, 6H). | 2 | |
127 | 699.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.69 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.70 (d, J= 2.2 Hz, 1H), 7.63-7.61 (m, 1H), 7.56 – 7.52 (m, 1H), 7.50 – 7.45 (m, 3H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.33 – 4.28 (m, 2H), 4.04 – 3.68 (m, 6H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.73 (s, 3H), 2.46 (s, 3H), 2.33 –1.92 (m, 6H). | 2 | |
128 | 712.3 | 1H NMR (500 MHz, DMSO- d 6) δ 9.98 (s, 1H), 9.90 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.75 (d, J= 2.1 Hz, 1H), 7.61 – 7.44 (m, 5H), 7.42 (d, J= 8.8 Hz, 1H), 7.33 (d, J= 7.9 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.35 – 4.26 (m, 2H), 4.04 – 3.70 (m, 4H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.30 – 1.90 (m, 8H), 1.73 – 1.61 (m, 2H). | 2 | |
129 | 689.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.19 (dd, J= 11.9, 2.0 Hz, 2H), 7.94 – 7.86 (m, 2H), 7.65 (dd, J= 7.9, 2.1 Hz, 1H), 7.63-7.61 (m, 1H), 7.56 – 7.44 (m, 3H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.40 – 4.25 (m, 2H), 4.06-4.01 (m, 1H), 3.87 – 3.79 (m, 1H), 3.78 – 3.74 (m, 1H), 3.69 (s, 2H), 3.11 – 2.78 (m, 5H), 2.30 – 1.90 (m, 6H). | 2 | |
130 | 739.3 | 1H NMR (500 MHz, DMSO- d 6) δ 13.03 (s, 1H), 10.94 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.12 (d, J= 2.2 Hz, 1H), 7.91-7.88 (m, 1H), 7.69-7.67 (m, 1H), 7.63 – 7.59 (m, 2H), 7.56 – 7.47 (m, 3H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.38 – 4.26 (m, 2H), 4.04 – 3.82 (m, 2H), 3.76 – 3.68 (m, 3H), 3.11 – 2.78 (m, 5H), 2.31 – 1.90 (m, 6H). | 2 | |
131 | 718.3 | 1H NMR (500 MHz, DMSO- d 6) δ 9.68 (s, 1H), 9.57 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.65 – 7.46 (m, 4H), 7.42 (d, J= 8.8 Hz, 1H), 7.05 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.42 – 4.27 (m, 2H), 4.04 – 3.70 (m, 3H), 3.69 (s, 2H), 3.15 – 2.82 (m, 5H), 2.32 – 2.22 (m, 2H), 2.22 (s, 3H), 2.18 – 2.09 (m, 2H), 2.08 – 1.58 (m, 6H). | 2 | |
132 | 735.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.97 (s, 1H), 11.15 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.06 (d, J= 2.2 Hz, 1H), 7.91-7.88 (m, 1H), 7.63-7.61 (m, 1H), 7.56 – 7.40 (m, 5H), 7.21 – 7.14 (m, 1H), 6.76-6.75 (m, 1H), 5.35-5.34 (m, 2H), 4.33 – 4.28 (m, 2H), 4.04 – 3.68 (m, 6H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.38 – 2.33 (m, 1H), 2.09 – 1.90 (m, 5H). | 2 | |
133 | 685.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.69-7.67 (m, 1H), 7.63-7.61 (m, 1H), 7.56 – 7.44 (m, 4H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.33 – 4.28 (m, 2H), 4.04– 3.68 (m, 5H), 3.11 – 2.78 (m, 8H), 2.38 – 2.33 (m, 1H), 2.09 – 1.90 (m, 5H). | 2 | |
134 | 685.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.710 (s, 1H), 10.15 (s, 1H), 8.22 (dd, J= 14.1, 1.8 Hz, 2H), 7.91-7.88 (m, 1H), 7.84 (t, J= 2.0 Hz, 1H), 7.63-7.61 (m, 1H), 7.56 – 7.50 (m, 2H), 7.50 – 7.45 (m, 2H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.33 – 4.28 (m, 2H), 4.04 – 3.78 (m, 5H), 3.10 – 2.78 (m, 5H), 2.33 – 1.90 (m, 6H). | 2 | |
135 | 699.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.53 (s, 1H), 10.67 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.93 – 7.86 (m, 2H), 7.67 (dd, J= 7.8, 2.2 Hz, 1H), 7.63-7.61 (m, 1H), 7.56 – 7.44 (m, 4H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 – 6.97 (m, 2H), 5.35-5.34 (m, 2H), 4.33 – 4.28 (m, 2H), 4.04 – 3.68 (m, 5H), 3.11 – 2.99 (m, 3H), 2.87 – 2.76 (m, 4H), 2.38 – 2.33 (m, 1H), 2.09 – 1.90 (m, 5H), 1.33 (t, J= 7.6 Hz, 3H). | 2 | |
136 | 693.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.07 – 8.00 (m, 2H), 7.88 (d, J= 1.6 Hz, 1H), 7.65-7.64 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.33 – 4.29 (m, 2H), 4.25 – 4.21 (m, 1H), 4.03 –3.70 (m, 5H), 3.33-3.29 (m, 2H), 3.04 – 2.97 (m, 2H), 2.91 – 2.82 (m, 5H), 2.19 – 2.10 (m, 2H). | 3 | |
137 | 693.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.17 (d, J= 1.7 Hz, 1H), 8.08 – 7.99 (m, 2H), 7.84 (t, J= 2.4 Hz, 1H), 7.56 – 7.39 (m, 4H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.50 – 6.40 (m, 1H), 5.34-5.31 (m, 2H), 4.37 – 4.28 (m, 2H), 4.26 – 4.17 (m, 1H), 4.03 – 3.70 (m, 5H), 3.35 – 3.26 (m, 2H), 3.06 – 2.95 (m, 2H), 2.92 – 2.82 (m, 2H), 2.34 – 2.15 (m, 2H). | 3 | |
138 | 708.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.32 (s, 1H), 10.54 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.12 (s, 1H), 7.96-7.92 (m, 1H), 7.70 – 7.62 (m, 2H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.41 – 4.23 (m, 2H), 4.13 (s, 3H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.97 (m, 2H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H). | 3 | |
139 | 696.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.92 (s, 1H), 10.71 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.18 – 8.14 (m, 1H), 7.96-7.92 (m, 1H), 7.69 – 7.62 (m, 2H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.41 – 4.25 (m, 2H), 4.04 – 3.70 (m, 5H), 3.31 – 3.27 (m, 2H), 3.04 – 2.97 (m, 2H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H). | 3 | |
140 | 720.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.52 (s, 1H), 10.83 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.03 (d, J= 2.1 Hz, 1H), 7.96-7.92 (m, 1H), 7.67 (d, J= 7.8 Hz, 1H), 7.58 (d, J= 7.9 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.42 – 4.23 (m, 2H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.17 – 3.11 (m, 1H), 3.04 – 2.97 (m, 2H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H), 1.65 (d, J= 6.6 Hz, 3H), 1.60 (d, J= 6.6 Hz, 3H). | 3 | |
141 | 678.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.31 (s, 1H), 10.09 (s, 1H), 8.23 (d, J= 1.8 Hz, 2H), 8.04 (t, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.69-7.67 (m, 1H), 7.55 – 7.49 (m, 2H), 7.49 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.44 – 4.23 (m, 2H), 4.04 – 3.67 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 3 | |
142 | 694.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.37 (s, 1H), 7.97 (d, J= 2.2 Hz, 1H), 7.87 (dd, J= 8.5, 2.0 Hz, 1H), 7.56 (dd, J= 8.8, 2.2 Hz, 1H), 7.53 – 7.40 (m, 5H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.42 – 4.24 (m, 2H), 4.02 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 –2.82 (m, 4H), 2.19 – 2.10 (m, 2H). | 3 | |
143 | 719.3 | 1H NMR (500 MHz, DMSO- d 6) δ 9.86 (s, 1H), 9.76 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.75 (d, J= 2.1 Hz, 1H), 7.62 (dd, J= 7.8, 2.0 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.35 – 7.28 (m, 2H), 7.21 (dd, J= 7.8, 2.2 Hz, 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.39 – 4.32 (m, 1H), 4.32 – 4.26 (m, 1H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 –2.82 (m, 4H), 2.30 – 2.19 (m, 2H), 2.17 – 2.09 (m, 2H), 1.73 – 1.61 (m, 2H). | 3 | |
144 | 680.2 | H NMR (500 MHz, DMSO- d 6) δ 8.66 (s, 1H), 8.40 (d, J= 8.1 Hz, 1H), 8.19 (d, J= 2.1 Hz, 1H), 7.91 (dd, J= 8.8, 2.0 Hz, 1H), 7.53-7.52 (m, 1H), 7.45 – 7.40 (m, 3H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.38 – 4.25 (m, 2H), 4.04 – 3.67 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 3 | |
145 | 675.3 | 1H NMR (500 MHz,三氯甲烷- d) δ8.43 (d, J= 2.0 Hz, 1H), 8.15 (d, J= 1.9 Hz, 1H), 7.85 -7.84 (m,2H), 7.63-7.58 (m, 2H), 7.49-7.43 (m, 2H), 7.43-7.37 (m, 12H), 6.80-6.65 (m, 2H), 5.22 (s, 2H), 4.31-4.28 (m, 2H), 4.17-4.10 (m, 1H), 4.02 -3.95 (m, 2H), 3.83-3.74 (m, 2H), 3.35-3.31 (m, 2H), 3.08 – 2.86 (m, 7H), 2.31 – 2.17 (m, 2H). | 3 | |
146 | 708.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.74 (s, 1H), 9.91 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.57 – 7.40 (m, 6H), 7.34 – 7.28 (m, 2H), 7.21 (dd, J= 7.8, 2.2 Hz, 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.35 – 4.26 (m, 2H), 4.08 – 3.82 (m, 4H), 3.75 – 3.69(m, 1H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 3 | |
147 | 694.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.54 (s, 2H), 10.01 (s, 1H), 8.31 (d, J= 2.1 Hz, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.84 (m, 2H), 7.53 – 7.44 (m, 3H), 7.42 (dd, J= 8.2, 1.3 Hz, 2H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.43 – 4.24 (m, 2H), 4.04 – 3.67 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 3 | |
148 | 678.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.24 (s, 1H), 8.44 (d, J= 7.1 Hz, 1H), 8.25 (d, J= 3.6 Hz, 1H), 8.23 (d, J= 1.7 Hz, 1H), 8.04 (d, J= 1.8Hz, 1H), 7.91-7.88 (m, 1H), 7.53 – 7.40 (m, 5H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.82 (d, J= 3.7 Hz, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.41-4.37 (m, 1H), 4.25 – 4.18 (m, 1H), 4.04 – 3.68 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.32 – 2.14 (m, 2H). | 3 | |
149 | 712.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.29 (s, 1H), 8.51 – 8.46 (m, 1H), 8.32 (dd, J= 12.7, 1.6 Hz, 2H), 8.04 (s, 1H), 7.91-7.88 (m, 1H), 7.62-7.60 (m, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.41-4.37 (m, 1H), 4.25 – 4.18 (m, 1H), 4.04 – 3.68 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.97 (m, 2H), 2.91 – 2.82 (m, 2H), 2.32 – 2.14 (m, 2H). | 3 | |
150 | 695.2 | 1H NMR (500 MHz, DMSO- d 6) δ 9.81 (s, 1H), 9.18 (s, 1H), 8.37 (d, J= 2.2 Hz, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.81 – 7.76 (m, 1H), 7.71 (dd, J= 7.8, 2.2 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.31 – 4.26 (m, 1H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.97 (m, 2H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H). | 3 | |
151 | 706.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.69 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.70 (d, J= 2.2 Hz, 1H), 7.53 – 7.40 (m, 5H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.42-4.38 (m, 1H), 4.32 – 4.28 (m, 1H), 4.04 – 3.67 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.46 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 3 | |
152 | 696.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.21 (dd, J= 11.9, 2.0 Hz, 2H), 7.93 – 7.90 (m, 2H), 7.65 (dd, J= 7.9, 2.1 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.43 – 4.21 (m, 2H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.19 – 2.10 (m, 2H). | 3 | |
153 | 710.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.55 (dd, J= 8.1, 2.2 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.45 – 7.40 (m, 3H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.43 – 4.21 (m, 2H), 4.08 – 3.67 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.43 (s, 3H), 2.38 – 2.33 (m, 1H), 2.05– 2.00 (m, 1H). | 3 | |
154 | 737.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.17 (s, 1H), 9.97 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.63 – 7.56 (m, 2H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.38 – 4.27 (m, 2H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.30 – 2.09 (m, 4H), 1.73 – 1.65 (m, 2H). | 3 | |
155 | 733.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.31 (s, 1H), 10.05 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.65 (d, J= 2.2 Hz, 1H), 7.57 – 7.56 (m, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.33 – 4.28 (m, 2H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.43 (s, 3H), 2.30 – 2.20 (m, 5H), 2.17 – 1.71 (m, 4H). | 3 | |
156 | 760.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.71 (s, 1H), 10.84 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.08 (d, J= 2.2 Hz, 1H), 7.91-7.88 (m, 1H), 7.86 (d, J= 2.2 Hz, 1H), 7.52 – 7.44 (m, 2H), 7.42 (dd, J= 8.2, 1.3 Hz, 2H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.33 – 4.28 (m, 2H), 4.08 – 3.67 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 –2.82 (m, 4H), 2.43 (s, 3H), 2.13 – 1.92 (m, 2H). | 3 | |
157 | 787.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.02 (s, 1H), 9.94 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.11 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.62 (d, J= 2.2 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.40 – 4.25 (m, 2H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.30 – 2.06 (m, 4H), 1.72 – 1.59 (m, 2H). | 3 | |
158 | 746.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.19 (d, J= 12.0Hz, 2H), 8.04 (d, J= 2.2 Hz, 1H), 7.99 (t, J= 2.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.53 – 7.43 (m, 3H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.42 – 4.23 (m, 2H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.19 – 2.10 (m, 2H). | 3 | |
159 | 706.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.11 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.97 – 7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.62 (dd, J= 8.4, 2.1 Hz, 1H), 7.56 – 7.48 (m, 2H), 7.48 – 7.43 (m, 2H), 7.42 (d, J= 1.8Hz, 1H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.44 – 3.97 (m, 4H), 3.93 (s, 1H), 3.90 (s, 3H), 3.87 – 3.74 (m, 2H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.19 – 2.10 (m, 2H). | 3 | |
160 | 726.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.91-7.88 (m, 1H), 7.86 – 7.82 (m, 2H), 7.53 – 7.44 (m, 2H), 7.40 (dd, J= 8.2, 1.3 Hz, 2H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.43 – 3.82 (m, 6H), 3.75 – 3.69(m, 1H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.13 – 1.92 (m, 2H). | 3 | |
161 | 746.2 | 1H NMR (500 MHz,三氯甲烷- d) δ12.12 (s, 1H), 11.51 (s, 1H), 8.03 (dd, J= 13.4, 2.2 Hz, 2H), 7.85 (dd, J= 8.7, 2.1 Hz, 1H), 7.62 – 7.50 (m, 2H), 7.42 – 7.31 (m, 4H), 7.26 – 7.13 (m, 2H), 6.83 (dd, J= 7.8, 1.2 Hz, 1H), 6.60 – 6.45 (m, 1H), 5.39 – 5.29 (m, 2H), 4.39-4.35 (m, 1H), 4.32 – 4.23 (m, 1H), 4.17-4.14 (m, 1H), 4.03 – 3.93 (m, 2H), 3.90 – 3.77 (m, 2H), 3.38 – 3.27 (m, 2H), 3.10 – 2.97 (m, 2H), 2.95 – 2.82 (m, 2H), 2.42-2.24 (m, 1H), 2.15 – 1.99(m, 1H). | 3 | |
162 | 718.3 | 1H NMR (500 MHz,三氯甲烷- d) δ11.49 (s, 1H), 10.35 (s, 1H), 8.07 (d, J= 24.1Hz, 2H), 7.69 – 7.59 (m, 2H), 7.58 – 7.37 (m, 5H), 7.20 – 7.04 (m, 2H), 6.86-6.80 (m, 1H), 6.37 – 6.34 (m, 1H), 5.50 – 5.42 (m, 2H), 4.35-4.33 (m, 1H), 4.31 – 4.24 (m, 1H), 4.17-4.14 (m, 1H), 4.05 – 3.75 (m, 4H), 3.40 – 3.22 (m, 2H), 3.12 – 2.82 (m, 4H), 2.43 – 1.94 (m, 3H), 1.11 – 0.87 (m, 4H). | 3 | |
163 | 786.3 | 1H NMR (500 MHz,三氯甲烷- d) δ12.08 (s, 1H), 11.28 (s, 1H), 8.11-7.86 (m, 3H), 7.83 (dd, J= 8.7, 2.1 Hz, 1H), 7.24 – 7.06 (m, 6H), 6.95 – 6.39 (m, 2H), 5.46 – 5.17 (m, 2H), 4.42-4.38 (m, 1H), 4.31 – 4.24 (m, 1H), 4.17 (dd, J= 15.6, 5.3 Hz, 1H), 4.02 – 3.69 (m, 4H), 3.38 – 3.23 (m, 2H), 3.13 – 2.80 (m, 4H), 2.46 – 1.93 (m, 3H), 1.17 – 0.83 (m, 4H). | 3 | |
164 | 732.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.09-8.02(m, 1H) , 8.84– 7.78 (m, 2H), 7.56 – 7.40 (m, 5H), 7.22 – 7.10 (m, 2H), 6.83-6.81 (m, 1H), 6.57 – 6.51 (m, 1H), 5.32 – 5.12 (m, 2H), 4.35 (d, J= 15.5 Hz, 1H), 4.30 – 4.24 (m, 1H), 4.17-4.13 (m, 1H), 4.03 – 3.67 (m, 4H), 3.41 – 2.92 (m, 6H), 2.69-2.43(m, 2H) ,2.05– 1.94 (m, 1H), 1.16 – 1.10(m ,2H), 0.99-0.84 (m, 2H). | 3 | |
165 | 689.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.37 (d, J= 2.0 Hz, 1H), 8.09 (d, J= 2.1 Hz, 1H), 7.81 (dd, J= 8.8, 2.0 Hz, 1H), 7.60 -7.58 (m, 2H), 7.52 (d, J= 8.0 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.42 – 7.34 (m, 2H), 6.89 (dd, J= 7.8, 1.2 Hz, 1H), 6.51-6.43 (m, 1H), 5.35 (s, 2H), 4.38-4.31 (m, 1H), 4.24-4.19 (m, 1H), 4.16-4.10 (m, 1H), 4.00-3.93 (m, 2H), 3.82-3.76 (m, 2H), 3.32 -3.28(m, 2H), 3.03-2.97 (m, 2H), 2.92 -2.89 m, 5H), 2.60 (s, 3H), 2.30 – 2.15 (m, 2H). | 3 | |
166 | 679.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.32 (d, J= 2.1 Hz, 1H), 8.07(d, J= 2.2 Hz, 1H), 7.85-7.80 (m, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.73-7.68 (m, 1H), 7.42 – 7.37 (m, 3H), 7.27 -7.17 (m, 3H), 6.83-6.81 (m, 1H), 6.59-6.52 (m, 1H), 5.31 – 5.24 (m, 2H), 4.32 -4.28 (m, 2H), 4.17-4.13 (m, 1H), 3.91 -3.79 (m, 4H), 3.32-3.08 – 3.02 (m, 4H), 2.91-2.87 (m, 2H), 2.30-2.04 (m, 2H). | 3 | |
167 | 693.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.32 (d, J= 2.1 Hz, 1H), 8.07(d, J= 2.2 Hz, 1H), 7.86-7.80 (m, 1H), 7.78 (d, J= 8.0 Hz, 1H), 7.74-7.68 (m, 1H), 7.42 – 7.37 (m, 2H), 7.27 -7.17 (m, 3H), 6.84 (dd, J= 7.8, 1.2 Hz, 1H), 6.59-6.52 (m, 1H), 5.31 – 5.24 (m, 2H), 4.32 -4.28 (m, 2H), 4.17-4.13 (m, 1H), 3.91 -3.79 (m, 4H), 3.32-3.08 – 3.02 (m, 4H), 2.91-2.87 (m, 2H), 2.74(s, 3H), 2.30-2.04 (m, 2H). | 3 | |
168 | 694.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.15 (s, 1H), 11.36 (s, 1H), 8.64 (s, 1H), 8.15 (d, J= 2.2 Hz, 1H), 7.83 (d, J= 8.8Hz, 1H), 7.45 – 7.34 (m,4H), 7.17-7.14 (m, 2H), 6.86 - 6.59 (m, 2H), 5.39 – 5.34 (m, 2H), 4.39- 4.29 (m, 2H), 4.17-4.13 (m, 1H), 3.93-3.87 (m, 2H), 3.85 – 3.77 (m, 2H), 3.38-3.29 (m, 2H), 3.05 – 3.02 (m, 2H), 2.93-2.91 (m, 2H), 2.34-2.14 (m, 2H). | 3 | |
169 | 742.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.09 (dd, J= 4.0, 2.0 Hz, 2H), 7.85 (dd, J= 8.8, 2.0 Hz, 1H), 7.47-7.45 (m, 2H), 7.44 – 7.42 (m, 1H), 7.37 – 7.34 (m, 2H), 7.21 – 7.15 (m, 3H), 6.76 -6.55 (m, 2H), 5.35 – 5.24 (m, 2H), 4.33-4.28 (m, 2H), 4.17 -4.11(m, 1H), 4.01 -3.93 (m, 2H), 3.85- 3.76 (m, 2H), 3.32-3.21 (m, 2H), 3.08 -2.89 (m, 3H), 2.65 (s, 3H), 2.28 – 2.15 (m, 2H). | 3 | |
170 | 720.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.08 (d, J= 2.1 Hz, 1H), 7.81-7.78 (m, 2H), 7.45 -7.37 (m, 5H), 7.10-7.05 (m, 2H), 6.83 (dd, J= 7.8, 1.2 Hz, 1H), 6.65-6.58 (m, 1H), 5.31 – 5.24 (m, 2H), 4.39-4.37 (m, 1H), 4.25-4.19 (m, 2H), 4.05 (d, J= 13.7 Hz, 1H), 3.93-3.89 (m, 2H), 3.76-3.68 (m, 1H), 3.32-3.25 (m, 2H), 3.08 – 2.88 (m, 9H), 2.25 – 2.15 (m, 2H), 1.35 (t, J= 7.6 Hz, 3H). | 3 | |
171 | 732.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.18 (s, 2H), 11.02 (s, 2H), 8.05 (d, J= 2.1 Hz, 2H), 7.86 – 7.80 (m, 4H), 7.50 (d, J= 2.2 Hz, 2H), 7.45-7.39 (m, 8H), 7.17-7.14 (m, 4H), 6.86-6.55 (m, 4H), 5.31 – 5.24 (m, 4H), 4.30-4.25 (m, 4H), 4.17-4.12 (m, 2H), 4.00 -3.93 (m, 4H), 3.82-3.76 (m, 2H), 3.50 – 3.44 (m, 2H), 3.32-3.03 (m, 8H), 2.99- 2.84(m, 10H), 2.28 – 2.17 (m, 4H), 1.14 – 1.06 (m, 8H). | 3 | |
172 | 742.2 | 1H NMR (500 MHz,三氯甲烷- d) δ8.09 (d, J= 2.1 Hz, 1H), 7.83 – 7.79 (m, 3H), 7.40 – 7.32 (m, 5H), 7.17-7.14 (m, 2H), 6.86 -6.55 (m, 2H), 5.32 – 5.24 (m, 2H), 4.31-4.28 (m, 2H), 4.17-4.12 (m, 1H), 4.05 (d, J= 13.7 Hz, 1H), 3.93-3.85 (m, 2H), 3.76-3.71 (m, 1H), 3.32-3.08 (m, 2H), 3.02 –2.84 (m, 6H), 2.27 – 2.19 (m, 2H). | 3 | |
173 | 720.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.55 (s, 1H), 9.65 (s, 1H), 8.07 (d, J= 2.1 Hz, 1H), 7.85 (dd, J= 8.8, 2.4 Hz, 1H), 7.45- 7.34 (m, 5H), 7.17-7.14 (m, 2H), 6.86 -6.55 (m, 2H), 5.31 – 5.24 (m, 2H), 4.35-4.28 (m, 2H), 4.17-4.16 (m, 1H), 4.01 (d, J= 13.7 Hz, 1H), 3.93 -3.85 (m, 2H), 3.86-3.75 (m, 1H), 3.32-3.27 (m, 2H), 3.04 -2.89 (m, 3H), 2.75 (d, J= 0.8 Hz, 3H), 2.51 (s, 3H), 2.35 – 2.27 (m, 2H). | 3 | |
174 | 710.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.06 (d, J= 2.1 Hz, 1H), 7.98 (d, J= 4.9 Hz, 1H), 7.85 (dd, J= 8.8, 2.0 Hz, 1H), 7.47 (t, J= 7.9 Hz, 1H), 7.42 – 7.35 (m, 3H), 7.33 (d, J= 8.0 Hz, 1H), 7.17-7.14 (m, 2H), 6.86-6.83 (m, 1H), 6.55 -6.51(m, 1H), 5.32 – 5.29 (m, 2H), 4.32 -4.28 (m, 2H), 4.17-4.11 (m, 1H), 4.00- 3.93 (m, 2H), 3.82 -3.76 (m, 2H), 3.36 -3.31(m, 2H), 3.01 -2.83 (m, 7H), 2.27 – 2.15 (m, 2H). | 3 | |
175 | 725.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.09 (d, J= 2.1 Hz, 1H), 7.82-7.76 (M, 1H), 7.63 (d, J= 4.9 Hz, 1H), 7.51 – 7.37 (m, 4H), 7.22 – 7.16 (m, 2H), 6.80-6.57 (m, 2H), 5.31 – 5.20 (m, 2H), 4.55 -4.38 (m, 2H), 4.17-4.11 (m, 1H), 4.03 (d, J= 13.7 Hz, 1H), 3.95-3.88 (m, 2H), 3.77-3.71 (m, 1H), 3.27– 3.02 (m, 3H), 3.00 – 2.95 (m, 3H), 2.65 (s, 3H), 2.30– 2.19 (m, 2H). | 3 | |
176 | 710.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.12 (s, 1H), 10.48 (s, 1H), 8.07 (d, J= 2.1 Hz, 1H), 7.80-7.71 (m, 2H), 7.42 – 7.33 (m, 5H), 7.17-7.12 (m, 2H), 6.85-6.80 (m, 1H), 6.55-6.48 (m, 1H), 5.39 – 5.29 (m, 2H), 4.31 -4.28 (m, 2H), 4.17-4.11 (m, 1H), 4.03-3.93 (m, 2H), 3.81-3.76 (m, 2H), 3.32-3.28 (m, 2H), 3.04 – 2.90 (m, 4H), , 2.30 – 2.19 (m, 2H). | 3 | |
177 | 701.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.09 (d, J = 2.0 Hz, 1H), 7.88 – 7.78 (m, 2H), 7.50 -7.37 (m, 7H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.33-5.29 (m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.11 – 2.90 (m, 7H) 2.25 – 2.15 (m, 2H). | 3 | |
178 | 724.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.78 (s, 1H), 9.95 (s, 1H), 8.09 (d, J= 2.2 Hz, 1H), 7.88-7.86 (m, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.51 – 7.37 (m, 6H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.31-5.29 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.18 – 3.00 (m, 4H), 2.39-2.33 (m, 1H), 2.21 (s, 3H), 2.18 – 2.13 (m, 3H), 1.69 – 1.63 (m, 2H). | 3 | |
179 | 728.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.31 (s, 1H), 8.35 (s, 1H), 8.09 (d, J= 2.2 Hz, 1H), 7.88-7.86 (m, 1H), 7.58– 7.43 (m, 8H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.31-5.29 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.18 – 3.00 (m, 4H), 2.39-2.33 (m, 1H), 2.20 – 2.14 (m, 3H), 1.71 – 1.63 (m, 2H). | 3 | |
180 | 687.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.28 (d, J = 1.7 Hz, 1H), 8.09 (d, J= 2.2 Hz, 1H), 7.89-7.82 (m, 1H), 7.88-7.86 (m, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.54 – 7.37 (m, 6H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.31-5.29 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.18 – 3.00 (m, 4H), 2.39-2.33 (m, 1H), 2.06-2.01 (m, 1H). | 3 | |
181 | 697.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.72 (s, 1H), 10.99 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.80 (d, J= 8.8 Hz, 1H), 7.69- 7.50 (m, 5H), 7.42 – 7.33 (m, 3H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.33-5.29 (m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.05 –2.98 (m, 2H), 2.91 (s, 3H), 2.88-2.85 (m, 2H), 2.65 (s, 3H), 2.25 – 2.15 (m, 2H). | 3 | |
182 | 710.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.98 (s, 1H), 9.49 (s, 1H), 8.09 (d, J= 2.0 Hz, 1H), 7.88-7.86 (m, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.62-7.59 (m, 1H), 7.51 – 7.37 (m, 6H), 7.29 (s, 1H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.31-5.29 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.18 – 3.00 (m, 4H), 2.39-2.33 (m, 1H), 2.20 – 2.11 (m, 2H), 2.07-2.03 (m, 1H), 1.70 – 1.64 (m, 2H). | 3 | |
183 | 733.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.04 (d, J= 4.0 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.51 – 7.33 (m, 7H), 7.17 (s, 1H), 6.88 (d, J= 8.0 Hz, 1H), 6.58-6.51 (m, 1H), 5.31-5.29 (m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.30 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.71 (s, 3H), 2.25 – 2.15 (m, 2H). | 3 | |
184 | 737.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.02 (s, 1H), 11.31 (s, 1H), 8.05-8.03 (m, 2H), 7.80 (d, J= 8.8 Hz, 1H), 7.64-7.55 (m, 2H), 7.51 – 7.37 (m, 6H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.31-5.29 (m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.08 – 2.97 (m, 2H), 2.88-2.85 (m, 2H), 2.25 – 2.15 (m, 2H). | 3 | |
185 | 723.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.09 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.55 – 7.39 (m, 8H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.33-5.29(m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.65 (s, 3H), 2.31 – 2.19 (m, 3H), 1.17 – 0.92 (m, 5H). | 3 | |
186 | 697.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.96 (s, 1H), 10.56 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.88 (d, J= 2.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.64-7.60 (m, 1H), 7.49 – 7.37 (m, 7H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.33-5.29 (m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.78-2.71 (m, 2H), 2.31 – 2.15 (m, 2H), 1.36 (t, J= 7.6 Hz, 3H). | 3 | |
187 | 683.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.32 (s, 1H), 10.67 (s, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.89 (d, J= 2.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.69-7.67 (m, 1H), 7.51 – 7.37 (m, 8H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.33-5.29(m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.95 (s, 3H), 2.93 – 2.84 (m, 2H), 2.25 – 2.15 (m, 2H). | 3 | |
188 | 683.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.79 (s, 1H), 10.75 (s, 1H), 8.16 (d, J= 1.7 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.86 – 7.80 (m, 2H), 7.52 (d, J= 2.2 Hz, 1H), 7.51 – 7.37 (m, 6H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.33-5.29(m, 2H), 4.39- 4.31 (m, 2H), 4.19-4.11 (m, 1H), 4.03-3.96 (m, 1H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.68 (s, 3H), 2.25 – 2.15 (m, 2H). | 3 | |
189 | 693.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.77 (s, 1H), 11.47 (s, 1H), 8.81-8.78 (m, 1H), 8.67 (d, J= 1.7 Hz, 1H), 8.09 (d, J= 2.2 Hz, 1H), 7.88-7.86 (m, 1H), 7.45 (t, J= 7.9 Hz, 1H), 7.42 – 7.34 (m, 3H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.05 – 2.87 (m, 7H), 2.39-2.33 (m, 1H), 2.06-2.01 (m, 1H). | 3 | |
190 | 694.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.69 (s, 1H), 8.07 (d, J= 2.2 Hz, 1H), 7.85 (dd, J= 8.7, 2.1 Hz, 1H), 7.47-7.39 (m, 4H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.08 – 3.02 (m, 1H), 2.99 (ddt, J= 7.0, 3.9, 1.0 Hz, 1H), 2.88-2.85 (m, 2H), 2.39-2.33 (m, 1H), 2.06-2.01 (m, 1H). | 3 | |
191 | 693.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.14 (d, J= 2.2 Hz, 1H), 7.88-7.85 (m, 2H), 7.73 (d, J= 7.6 Hz, 1H), 7.47-7.39 (m, 4H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.07 – 3.00 (m,2H), 2.88-2.85 (m, 2H), 2.39-2.33 (m, 1H), 2.06-2.01 (m, 1H). | 3 | |
192 | 693.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.18 (d, J= 2.2 Hz, 1H), 7.88-7.85 (m, 2H), 7.73 (d, J= 7.6 Hz, 1H), 7.45-7.39 (m, 4H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.07 – 3.00 (m,2H), 2.88-2.85 (m, 2H), 2.39-2.33 (m, 1H), 2.06-2.01 (m, 1H). | ||
193 | 681.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23 (d, J = 2.0 Hz, 1H), 8.09 (d, J= 2.2 Hz, 1H), 7.88-7.86 (m, 1H), 7.76-7.71 (m, 2H), 7.48-7.42 (m, 1H), 7.40 – 7.37 (m, 1H), 7.21-7.10 (m, 3H), 6.79 (d, J = 7.7Hz, 1H), 5.31-5.30 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.85-3.70 (m, 4H), 3.01-2.77 (m, 3H), 2.68-2.61 (m, 2H), 2.39-2.33 (m, 1H), 2.10 – 1.95 (m, 6H). | 3 | |
194 | 695.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.60 (s, 1H), 8.09 (d, J= 2.2 Hz, 1H), 8.01 (d, J= 2.2 Hz, 1H), 7.88-7.86 (m, 1H), 7.55 (d, J= 2.2 Hz, 1H), 7.48-7.42 (m, 1H), 7.42 – 7.38 (m, 2H), 7.21-7.10 (m, 3H), 6.79 (d, J = 7.7Hz, 1H), 5.31-5.30 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.85-3.70 (m, 4H), 3.01-2.77 (m, 3H), 2.68 (s, 3H), 2.65 (ddd, J= 12.5, 8.8, 6.4 Hz, 2H), 2.39-2.33 (m, 1H), 2.10 – 1.95 (m, 6H). | 3 | |
195 | 696.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.95 (s, 1H), 11.76 (s, 1H), 8.68 (s, 1H), 8.09 (d, J= 2.2 Hz, 1H), 7.85 (dd, J= 8.8, 2.2 Hz, 1H), 7.48-7.42 (m, 1H), 7.42 – 7.38 (m, 2H), 7.21-7.10 (m, 3H), 6.79 (d, J = 7.7Hz, 1H), 5.31-5.30 (m, 2H), 4.39-4.30 (m, 2H), 4.19-4.11 (m, 1H), 3.85-3.70 (m, 4H), 3.01-2.77 (m, 3H), 2.68-2.61 (m, 2H), 2.39-2.33 (m, 1H), 2.08 – 1.93 (m, 6H). | 3 | |
196 | 710.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.69 (s, 1H), 10.51 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.75-7.73 (m, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33-4.21 (m, 2H), 4.02– 3.93 (m, 3H), 3.89-3.78 (m, 2H), 3.35-3.28 (m, 2H), 3.03– 2.97 (m, 2H), 2.91 – 2.84 (m, 5H), 2.31-2.15 (m, 2H). | 4 | |
197 | 706.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.47 (s, 1H), 10.33 (s, 1H), 8.44 (d, J= 2.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.82 (d, J= 2.1 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33-4.21 (m, 2H), 4.02– 3.93 (m, 3H), 3.89-3.78 (m, 2H), 3.35-3.28 (m, 2H), 3.05 – 2.95 (m, 5H), 2.88-2.85 (m, 2H), 2.68 (s, 3H), 2.31-2.18 (m, 2H). | 4 | |
198 | 675.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.17-7.8.10(m, 2H), 7.82– 7.78 (m, 1H), 7.66 – 7.63 (m, 1H), 7.47 – 7.42 (m, 4H), 7.20 – 7.13 (m, 2H), 6.89 – 6.84 (m, 1H), 6.58 – 6.53 (m, 1H), 5.35 – 5.24 (m, 2H), 4.39 – 4.13 (m, 3H), 4.00-3.70 (m, 6H), 3.36 – 3.28 (m, 2H), 3.08 – 2.90 (m, 5H), 2.95 – 2.84 (m, 2H), 2.39 – 2.09 (m, 2H). | 4 | |
199 | 692.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.81 (s, 1H), 10.29 (s, 1H), 8.15 (d, J= 1.7 Hz, 1H), 7.99 – 7.94 (m, 1H), 7.90 – 7.87 (m, 1H), 7.80-7.65 (m, 2H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.05-4.01 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.18 – 3.00 (m, 4H), 2.63 (s, 3H), 2.39-2.35 (m, 1H), 2.06-2.01 (m, 1H). | 4 | |
200 | 720.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.52 (d, J = 2.0 Hz, 1H), 7.99 – 7.96 (m, 1H), 7.90-7.81 (m, 2H), 7.58-7.52 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.12-4.08 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.10 – 2.97 (m, 3H), 2.88-2.85 (m, 2H), 2.39-2.35 (m, 1H), 2.07-2.03 (m, 1H), 1.65 (s, 2H), 1.66 (d, J= 6.6 Hz, 3H). | 4 | |
201 | 708.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.45 (d, J = 2.0 Hz, 1H), 7.99 – 7.96 (m, 1H), 7.88 (dd, J= 7.8, 2.0 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.58-7.52 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.14 (s, 3H), 4.05 -3.85(m, 5H), 3.35-3.28 (m, 2H), 3.07 – 3.00 (m,2H), 2.88-2.85 (m, 2H), 2.36-2.31 (m, 1H), 2.06-2.01 (m, 1H). | 4 | |
202 | 696.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.37 (s, 1H), 10.87 (s, 1H), 8.57-8.54 (m, 1H), 7.99 – 7.96 (m, 1H), 7.93 (dd, J= 7.8, 2.0 Hz, 1H), 7.75 (d, J= 7.9 Hz, 1H), 7.58-7.52 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.12-4.08 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.05 – 3.00 (m, 2H), 2.88-2.85 (m, 2H), 2.39-2.35 (m, 1H), 2.06-2.01 (m, 1H). | 4 | |
203 | 719.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.99 (s, 2H), 9.52 (s, 2H), 8.23(d, J = 2.0 Hz, 2H), 7.95 – 7.91 (m, 4H), 7.51-7.48 (m, 2H), 7.46 – 7.40 (m, 8H), 7.17-7.11 (m, 6H), 6.88-6.81 (m, 2H), 6.57-6.53 (m, 2H), 5.33 – 5.24 (m, 4H), 4.34-4.28 (m, 4H), 4.06–3.83 (m, 6H), 3.80 – 3.75 (m, 4H), 3.36-3.32 (m, 4H), 3.05 – 2.84 (m, 8H), 2.30-2.22 (m, 6H), 2.01-1.72(m, 6H). | 4 | |
204 | 678.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.30 (d, J= 1.7 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.66 (d, J= 8.2 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.36-4.29 (m, 2H), 4.02– 3.93 (m, 3H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.25 – 2.15 (m, 2H). | 4 | |
205 | 696.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.14 (d, J= 1.7 Hz, 1H), 8.04-8.02 (m, 1H), 7.83 – 7.77 (m, 2H), 7.58-7.52 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.12-4.08 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.05 – 3.00 (m, 2H), 2.88-2.85 (m, 2H), 2.39-2.35 (m, 1H), 2.06-2.01 (m, 1H). | 4 | |
206 | 712.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.99 (s, 1H), 8.97 (d, J= 7.1 Hz, 1H), 8.38 (d, J= 1.6 Hz, 1H), 8.03 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.87 (dd, J= 7.1, 1.2 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33-4.21 (m, 2H), 4.02– 3.93 (m, 3H), 3.89-3.78 (m, 2H), 3.35-3.28 (m, 2H), 3.03– 2.97 (m, 2H),2.88-2.85 (m, 2H), 2.31-2.15 (m, 2H). | 4 | |
207 | 676.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.57 (s, 1H), 7.95 (d, J= 2.2 Hz, 1H), 7.66-7.56 (m, 2H), 7.53 – 7.40 (m, 5H), 7.29 – 7.26 (m, 2H), 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.42 – 4.24 (m, 2H), 4.02 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 –2.82 (m, 4H), 2.19 – 2.10 (m, 2H) | 4 | |
208 | 737.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.31 (s, 2H), 8.28 (s, 2H), 7.95 (dd, J= 16.1, 2.1 Hz, 4H), 7.79 (dd, J= 8.1, 2.2 Hz, 2H), 7.51-7.48 (m, 2H), 7.46 – 7.40 (m, 8H), 7.21 – 7.13 (m, 3H), 6.88-6.81 (m, 2H), 6.57-6.53 (m, 2H), 5.33 – 5.24 (m, 4H), 4.34-4.25 (m, 4H), 4.06–3.83 (m, 6H), 3.80 – 3.75 (m, 4H), 3.35-3.31(m, 4H), 3.05 – 2.84 (m, 8H), 2.30-2.22 (m, 6H), 2.14-2.08 (m, 2H), 1.78 – 1.64 (m, 4H). | 4 | |
209 | 733.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.36 (s, 1H), 8.97 (s, 1H), 7.95-7.93 (m, 2H), 7.85 (d, J= 2.1 Hz, 1H), 7.58-7.52 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.12-4.08 (m, 1H), 3.97 -3.85(m, 4H), 3.36-3.31 (m, 2H), 3.18 – 3.00 (m, 4H), 2.39-2.35 (m, 1H), 2.26 (s, 3H), 2.21 – 2.14 (m, 1H), 2.17 – 2.10 (m, 1H), 2.07-2.03 (m, 1H), 1.69 – 1.63 (m, 2H). | 4 | |
210 | 760.2 | 1H NMR (500 MHz,三氯甲烷- d) δ8.37 (d, J= 2.2 Hz, 1H), 8.28-8.26 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.36-4.29 (m, 2H), 4.02– 3.93 (m, 3H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.91 – 2.84 (m, 5H), 2.25 – 2.15 (m, 2H). | 4 | |
211 | 770.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.28 (d, J= 2.2 Hz, 1H), 8.13 (d, J= 2.2 Hz, 1H), 7.96-7.92 (m, 1H), 7.62 (d, J= 2.2 Hz, 1H), 7.52 – 7.49 (m, 1H), 7.47 – 7.43 (m, 3H), 7.29 – 7.26 (m, 2H), 1H), 6.85-6.83 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.40 – 4.25 (m, 2H), 4.04 – 3.70 (m, 5H), 3.34 – 3.27 (m, 2H), 3.04 – 2.82 (m, 4H), 2.30 – 2.06 (m, 4H), 1.72 – 1.59 (m, 2H). | 4 | |
212 | 746.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.32 (d, J= 1.7 Hz, 1H), 8.30 (d, J= 2.2 Hz, 1H), 7.99 – 7.96 (m, 1H), 7.84 (t, J= 2.0 Hz, 1H), 7.58-7.52 (m, 1H), 7.46 – 7.39 (m, 4H), 7.28 – 7.21 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.32-4.28 (m, 2H), 4.12-4.08 (m, 1H), 3.97 -3.85(m, 4H), 3.35-3.28 (m, 2H), 3.18 – 3.00 (m, 4H), 2.39-2.35 (m, 1H), 2.06-2.01 (m, 1H). | 4 | |
213 | 743.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.37 (d, J= 2.2 Hz, 1H), 8.28-8.26 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.49– 7.39 (m, 5H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.36-4.29 (m, 2H), 4.02– 3.93 (m, 3H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.91 – 2.84 (m, 5H), 2.25 – 2.15 (m, 2H). | 4 | |
214 | 726.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.79 (s, 1H), 10.71 (s, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.04-8.02 (m, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.36-4.29 (m, 2H), 4.02– 3.93 (m, 3H), 3.87-3.76 (m, 2H), 3.35-3.30 (m, 2H), 3.03 – 2.94 (m, 2H), 2.95 – 2.84 (m, 5H), 2.25 – 2.15 (m, 2H). | 4 | |
215 | 746.2 | 1H NMR (500 MHz,三氯甲烷- d) δ8.49 (d, J= 1.4 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.90 (d, J= 7.9 Hz, 1H), 7.75 (d, J= 7.9 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.19 – 7.13 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.36-4.29 (m, 2H), 4.02– 3.93 (m, 3H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.25 – 2.15 (m, 2H). | 4 | |
216 | 718.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.38 (d, J= 1.4 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 7.8Hz, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.36-4.29 (m, 2H), 4.02– 3.93 (m, 3H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.34 – 2.18 (m, 3H), 1.07 – 0.93 (m, 4H). | 4 | |
217 | 742.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.53 (d, J= 2.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.57-7.51 (m, 1H), 7.46 – 7.39 (m, 4H), 7.18-7.11 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 6.58-6.51 (m, 1H), 5.32 – 5.24 (m, 2H), 4.36-4.29 (m, 2H), 4.02– 3.93 (m, 3H), 3.87-3.76 (m, 2H), 3.35-3.31 (m, 2H), 3.03 – 2.94 (m, 2H), 2.88-2.85 (m, 2H), 2.68 (s, 3H), 2.25 – 2.15 (m, 2H). | 4 | |
218 | 732.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.40 (s, 1H), 10.28 (s, 1H), 8.34 (d, J= 2.2 Hz, 1H), 7.90 (d, J= 2.0 Hz, 1H), 7.84 – 7.80 (m, 1H), 7.55 (dd, J= 8.6, 2.0 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.42 – 7.34 (m, 2H), 7.17-7.15 (m, 2H), 6.83-6.81 (m, 1H), 6.55-6.52 (m, 1H), 5.35 – 5.24 (m, 2H), 4.35 (dd, J= 15.6, 5.2 Hz, 1H), 4.28-4.25 (m, 1H), 4.06 – 3.97 (m, 2H), 3.93 (d, J= 13.7 Hz, 1H), 3.85-3.82 (m, 1H), 3.76-3.74 (m, 1H), 3.32-3.28 (m, 2H), 3.05-3.01 (m, 1H), 3.00 -2.97(m, 1H), 2.89 -2.86(m, 2H), 2.68 (s, 3H), 2.33 – 2.24 (m, 2H), 2.24 – 2.18 (m, 1H), 1.07 – 0.92 (m, 4H). | 4 | |
219 | 728.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.43 (s, 1H), 10.38 (s, 1H), 8.65 (d, J= 1.6 Hz, 1H), 7.90 (d, J= 1.8 Hz, 1H), 7.92 (dd, J= 7.9, 1.8Hz, 1H), 7.76 (d, J= 7.9 Hz, 1H), 7.55 (dd, J= 8.6, 2.0 Hz, 1H), 7.49 – 7.43 (m, 2H), 7.42 – 7.34 (m, 2H), 7.21 – 7.12 (m, 3H), 6.83-6.81 (m, 1H), 6.55 -6.51(m, 1H), 5.35 – 5.24 (m, 2H), 4.35 (dd, J= 15.6, 5.2 Hz, 1H), 4.28-4.24 (m, 1H), 4.06 – 3.97 (m, 2H), 3.93 (d, J= 13.7 Hz, 1H), 3.85-3.82 (m, 1H), 3.76-3.74 (m, 1H), 3.32-3.30 (m, 2H), 3.05-3.03 (m, 1H), 3.00-2.97 (m, 1H), 2.89-2.87 (m, 2H), 2.31 – 2.15 (m, 2H). | 4 | |
220 | 742.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.44 (s, 1H), 10.21 (s, 1H), 8.44-8.42 (m, 2H), 8.05 (d, J= 2.1 Hz, 2H), 7.90 (d, J= 2.1 Hz, 2H), 7.60 – 7.52 (m, 3H), 7.49 – 7.33 (m, 10H), 7.17-7.15 (m, 4H), 6.86 -6.84(m, 2H), 6.55-6.51 (m, 2H), 5.35 – 5.24 (m, 4H), 4.35-4.31 (m, 2H), 4.28-4.21 (m, 2H), 4.06 – 3.97 (m, 4H), 3.93 (d, J= 13.7 Hz, 2H), 3.85-3.81 (m, 2H), 3.76 -3.73(m, 2H), 3.32 -3.29(m, 4H), 3.05-3.01 (m, 2H), 3.00 -2.98(m, 2H), 2.94 – 2.87 (m, 9H), 2.86-2.81 (m, 1H), 2.30 – 2.22 (m, 4H). | 4 | |
221 | 709.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.46 (d, J= 5.0 Hz, 1H), 7.92 (d, J= 2.0 Hz, 1H), 7.58-7.42 (m, 4H), 7.42 – 7.34 (m, 2H), 7.21 – 7.13 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.37 – 4.33 (m, 1H), 4.31 – 4.24 (m, 1H), 4.06 – 3.97 (m, 2H), 3.96 –3.70 (m, 3H), 3.36 – 3.28 (m, 2H), 3.08 –2.97 (m, 2H), 2.95 (s, 3H), 2.93 –2.30 (m, 3H), 2.09 – 1.99 (m, 1H). | 4 | |
222 | 723.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 7.92 (d, J= 2.0 Hz, 1H), 7.78 (d, J= 5.2 Hz, 1H), 7.57 – 7.55 (s, 1H), 7.49 – 7.45(m, 2H), 7.42– 7.13 (m, 4H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.35 –4.27 (m, 2H), 4.06 – 3.97 (m, 2H), 3.96 –3.70 (m, 3H), 3.36– 2.97 (m, 4H), 2.93 – 2.84 (m, 2H), 2.65 (s, 3H), 2.52 (s, 3H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H). | 4 | |
223 | 719.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.58 (d, J= 1.8Hz, 1H), 7.90 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 2H), 7.55 – 7.42 (m, 2H), 7.42 – 7.34 (m, 3H), 7.21 – 7.13 (m, 2H), 6.89 – 6.83 (m, 2H), 5.35 – 5.24 (m, 2H), 4.35 – 4.24 (m, 2H), 4.06 – 3.97 (m, 2H), 3.96 –3.70 (m, 3H), 3.36 – 3.28 (m, 2H), 3.12 – 2.97 (m, 3H), 2.93 – 2.84 (m, 2H), 2.09 – 1.99 (m, 2H), 1.65 (d, J= 6.7 Hz, 3H), 1.61 (s, 3H). | 4 | |
224 | 709.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 7.95 – 7.89 (m, 2H), 7.57 – 7.55 (s, 1H), 7.49 – 7.45(m, 3H), 7.42 –7.13 (m, 4H), 6.88 –6.84 (m, 3H), 5.35 – 5.24 (m, 2H), 4.35 –4.27 (m, 2H), 4.06 –3.70 (m, 5H), 3.36 – 3.28 (m, 2H), 3.08 –2.97 (m, 2H), 2.93 – 2.84 (m, 2H), 2.58 (s, 3H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H). | 4 | |
225 | 700.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.25 (d, J= 2.2 Hz, 1H), 7.90 (d, J= 2.1 Hz, 1H), 7.76 – 7.73 (m, 1H), 7.53 –7.42 (m, 5H), 7.40 – 7.33 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.37 – 4.33 (m, 1H), 4.31 – 4.24 (m, 1H), 4.06 – 3.97 (m, 2H), 3.96 –3.70 (m, 3H), 3.36 – 3.28 (m, 2H), 3.08 –2.97 (m, 2H), 2.96 (s, 3H), 2.91 – 2.86 (m, 2H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H). | 4 | |
226 | 723.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.82 (s, 1H), 7.96 (m, 2H), 7.85 (d, J= 2.2 Hz, 1H), 7.55 – 7.44 (m, 5H), 7.40 – 7.33 (m, 2H), 6.89 – 6.84 (m, 1H), 6.55 (s, 1H), 5.35 – 5.24 (m, 2H), 4.35 –4.27 (m, 2H), 4.06 – 3.98 (m, 1H), 3.93 – 3.81 (m, 2H), 3.81 – 3.73 (m, 2H), 3.36 – 3.28 (m, 2H), 3.08 – 2.97 (m, 2H), 2.93 – 2.84 (m, 2H), 2.26 (s, 3H), 2.32 –2.14 (m, 3H), 2.17 – 2.10 (m, 1H), 1.71 – 1.62 (m, 2H). | 4 | |
227 | 727.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.28 (s, 1H), 7.95 (m, 2H), 7.82 – 7.77 (m, 1H), 7.58– 7.44 (m, 5H), 7.40 – 7.33 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.39 – 4.24 (m, 2H), 4.06 – 3.98 (m, 1H), 3.93 (d, J= 13.9 Hz, 1H), 3.89 – 3.73 (m, 3H), 3.36 – 3.28 (m, 2H), 3.08 –2.84 (m, 4H), 2.32 –2.11 (m, 4H), 1.73 – 1.64 (m, 2H). | 4 | |
228 | 732.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.53 (d, J= 2.1 Hz, 1H), 7.90 (d, J= 2.0 Hz, 1H), 7.84– 7.52 (m, 2H), 7.50 – 7.44 (m, 4H), 7.40 – 7.33 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.35 –4.27 (m, 2H), 4.06 –3.70 (m, 5H), 3.36 – 3.28 (m, 2H), 3.08 –2.84 (m, 4H), 2.66 (s, 3H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H). | 4 | |
229 | 696.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.34 (d, J= 2.2 Hz, 1H), 7.90 (d, J= 2.1 Hz, 1H), 7.84 – 7.80 (m, 1H), 7.55 –7.41 (m, 5H), 7.40 – 7.33 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.37 – 4.33 (m, 1H), 4.33 –3.97 (m, 3H), 3.96 – 3.83 (m, 2H), 3.78 – 3.74 (m, 1H), 3.36 – 3.28 (m, 2H), 3.10 –2.97 (m, 2H), 2.97 (s, 3H), 2.93 – 2.84 (m, 2H), 2.68 (s, 3H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H). | 4 | |
230 | 709.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.09 (s, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.90 (d, J= 2.2 Hz, 1H), 7.91 (m, 1H), 7.53 –7.42 (m, 5H), 7.40 – 7.33 (m, 2H), 7.15 (d, J= 7.7 Hz, 1H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.38 –4.26 (m, 2H), 4.06 – 3.98 (m, 1H), 3.93 (d, J= 13.9 Hz, 1H), 3.90 – 3.70 (m, 3H), 3.36 – 3.28 (m, 2H), 3.08– 2.97 (m, 2H), 2.93 – 2.84 (m, 2H), 2.34 – 2.15 (m, 3H), 2.18 – 2.11 (m, 1H), 1.70 – 1.65 (m, 2H). | 4 | |
231 | 696.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.46 (d, J= 1.4 Hz, 1H), 7.90 (d, J= 2.1 Hz, 1H), 7.94 – 7.73 (m, 2H), 7.53 –7.42 (m, 5H), 7.40 – 7.33 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.37 – 4.33 (m, 1H), 4.33 –3.97 (m, 3H), 3.96 –3.70 (m, 3H), 3.36 – 3.28 (m, 2H), 3.08 – 3.02 (m, 1H), 3.02 – 2.97 (m, 1H), 2.93 – 2.84 (m, 2H), 2.83 – 2.75 (m, 2H), 2.40 – 2.30 (m, 1H), 2.09 – 1.99 (m, 1H), 1.38 (d, J= 10.4 Hz, 3H). | 4 | |
232 | 736.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 7.90 (d, J= 1.8 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.79 (d, J= 7.9 Hz, 1H), 7.55 (s, 1H), 7.50 – 7.44 (m, 4H), 7.40 – 7.33 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.37 – 4.33 (m, 1H), 4.33 –3.97 (m, 3H), 3.96 –3.70 (m, 3H), 3.36 –3.02 (m, 3H), 3.02 – 2.97 (m, 1H), 2.93 – 2.84 (m, 2H), 2.36 – 2.31 (m, 1H), 2.09 – 1.99 (m, 1H). | 4 | |
233 | 722.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.34 (d, J= 2.2 Hz, 1H), 7.90 (d, J= 2.0 Hz, 1H), 7.84 – 7.80 (m, 1H), 7.53 –7.42 (m, 5H), 7.40 – 7.33 (m, 2H), 6.88 –6.84 (m, 2H), 5.35 – 5.24 (m, 2H), 4.41 – 4.39 (m, 1H), 4.33 –3.97 (m, 3H), 3.96 –3.70 (m, 3H), 3.36 –3.02 (m, 3H), 3.02 – 2.97 (m, 1H), 2.93 – 2.84 (m, 2H), 2.68 (s, 3H), 2.39 – 2.27 (m, 2H), 2.09 – 1.99 (m, 1H), 1.07 – 0.92 (m, 4H). | 4 | |
234 | 692.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.35 (s, 1H), 10.43 (s, 1H), 8.89 (d, J= 1.7 Hz, 1H), 8.61 (s, 1H), 7.97 (d, J= 2.2 Hz, 1H), 7.59 – 7.57 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.33 – 5.29 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.89– 3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.48 (s, 3H), 2.19 – 2.10 (m, 2H). | 4 | |
235 | 682.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.42 (d, J= 1.8 Hz, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.63 – 7.50 (m, 3H), 7.52 – 7.44 (m, 3H), 7.44 – 7.40 (m, 1H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.95 (m, 2H), 3.95 – 3.82 (m, 2H), 3.75 – 3.69(m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.43 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 4 | |
236 | 682.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.55-8.53 (m, 1H), 8.14 (d, J= 1.7 Hz, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.88 (d, J= 2.1 Hz, 1H), 7.63 – 7.50 (m, 3H), 7.52 – 7.44 (m, 3H), 7.42 – 7.40 (m, 1H), 6.83-6.81 (m, 1H), 6.47 – 6.45 (m, 1H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.82 (m, 4H), 3.75 – 3.69(m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.61 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 4 | |
237 | 692.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.12 (s, 1H), 10.97 (s, 1H), 9.07 (s, 1H), 8.30 (s, 1H), 7.95 (d, J= 2.2 Hz, 1H), 7.59 – 7.57 (m, 1H), 7.53 – 7.41 (m, 4H), 7.35 – 7.29 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.89– 3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.42 (s, 3H), 2.29 – 2.17 (m, 2H). | 4 | |
238 | 693.2 | 1H NMR (500 MHz, DMSO- d 6) δ 7.94 (d, J= 2.2 Hz, 1H), 7.61 – 7.55 (s, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.50 (s, 3H), 2.19 – 2.10 (m, 2H). | 4 | |
239 | 692.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.06 (d, J= 7.9 Hz, 1H), 8.08 (d, J= 7.6 Hz, 1H), 7.95 (d, J= 2.2 Hz, 1H), 7.59 – 7.57 (m, 1H), 7.53-7.52 (m, 1H), 7.49 – 7.45(m, 2H), 7.46 – 7.40 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.52 (s, 3H), 2.19 – 2.10 (m, 2H). | 4 | |
240 | 693.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.38 (s, 1H), 10.65 (s, 1H), 9.02 (s, 1H), 7.94 (d, J= 2.2 Hz, 1H), 7.61 – 7.55 (s, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.51 (s, 3H), 2.19 – 2.10 (m, 2H). | 4 | |
241 | 678.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.56 (s, 1H), 8.33 (t, J= 1.2 Hz, 1H), 8.00 – 7.95 (m, 3H), 7.55 – 7.53 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H). | 4 | |
242 | 692.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.15 (d, J= 2.2 Hz, 1H), 8.00 – 7.95 (m, 2H), 7.55 – 7.53 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.05 – 3.98 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.70 (s, 3H), 2.19 – 2.10 (m, 2H). | 4 | |
243 | 731.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.42 (d, J= 1.4 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.92 (dd, J= 7.8, 1.7 Hz, 1H), 7.65 (d, J= 7.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.38 – 5.33 (m, 1H), 5.36 – 5.28 (m, 3H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.91 – 3.82 (m, 2H), 3.75 – 3.69(m, 3H), 3.64 – 3.56 (m, 2H), 3.20 (d, J= 8.0 Hz, 1H), 2.38 – 2.33 (m, 4H), 2.12 – 2.00 (m, 2H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H). | 4 | |
244 | 723.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.24 (d, J= 2.2 Hz, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.59 – 7.57 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.33 – 4.29 (m, 1H), 4.32 – 4.26 (m, 1H), 3.93 – 3.84 (m, 2H), 3.76 – 3.68 (m, 3H), 3.64 – 3.56 (m, 2H), 3.20 (d, J= 8.0 Hz, 1H), 2.42 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H), 2.12 – 2.05 (m, 1H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H). | 4 | |
245 | 719.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.05 (s, 1H), 10.26 (s, 1H), 8.32 (d, J= 2.2 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.80 (d, J= 2.2 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.33 – 4.29 (m, 1H), 4.30 – 4.26 (m, 1H), 3.93 – 3.84 (m, 2H), 3.76 – 3.68 (m, 3H), 3.64 – 3.56 (m, 2H), 3.21-3.18 (m, 1H), 2.72 (s, 3H), 2.45 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H), 2.12 – 2.05 (m, 1H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H). | 4 | |
246 | 705.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.42 (d, J= 1.8 Hz, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.56 (dd, J= 8.7, 1.8 Hz, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.93 – 3.82 (m, 2H), 3.75 – 3.69(m, 3H), 3.64 – 3.56 (m, 2H), 3.21-3.18 (m, 1H), 2.43 (s, 3H), 2.38 – 2.33 (m, 1H), 2.12 – 2.00 (m, 2H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H). | 4 | |
247 | 746.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.23 (s, 1H), 10.12 (s, 1H), 8.08 (d, J= 2.2 Hz, 1H), 7.95 (d, J= 2.2 Hz, 1H), 7.88 (d, J= 2.1 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.93 – 3.79 (m, 2H), 3.78 – 3.68 (m, 3H), 3.64 – 3.56 (m, 2H), 3.21-3.18 (m, 1H), 2.21 (s, 3H), 2.30 – 2.05 (m, 5H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H), 1.72 – 1.61 (m, 2H). | 4 | |
248 | 739.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.30 (d, J= 2.2 Hz, 1H), 8.04 – 7.99 (m, 2H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.33 – 4.29 (m, 1H), 4.32 – 4.26 (m, 1H), 3.93 – 3.84 (m, 2H), 3.76 – 3.68 (m, 3H), 3.64 – 3.56 (m, 2H), 3.21-3.18 (m, 1H), 2.45 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H), 2.12 – 2.05 (m, 1H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H). | 4 | |
249 | 721.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.66 (s, 1H), 10.53 (s, 1H), 10.04 (s, 1H), 8.25 (d, J= 2.2 Hz, 1H), 8.08 (d, J= 2.2 Hz, 1H), 7.83 (d, J= 2.2 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.93 – 3.79 (m, 2H), 3.78 – 3.68 (m, 3H), 3.64 – 3.56 (m, 2H), 3.20 (d, J= 8.0 Hz, 1H), 2.30 (s, 3H), 2.29 – 2.17 (m, 2H), 2.12 – 2.05 (m, 1H), 1.99 – 1.93 (m, 1H), 1.96 – 1.89 (m, 2H), 1.84 – 1.76 (m, 2H). | 4 | |
250 | 719.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.43 (d, J= 2.1 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.73 (d, J= 7.9 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.93 – 3.82 (m, 2H), 3.75 – 3.69(m, 3H), 3.64 – 3.56 (m, 2H), 3.21-3.18 (m, 1H), 2.87 – 2.76 (m, 2H), 2.38 – 2.33 (m, 1H), 2.12 – 2.00 (m, 2H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H), 1.33 (t, J= 7.6 Hz, 3H). | 4 | |
251 | 732.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.49 (s, 1H), 10.11 (s, 1H), 8.53 (d, J= 1.4 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 3H), 7.35 – 7.26 (m, 2H), 7.15 – 7.09 (m, 1H), 6.80 – 6.77 (m, 1H), 5.35-5.34 (m, 2H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.93 – 3.82 (m, 2H), 3.75 – 3.69(m, 1H), 3.22 (t, J= 4.4 Hz, 1H), 3.17 – 3.07 (m, 1H), 2.99 – 2.90 (m, 1H), 2.38 – 2.33 (m, 1H), 2.10 – 1.88 (m, 5H), 1.83 – 1.70 (m, 4H), 1.65– 1.57 (m, 8H). | 4 | |
252 | 730.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.22 (d, J= 1.4 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 3H), 7.35 – 7.26 (m, 2H), 7.15 – 7.09 (m, 1H), 6.80 – 6.77 (m, 1H), 5.35-5.34 (m, 2H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.93 – 3.82 (m, 2H), 3.75 – 3.69(m, 1H), 3.22 (t, J= 4.4 Hz, 1H), 2.97 – 2.90 (m, 1H), 2.38 – 2.33 (m, 2H), 2.10 – 1.88 (m, 5H), 1.83 – 1.70 (m, 4H), 1.62 – 1.54 (m, 2H), 1.03 – 0.89 (m, 4H). | 4 | |
253 | 774.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.39 (s, 1H), 10.59 (s, 1H), 8.38-8.37 (m, 1H), 8.27 (d, J= 2.0 Hz, 1H), 8.08 (d, J= 2.2 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.52 – 7.45 (m, 2H), 7.37 – 7.34(m, 1H), 7.32 – 7.28 (m, 1H), 7.25 – 7.19 (m, 1H), 6.57 – 6.53 (m, 1H), 6.23 – 6.19 (m, 1H), 5.35-5.34 (m, 2H), 4.44 – 4.36 (m, 1H), 4.33 – 4.29 (m, 1H), 3.93 – 3.79 (m, 2H), 3.78 – 3.68 (m, 3H), 3.64 – 3.56 (m, 2H), 3.21-3.18 (m, 1H), 2.43 (s, 3H), 2.19 – 2.10 (m, 2H), 2.12 – 2.05 (m, 1H), 1.99 – 1.89 (m, 3H), 1.84 – 1.76 (m, 2H). | 4 | |
254 | 751.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.85 (s, 1H), 8.38 (s, 1H), 8.02-7.95 (m, 1H), 7.73-7.71 (m, 1H), 7.52-7.49 (m, 2H), 7.40-7.34 (m, 2H), 7.16-7.10 (m, 2H), 6.56-6.53 (m, 1H), 6.12 (d, J= 7.2Hz, 1H), 5.21 (s, 2H), 4.41 – 4.35 (m, 2H), 3.90 – 3.81 (m, 3H), 3.67-3.60 (m, 4H), 3.25-3.21 (m, 1H), 2.30 – 2.11 (m, 3H), 2.01 – 1.96 (m, 5H), 1.99 – 1.93 (m, 1H), 1.75-1.69 (m, 3H). | ||
255 | 746.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.23 (d, J= 2.2 Hz, 1H), 8.12 (d, J= 1.9 Hz, 1H), 7.68 -7.59 (m, 2H), 7.51 – 7.49 (m, 1H), 7.43– 7.36 (m, 3H), 7.19-7.12 (m, 2H), 6.84-6.82 (m, 1H), 6.66 – 6.63 (m, 1H), 5.39 – 5.34 (m, 2H), 4.47 – 4.41 (m, 3H), 3.80 - 3.74 (m, 2H), 3.60 – 3.51 (m, 2H), 3.11-3.07 (m, 4H), 2.90 (s, 3H), 2.22 – 2.15 (m, 2H). | ||
256 | 741.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.69 (s, 1H), 10.89 (s, 1H), 8.26 (d, J= 2.2 Hz, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.80 (d, J= 2.2 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.53 – 7.46 (m, 2H), 7.49 – 7.45(m, 1H), 7.46 – 7.40 (m, 1H), 7.35 – 7.26 (m, 2H), 6.89 – 6.83 (m, 1H), 6.58 – 6.52 (m, 1H), 5.34-5.31 (m, 2H), 4.44 – 4.36 (m, 2H), 4.36 – 4.30 (m, 1H), 3.90 – 3.82 (m, 1H), 3.75 – 3.69(m, 1H), 3.61 – 3.56 (m, 2H), 3.36 – 3.26 (m, 2H), 3.12 – 3.02 (m, 2H), 2.72 (s, 3H), 2.45 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 4 | |
257 | 727.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.42 (d, J= 1.8 Hz, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.53 – 7.46 (m, 2H), 7.49 – 7.45(m, 1H), 7.46 – 7.40 (m, 1H), 7.35 – 7.26 (m, 2H), 6.89 – 6.83 (m, 1H), 6.58 – 6.52 (m, 1H), 5.34-5.31 (m, 2H), 4.44 – 4.36 (m, 2H), 4.36 – 4.30 (m, 1H), 3.90 – 3.82 (m, 1H), 3.75 – 3.69(m, 1H), 3.61 – 3.56 (m, 2H), 3.36 – 3.26 (m, 2H), 3.13 – 3.02 (m, 2H), 2.43 (s, 3H), 2.36 – 2.28 (m, 1H), 2.09 – 2.02(m, 1H). | 4 | |
258 | 753.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.49 (d, J= 1.4 Hz, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.53 – 7.46 (m, 2H), 7.49 – 7.45(m, 1H), 7.46 – 7.40 (m, 1H), 7.35 – 7.26 (m, 2H), 6.89 – 6.83 (m, 1H), 6.58 – 6.52 (m, 1H), 5.34-5.31 (m, 2H), 4.44 – 4.36 (m, 2H), 4.35 (s, 1H), 4.38 – 4.30 (m, 1H), 3.90 – 3.82 (m, 1H), 3.75 – 3.69(m, 1H), 3.61 – 3.56 (m, 2H), 3.36 – 3.26 (m, 2H), 3.13 – 3.02 (m, 2H), 2.38 – 2.33 (m, 2H), 2.09 – 2.02(m, 1H), 1.03 – 0.89 (m, 4H). | 4 | |
259 | 749.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.64 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.98 (d, J= 2.1 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.59 – 7.57 (m, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.49 – 7.45(m, 3H), 7.35 – 7.26 (m, 2H), 7.19 – 7.18 (m, 1H), 7.04 (d, J= 1.7 Hz, 1H), 6.80 – 6.77 (m, 1H), 5.35-5.34 (m, 2H), 5.22 (s, 2H), 3.90 – 3.83 (m, 2H), 3.71 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.42 (s, 3H), 2.08 – 1.90 (m, 4H), 1.28 (t, J= 6.3 Hz, 3H). | 4 | |
260 | 695.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.83 (s, 1H), 10.46 (s, 1H), 8.32 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.80 (d, J= 2.0 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.47 (s, 1H), 7.45 (d, J= 5.0 Hz, 1H), 7.35 – 7.26 (m, 2H), 7.19 – 7.18 (m, 1H), 6.80 – 6.77 (m, 1H), 5.35-5.34 (m, 2H), 4.33 (t, J= 4.4 Hz, 2H), 3.73 (t, J= 4.4 Hz, 2H), 3.69 (s, 2H), 3.38 (s, 3H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.72 (s, 3H), 2.42 (s, 3H), 2.03 – 1.86 (m, 4H). | 4 | |
261 | 735.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.50 (s, 1H), 8.42 (d, J= 1.8 Hz, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.35 – 7.26 (m, 2H), 7.19 – 7.18 (m, 1H), 6.80 – 6.77 (m, 1H), 5.35-5.34 (m, 2H), 4.40 (t, J= 7.3 Hz, 2H), 3.92 (t, J= 7.3 Hz, 2H), 3.69 (s, 2H), 3.11 – 2.99 (m, 3H), 2.87 – 2.78 (m, 2H), 2.43 (s, 3H), 2.03 – 1.86 (m, 4H). | 4 | |
262 | 709.2 | 1H NMR (500 MHz, DMSO- d 6) δ 7.99 – 7.92 (m, 2H), 7.82 (d, J= 2.2 Hz, 1H), 7.75 – 7.72 (m, 1H), 7.57 – 7.55 (s, 1H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.43 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 4 | |
263 | 691.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.67 (s, 1H), 10.69 (s, 1H), 7.99 – 7.92 (m, 2H), 7.88 (d, J= 2.2 Hz, 1H), 7.75 – 7.72 (m, 1H), 7.68 – 7.66 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.85 (m, 2H), 2.80 (s, 3H), 2.32 – 2.24 (m, 1H), 2.22– 2.17 (m, 1H). | 3 | |
264 | 705.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.98 (s, 1H), 8.04-8.02 (m, 1H), 7.89 – 7.84 (m, 2H), 7.70 (d, J= 2.2 Hz, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.73 (s, 3H), 2.46 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 33 | |
265 | 695.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.18 – 8.16 (m, 1H), 8.04-8.02 (m, 1H), 7.97 – 7.94 (m, 1H), 7.75 – 7.72 (m, 1H), 7.70 – 7.62 (m, 2H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | ||
266 | 718.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.34 (s, 1H), 10.20 (s, 1H), 7.99 (d, J= 1.7 Hz, 1H), 7.95– 7.70 (m, 3H), 7.62 (m, 1H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.35 –7.19 (m, 3H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.30 – 2.18 (m, 2H), 2.15 - 1.91 (m, 4H). | 3 | |
267 | 732.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.19 (s, 1H), 9.93 (s, 1H), 7.99 (d, J= 1.7 Hz, 1H), 7.97 – 7.95 (m, 1H), 7.75 – 7.72 (m, 1H), 7.65 (d, J= 2.2 Hz, 1H), 7.57 – 7.50 (m, 2H), 7.49 – 7.19 (m, 4H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.30 – 2.20 (m, 2H), 2.22 (s, 3H), 2.18-2.08 (m, 2H), 1.72 – 1.61 (m, 2H). | 3 | |
268 | 681.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.79 (s, 1H), 8.23 (d, J= 1.8 Hz, 1H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.42 – 7.36 (m, 2H), 7.34 – 7.28 (m, 2H), 7.25 – 7.19 (m, 1H), 6.91 – 6.83 (m, 2H), 6.47 – 6.45 (m, 1H), 6.28 – 6.23 (m, 1H), 6.16 (t, J= 5.3 Hz, 1H), 5.34-5.31 (m, 2H), 4.51 – 4.40 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H). | 3 | |
269 | 711.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.09 (d, J= 2.4 Hz, 1H), 8.04-8.02 (m, 1H), 7.97 – 7.95 (m, 1H), 7.75 – 7.72 (m, 1H), 7.66 – 7.58 (m, 2H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
270 | 693.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.54 (s, 2H), 10.16 (s, 1H), 8.31 (d, J= 2.1 Hz, 1H), 8.04-8.02 (m, 1H), 7.97 – 7.95 (m, 1H), 7.86 (d, J= 8.0 Hz, 1H), 7.75 – 7.72 (m, 1H), 7.53 – 7.45 (m, 2H), 7.49 – 7.40 (m, 2H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.95 (m, 2H), 3.95 – 3.82 (m, 2H), 3.78 – 3.69 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 3 | |
271 | 736.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.35 (s, 1H), 9.97 (s, 1H), 7.99 (d, J= 1.7 Hz, 1H), 7.97 – 7.95 (m, 1H), 7.75 – 7.72 (m, 1H), 7.63 – 7.56 (m, 2H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.30 – 2.18 (m, 2H), 2.21 – 2.13 (m, 1H), 2.15 – 2.08 (m, 1H), 1.73 – 1.62 (m, 2H). | 3 | |
272 | 759.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.65 (s, 1H), 10.77 (s, 1H), 8.08 (d, J= 2.2 Hz, 1H), 8.04-8.02 (m, 1H), 7.95 - 7.86 (m, 2H), 7.75 – 7.72 (m, 1H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.46 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
273 | 786.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.23 (s, 1H), 9.94 (s, 1H), 8.11 (d, J= 2.2 Hz, 1H), 7.99 (d, J= 1.7 Hz, 1H), 7.97 – 7.95 (m, 1H), 7.75 – 7.72 (m, 1H), 7.62 (d, J= 2.2 Hz, 1H), 7.53-7.52 (m, 1H), 7.49 – 7.40 (m, 2H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H), 2.15 – 2.04 (m, 4H). | 3 | |
274 | 700.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 11.01 (s, 1H), 7.99 – 7.92 (m, 2H), 7.82 (d, J= 2.2 Hz, 1H), 7.75 – 7.72 (m, 1H), 7.63 – 7.59 (m, 1H), 7.57 – 7.45 (m, 4H), 7.45 – 7.40 (m, 1H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.43 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
275 | 682.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.67 (s, 1H), 10.69 (s, 1H), 7.99 – 7.92 (m, 2H), 7.88 (d, J= 2.2 Hz, 1H), 7.75 – 7.72 (m, 1H), 7.68 – 7.66 (m, 1H), 7.62 – 7.57 (m, 1H), 7.56 – 7.47 (m, 2H), 7.51 – 7.40 (m, 3H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.84 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
276 | 696.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.88 (s, 1H), 8.04-8.02 (m, 1H), 7.89 – 7.84 (m, 2H), 7.70 (d, J= 2.2 Hz, 1H), 7.63 – 7.59 (m, 1H), 7.56 – 7.52 (m, 1H), 7.52 – 7.47 (m, 2H), 7.50 – 7.45 (m, 1H), 7.45 – 7.40 (m, 1H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.73 (s, 3H), 2.46 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
277 | 709.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.28 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.77 -7.75 (m, 2H), 7.69 – 7.65 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.42 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
278 | 691.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.27 (s, 1H), 8.42 (d, J= 1.8 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.75 (d, J= 2.2 Hz, 1H), 7.73 – 7.64 (m, 2H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.43 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
279 | 705.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.85 (s, 1H), 10.29 (s, 1H), 8.32 (d, J= 2.2 Hz, 1H), 7.80 (d, J= 2.2 Hz, 1H), 7.75 (d, J= 2.2 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.72 (s, 3H), 2.45 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
280 | 695.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.97 (s, 1H), 10.36 (s, 1H), 8.63 – 8.58 (m, 1H), 7.97 – 7.95 (m, 1H), 7.78 – 7.73 (m, 2H), 7.70 – 7.66 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
281 | 718.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.13 (s, 1H), 9.90 (s, 1H), 8.09 (d, J= 1.7 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.75 (d, J= 2.1 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.53 – 7.43 (m, 3H), 7.46 – 7.40 (m, 1H), 7.33 – 7.28 (m, 1H), 7.25 – 7.16 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.30 – 2.18 (m, 2H), 2.21 – 2.12 (m, 1H), 2.11 – 1.97 (m, 1H), 1.72 – 1.61 (m, 2H). | 3 | |
282 | 732.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.07 (s, 1H), 9.93 (s, 1H), 7.95 (d, J= 2.2 Hz, 1H), 7.88 (d, J= 2.1 Hz, 1H), 7.75 (d, J= 2.1 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.30 – 2.18 (m, 2H), 2.21 (s, 3H), 2.18-1.72 (m, 4H). | 3 | |
283 | 695.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.50 (t, J= 2.0 Hz, 1H), 8.35 (d, J= 1.8 Hz, 1H), 7.83 – 7.80 (m, 1H), 7.75 (d, J= 2.1 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.19 – 2.10 (m, 2H). | 3 | |
284 | 711.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.87 (s, 1H), 10.21 (s, 1H), 8.49 (d, J= 1.4 Hz, 1H), 7.93 – 7.91 (m, 1H), 7.77 – 7.73 (m, 2H), 7.70 – 7.66 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
285 | 693.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.57 (d, J= 2.1 Hz, 1H), 7.82 – 7.80 (m, 1H), 7.75 (d, J= 2.2 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.53 – 7.40 (m, 5H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.82 (m, 4H), 3.75 – 3.69(m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H). | 3 | |
286 | 736.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.17 (s, 1H), 10.03 (s, 1H), 7.90 (d, J= 2.2 Hz, 1H), 7.84 – 7.81 (m, 1H), 7.75 (d, J= 2.1 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.53 – 7.42 (m, 3H), 7.46 – 7.40 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.30 – 2.18 (m, 2H), 2.21 – 1.69 (m, 4H). | 3 | |
287 | 759.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.38-8.37 (m, 1H), 8.27 (d, J= 2.0 Hz, 1H), 7.75 (d, J= 2.2 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.45 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
288 | 786.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.36 (s, 1H), 9.85 (s, 1H), 8.25 (d, J= 2.2 Hz, 1H), 8.08 (d, J= 2.2 Hz, 1H), 7.75 (d, J= 2.1 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.53 –7.49(m,3H), 7.43-7.32 (m, 1H), 7.35 – 7.26 (m, 2H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.37 – 4.26 (m, 2H), 4.06 – 3.99 (m, 1H), 3.77-3.68 (m, 4H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.30 – 2.18 (m, 2H), 2.22 – 1.72 (m, 4H). | 3 | |
289 | 700.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.43 (s, 1H), 10.28 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.75 (d, J= 2.2 Hz, 1H), 7.69 – 7.65 (m, 1H), 7.63 – 7.59 (m, 1H), 7.56 – 7.52 (m, 1H), 7.52 – 7.44 (m, 3H), 7.45 – 7.43 (m, 1H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.42 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
290 | 682.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.42 (d, J= 1.8 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.77 (d, J= 2.2 Hz, 1H), 7.70 – 7.64 (m, 2H), 7.61 – 7.58 (m, 1H), 7.56 – 7.52 (m, 1H), 7.52 – 7.44 (m, 3H), 7.45 – 7.43 (m, 1H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.43 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
291 | 696.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.45 (s, 1H), 10.27 (s, 1H), 8.32 (d, J= 2.2 Hz, 1H), 7.80 (d, J= 2.2 Hz, 1H), 7.75 (d, J= 2.2 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.63 – 7.59 (m, 1H), 7.56 – 7.52 (m, 1H), 7.52 – 7.47 (m, 2H), 7.50 – 7.44 (m, 1H), 7.47 – 7.40 (m, 1H), 6.86– 6.69 (m, 2H), 5.34-5.31 (m, 2H), 4.38 – 4.24 (m, 2H), 4.10 –3.88 (m, 4H), 3.77 – 3.70 (m, 1H), 3.35– 2.94 (m, 4H), 2.91 – 2.82 (m, 2H), 2.72 (s, 3H), 2.45 (s, 3H), 2.32 – 2.24 (m, 1H), 2.20– 2.14 (m, 1H). | 3 | |
292 | 722.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.92 (s, 1H), 10.71 (s, 1H), 8.22 – 8.14 (m, 2H), 7.92 – 7.89 (m, 1H), 7.69 – 7.62 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
293 | 752.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.75 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.87 – 7.82 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.44 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
294 | 744.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.64 (s, 1H), 10.83 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.15 – 8.11 (m, 1H), 7.92 – 7.89 (m, 1H), 7.70 – 7.66 (m, 1H), 7.62 – 7.55 (m, 2H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.38 – 2.33 (m, 2H), 2.09 – 1.98(m, 4H), 0.96-0.66 (m, 4H). | 5 | |
295 | 786.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.71 (s, 1H), 10.84 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.08 (d, J= 2.2 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.86 (d, J= 2.2 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.46 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
296 | 786.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 11.11 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.62 – 7.59 (m, 1H), 7.49 (d, J= 2.2 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.74 (s, 2H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.92 (s, 3H). | 5 | |
297 | 772.2 | 1H NMR (500 MHz, DMSO- d 6) δ 13.03 (s, 1H), 10.94 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.12 (d, J= 2.2 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.67 – 7.65 (m, 1H), 7.63 – 7.56 (m, 2H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
298 | 727.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.63 – 7.59 (m, 1H), 7.57 – 7.52 (m, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.43 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.82 (s, 3H). | 5 | |
299 | 723.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.78 – 7.73 (m, 1H), 7.70 (d, J= 2.2 Hz, 1H), 7.48-7.47 (m, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 3H), 6.98 – 6.93 (m, 1H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.74 (m, 2H), 2.73 (s, 3H), 2.46 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
300 | 728.3 | 1H NMR (500 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.62 – 7.58 (m, 1H), 7.57 – 7.56 (m, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.04 – 6.98 (m, 2H), 6.11 – 6.07 (m, 1H), 4.39 – 4.21 (m, 2H), 4.19 – 3.90 (m, 4H), 3.76 – 3.69 (m, 1H), 3.35 – 3.28 (m, 2H), 3.24 – 2.85 (m, 4H), 2.43 (s, 3H), 2.41 – 2.20 (m, 2H), 1.82 (s, 3H). | 5 | |
301 | 760.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.01 (s, 1H), 9.93 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 4H), 3.35 – 2.72 (m, 6H), 2.38 – 2.33 (m, 1H), 2.22 (s, 3H), 2.19 – 1.88 (m, 8H). | 5 | |
302 | 767.2 | 1H NMR (500 MHz, DMSO- d 6) δ8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.87 – 7.82 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.30 (m, 1H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.44 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H), 0.93(d, J=8.4Hz, 3H). | 5 | |
303 | 735.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.64 (s, 1H), 10.53 (s, 1H), 9.97 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.16 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 3H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 4H), 3.35 – 2.73 (m, 6H), 2.38 – 2.33 (m, 1H), 2.28 (s, 3H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
304 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.64 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.62 – 7.54 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 2.72 (m, 6H), 2.42 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
305 | 733.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.38 (s, 1H), 10.76 (s, 1H), 8.32 (d, J= 2.1 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 2.72 (m, 6H), 2.70 (s, 3H), 2.44 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
306 | 719.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.50 (s, 1H), 8.42 (d, J= 1.8Hz, 1H), 7.97 (s, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 2.73 (m, 6H), 2.43 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
307 | 760.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.31 (s, 1H), 9.93 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 4H), 3.35 – 2.72 (m, 6H), 2.38 – 2.33 (m, 1H), 2.22 (s, 3H), 2.18 – 1.72 (m, 8H). | 5 | |
308 | 753.2 | 1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.85 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.87 – 7.82 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.85 – 3.77 (m, 4H), 3.35 – 2.72 (m, 6H), 2.44 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
309 | 735.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.64 (s, 1H), 10.53 (s, 1H), 9.97 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 8.16 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 3H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 4H), 3.35 – 2.73 (m, 6H), 2.38 – 2.33 (m, 1H), 2.28 (s, 3H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
310 | 724.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.55 (s, 1H), 10.52 (s, 1H), 8.43 (d, J= 1.3 Hz, 1H), 7.97 (s, 1H), 7.92 – 7.91 (m, 1H), 7.79 – 7.73 (m, 2H), 7.72 (d, J= 5.2 Hz, 1H), 7.63 – 7.53 (m, 2H), 7.46 (d, J= 8.8 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 3.31 (m, 1H), 3.31 – 3.27 (m, 1H), 2.89 – 2.73 (m, 6H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H), 1.33 – 1.14 (m, 3H). | 5 | |
311 | 738.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.49 (s, 1H), 10.32 (s, 1H), 8.53 (d, J= 2.0 Hz, 1H), 7.97 (s, 1H), 7.92 – 7.91 (m, 1H), 7.80 – 7.72 (m, 3H), 7.63 – 7.53 (m, 2H), 7.46 (d, J= 8.8 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 3.27 (m, 2H), 3.17 – 3.07 (m, 1H), 2.89 – 2.73 (m, 4H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H), 1.65 (d, J= 6.5 Hz, 3H), 1.60 (d, J= 6.5 Hz, 3H). | 5 | |
312 | 736.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.61 (s, 1H), 10.32 (s, 1H), 8.49 (d, J= 1.8Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.80 – 7.73 (m, 2H), 7.76 – 7.73 (m, 1H), 7.63 – 7.53 (m, 2H), 7.46 (d, J= 8.8 Hz, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 2.72 (m, 6H), 2.34 – 2.14 (m, 3H), 1.99 (s, 3H), 1.13 – 0.89 (m, 4H). | 5 | |
313 | 787.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.75 (s, 1H), 10.78 (s, 1H), 8.36 (d, J= 2.1 Hz, 1H), 8.27 (d, J= 2.1 Hz, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.90 – 3.67 (m, 4H), 3.35 – 2.72 (m, 6H), 2.45 (s, 3H), 2.36 – 2.03 (m, 2H), 1.99 (s, 3H). | 5 | |
314 | 764.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.50 (s, 1H), 10.03 (s, 1H), 7.99 – 7.94 (m, 2H), 7.84 – 7.81 (m, 1H), 7.62 – 7.54 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.90 – 3.67 (m, 4H), 3.35 – 2.72 (m, 6H), 2.36 – 2.03 (m, 4H), 1.99 (s, 3H), 1.71 – 1.60 (m, 2H). | 5 | |
315 | 745.3 | 1H NMR (500 MHz, DMSO- d 6) δ 13.27 (s, 1H), 10.59 (s, 1H), 8.56 (d, J= 1.8Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.65 (d, J= 7.9 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 5.38 – 5.34 (m, 1H), 5.32 – 5.28 (m, 1H), 4.39 – 4.21 (m, 2H), 4.04 – 3.97 (m, 1H), 3.85 – 3.77 (m, 4H), 3.35 – 2.72 (m, 6H), 2.32 (s, 3H), 2.31 – 2.23 (m, 1H), 2.20– 2.14 (m, 1H), 1.99 (s, 3H). | 5 | |
316 | 759.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.64 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.80 – 7.73 (m, 2H), 7.76 – 7.73 (m, 1H), 7.67 – 7.65 (m, 1H), 7.63 – 7.54 (m, 2H), 7.48 (d, J= 8.0 Hz, 1H), 7.20 (d, J= 0.8 Hz, 1H), 7.20 – 7.16 (m, 2H), 7.08 – 7.02 (m, 1H), 4.38 – 4.18 (m, 4H), 4.01 – 3.94 (m, 1H), 3.88 – 3.68 (m, 2H), 2.42 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
317 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.05 (s, 1H), 10.46 (s, 1H), 8.32 (d, J= 2.1 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.80 (d, J= 2.0 Hz, 1H), 7.76– 7.74 (m, 2H), 7.69 – 7.65 (m, 1H), 7.63 – 7.53 (m, 2H), 7.48 (d, J= 8.0 Hz, 1H), 7.45 – 7.41 (m, 2H), 7.35 – 7.29 (m, 1H), 7.20 – 7.16 (m, 1H), 7.08 – 7.05 (m, 1H), 4.38 – 4.30 (m, 1H), 4.24 – 4.16 (m, 2H), 4.15 – 4.07(m, 2H), 3.88 – 3.68 (m, 2H), 2.72 (s, 3H), 2.45 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
318 | 750.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.50 (s, 1H), 8.42 (d, J= 1.8Hz, 1H), 7.97 (s, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.53 – 7.42 (m, 3H), 7.42 – 7.34 (m, 2H), 7.25 – 7.24 (m, 1H), 7.18 – 7.17(m, 1H), 7.08 – 7.02 (m, 1H), 4.38 – 4.30 (m, 1H), 4.24 – 3.94 (m, 4H), 3.88 – 3.68 (m, 2H), 2.43 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
319 | 791.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.34 (s, 1H), 9.93 (s, 1H), 7.99 – 7.93 (m, 2H), 7.88 (d, J= 2.1 Hz, 1H), 7.67 – 7.65 (m, 1H), 7.62 – 7.56 (m, 2H), 7.51 – 7.42 (m, 2H), 7.25 – 7.23 (m, 2H), 7.20 – 7.16 (m, 2H), 7.08 – 7.02 (m, 1H), 4.38 – 4.30 (m, 4H), 4.01 – 3.77 (m, 3H), 2.38 – 2.33 (m, 1H), 2.21 (s, 3H), 2.20 – 2.00 (m, 3H), 1.99 (s, 3H), 1.72 – 1.65 (m, 1H), 1.67 – 1.61 (m, 1H). | 5 | |
320 | 784.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.43 (s, 1H), 10.60 (s, 1H), 8.30 (d, J= 2.1 Hz, 1H), 8.01 (d, J= 2.1 Hz, 1H), 7.97 (s, 1H), 7.62 – 7.56 (m, 2H), 7.53 – 7.45 (m, 2H), 7.47 – 7.42 (m, 1H), 7.42 – 7.34 (m, 2H), 7.25 – 7.24 (m, 1H), 7.18 – 7.17(m, 1H), 7.08 – 7.02 (m, 1H), 4.38 – 4.30 (m, 1H), 4.24 – 3.94 (m, 4H), 3.88 – 3.68 (m, 2H), 2.45 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
321 | 766.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.66 (s, 1H), 10.53 (s, 1H), 10.23 (s, 1H), 8.25 (d, J= 2.1 Hz, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.83 (d, J= 2.4 Hz, 1H), 7.67 – 7.65 (m, 1H), 7.62 – 7.56 (m, 2H), 7.51 – 7.42 (m, 2H), 7.25 – 7.23 (m, 2H), 7.20 – 7.16 (m, 2H), 7.08 – 7.02 (m, 1H), 4.38 – 4.30 (m, 4H), 4.01 – 3.77 (m, 3H), 2.36 – 2.31 (m, 1H), 2.30 (s, 3H), 2.09 – 2.02(m, 1H), 1.99 (s, 3H). | 5 | |
322 | 720.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.50 (s, 1H), 8.42 (d, J= 1.8Hz, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.68 – 7.66 (m, 1H), 7.62 – 7.56 (m, 2H), 7.51 – 7.42 (m, 2H), 7.25 – 7.24 (m, 1H), 7.17 – 7.15 (m, 1H), 7.11 – 6.98 (m, 3H), 4.38 – 3.97 (m, 5H), 3.87 – 3.73 (m, 2H), 2.43 (s, 3H), 2.19 – 2.10 (m, 2H), 1.98 (s, 3H). | 5 | |
323 | 769.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.49 (s, 1H), 10.32 (s, 1H), 8.53 (d, J= 1.8Hz, 1H), 7.97 (s, 1H), 7.92 – 7.91 (m, 1H), 7.80 – 7.72 (m, 3H), 7.63 – 7.53 (m, 2H), 7.53 – 7.45 (m, 2H), 7.42 – 7.34 (m, 2H), 7.18 – 7.17(m, 1H), 7.08 – 7.04 (m, 1H), 4.38 – 4.30 (m, 1H), 4.24 – 3.94 (m, 4H), 3.88 – 3.17 (m, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H), 1.65 (d, J= 6.5 Hz, 3H), 1.60 (d, J= 6.5 Hz, 3H). | 5 | |
324 | 772.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.61 (s, 1H), 10.32 (s, 1H), 8.49 (d, J= 1.8Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.77 (d, J= 7.9 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.62 – 7.56 (m, 2H), 7.51 – 7.42 (m, 2H), 7.25 – 7.23 (m, 1H), 7.24 – 7.21 (m, 1H), 7.20 (d, J= 2.1 Hz, 1H), 7.19 – 7.11 (m, 2H), 4.38 – 4.20 (m, 2H), 4.17 – 3.68 (m, 5H), 2.35 – 2.23 (m, 5H), 2.20– 2.14 (m, 1H), 1.99 (s, 3H), 1.03 – 0.89 (m, 4H). | 5 | |
325 | 791.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.75 (s, 1H), 10.78 (s, 1H), 8.36 (d, J= 2.1 Hz, 1H), 8.27 (d, J= 2.1 Hz, 1H), 7.90 (d, J= 2.0 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.69 – 7.65 (m, 1H), 7.63 – 7.53 (m, 2H), 7.48 (d, J= 8.0 Hz, 1H), 7.45 – 7.41 (m, 2H), 7.35 – 7.29 (m, 1H), 7.20 – 7.16 (m, 1H), 7.08 – 7.05 (m, 1H), 4.38 – 4.28 (m, 2H), 4.21 – 4.16 (m, 1H), 4.15 – 4.07(m, 2H), 3.90 – 3.67 (m, 2H), 2.45 (s, 3H), 2.36 – 2.03 (m, 2H), 1.99 (s, 3H). | 5 | |
326 | 795.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.50 (s, 1H), 10.03 (s, 1H), 7.99 – 7.94 (m, 2H), 7.84 – 7.81 (m, 1H), 7.67 – 7.65 (m, 1H), 7.62 – 7.54 (m, 2H), 7.51 – 7.42 (m, 2H), 7.25 – 7.23 (m, 2H), 7.20 – 7.16 (m, 2H), 7.08 – 7.02 (m, 1H), 4.38 – 4.30 (m, 4H), 4.01 – 3.77 (m, 3H), 2.38 – 2.33 (m, 1H), 2.18 – 1.65 (m, 4H), 1.19-0.89 (m, 4H) | 5 | |
327 | 776.2 | 1H NMR (500 MHz, DMSO- d 6) δ 13.27 (s, 1H), 10.59 (s, 1H), 8.56 (d, J= 1.8Hz, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.68 – 7.66 (m, 2H), 7.62 – 7.56 (m, 2H), 7.51 – 7.42 (m, 2H), 7.25 – 7.23 (m, 2H), 7.20 – 7.16 (m, 2H), 7.08 – 7.02 (m, 1H), 5.38 – 5.33 (m, 1H), 5.33 – 5.28 (m, 1H), 4.38 – 4.18 (m, 4H), 4.00 – 3.93 (m, 1H), 3.88 – 3.68 (m, 2H), 2.34 – 2.28 (m, 3H), 2.31 – 2.23 (m, 1H), 2.20– 2.14 (m, 1H), 2.03 (s, 3H). | 5 | |
328 | 723.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.22 – 8.14 (m, 2H), 7.92 – 7.89 (m, 1H), 7.70 – 7.62 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.85 – 3.77 (m, 4H), 3.35 – 2.72 (m, 6H), 2.32 – 2.14 (m, 2H), 2.01 (s, 3H). | 5 | |
329 | 767.2 | 1H NMR (500 MHz, DMSO- d 6) δ8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.87 – 7.82 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 6.98 (m, 4H), 6.11 – 6.08 (m, 1H), 4.37 – 4.33 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 –3.80 (m, 3H), 3.80 – 3.67 (m, 2H), 3.35 – 3.30 (m, 1H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.44 (s, 3H), 2.38 – 2.33 (m, 1H), 2.09 – 2.02(m, 1H), 1.98 (s, 3H), 0.93(d, J=8.4Hz, 3H). | ||
330 | 745.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.64 (s, 1H), 10.83 (s, 1H), 8.23 (d, J= 2.0 Hz, 1H), 8.13 (d, J= 2.0 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.70 – 7.66 (m, 1H), 7.62 – 7.55 (m, 2H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.85 – 3.77 (m, 4H), 3.35 – 3.27 (m, 2H), 2.89 – 2.81 (m, 2H), 2.80 – 2.72 (m, 2H), 2.34 – 2.14 (m, 3H), 1.99 (s, 3H), 1.14-0.81 (m, 4H). | 5 | |
331 | 789.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.71 (s, 1H), 10.84 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.86 (d, J= 2.1 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.46 (s, 3H), 2.32 – 2.14 (m, 2H), 2.02 – 1.85 (m, 7H). | 5 | |
332 | 789.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.71 (s, 1H), 10.84 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.08 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.86 (d, J= 2.1 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.46 (s, 3H), 2.32 – 2.14 (m, 2H), 2.04 – 1.87 (m, 7H). | 5 | |
333 | 775.2 | 1H NMR (500 MHz, DMSO- d 6) δ 13.03 (s, 1H), 10.94 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.12 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.67 – 7.65 (m, 1H), 7.63 – 7.56 (m, 2H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.32 – 2.14 (m, 2H), 2.02 – 1.87 (m, 7H). | 5 | |
334 | 730.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.63 – 7.59 (m, 1H), 7.57 – 7.52 (m, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.43 (s, 3H), 2.32 – 2.14 (m, 2H), 2.05– 1.85 (m, 7H). | 5 | |
335 | 726.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.69 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.78 – 7.73 (m, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.47-7.41 (m, 2H), 7.02 – 6.90 (m, 5H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 3.23 – 2.89 (m, 3H), 2.73 (s, 3H), 2.69 – 2.61 (m, 2H), 2.46 (s, 3H), 2.32 – 2.14 (m, 2H), 2.02 – 1.85 (m, 7H). | 5 | |
336 | 721.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.67 (s, 1H), 10.56 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.68 – 7.66 (m, 1H), 7.62 – 7.59 (m, 1H), 7.49 – 7.40 (m, 3H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.79 (m, 5H), 2.69 – 2.61 (m, 2H), 2.32 – 2.14 (m, 2H), 2.07 – 1.84 (m, 7H). | 5 | |
337 | 762.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.01 (s, 1H), 9.93 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 4H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.38 – 2.33 (m, 1H), 2.22 (s, 3H), 2.17 – 2.08 (m, 2H), 2.08 – 2.01 (m, 1H), 2.07 – 1.93 (m, 7H), 1.72 – 1.61 (m, 2H). | 5 | |
338 | 755.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.75 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.87 – 7.82 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.44 (s, 3H), 2.32 – 2.14 (m, 2H), 2.04 – 1.87 (m, 7H). | 5 | |
339 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.64 (s, 1H), 10.53 (s, 1H), 9.97 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.16 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.42 (d, J= 1.3 Hz, 1H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.38 – 2.33 (m, 1H), 2.28 (s, 3H), 2.09 – 1.85 (m, 8H). | 5 | |
340 | 739.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.79 – 7.73 (m, 2H), 7.63 – 7.59 (m, 1H), 7.57 – 7.52 (m, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.43 (s, 3H), 2.32 – 2.14 (m, 2H), 2.02 – 1.85 (m, 7H). | 5 | |
341 | 735.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.69 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.78 – 7.73 (m, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.47-7.41 (m, 2H), 7.02 – 6.90 (m, 5H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 3.23 – 2.89 (m, 3H), 2.73 (s, 3H), 2.69 – 2.61 (m, 2H), 2.46 (s, 3H), 2.32 – 2.14 (m, 2H), 2.02 – 1.85 (m, 7H). | 5 | |
342 | 721.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.67 (s, 1H), 10.56 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.68 – 7.66 (m, 1H), 7.62 – 7.59 (m, 1H), 7.49 – 7.40 (m, 3H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.79 (m, 5H), 2.69 – 2.61 (m, 2H), 2.32 – 2.14 (m, 2H), 2.02 – 1.85 (m, 7H). | 5 | |
343 | 762.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.04 (s, 1H), 9.93 (s, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.65 (d, J= 2.1 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.55 (d, J= 2.0 Hz, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.38 – 2.33 (m, 1H), 2.22 (s, 3H), 2.17 – 2.08 (m, 2H), 2.08 – 2.01 (m, 1H), 2.07 – 1.93 (m, 7H), 1.72 – 1.61 (m, 2H). | 5 | |
344 | 755.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.75 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.87 – 7.82 (m, 2H), 7.62 – 7.59 (m, 1H), 7.47 – 7.40 (m, 2H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.07 – 4.03 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.44 (s, 3H), 2.32 – 2.14 (m, 2H), 2.00 – 1.82 (m, 7H). | 5 | |
345 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 10.74 (s, 1H), 10.63 (s, 1H), 9.97 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.16 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.62 – 7.59 (m, 1H), 7.47 – 7.41 (m, 2H), 7.42 (d, J= 1.3 Hz, 1H), 7.25 – 7.24 (m, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.38 – 2.33 (m, 1H), 2.28 (s, 3H), 2.09 – 1.85 (m, 8H). | 5 | |
346 | 726.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.55 (s, 1H), 10.52 (s, 1H), 8.43 (d, J= 1.2 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.79 – 7.73 (m, 2H), 7.72 (d, J= 5.2 Hz, 1H), 7.63 – 7.53 (m, 2H), 7.46 (d, J= 8.8 Hz, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.05 – 3.98 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.79 (m, 3H), 2.82 – 2.77 (m, 1H), 2.69 – 2.61 (m, 2H), 2.32 – 2.14 (m, 2H), 2.02 – 1.85 (m, 7H), 1.36 – 1.30 (m, 3H). | 5 | |
347 | 740.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.49 (s, 1H), 10.32 (s, 1H), 8.53 (d, J= 1.8Hz, 1H), 7.97 (s, 1H), 7.92 – 7.91 (m, 1H), 7.80 – 7.72 (m, 3H), 7.63 – 7.53 (m, 2H), 7.46 (d, J= 8.8 Hz, 1H), 7.02 – 6.96 (m, 1H), 6.99 – 6.90 (m, 2H), 4.39 – 4.21 (m, 2H), 4.05 – 3.98 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 3.17 – 3.07 (m, 1H), 2.97 – 2.89 (m, 1H), 2.87 – 2.69 (m, 4H), 2.32 – 2.14 (m, 2H), 2.02 – 1.85 (m, 7H), 1.69 (d, J= 6.5 Hz, 3H), 1.63 (d, J= 6.5 Hz, 3H). | 5 | |
348 | 738.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.61 (s, 1H), 10.32 (s, 1H), 8.49 (d, J= 1.8Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.80 – 7.73 (m, 2H), 7.76 – 7.73 (m, 1H), 7.63 – 7.53 (m, 2H), 7.46 (d, J= 8.8 Hz, 1H), 7.02 – 6.93 (m, 3H), 4.39 – 4.21 (m, 2H), 4.05 – 3.98 (m, 1H), 3.88 – 3.68 (m, 2H), 3.69 (s, 2H), 2.97 – 2.90 (m, 1H), 2.87 – 2.69 (m, 4H), 2.35 – 2.23 (m, 3H), 2.02 – 1.85 (m, 7H), 1.13 – 0.89 (m, 4H). | 5 | |
349 | 778.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.97 (s, 1H), 11.15 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.06 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.53 – 7.46 (m, 2H), 7.45 – 7.40 (m, 2H), 7.39 – 7.30 (m, 2H), 7.21 – 6.93 (m, 1H), 6.91 –6.47 (m, 3H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.73 (s, 3H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
350 | 753.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.57 – 7.55 (s, 1H), 7.53 – 7.51 (m, 1H), 7.45 – 7.40 (m, 2H), 7.39 – 7.33 (m, 2H), 6.88 – 6.47 (m, 2H), 5.42 – 5.33 (m, 2H), 5.11 – 4.79 (m, 1H), 4.30 – 4.00 (m, 2H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.46 (s, 3H), 2.43 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
351 | 764.2 | 1H NMR (500 MHz, DMSO- d 6) δ 10.17 (s, 1H), 9.97 (s, 1H), 8.22 – 8.23(m, 1H), 7.92 – 7.89 (m, 1H), 7.70 (s, 1H), 7.63 – 7.56 (m, 2H), 7.53 – 7.46 (m, 2H), 7.45 – 7.40 (m, 2H), 7.35 (d, J= 9.6 Hz, 1H), 6.88 – 6.47 (m, 2H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.90 – 3.67 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.45 (s, 3H), 2.38 – 2.33 (m, 1H), 2.19 – 1.69 (m, 5H). | 3 | |
352 | 798.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.95 (s, 1H), 10.87 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 1H), 7.86 (d, J= 2.1 Hz, 1H), 7.62 (d, J= 2.0 Hz, 1H), 7.57 – 7.56 (m, 1H), 7.53 – 7.51 (m, 1H), 7.46 – 7.40 (m, 2H), 7.35 (d, J= 2.0 Hz, 2H), 7.00 (s, 1H), 6.88 – 6.47 (m, 2H), 5.33 (d, J= 6.0 Hz, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.46 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
353 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.22 – 8.23(m, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.58 – 7.46 (m, 3H), 7.45 – 7.40 (m, 2H), 7.35 (d, J= 9.6 Hz, 1H), 6.91 –6.47 (m, 3H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.43 (s, 3H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
354 | 753.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.69 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.53 (d, J= 9.7 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.45 – 7.40 (m, 2H), 7.36 (d, J= 9.6 Hz, 1H), 6.88 – 6.85 (m, 1H), 6.79 (s, 1H), 6.47 – 6.45 (m, 1H), 5.33 (d, J= 6.0 Hz, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.73 (s, 3H), 2.46 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
355 | 719.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.67 (s, 1H), 10.56 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.68 – 7.66 (m, 1H), 7.55 – 7.44 (m, 3H), 7.44 – 7.40 (m, 2H), 7.35 (d, J= 9.6 Hz, 1H), 6.91 –6.47 (m, 3H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.84 (s, 3H), 2.44 (s, 3H), 2.13 – 2.08 (m, 2H). | 3 | |
356 | 773.3 | 1H NMR (500 MHz, DMSO- d 6) δ 13.03 (s, 1H), 10.94 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 8.12 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.67 – 7.65 (m, 1H), 7.60 (d, J= 7.9 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.45 – 7.40 (m, 2H), 7.35 (d, J= 9.6 Hz, 1H), 6.91 –6.47 (m, 3H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.43 (s, 3H), 2.16- 2.10 (m, 2H). | 3 | |
357 | 753.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.05 (s, 1H), 10.46 (s, 1H), 8.32 (d, J= 2.1 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.59 – 7.40 (m, 5H), 7.36 (d, J= 9.6 Hz, 1H), 6.88 – 6.85 (m, 1H), 6.79 (s, 1H), 6.47 – 6.45 (m, 1H), 5.33 (d, J= 6.0 Hz, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.72 (s, 3H), 2.45 (s, 3H), 2.19 – 2.11 (m, 2H). | 3 | |
358 | 719.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.68 – 7.66 (m, 1H), 7.55 – 7.44 (m, 3H), 7.44 – 7.40 (m, 2H), 7.35 (d, J= 9.6 Hz, 1H), 6.91 –6.47 (m, 3H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.84 (s, 3H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
359 | 773.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 8.12 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.67 – 7.65 (m, 1H), 7.60 (d, J= 7.9 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.45 – 7.40 (m, 2H), 7.35 (d, J= 9.6 Hz, 1H), 6.91 –6.47 (m, 3H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
360 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.22 – 8.23(m, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.58 – 7.46 (m, 3H), 7.45 – 7.40 (m, 2H), 7.35 (d, J= 9.6 Hz, 1H), 6.91 –6.47 (m, 3H), 5.38 – 5.27 (m, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.43 (s, 3H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
361 | 703.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.42 (d, J= 1.8Hz, 1H), 7.97 (s, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.53 – 7.40 (m, 3H), 6.86 – 6.84 (m, 1H), 6.47 – 6.45 (m, 1H), 5.31 (d, J= 1.3 Hz, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.90 – 3.67 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.43 (s, 3H), 2.38 – 2.33 (m, 1H), 2.29 (s, 3H), 2.09 – 2.02(m, 1H). | 3 | |
362 | 707.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.24 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.59 – 7.57 (m, 1H), 7.53 – 7.40 (m, 3H), 6.90 – 6.81 (m, 2H), 6.47 – 6.45 (m, 1H), 5.33 (s, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.43 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
363 | 707.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.29 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.57 – 7.55 (s, 1H), 7.53 – 7.51 (m, 1H), 7.45 – 7.40 (m, 2H), 6.90 – 6.81 (m, 2H), 6.47 – 6.45 (m, 1H), 5.33 (s, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.48 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
364 | 703.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.69 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.45 – 7.40 (m, 2H), 6.90 – 6.81 (m, 2H), 6.47 – 6.45 (m, 1H), 5.33 (s, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.78 (s, 3H), 2.49 (s, 3H), 2.17 – 2.07 (m, 2H). | 3 | |
365 | 757.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.25 (d, J= 2.0 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.52 – 7.49 (m, 2H), 7.45 – 7.40 (m, 2H), 6.90 – 6.81 (m, 2H), 6.47 – 6.45 (m, 1H), 5.33 (s, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.92 (m, 4H), 2.90 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
366 | 715.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.20 (d, J= 2.1 Hz, 1H), 8.18 – 8.07 (m, 2H), 7.92 – 7.89 (m, 2H), 7.74 (d, J= 8.3 Hz, 1H), 7.68 – 7.66 (m, 1H), 7.59 – 7.55 (m, 1H), 7.55 – 7.40 (m, 5H), 7.35 (d, J= 8.2 Hz, 1H), 6.88 – 6.47 (m, 2H), 5.56 – 5.45 (m, 2H), 5.11 – 4.79 (m, 1H), 4.32 – 4.28 (m, 1H), 4.08 – 4.04 (m, 1H), 4.01 – 3.89 (m, 2H), 3.87 – 3.73 (m, 2H), 3.34 – 3.27 (m, 2H), 3.04 – 2.92 (m, 4H), 2.84 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
367 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.44 (s, 1H), 10.82 (s, 1H), 8.23 (d, J= 2.0 Hz, 1H), 8.11 (s, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.57 – 7.55 (s, 1H), 7.53 – 7.51 (m, 1H), 7.45 – 7.40 (m, 2H), 7.37 (d, J= 8.6 Hz, 1H), 6.88 – 6.47 (m, 2H), 5.55 – 5.43 (m, 2H), 5.11 – 4.79 (m, 1H), 4.32 – 4.28 (m, 1H), 4.07 – 4.03 (m, 1H), 3.97 (d, J= 13.8 Hz, 1H), 3.92 (d, J= 13.8 Hz, 1H), 3.90 (s, 3H), 3.87 – 3.73 (m, 2H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.43 (s, 3H), 2.19 – 2.10 (m, 2H). | 3 | |
368 | 709.3 | 1H NMR (500 MHz, DMSO- d 6) δ8.30 (d, J= 8.0 Hz, 1H), 8.23 (d, J= 2.0 Hz, 1H), 8.13 – 8.08 (m, 1H), 8.00 – 7.95 (m, 1H), 7.92 – 7.89 (m, 2H), 7.72 – 7.62 (m, 2H), 7.53 – 7.40 (m, 5H), 6.88 – 6.47 (m, 2H), 5.62 (d, J= 1.3 Hz, 2H), 5.11 – 4.79 (m, 1H), 4.32 – 4.28 (m, 1H), 4.07 – 4.03 (m, 1H), 3.97 (d, J= 13.7 Hz, 1H), 3.95 – 3.82 (m, 2H), 3.75 – 3.69(m, 1H), 3.34 – 3.27 (m, 2H), 3.04 – 2.91 (m, 4H), 2.80 (s, 3H), 2.36 – 2.03 (m, 2H). | 3 | |
369 | 711.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.67 (s, 1H), 10.56 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.91 (m, 2H), 7.87 – 7.82 (m, 1H), 7.68 – 7.66 (m, 1H), 7.53 – 7.34 (m, 5H), 7.30 – 7.25 (m, 1H), 6.88 – 6.47 (m, 2H), 5.38 (d, J= 1.3 Hz, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.74 (m, 4H), 3.34 – 3.27 (m, 2H), 3.04 – 2.97 (m, 2H), 2.91 – 2.79 (m, 8H), 2.19 – 2.10 (m, 2H). | 3 | |
370 | 721.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.50 (s, 1H), 8.42 (d, J= 1.8Hz, 1H), 7.97 (s, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.54 – 7.43 (m, 4H), 7.35 (d, J= 9.6 Hz, 1H), 7.19 – 7.18 (m, 1H), 6.89 (s, 1H), 6.81 – 6.78 (m, 1H), 5.33 (s, 1H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.87 – 3.68 (m, 4H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H), 2.08 – 1.90 (m, 5H). | 2 | |
371 | 775.3 | 1H NMR (500 MHz, DMSO- d 6) δ 13.14 (s, 1H), 10.59 (s, 1H), 8.50 (d, J= 1.3 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.95 – 7.90 (m, 1H), 7.79 (d, J= 7.9 Hz, 1H), 7.54 – 7.43 (m, 4H), 7.35 (d, J= 9.6 Hz, 1H), 7.19 – 7.18 (m, 1H), 6.89 (s, 1H), 6.81 – 6.78 (m, 1H), 5.33 (s, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.87 – 3.68 (m, 4H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
372 | 737.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.64 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.60 – 7.43 (m, 4H), 7.35 (d, J= 9.6 Hz, 1H), 7.19 – 7.18 (m, 1H), 6.89 (s, 1H), 6.81 – 6.78 (m, 1H), 5.33 (s, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.87 – 3.68 (m, 4H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
373 | 705.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.60 (s, 1H), 10.50 (s, 1H), 8.42 (d, J= 1.8Hz, 1H), 7.97 (s, 1H), 7.91 – 7.90 (m, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.53 – 7.47 (m, 2H), 7.19 – 7.18 (m, 1H), 6.81 – 6.79 (m, 1H), 5.31 (s, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.90 – 3.67 (m, 2H), 3.69 (s, 2H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.43 (s, 3H), 2.36 – 2.27 (m, 4H), 2.09 – 1.90 (m, 5H). | 2 | |
374 | 709.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.64 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.59 – 7.57 (m, 1H), 7.53 – 7.47 (m, 2H), 7.19 – 7.18 (m, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.81 – 6.79 (m, 1H), 5.33 (s, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.87 – 3.68 (m, 4H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.42 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
375 | 709.2 | 1H NMR (500 MHz, DMSO- d 6) δ 12.40 (s, 1H), 10.64 (s, 1H), 8.24 (d, J= 2.2 Hz, 1H), 7.97 (d, J= 1.8 Hz, 1H), 7.80 – 7.77 (m, 1H), 7.59 – 7.57 (m, 1H), 7.53 – 7.47 (m, 2H), 7.19 – 7.18 (m, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.81 – 6.79 (m, 1H), 5.33 (s, 2H), 5.11 – 4.79 (m, 1H), 4.34 – 3.98 (m, 2H), 3.87 – 3.68 (m, 4H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.42 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
376 | 705.3 | 1H NMR (500 MHz, DMSO- d 6) δ 12.00 (s, 1H), 10.69 (s, 1H), 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 1H), 7.70 (d, J= 2.1 Hz, 1H), 7.53 – 7.46 (m, 2H), 7.42 (d, J= 8.8 Hz, 1H), 7.19 – 7.18 (m, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.81 – 6.79 (m, 1H), 5.33 (s, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.68 (m, 4H), 3.11 – 3.00 (m, 3H), 2.87 – 2.78 (m, 2H), 2.73 (s, 3H), 2.46 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
377 | 759.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 7.92 – 7.89 (m, 2H), 7.53 – 7.46 (m, 2H), 7.42 (d, J= 8.8 Hz, 1H), 7.19 – 7.18 (m, 1H), 6.87 (d, J= 8.0 Hz, 1H), 6.81 – 6.79 (m, 1H), 5.33 (s, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.68 (m, 4H), 3.10 – 3.01 (m, 3H), 2.87 – 2.78 (m, 2H), 2.73 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
378 | 717.3 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.1 Hz, 1H), 8.18 – 8.13 (m, 1H), 8.13 – 8.07 (m, 1H), 7.92 – 7.89 (m, 2H), 7.74 (d, J= 8.3 Hz, 1H), 7.68 – 7.66 (m, 1H), 7.62 – 7.55 (s, 1H), 7.55 – 7.45 (m, 3H), 7.42 (d, J= 8.8 Hz, 1H), 7.35 (d, J= 8.2 Hz, 1H), 7.19 – 7.18 (m, 1H), 6.83 – 6.80 (m, 1H), 5.51 (s, 2H), 4.39 – 4.08(m, 3H), 3.87 – 3.68 (m, 4H), 3.11 – 3.01 (m, 5H), 2.87 – 2.78 (m, 2H), 2.19 – 2.10 (m, 2H), 2.08 – 1.90 (m, 5H). | 2 | |
379 | 739.2 | 1H NMR (500 MHz, DMSO- d 6) δ 8.23 (d, J= 2.0 Hz, 1H), 8.11 (s, 1H), 7.92 – 7.89 (m, 1H), 7.82 (d, J= 2.2 Hz, 1H), 7.63 (d, J= 8.0 Hz, 1H), 7.57 – 7.55 (s, 1H), 7.53 – 7.51 (m, 1H), 7.42 – 7.37 (m, 2H), 7.19 – 7.18 (m, 1H), 6.80 – 6.77 (m, 1H), 5.49 (s, 2H), 4.39 – 4.08(m, 3H), 3.90 (s, 3H), 3.87 – 3.68 (m, 4H), 3.11 – 3.03 (m, 3H), 2.87 – 2.78 (m, 2H), 2.43 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.86 (m, 4H). | 2 | |
380 | 711.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.01 (s, 1H), 10.39 (s, 1H), 8.24 (d, J= 8.1 Hz, 1H), 8.07-8.05 (m, 2H), 7.93 (dd, J= 8.1, 1.2 Hz, 1H), 7.86-7.83 (m, 2H), 7.70 – 7.62 (m, 2H), 7.50-7.46 (m, 2H), 7.44-7.37 (m, 2H), 7.13 – 7.11 (m, 2H), 5.62 (s, 2H), 4.38-4.17 (m, 3H), 3.80 -3.69 (m, 4H), 3.03-2.78 (m, 6H), 2.65- 2.34(m, 3H), 2.02 – 1.93 (m, 6H). | 2 | |
381 | 713.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.91 (s, 1H), 10.24 (s, 1H), 8.00-7.88 (m, 2H), 7.83 – 7.77 (m, 2H), 7.63 (d, J= 7.8Hz, 1H), 7.47 – 7.32 (m, 4H), 7.21 (dd, J= 8.1, 1.2 Hz, 1H), 7.18 – 7.13 (m, 1H), 6.81 (d, J= 7.7Hz, 1H), 5.46 (s, 2H), 4.35-4.17 (m, 3H), 3.81-3.75 (s, 4H), 3.03 -2.90 (m, 3H), 2.80-2.78 (m, 5H), 2.65 - 2.37 (m, 4H), 2.05 – 1.94 (m, 4H). | 2 | |
382 | 716.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.39 (d, J= 2.0 Hz, 1H), 8.15 (d, J= 1.9 Hz, 1H), 7.85-7.84 (m, 1H), 7.65 -7.61 (m, 2H), 7.50-7.48 (m, 2H), 7.42 (d, J= 8.5 Hz, 1H), 7.03-6.98 (m, 3H), 6.17-6.13 (m, 1H), 4.35 – 4.31 (m, 1H), 4.28 – 4.21 (m, 2H), 3.90- 3.82 (m, 4H), 3.34-3.31 (m, 2H), 2.94-2.85 (m, 5H), 2.77 – 2.73 (m, 2H), 2.65 (s, 2H), 2.32 – 2.20 (m, 2H). | 5 | |
383 | 716.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.39 (d, J= 2.0 Hz, 1H), 8.15 (d, J= 1.9 Hz, 1H), 7.85-7.84 (m, 1H), 7.65 -7.61 (m, 2H), 7.50-7.48 (m, 2H), 7.42 (d, J= 8.5 Hz, 1H), 7.03-6.98 (m, 3H), 6.17-6.13 (m, 1H), 4.35 – 4.31 (m, 1H), 4.28 – 4.21 (m, 2H), 3.90- 3.82 (m, 4H), 3.34-3.31 (m, 2H), 2.94-2.85 (m, 5H), 2.77 – 2.73 (m, 2H), 2.65 (s, 2H), 2.32 – 2.20 (m, 2H). | 5 | |
384 | 733.3 | 1H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.76 (s, 1H), 8.32 (d, J= 2.1 Hz, 1H), 7.95 (d, J= 1.8 Hz, 1H), 7.83 (d, J= 2.1 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 2.72 (m, 6H), 2.70 (s, 3H), 2.44 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
385 | 733.3 | 1H NMR (500 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.76 (s, 1H), 8.32 (d, J= 2.1 Hz, 1H), 7.95 (d, J= 1.8 Hz, 1H), 7.83 (d, J= 2.1 Hz, 1H), 7.62 – 7.56 (m, 2H), 7.49 – 7.45(m, 2H), 7.25 – 7.24 (m, 1H), 7.20 – 7.16 (m, 1H), 7.05 – 6.98 (m, 2H), 6.11 – 6.08 (m, 1H), 4.39 – 3.68 (m, 7H), 3.35 – 2.72 (m, 6H), 2.70 (s, 3H), 2.44 (s, 3H), 2.32 – 2.14 (m, 2H), 1.99 (s, 3H). | 5 | |
386 | 751.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.25 (d, J= 2.0 Hz, 1H), 8.20 (d, J= 2.2 Hz, 1H), 7.91 (d, J= 1.9 Hz, 1H), 7.73-7.72 (m, 1H), 7.60 -7.52 – 7.44 (m, 5H), 7.10-6.99 (m, 4H), 4.35 – 4.21 (m, 4H), 4.05-4.01 (m, 1H), 3.90- 3.78 (m, 2H), 2.99 (s, 2H), 2.26-2.15 (m, 2H). | 5 | |
387 | 751.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.25 (d, J= 2.0 Hz, 1H), 8.20 (d, J= 2.2 Hz, 1H), 7.91 (d, J= 1.9 Hz, 1H), 7.73-7.72 (m, 1H), 7.60 -7.52 – 7.44 (m, 5H), 7.10-6.99 (m, 4H), 4.35 – 4.21 (m, 4H), 4.05-4.01 (m, 1H), 3.90- 3.78 (m, 2H), 2.99 (s, 2H), 2.26-2.15 (m, 2H). | 5 | |
388 | 787.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.02 (d, J= 1.9 Hz, 1H), 7.93 (d, J= 2.2 Hz, 1H), 7.87 – 7.85 (m, 2H), 7.58-7.55 (m, 1H), 7.38 -7.32 (m, 2H), 7.16 -7.13 (m, 2H), 6.97 – 6.91 (m, 2H), 6.21-6.16 (m, 1H), 4.35 – 4.30 (m, 1H), 4.17 – 4.11 (m, 2H), 3.92 -3.83 (m, 2H), 3.85 – 3.74 (m, 2H), 3.39-3.33 (m, 2H), 2.95 (s, 3H), 2.90-2.79 (m, 4H), 2.33 – 2.30 (m, 1H), 2.27 – 2.22 (m, 1H). | 5 | |
389 | 787.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.02 (d, J= 1.9 Hz, 1H), 7.93 (d, J= 2.2 Hz, 1H), 7.87 – 7.85 (m, 2H), 7.58-7.55 (m, 1H), 7.38 -7.32 (m, 2H), 7.16 -7.13 (m, 2H), 6.97 – 6.91 (m, 2H), 6.21-6.16 (m, 1H), 4.35 – 4.30 (m, 1H), 4.17 – 4.11 (m, 2H), 3.92 -3.83 (m, 2H), 3.85 – 3.74 (m, 2H), 3.39-3.33 (m, 2H), 2.95 (s, 3H), 2.90-2.79 (m, 4H), 2.33 – 2.30 (m, 1H), 2.27 – 2.22 (m, 1H). | 5 | |
390 | 705.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.65 (s, 1H), 9.63 (d, J= 7.3 Hz, 1H), 8.32 (d, J= 2.2 Hz, 1H), 7.90 (d, J= 2.1 Hz, 1H), 7.82 (d, J= 2.1 Hz, 1H), 7.51 (d, J= 8.7 Hz, 1H), 7.49 – 7.45(m, 4H), 7.21 – 7.13 (m, 2H), 7.13 (d, J= 7.6 Hz, 1H), 6.80 -6.55 (m, 2H), 5.32 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.05 –3.93 (m, 3H), 3.83-3.76 (m, 2H), 3.34-2.85 (m, 6H), 2.67– 2.17 (m, 5H). | 3 | |
391 | 675.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.04 (s, 1H), 10.57 (s, 1H), 8.53 (d, J= 2.0 Hz, 1H), 8.40 (d, J= 1.4 Hz, 1H), 7.94 (d, J= 2.1 Hz, 1H), 7.90 (d, J= 7.9 Hz, 1H), 7.81 (d, J= 7.9 Hz, 1H), 7.55- 7.50 (m, 3H), 7.46 – 7.44 (m, 2H), 7.35 (d, J= 8.1Hz, 1H), 6.95-6.92 (m, 2H), 5.26 (s, 2H), 4.33-4.28 (m, 2H), 4.05 –3.93 (m, 3H), 3.80 -3.76 (m, 2H), 3.32– 2.97 (m, 4H), 2.91 -2.89 (m, 5H), 2.30 – 2.15 (m, 2H). | 3 | |
392 | 688.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.08 (s, 1H), 9.96 (s, 1H), 8.59 (d, J= 2.0 Hz, 1H), 8.17-8.13 (m, 1H), 7.93 (d, J= 2.1 Hz, 1H), 7.90 (d, J= 7.3Hz, 1H), 7.55-7.50 (m, 3H), 7.45 – 7.44 (m, 2H), 7.36-7.32(m, 2H), 6.80-6.55 (m, 2H), 5.24 (s, 2H), 4.33-4.28 (m, 2H), 4.06 –3.85 (m, 4H), 3.56-3.32 (m, 3H), 3.09 -2.89 (m, 4H), 2.33-2.24 (m, 8H). | 3 | |
393 | 677.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.99 (s, 1H), 9.01 (d, J= 6.6 Hz, 1H), 8.05-7.96 (m, 2H), 7.83 (d, J= 7.3Hz, 1H), 7.54 (d, J= 8.7Hz, 1H), 7.45 – 7.42 (m, 3H), 7.39 – 7.34 (m, 2H), 7.21 – 7.13 (m, 3H), 6.84-6.70 (m, 2H), 6.55 -6.51(m, 1H), 5.32 – 5.24 (m, 2H), 4.32-4.28 (m, 2H), 4.03-3.76 (m, 5H), 3.32-2.89 (m, 8H). | 3 | |
394 | 691.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.90 (s, 1H), 9.53 (d, J= 6.6 Hz, 1H), 8.06-7.96 (m, 2H), 7.82 (d, J= 7.3Hz, 1H), 7.58 (d, J= 8.7Hz, 1H), 7.48 – 7.43 (m, 3H), 7.40 – 7.34 (m, 2H), 7.21 – 7.13 (m, 3H), 6.79-6.70 (m, 1H), 6.53 -6.51(m, 1H), 5.39 – 5.24 (m, 2H), 4.30-4.22 (m, 5H), 4.01-3.76 (m, 5H), 3.31-2.89 (m, 8H). | 3 | |
395 | 720.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.19 (s, 1H), 10.68 (s, 1H), 8.64 (d, J= 1.4 Hz, 1H), 7.97 (d, J= 2.1 Hz, 1H), 7.90 (d, J= 7.8Hz, 1H), 7.69 (d, J= 7.9 Hz, 1H), 7.53 (d, J= 8.7Hz, 1H), 7.51 – 7.48 (m, 4H), 7.21 – 7.13 (m, 2H), 6.80 -6.55 (m, 2H), 5.31 – 5.24 (m, 2H), 4.33 -4.28 (m, 2H), 4.05 – 3.94 (m, 2H), 3.95-3.76 (m, 3H), 3.30-2.89 (m, 9H), 2.32 – 2.15 (m, 2H). | 3 | |
396 | 651.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.91 (s, 1H), 8.41 (d, J= 1.7 Hz, 1H), 8.34 (d, J= 1.7 Hz, 1H), 7.74 (d, J= 1.7 Hz, 1H), 7.71 (d, J= 3.7 Hz, 1H), 7.43 – 7.33 (m, 5H), 7.17-7.16 (m, 2H), 6.85- 6.80 (m, 2H), 6.57-6.53 (m, 1H), 5.39 – 5.36 (m, 2H), 4.33-4.28 (m, 2H), 4.17-4.16 (m, 1H), 4.00-3.93 (m, 1H), 3.81-3.76 (m, 2H), 3.32-3.29 (m, 2H), 3.08 – 3.02 (m, 1H), 3.02 – 2.97 (m, 1H), 2.89-2.81 (m, 2H), 2.32 – 2.15 (m, 2H). | 3 | |
397 | 665.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.49 (d, J= 1.7 Hz, 1H), 8.23 (d, J= 1.7 Hz, 1H), 7.85 (d, J= 1.7 Hz, 1H), 7.46-7.44 (m, 1H), 7.45 (t, J= 7.9 Hz, 1H), 7.42 – 7.38(m, 3H), 7.20 – 7.16 (m, 2H), 6.87-6.84 (m, 1H), 6.58-6.51 (m, 2H), 5.39 – 5.34 (m, 2H), 4.39-4.28 (m, 2H), 4.16-4.14 (m, 1H), 4.05-3.95 (m, 2H), 3.83-3.76 (m, 2H), 3.32– 2.97 (m, 4H), 2.89-2.80 (m, 2H), 2.32 – 2.15 (m, 2H). | 3 | |
398 | 720.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.89 (s, 1H), 8.17 – 8.09 (m, 2H), 7.53-7.47 (m, 2H), 7.44 – 7.35 (m, 3H), 7.26 – 7.15 (m, 2H), 6.85-6.75 (m, 2H), 5.45 – 5.34 (m, 2H), 4.26-4.23 (m, 2H), 4.16-4.13(m, 1H), 4.05-3.93 (m, 2H), 3.86 -3.76 (m, 2H), 3.34-2.85 (m, 6H), 2.33 – 2.15 (m, 2H). | 3 | |
399 | 720.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.85 (s, 1H), 8.43 (d, J= 8.0 Hz, 1H), 8.21 – 8.09 (m, 2H), 7.50-7.45 (m, 2H), 7.41 – 7.34 (m, 2H), 7.20 – 7.16 (m, 2H), 6.85 (d, J= 7.8Hz, 1H), 6.53-6.52 (m, 1H), 5.33 – 5.26 (m, 2H), 4.36-4.29 (m, 1H), 4.28-4.25 (m, 1H), 4.20-3.93 (m, 3H), 3.85-3.76 (m, 2H), 3.34-2.85 (m, 6H), 2.33 – 2.15 (m, 2H). | 3 | |
400 | 667.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.59 (s, 1H), 8.15 (d, J= 2.1 Hz, 1H), 7.85 (d, J= 8.7 Hz, 1H), 7.46 – 7.37 (m, 4H), 7.25 (s, 1H), 7.15-7.07 (m, 3H), 6.62-6.52 (m, 2H), 5.33 – 5.24 (m, 2H), 5.04 -4.95 (m, 2H), 4.37 (dd, J= 15.5, 5.3 Hz, 1H), 4.29-4.21 (m, 2H), 4.00-3.93 (m, 2H), 3.88-3.76 (m, 2H), 3.34-2.85 (m, 6H), 2.22 – 2.15 (m, 2H). | 2 | |
401 | 667.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 9.95 (s, 1H), 8.65 (s, 1H), 8.05 (d, J= 2.1 Hz, 1H), 7.80-7.79(m, 2H), 7.42 – 7.37 (m, 3H), 7.32-7.17 (m, 3H), 6.85-6.55 (m, 2H), 6.20 (d, J= 6.8 Hz, 1H), 5.36 – 5.24 (m, 2H), 4.45-4.38 (m, 2H), 4.27 (d, J= 15.6Hz, 1H), 4.03-3.90 (m, 3H), 3.76-3.71 (m, 1H), 3.34-2.85 (m, 6H), 2.31 – 2.15 (m, 2H). | 2 | |
402 | 683.2 | 1H NMR (500 MHz,三氯甲烷- d) δ8.40 (d, J= 5.9 Hz, 1H), 8.01 (d, J= 2.1 Hz, 1H), 7.85-7.78 (m, 2H), 7.50 -7.45 (m, 2H), 7.42 – 7.39 (m, 3H), 7.19 (d, J= 17.6Hz, 2H), 6.87-6.79 (m, 2H), 6.53-6.50 (m, 1H), 5.35 – 5.24 (m, 2H), 4.38 (d, J= 15.5, 1H), 4.29 -4.17 (m, 2H), 4.00 (d, J= 13.7 Hz, 1H), 3.93-3.85 (m, 2H), 3.76-3.70 (m, 1H), 3.34-2.85 (m, 6H), 2.31 – 2.15 (m, 2H). | 2 | |
403 | 685.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.15 (d, J= 2.1 Hz, 1H), 7.93 (d, J= 4.9 Hz, 1H), 7.87 (m, 1H), 7.43 (t, J= 7.9 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.30 (dd, J= 8.1, 1.2 Hz, 1H), 7.16-7.12 (m, 2H), 6.87-6.55 (m, 2H), 5.31 – 5.24 (m, 2H), 4.30-4.17 (m, 3H), 4.02-3.95 (m, 2H), 3.88 -3.79 (m, 2H), 3.33-3.02 (m, 6H), 2.30 – 2.11 (m, 2H). | 2 | |
404 | 668.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.04 (d, J= 2.1 Hz, 1H), 7.70- 7.59 (m, 4H), 7.42 – 7.34 (m, 3H), 7.17-7.12 (m, 2H), 6.84 (m, 1H), 6.51-6.34 (m, 2H), 5.35 – 5.31 (m, 2H), 4.35-4.28 (m, 2H), 4.18-4.13 (m, 1H), 4.04- 3.93 (m, 1H), 3.80-3.76 (m, 1H), 3.34-2.89 (m, 6H), 2.31 – 2.15 (m, 2H). | 2 | |
405 | 712.0 | 1H NMR (500 MHz,三氯甲烷- d) δ 7.62-7.55 (m, 2H), 7.40 – 7.37 (m, 3H), 7.18-7.15 (m, 2H), 6.81 (d, J= 7.8Hz, 1H), 6.52-6.51 (m, 1H), 5.31 – 5.24 (m, 2H), 4.31 -4.27 (m, 2H), 4.02 -3.95 m, 2H), 3.90 – 3.79 (m, 2H), 3.70-3.34 (m, 2H), 3.33 -3.28(m, 1H), 3.00 -2.69 (m, 8H), 2.32-2.04 (m, 2H). | 2 | |
406 | 699.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 8.54 (d, J= 2.0 Hz, 1H), 7.84 (d, J= 2.2 Hz, 1H), 7.63 – 7.59 (m, 2H), 7.50 – 7.44 (m, 4H), 6.85-6.75 (m, 2H), 5.55 (s, 2H), 4.34-4.30 (m, 2H), 4.05– 3.79 (m, 5H), 3.44 -3.34 (m, 2H), 3.20-2.97 (m, 7H), 2.34 -2.04 (m, 2H). | 2 | |
407 | 762.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 13.41 (s, 1H), 10.55 (s, 1H), 8.55 (d, J= 2.0 Hz, 1H), 8.21 (d, J= 2.2 Hz, 1H), 7.98 (d, J= 1.9 Hz, 1H), 7.71-7.68 (m, 2H), 7.55-7.54 (m, 2H),7.49 – 7.42 (m, 4H), 7.22 (d, J= 8.1 Hz, 2H), 7.01 (d, J= 1.7 Hz, 1H), 6.75-6.74 (m, 1H), 5.33 (s, 2H), 5.26 (s, 2H), 4.24 (s, 2H), 3.87-3.86 (m, 2H), 3.10 (s, 3H), 1.43 (d, J= 5.9 Hz, 3H). | 1 | |
408 | 748.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 13.43 (s, 1H), 10.55 (s, 1H), 8.21 (d, J= 2.2 Hz, 1H), 7.98 (d, J= 1.9 Hz, 1H), 7.71-7.69 (m, 1H), 7.52-7.48 (m, 4H), 7.42 – 7.37 (m, 2H), 7.17 – 7.13 (m, 2H), 7.01 (d, J= 1.7 Hz, 1H), 6.86 (dd, J= 7.8, 1.2 Hz, 1H), 6.52-6.50 (m 1H), 5.30 – 5.28 (m, 4H), 4.00 (s, 2H), 3.87-3.86 (m, 2H), 3.30-3.29 (m, 2H), 3.06 – 3.02 (m, 2H), 2.90 – 2.85 (m, 5H), 1.36 (t, J= 5.8 Hz, 3H). | 2 | |
409 | 789.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 13.33 (s, 1H), 10.45 (s, 1H), 8.38 (d, J= 2.0 Hz, 1H), 8.27 (d, J= 2.2 Hz, 1H), 7.98 (d, J= 1.9 Hz, 1H), 7.70-7.66 (m, 2H), 7.49 – 7.47 (m, 3H), 7.44 – 7.42 (m, 2H), 7.09 (t, J= 7.6 Hz, 1H), 7.02 – 6.98 (m, 4H), 5.30 (s, 2H), 4.24 (d, J= 2.4 Hz, 2H), 3.89-3.87 (m, 2H), 3.10 (s, 3H), 1.34 (t, J= 5.8 Hz, 3H). | 1,5 | |
410 | 758.3 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.59 (s, 2H), 10.58 (s, 2H), 8.33 (d, J= 2.0 Hz, 2H), 8.20 (d, J= 2.2 Hz, 2H), 7.98 (d, J= 1.9 Hz, 2H), 7.70-7.66 (m, 2H), 7.52 – 7.49 (m, 4H), 7.44 – 7.42 (m, 4H), 7.06 (dd, J= 7.7, 2.3 Hz, 2H), 7.01 – 6.96 (m, 4H), 6.94 (s, 1H), 6.05-6.03 (m, 2H), 5.31 (d, J= 0.7 Hz, 4H), 3.92-3.88 (m, 8H), 3.33 -3.30 (m, 4H), 3.11 (s, 6H), 2.83-2.80 – 2.71 (m, 8H), 1.33 (t, J= 5.8 Hz, 6H). | 5 | |
411 | 789.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.97 (s, 1H), 10.53 (s, 1H), 8.38 (d, J= 2.0 Hz, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.98 (d, J= 1.9 Hz, 1H), 7.73 (dd, J= 8.1, 2.2 Hz, 1H), 7.61 (d, J= 7.9 Hz, 1H), 7.49 – 7.47 (m, 3H), 7.44 – 7.42 (m, 2H), 7.13 (t, J= 7.6 Hz, 1H), 7.02 – 6.99 (m, 4H), 5.32 (s, 2H), 4.24 (d, J= 2.4 Hz, 2H), 3.86-3.83 (m, 2H), 3.10 (s, 3H), 1.34 (t, J= 5.8 Hz, 3H). | 1,5 | |
412 | 789.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 12.97 (s, 1H), 10.54 (s, 1H), 8.38 (d, J= 2.0 Hz, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.98 (d, J= 1.9 Hz, 1H), 7.73 (dd, J= 8.1, 2.2 Hz, 1H), 7.61 (d, J= 7.9 Hz, 1H), 7.49 – 7.47 (m, 3H), 7.44 – 7.42 (m, 2H), 7.13 (t, J= 7.6 Hz, 1H), 7.02 – 6.98 (m, 4H), 5.32 (s, 2H), 4.24 (d, J= 2.4 Hz, 2H), 3.86-3.83 (m, 2H), 3.11 (s, 3H), 1.34 (t, J= 5.8 Hz, 3H). | 1,5 | |
413 | 741.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.32 (s, 1H), 8.20 (d, J= 2.4 Hz, 1H), 7.92 (d, J= 2.0 Hz, 1H), 7.75-7.73 (m, 1H), 7.60 – 7.58 (m, 1H), 7.56-7.55 (m, 1H), 7.45 – 7.42 (m, 3H), 7.33-7.32 (m, 1H), 7.21 – 7.19 (m, 2H), 7.10-7.08 (m, 1H), 6.47-6.46 (m, 1H), 5.32 – 5.29 (m, 2H), 4.30-4.28 (m, 2H), 4.13-4.10 (m, 2H), 3.93-3.87 (m, 2H), 3.73-3.71 (m, 1H), 2.95 (s, 2H), 2.21 – 2.18 (m, 2H). | 1,5 | |
414 | 779.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 10.36 (s, 1H), 8.20 (d, J= 2.4 Hz, 1H), 7.89 (d, J= 2.0 Hz, 1H), 7.75-7.74 (m, 1H), 7.60 – 7.59 (m, 1H), 7.52 – 7.46 (m, 6H), 7.19 – 7.13 (m, 3H), 7.02 (d, J= 1.7 Hz, 1H), 6.47-6.46 (m, 1H), 5.31 (s, 2H), 5.29 (d, J= 1.0 Hz, 2H), 4.10 (d, J= 1.0 Hz, 2H), 3.85-3.82 (m, 2H), 2.92 (s, 3H), 1.29 (d, J= 6.0 Hz, 2H). | 1,5 | |
415 | 779.2 | 1H NMR (500 MHz,三氯甲烷- d) δ10.36 (s, 1H), 8.20 (d, J= 2.2 Hz, 1H), 7.89 (d, J= 2.0 Hz, 1H), 7.75-7.74 (m, 1H), 7.62-7.60 (m, 1H), 7.52 -7.47 (m, 4H), 7.41-7.38 (m, 1H), 7.31 – 7.26 (m, 2H), 7.18 – 7.14 (m, 2H), 7.01 (d, J= 1.7 Hz, 1H), 6.73-6.71 (m, 1H), 5.31 – 5.29 (m, 4H), 4.20 (s, 2H), 3.85-3.82 (m, 2H), 2.95 (s, 3H), 1.29 (d, J= 5.9 Hz, 2H). | 1,5 | |
416 | 753.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.34 (s, 1H), 10.09 (s, 1H), 8.22 (d, J= 2.2 Hz, 1H), 7.91 (d, J= 1.9 Hz, 1H), 7.73-7.71 (m, 1H), 7.60 – 7.56 (m, 3H), 7.50 – 7.47 (m, 2H), 7.33-7.30 (m, 1H), 7.10-7.06 (m, 3H), 6.68 (dd, J= 7.8, 1.2 Hz, 1H), 5.33 – 5.29 (m, 2H), 4.72 – 4.71 (m, 2H), 4.32-4.39 (m, 2H), 4.11 – 4.08 (m, 2H), 3.95-3.92 (m, 1H), 3.81-3.77 (m, 2H), 3.73 – 3.71 (m, 1H), 2.93 (s, 3H), 2.25 – 2.19 (m, 2H). | 1,5 | |
417 | 757.2 | 1H NMR (500 MHz,三氯甲烷- d) δ 11.37 (s, 1H), 10.15 (s, 1H), 8.20 (d, J= 2.2 Hz, 1H), 8.00 (d, J= 1.9 Hz, 1H), 7.70-7.66 (m, 3H), 7.50 – 7.47 (m, 3H), 7.38-7.35( m, 1H), 7.21 – 7.18 (m, 3H), 6.70-6.68 (m, 1H), 5.32 – 5.29 (m, 2H), 4.60-4.57 (m, 2H), 4.30-4.28 (m, 1H), 4.10 – 4.06 (m, 2H), 3.89– 3.88 (m, 2H), 3.72-3.69 (m, 2H), 2.94 (s, 3H). | 1,5 |
實施例
2
體外活性評價
GLP-1R cAMP
水平測試
1.
材料
(1)試劑
cAMP檢測試劑盒,Cisbio (Cat # 62AM4PEJ)
1M HEPES, Invitrogen (Cat # 15630-106)
1X HBSS, Invitrogen (Cat # 14025)
BSA,Sigma (Cat # B2064-100G)
IBMX, Sigma (Cat # I5879)
GLP-1(7-37),Hao Yuan (HY-P0055)
(
2
)細胞株
該細胞株由上海藥明康得構建。詳情見下表。
靶點 | 宿主細胞 | 選殖 |
GLP-1R | HEK293 | N/A |
( 3 )儀器OptiPate-384,白色,PerkinElmer(Cat # 6007290);
384孔板,Labcyte(Cat#P-05525);
EnVision,PerkinElmer;
Vi-cell計數器,Beckman(Cat# Vi-CELL™ XR 細胞活力分析儀)。
2.
方法
a) 製備化合物板:
待測化合物做10個點3倍稀釋,起始濃度為100μM,Bravo完成稀釋
參照化合物GLP-1(7-37)做10個點4倍稀釋,起始濃度為500nM,Bravo完成稀釋。
b) 轉移化合物:
1) 使用Echo轉移100 nL化合物至OptiPlate-384板。
2) 將OptiPlate-384板在1000 rpm離心5秒。
c) 細胞懸液的製備
1) 將一支GLP-1R細胞凍存管迅速置於37℃溫水中解凍。
2) 將細胞懸液轉移至15 mL離心管中,用10mL HBSS輕柔沖洗。
3) 將離心管在1000 rpm室溫離心1分鐘。
4) 棄去上清。
5) 輕柔打散底部細胞並再用10 mL HBSS輕柔沖洗,離心沉降細胞,最後用實驗緩衝液重懸細胞。
6) 利用Vi-cell測量細胞密度與活度。
7) 用實驗緩衝液將GLP-1R細胞濃度稀釋至1.0*10
5/mL。
8) 在OptiPlate-384板中轉入10μL釋好的細胞懸液,使每孔細胞量為1000 個細胞/well。
d) 加入檢測試劑:
1) 在OptiPlate-384板空孔中加入10μL 800nM梯度稀釋好的cAMP標準品。
2) 加入10μLcAMP檢測試劑。
3) 用TopSeal-A膜覆蓋OptiPlate-384板,室溫培養60分鐘。揭去TopSeal-A,在EnVision讀數。
2)
分析方法
a) 標準曲線:
在Prism5.0軟體中新建log(抑制劑) vs 回應 – 可變斜率模式,將標準曲線濃度(x)及其對應的665\615資料(y)代入模型中,將標準曲線濃度(橫坐標)進行x=log(x)轉換,並藉由轉換後的xy做標準曲線。
b) cAMP水平轉化:
將全板665\615資料轉置為一列資料,代入標準曲線濃度(x)與665\615資料(y)表格中的y中,將軟體自動轉化對應的x(內插值(interpolated) x)複製出表格,再藉由公式x=10^(x)轉換為cAMP水平,並將資料重新轉置為384分佈。
c) 活性%計算公式:
活性%= (cAMP水平-LC) / (HC-LC)*100%
Z 因素(因子,factor): 1-3*(STD_HC + STD_HC) / (HC-LC)
測試窗(Assay Window): HC / LC
LC:加入DMSO孔的平均cAMP水平(level)
HC:加入最高濃度參比化合物孔的平均cAMP水平
d) 樣品曲線:
在Prism5.0軟體中新建log(促效劑) vs 回應 – 可變斜率模式,將樣品濃度(x)及其對應的活性%資料(y)代入模型中,將標準曲線濃度(橫坐標)進行x=log(x)轉換,並藉由轉換後的xy做樣品曲線。
表2 GLP-1R促效劑cAMP刺激試驗中化合物的生物活性
樣品 | EC50(nM) | 樣品 | EC50(nM) | 樣品 | EC50(nM) | 樣品 | EC50(nM) |
1 | 4152 | 106 | 2.31 | 211 | 1.02 | 316 | 0.54 |
2 | 0.32 | 107 | 1.83 | 212 | 2.96 | 317 | 0.32 |
3 | 0.56 | 108 | 2.39 | 213 | 0.78 | 318 | 1.53 |
4 | 0.14 | 109 | 46.97 | 214 | 1.21 | 319 | 0.43 |
5 | 0.12 | 110 | 4.45 | 215 | 2.11 | 320 | 13.67 |
6 | 1.21 | 111 | 2.34 | 216 | 0.82 | 321 | 0.94 |
7 | 0.35 | 112 | 6.18 | 217 | 0.79 | 322 | 31.92 |
8 | 1.33 | 113 | 4.38 | 218 | 1.63 | 323 | 2.73 |
9 | 2982 | 114 | 1.04 | 219 | 1.21 | 324 | 2.95 |
10 | 993 | 115 | 0.87 | 220 | 0.44 | 325 | 1.05 |
11 | 567.4 | 116 | 0.92 | 221 | 2.13 | 326 | 0.64 |
12 | 121.7 | 117 | 10.21 | 222 | 3.56 | 327 | 3.96 |
13 | 189.2 | 118 | 8.31 | 223 | 0.95 | 328 | 12.73 |
14 | 447.4 | 119 | 0.63 | 224 | 3.29 | 329 | 1.66 |
15 | 25.65 | 120 | 15.32 | 225 | 0.18 | 330 | 0.88 |
16 | 145.7 | 121 | 4.23 | 226 | 0.12 | 331 | 1.27 |
17 | 403.9 | 122 | 3.21 | 227 | 0.22 | 332 | 1.58 |
18 | 411 | 123 | 5.49 | 228 | 1.26 | 333 | 2.19 |
19 | 175.8 | 124 | 0.17 | 229 | 0.21 | 334 | 0.61 |
20 | 3239 | 125 | 0.55 | 230 | 0.09 | 335 | 0.97 |
21 | 160.3 | 126 | 0.18 | 231 | 0.87 | 336 | 1.03 |
22 | 1369 | 127 | 0.15 | 232 | 1.26 | 337 | 0.45 |
23 | >10000 | 128 | 0.3 | 233 | 0.92 | 338 | 1.32 |
24 | 90.06 | 129 | 1.14 | 234 | 3.87 | 339 | 0.39 |
25 | 756.5 | 130 | 1.34 | 235 | 0.42 | 340 | 0.28 |
26 | >10000 | 131 | 1.21 | 236 | 1.04 | 341 | 0.31 |
27 | 128.8 | 132 | 0.74 | 237 | 8.71 | 342 | 0.91 |
28 | 75.69 | 133 | 0.38 | 238 | 11.92 | 343 | 0.54 |
29 | >10000 | 134 | 0.85 | 239 | 3.19 | 344 | 1.02 |
30 | 1383 | 135 | 1.25 | 240 | 20.73 | 345 | 0.21 |
31 | 37.23 | 136 | 2.19 | 241 | 0.31 | 346 | 0.76 |
32 | 111.7 | 137 | 5.49 | 242 | 0.17 | 347 | 0.81 |
33 | 61 | 138 | 8.92 | 243 | 0.48 | 348 | 0.91 |
34 | 90.06 | 139 | 15.23 | 244 | 0.33 | 349 | 1.61 |
35 | >10000 | 140 | 2.97 | 245 | 0.51 | 350 | 0.51 |
36 | >10000 | 141 | 3.29 | 246 | 0.91 | 351 | 0.19 |
37 | 106.1 | 142 | 0.21 | 247 | 0.83 | 352 | 1.03 |
38 | 17.68 | 143 | 0.75 | 248 | 1.28 | 353 | 0.44 |
39 | 285.7 | 144 | 23.36 | 249 | 0.44 | 354 | 0.21 |
40 | 36.45 | 145 | 0.45 | 250 | 1.49 | 355 | 0.78 |
41 | 376.3 | 146 | 23.98 | 251 | 2.22 | 356 | 2.21 |
42 | >10000 | 147 | 0.68 | 252 | 1.03 | 357 | 0.41 |
43 | 256.1 | 148 | 21.07 | 253 | 2.01 | 358 | 0.98 |
44 | 4.36 | 149 | 34.65 | 254 | 1.92 | 359 | 1.62 |
45 | 1.39 | 150 | 5.78 | 255 | 0.32 | 360 | 0.19 |
46 | 42.42 | 151 | 0.6 | 256 | 12.53 | 361 | 0.9 |
47 | 9.6 | 152 | 0.64 | 257 | 15.11 | 362 | 0.85 |
48 | 4.36 | 153 | 0.59 | 258 | 31.75 | 363 | 0.41 |
49 | 2.47 | 154 | 0.45 | 259 | 0.91 | 364 | 0.38 |
50 | 34.05 | 155 | 0.55 | 260 | 1.03 | 365 | 1.32 |
51 | 133.5 | 156 | 0.68 | 261 | 0.81 | 366 | 5.97 |
52 | 12.78 | 157 | 0.77 | 262 | 3.12 | 367 | 3.92 |
53 | 114.2 | 158 | 1.03 | 263 | 5.78 | 368 | 9.19 |
54 | 79.72 | 159 | 9.74 | 264 | 4.22 | 369 | 2.91 |
55 | 1.83 | 160 | 0.98 | 265 | 45.9 | 370 | 5.12 |
56 | 0.97 | 161 | 0.87 | 266 | 3.19 | 371 | 3.19 |
57 | 1.41 | 162 | 1.23 | 267 | 1.99 | 372 | 0.65 |
58 | 4.35 | 163 | 0.99 | 268 | 3.64 | 373 | 0.39 |
59 | 7.2 | 164 | 1.68 | 269 | 10.78 | 374 | 0.55 |
60 | 22.28 | 165 | 0.88 | 270 | 1.02 | 375 | 1.01 |
61 | 6.75 | 166 | 0.76 | 271 | 0.97 | 376 | 0.98 |
62 | 0.51 | 167 | 0.68 | 272 | 3.21 | 377 | 3.41 |
63 | 0.49 | 168 | 10.48 | 273 | 2.78 | 378 | 1.03 |
64 | 150.8 | 169 | 1.02 | 274 | 1.65 | 379 | 3.12 |
65 | 1.75 | 170 | 3.55 | 275 | 6.21 | 380 | 6.91 |
66 | 1.41 | 171 | 9.53 | 276 | 0.65 | 381 | 1.99 |
67 | 5.89 | 172 | 1.63 | 277 | 0.76 | 382 | 0.1 |
68 | 142.5 | 173 | 31.47 | 278 | 3.18 | 383 | 1.92 |
69 | 70.47 | 174 | 2.13 | 279 | 0.95 | 384 | 0.08 |
70 | 1.9 | 175 | 1.23 | 280 | 21.03 | 385 | 0.61 |
71 | 132.1 | 176 | 0.87 | 281 | 1.21 | 386 | 0.15 |
72 | 0.61 | 177 | 0.23 | 282 | 4.32 | 387 | 0.86 |
73 | 0.52 | 178 | 0.19 | 283 | 10.23 | 388 | 0.82 |
74 | >10000 | 179 | 0.76 | 284 | 9.85 | 389 | 2.81 |
75 | >10000 | 180 | 1.06 | 285 | 0.42 | 390 | 5.21 |
76 | 9.04 | 181 | 0.21 | 286 | 0.21 | 391 | 0.91 |
77 | 1.9 | 182 | 0.32 | 287 | 2.98 | 392 | 10.12 |
78 | 23.11 | 183 | 0.76 | 288 | 3.87 | 393 | 15.21 |
79 | 76.45 | 184 | 1.57 | 289 | 0.99 | 394 | 21.09 |
80 | 2.05 | 185 | 1.32 | 290 | 1.2 | 395 | 10.34 |
81 | 14.5 | 186 | 2.12 | 291 | 0.75 | 396 | 145.87 |
82 | 115.9 | 187 | 0.2 | 292 | 8.73 | 397 | 127.19 |
83 | 3.76 | 188 | 1.19 | 293 | 0.99 | 398 | 110.03 |
84 | 17.95 | 189 | 3.54 | 294 | 1.02 | 399 | >10000 |
85 | 0.41 | 190 | 9.27 | 295 | 2.19 | 400 | 104.39 |
86 | 0.75 | 191 | 3.69 | 296 | 1.92 | 401 | 21.83 |
87 | 10.05 | 192 | 9.87 | 297 | 3.65 | 402 | 73.19 |
88 | 4.45 | 193 | 0.21 | 298 | 0.37 | 403 | 23.19 |
89 | 87.84 | 194 | 0.33 | 299 | 0.16 | 404 | 19.76 |
90 | 1.59 | 195 | 2.31 | 300 | 0.19 | 405 | 39.87 |
91 | 26.16 | 196 | 0.17 | 301 | 0.18 | 406 | 99.17 |
92 | 18.65 | 197 | 0.19 | 302 | 1.07 | 407 | 0.16 |
93 | 29.81 | 198 | 0.35 | 303 | 0.91 | 408 | 0.21 |
94 | 371.7 | 199 | 0.47 | 304 | 0.18 | 409 | 0.42 |
95 | 62 | 200 | 0.82 | 305 | 0.19 | 410 | 0.31 |
96 | 74.34 | 201 | 1.99 | 306 | 0.56 | 411 | 0.33 |
97 | 139.6 | 202 | 2.21 | 307 | 0.21 | 412 | 3.1 |
98 | 16.94 | 203 | 0.24 | 308 | 3.12 | 413 | 0.49 |
99 | 42.42 | 204 | 0.63 | 309 | 0.87 | 414 | 0.57 |
100 | 0.98 | 205 | 0.98 | 310 | 0.93 | 415 | 0.71 |
101 | 0.75 | 206 | 5.91 | 311 | 0.39 | 416 | 0.37 |
102 | 1.33 | 207 | 0.43 | 312 | 0.99 | 417 | 0.65 |
103 | 0.83 | 208 | 0.25 | 313 | 1.39 | ||
104 | 1.05 | 209 | 0.32 | 314 | 0.63 | ||
105 | 0.78 | 210 | 0.39 | 315 | 1.03 |
B.Tag
-lite 結合試驗
1.
材料
1) 細胞株該細胞株由上海藥明康得構建。詳情見下表。
靶點 | 宿主細胞 | 選殖 |
GLP-1 | HEK293 | N/A |
2)
試劑與耗材
名稱 | 貨號 | 廠家 |
SNAP-Lumi4-Tb-5 nmoles | SSNPTBD | Cisbio |
GLP-1受體紅色促效劑(receptors red agonist) | L0030RED | Cisbio |
Tag-lite標記介質(labeling medium) (5×) | LABMED | Cisbio |
DMEM | 11965-092 | Gibco |
FBS | FSP500 | Excell |
青黴素/鏈黴素(100x) | SV30010 | Hyclone |
G418 | 10131-027 | Gibco |
TE | 25300-062 | Gibco |
3)
儀器
名稱 | 型號 | 廠家 |
EnVision | envision2014 | PerkinElmer |
Vi-cell計數器 | Vi-CELL™ XR細胞活力分析儀 | Beckman |
Bravo | Bravo V11 | Agilent |
ECHO | ECHO 655 | Labcyte |
離心機 | Allegra™ 25R離心機 | Beckman |
恆溫箱(Incubator) | 1153447 | Thermo |
2.
方法
第 1 天:細胞鋪板1) 棄去細胞培養基。
2) 加入DPBS清洗細胞並吸去。
3) 加入3 mL 0.05%胰酶,37℃培養1分鐘,顯微鏡觀察細胞狀態。
4) 輕拍培養皿,細胞脫離底部,加入10 mL細胞培養基,吹打均勻。轉移細胞懸液至離心管中。
5) 1000轉/分鐘,離心5分鐘。輕輕棄去培養基,注意不要碰到底部細胞。
6) 加入培養基重懸細胞,用槍頭吹散細胞。
7) 用細胞計數儀對細胞進行計數和活力測定。
8) 用培養基將細胞稀釋至0.9 × 10
6個細胞/mL,2 mL/孔加入6孔細胞板。
9) 5% CO
2,37°C培養箱培養過夜。
第 2 天:1) 用ddH
2O將5× Tag-lite標記介質稀釋至1×。
2) 將SNAP-Lumi4-Tb用1×Tag-lite緩衝液按照1:1000進行稀釋。
3) 將6孔板中的培養基去除,加入1 mL/孔配製好的SNAP-Lumi4-Tb溶液,置於37℃ 5% CO
2培養箱1小時進行培養。
4) 培養完成後,將6孔板中液體去除,加入Tag-lite緩衝液清洗2次。
5) 用胰酶將細胞消化下來,離心去除胰酶後,用Tag-lite緩衝液重懸至1×10
6個細胞/mL。
6) 待測化合物和參考化合物藉由Echo 3倍連續稀釋成10個點,並轉移100nL至反應板中。
7) 加入10 µL帶有標籤的細胞到反應板中,每孔細胞數量為10000個,1000rpm離心1min。
8) 室溫培養30 min。
9) 用Echo轉移50nL GLP-1受體紅色促效劑到反應板中,終濃度為4.917 nM。
10) 將反應板室溫培養2h後用Envision讀數。最終數值為665nm處與615nm處發射光的比值。
11) 結果分析
a) 抑制率%計算公式:
抑制率% = 100% - (比率-LC) / (HC-LC)*100%
Z因素: 1-3*(STD_HC + STD_HC) / (HC-LC)
測試窗: HC / LC
HC:加入DMSO孔的平均比率
LC:加入最高濃度參比化合物孔的平均比率
b) 用GraphPad Prism 5.0 中的“log(抑制劑) vs. 回應 – 可變斜率”模型進行各樣品量效曲線的擬合,將樣品濃度(x)及其對應的抑制率%資料(y)代入模型中,將樣品濃度(橫坐標)進行x=log(x)轉換,並藉由轉換後的xy做樣品曲線,得到IC
50。
c) 根據樣品IC
50和紅色促效劑Kd計算出樣品Ki。公式中S為紅色促效劑實際使用濃度。
表3 Tag-lite結合試驗中化合物的生物活性
樣品 | IC50(nM) | Ki | 樣品 | IC50(nM) | Ki | 樣品 | IC50(nM) | Ki |
2 | 345.2 | 164.55 | 151 | 1048 | 519.32 | 354 | 2137 | 1057.5 |
3 | 1750 | 876.24 | 153 | 1451 | 872.72 | 382 | 689.2 | 341.5 |
5 | 1705 | 910.51 | 154 | 1582.3 | 904.1 | 383 | 1477 | 899.3 |
62 | 2632 | 1317.87 | 166 | 2651 | 1324.4 | 384 | 109.9 | 68.32 |
80 | 2325 | 1164.15 | 178 | 875.32 | 429.66 | 385 | 158.1 | 82.7 |
85 | 143.2 | 71.7 | 196 | 152.3 | 87.9 | 386 | 119.6 | 69.9 |
88 | 1838 | 920.31 | 197 | 165.3 | 84 | 387 | 346.3 | 204.7 |
90 | 1898 | 950.35 | 203 | 158 | 90.3 | 391 | 115.8 | 70.3 |
100 | 1261 | 893.31 | 207 | 149 | 82.37 | 407 | 180.2 | 110.5 |
101 | 1281 | 641.41 | 229 | 121.5 | 75.91 | 408 | 105.9 | 68.4 |
103 | 1552 | 885.3 | 244 | 189.2 | 110.1 | 409 | 486.3 | 237.3 |
105 | 1945 | 1004.3 | 245 | 146 | 82.3 | 411 | 119.7 | 72.6 |
126 | 1398 | 806.2 | 276 | 2456 | 1005.6 | 413 | 28.02 | 14.13 |
127 | 1252 | 743.5 | 334 | 1213 | 692.3 | 414 | 31.7 | 15.56 |
134 | 1838 | 903.9 | 335 | 1107 | 615.4 | 415 | 232.78 | 116.63 |
142 | 2011 | 1001.42 | 340 | 123 | 88.5 | 416 | 54.3 | 29.33 |
145 | 1922 | 956.21 | 341 | 158.3 | 95.5 | 417 | 136.7 | 69.21 |
147 | 1749 | 841.2 | 342 | 140.4 | 72.2 |
無
無。
無。
Claims (8)
- 一種式I-A-1的化合物、或其藥學上可接受的鹽, 其中, R 1是C 1-6烷基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-S-R 1b,-S(O)R 1b,-S(O)(NH)R 1b,-S(O) 2R 1b,-S(O) 2N(R 1b)(R 1c),-S(O)(NR 1b)R 1c,-C(O)N(R 1b)(R 1c),-C(O)R 1b,或-C(O)OR 1c,其中所述烷基、鹵代烷基、環烷基、芳基、5-10員雜芳基或雜環基各自可選地被一至四個Z 1取代,並且其中任何兩個Z 1可以與它們所連接的原子結合以形成C 3-10環烷基或雜環基或C 6-10芳基或5-10員雜芳基; 環A是C 3-10環烷基,雜環基,C 6-10芳基或5-10員雜芳基,所述C 3-10環烷基,雜環基,C 6-10芳基或5-10員雜芳基各自可選地被1至4個Z 1a取代; 環B是C 3-10環烷基,雜環基,C 6-10芳基或5-10員雜芳基,所述C 3-10環烷基,雜環基,C 6-10芳基或5-10員雜芳基各自可選地被1至4個R 4取代; 環A和環B各自包含0-3個雙鍵; R 2是H,C 1-6烷基,-C 1-6烷基-烷氧基,-C 1-6烷基-環烷氧基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-OR 2a,-S-R 2a,-S(O)R 2a,-S(O)(NH)R 2a,-S(O) 2R 2a,-S(O) 2N(R 2a)(R 2b),或-S(O)(NR 2a)R 2b,其中,烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1取代;並且其中任何兩個Z 1可以與它們所連接的原子結合以形成C 3-10環烷基或雜環基或C 6-10芳基或5-10員雜芳基; X各自獨立地為-N=,-C(H)=,或-C(R 8)=; 每個R 3和R 3’獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-NO 2,-OR 3a,-C(O)R 3a,-CH 2C(O)OR 3a,-C(O)OR 3a,-C(O)N(R 3a)(R 3b),-N(R 3a)C(O)R 3b,-N(R 3a)C(O)OR 3b,-N(R 3a)C(O)N(R 3b) 2,-C(O)NHS(O) 2R 3a,-C(O)NR 3aS(O) 2R 3b,-C(O)NR 3aS(O) 2NR 3bR 3c,-C(O)NR 3a-S(O)(=NR 3b)R 3c,-S(O) 2R 3a,-S(O) 2OR 3a,-S(O) 2N(R 3a)(R 3b),-N(R 3a)S(O) 2R 3b,-S(O) 2NHC(O)R 3a,-S(O)(=NR 3a)R 3b,-S(O)(=NR 3a)NR 3b,-S(=NR 3a)(=NR 3b)R 3c,-P(O)(OR 3a)(R 3b),-P(O)(OR 3a)(OR 3b),-B(OR 3a)(OR 3b),或-O-C 1-6烷基-C(O)OR 3a,其中,所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R 3d取代; 每個R 3a,R 3b,和R 3c獨立地是H,C 1-6烷基,C 6-10芳基,5-10員雜芳基,C 1-6鹵代烷基,C 2-8烷氧基烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-N(R 9a)C(O)-O-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-O-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,- CH 2CH(N(R 9a) 2)C(O)OR 9b,-P(O)(OR 9c) 2,-OP(O)(OR 9c) 2,-CH 2P(O)(OR 9c) 2,- CH 2OP(O)(OR 9c) 2,-OCH 2P(O)(OR 9c) 2,-C(O)OCH 2P(O)(OR 9c) 2,-P(O)(R 9c)(OR 9d) ,-OP(O)(R 9c)(OR 9d) ,-CH 2P(O)(R 9c)(OR 9d) ,-OCH 2P(O)(R 9c)(OR 9d) ,-C(O)OCH 2P(O)(R 9c)(OR 9d) ,-P(O)(N(R 9c) 2) 2,- OP(O)(N(R 9c) 2) 2,-CH 2P(O)(N(R 9c) 2) 2,-OCH 2P(O)(N(R 9c) 2) 2,- C(O)OCH 2P(O)(N(R 9c) 2) 2,-P(O)(N(R 9c) 2)(OR 9d) ,-OP(O)(N(R 9c) 2)(OR 9d) ,-CH 2P(O)(N(R 9c) 2)(OR 9d) ,-OCH 2P(O)(N(R 9c) 2)(OR 9d) ,-C(O)OCH 2P(O)(N(R 9c) 2)(OR 9d) ,-P(O)(R 9c)(N(R 9d) 2) ,-OP(O)(R 9c)(N(R 9d) 2) ,-CH 2P(O)(R 9c)(N(R 9d) 2) ,-OCH 2P(O)(R 9c)(N(R 9d) 2) ,- C(O)OCH 2P(O)(R 9c)(N(R 9d) 2),C 1-6烷基-雜環基,C 1-6烷基-芳基,或C 1-6烷基-(5-10員)雜芳基,其中所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個R 4獨立地是H、-OH、CH 2OH、C 1-9烷基,C 1-8鹵代烷基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 4a,-C(O)R 4a,-C(O)O-R 4a,-C(O)N(R 4a)(R 4b),-N(R 4a)(R 4b),-N(R 4a) 2(R 4b) +,-N(R 4a)-C(O)R 4b,-N(R 4a)C(O)O(R 4b),-N(R 4a)C(O)N(R 4b)(R 4c),-N(R 4a)S(O) 2(R 4b),-N(R 4a)S(O) 2-N(R 4b)(R 4c),-N(R 4a)S(O) 2O(R 4b),-OC(O)R 4a,-OC(O)OR 4a,-OC(O)-N(R 4a)(R 4b),-S-R 4a,-S(O)R 4a,-S(O)(NH)R 4a,-S(O) 2R 4a,-S(O) 2N(R 4a)(R 4b),-S(O)(NR 4a)R 4b,或-Si(R 4a) 3;其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基,或5-10員雜芳基各自可選地被1至4個Z 1b取代;或者,兩個連接在相鄰環原子上的R 4基團與它們所連接的原子結合以形成C 5-10環烷基或雜環基,它們各自可選地被1至4個Z 1b取代; 每個R 5a和R 5b獨立地是H,C 1-6烷基,C 1-6烷氧基,C 1-6鹵代烷基,C 2-6烷氧基烷基,鹵素,C 3-10環烷基,雜環基,-C 1-6烷基-N(R 9a)(R 9b),-CN,-OR 5a1,或-N(R 5a1)(R 5a2); 或者,R 5a和R 5b與它們所連接的原子組合以形成C 3-10環烷基或雜環基,它們各自可選地被1至4個R 5a3取代; 或者,R 5a或R 5b與環A上的任意取代基環合組合以形成C 5-10環烷基或雜環基,它們各自可選地被1至4個R 5a3取代; 每個R 5a1和R 5a2獨立地是H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、C 6-10芳基,或5-10員雜芳基,其中所述環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R 5a4取代; V是-C(O)-,-O-,-N(R 6a)-,或-C(R 6b)(R 6c)-; R 6a是H,C 1-6烷基,C 3-10環烷基,雜環基,-S(O) 2R 6a1,或-S(O) 2N(R 6a1)(R 6a2),其中,所述環烷基或雜環基各自可選地被C 1-6烷基、F或-CN取代; 每個R 6b和R 6c獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 2-6烷氧基烷基,鹵素,C 3-10環烷基,雜環基,-C 1-6烷基-N(R 9a)(R 9b),-CN,-OR 6c1,或-N(R 6c2)(R 6c3),其中所述烷基、環烷基或雜環基各自可選地被1至4個R 6b1取代;或R 6b和R 6c與它們所連接的原子結合以形成C 3-10環烷基或雜環基,它們各自可選地被1至4個R 6b1取代;或R 6a或R 6c與一個R 4基團和它們所連接的原子結合以形成C 5-10環烷基或雜環基,它們各自可選地被1至4個R 10取代; Y是-N(R 7)-,-O-,-S-,-S(O)-,-S(O) 2-,-S(O)(=NH)-,或-S(O)(=NR 7)-; 每個R 3d,R 5a3,R 5a4,R 6b1,和R 10獨立地為H,C 1-6烷基,C 1-6鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO 2R 3e,-NO 2,或-C(O)N(R 2a)(R 2b),其中所述雜環基或5-10員雜芳基各自可選地被C 1-6烷基、C 1-6鹵代烷基或C 1-6鹵代烷氧基取代; 每個R 6a1,R 6a2,R 6c1,R 6c2,R 6c3和R 7獨立地是H,C 1-6烷基或C 3-10環烷基; 每個R 8獨立地是C 1-9烷基,C 1-8鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基) 2; 每個R 9a和R 9b獨立地是H,C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3; 或R 9a和R 9b融合形成一個3-10員雜環基,其可選地被C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3取代; 每個Z 1獨立地是C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3,其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1a取代; 每個Z 1a獨立地是H,-OH,C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3, 其中所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個Z 1b獨立地是H,C 1-9烷基,C 1-8鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 2-6烯基),-O(C 2-6炔基),-O(C 3-15環烷基),-O(雜環基),-O(C 6-10芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 2-6烯基),-NH(C 2-6炔基),-NH(C 3-15環烷基),-NH(雜環基),-NH(C 6-10芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基) 2,-N(C 2-6烯基) 2,-N(C 2-6炔基) 2,-N(C 3-15環烷基) 2,-N(雜環基) 2,-N(C 6-10芳基) 2,-N(5-10員雜芳基) 2,-N(C 1-9烷基)(C 1-8鹵代烷基),-N(C 1-9烷基)(C 2-6烯基),-N(C 1-9烷基)(C 2-6炔基),-N(C 1-9烷基)(C 3-15環烷基),-N(C 1-9烷基)(雜環基),-N(C 1-9烷基)(C 6-10芳基),-N(C 1-9烷基)(5-10員雜芳基),-C(O)(C 1-9烷基),-C(O)(C 1-8鹵代烷基),-C(O)(C 2-6烯基),-C(O)(C 2-6炔基),-C(O)(C 3-15環烷基),-C(O)(雜環基),-C(O)(C 6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C 1-9烷基),-C(O)O(C 1-8鹵代烷基),-C(O)O(C 2-6烯基),-C(O)O(C 2-6炔基),-C(O)O(C 3-15環烷基),-C(O)O(雜環基),-C(O)O(C 6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH 2,-C(O)NH(C 1-9烷基),-C(O)NH(C 1-8鹵代烷基),-C(O)NH(C 2-6烯基),-C(O)NH(C 2-6炔基),-C(O)NH(C 3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C 6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C 1-9烷基) 2,-C(O)N(C 1-8鹵代烷基) 2,-C(O)N(C 2-6烯基) 2,-C(O)N(C 2-6炔基) 2,-C(O)N(C 3-15環烷基) 2,-C(O)N(雜環基) 2,-C(O)N(C 6-10芳基) 2,-C(O)N(5-10員雜芳基) 2,-NHC(O)(C 1-9烷基),-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 2-6烯基),-NHC(O)(C 2-6炔基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C 6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6烯基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C 6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C 1-9烷基),-NHC(O)NH(C 1-8鹵代烷基),-NHC(O)NH(C 2-6烯基),-NHC(O)NH(C 2-6炔基),-NHC(O)NH(C 3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C 6-10芳基),-NHC(O)NH(5-10員雜芳基),-NHS(O)(C 1-9烷基),-N(C 1-9烷基)(S(O)(C 1-9烷基),-S(C 1-9烷基),-S(C 1-8鹵代烷基),-S(C 2-6烯基),-S(C 2-6炔基),-S(C 3-15環烷基),-S(雜環基),-S(C 6-10芳基),-S(5-10員雜芳基),-S(O)N(C 1-9烷基) 2,-S(O)(C 1-9烷基),-S(O)(C 1-8鹵代烷基),-S(O)(C 2-6烯基),-S(O)(C 2-6炔基),-S(O)(C 3-15環烷基),-S(O)(雜環基),-S(O)(C 6-10芳基),-S(O)(5-10員雜芳基),-S(O) 2(C 1-9烷基),-S(O) 2(C 1-8鹵代烷基),-S(O) 2(C 2-6烯基),-S(O) 2(C 2-6炔基),-S(O) 2(C 3-15環烷基),-S(O) 2(雜環基),-S(O) 2(C 6-10芳基),-S(O) 2(5-10員雜芳基),-S(O)(NH)(C 1-9烷基),-S(O) 2NH(C 1-9烷基),或者-S(O) 2N(C 1-9烷基) 2, 其中所述烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團取代:C 1-9烷基,C 1-8鹵代烷基,鹵素,-OH,-NH 2,CO 2H-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 3-15環烷基) 2,-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C 1-9烷基),S(O) 2(C 1-9烷基),-S(O) 2(C 1-8鹵代烷基),-S(O) 2(C 3-15環烷基),-S(O) 2(雜環基),-S(O) 2(芳基),-S(O) 2(5-10員雜芳基),-S(O)(NH)(C 1-9烷基),-S(O) 2NH(C 1-9烷基),或-S(O) 2N(C 1-9烷基) 2; 每個R 1b,R 1c,R 2a,R 2b,R 4a,R 4b,R 4c,R 9c,R 9d,R 12a,R 12b,和R 12c獨立地是H,-OH,C 1-9烷基,C 2-6烯基,C 2-6炔基,C 3-15環烷基,雜環基,C 6-10芳基,或5-10員雜芳基,其中所述烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代;並且 每個R 3e獨立地是H,C 1-6烷基,C 1-6鹵代烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基,-C 1-4烷基-O-C(O)-O-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-P(O)(OR 9c) 2,-CH 2P(O)(OR 9c) 2,-OCH 2P(O)(OR 9c) 2,-C(O)OCH 2P(O)(OR 9c) 2,-P(O)(R 9c)(OR 9d),-OP(O)(R 9c)(OR 9d),-CH 2P(O)(R 9c)(OR 9d),-C(O)OCH 2P(O)(R 9c)(OR 9d),-P(O)(N(R 9c) 2) 2,-CH 2P(O)(N(R 9c) 2) 2,-C(O)OCH 2P(O)(N(R 9c) 2) 2,-P(O)(N(R 9c) 2)(OR 9d),-CH 2P(O)(N(R 9c) 2)(OR 9d),-C(O)OCH 2P(O)(N(R 9c) 2)(OR 9d),-P(O)(R 9c)(N(R 9d) 2),-CH 2P(O)(R 9c)(N(R 9d) 2),或者-C(O)OCH 2P(O)(R 9c)(N(R 9d) 2), 其中所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代;其中,每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;並且其中,每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子。
- 如請求項1所述之化合物、或其藥學上可接受的鹽,其中所述化合物是具有式I-A-2或式I-A-3的化合物, 其中,C環是C 3-10環烷基,雜環基,C 6-10芳基或5-10員雜芳基,其各自可選地被1-4個Z 1取代; Y 1-V是N-CH 2,N-CH(CH 3),N-CF 2,CH-CH 2,CH-CF 2,CH-NH,N-S(O),N-S(O) 2,N-C(O),CH-C(O)或環丙烷基; Y 2是C,CH或N; R 2是H,C 1-6烷基,C 1-6烷基-烷氧基,-C 1-6烷基-環烷氧基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-OR 2a,-S-R 2a,-S(O)R 2a,-S(O)(NH)R 2a,-S(O) 2R 2a,-S(O) 2N(R 2a)(R 2b),或-S(O)(NR 2a)R 2b,其中,所述烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1取代並且其中任何兩個Z 1可以與它們所連接的原子結合以形成C 3-10環烷基或雜環基或C 6-10芳基或5-10員雜芳基; X各自獨立地為-N=,-C(H)=,或-C(R 8)=; 每個R 3和R 3’獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-NO 2,-OR 3a,-C(O)R 3a,-CH 2C(O)OR 3a,-C(O)OR 3a,-C(O)N(R 3a)(R 3b),-N(R 3a)C(O)R 3b,-N(R 3a)C(O)OR 3b,-N(R 3a)C(O)N(R 3b) 2,-C(O)NHS(O) 2R 3a,-C(O)NR 3aS(O) 2R 3b,-C(O)NR 3aS(O) 2NR 3bR 3c,-C(O)NR 3a-S(O)(=NR 3b)R 3c,-S(O) 2R 3a,-S(O) 2OR 3a,-S(O) 2N(R 3a)(R 3b),-N(R 3a)S(O) 2R 3b,-S(O) 2NHC(O)R 3a,-S(O)(=NR 3a)R 3b,-S(O)(=NR 3a)NR 3b,-S(=NR 3a)(=NR 3b)R 3c,-P(O)(OR 3a)(R 3b),-P(O)(OR 3a)(OR 3b),-B(OR 3a)(OR 3b),或-O-C 1-6烷基-C(O)OR 3a,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R 3d取代; 每個R 3a,R 3b和R 3c獨立地是H,C 1-6烷基,C 6-10芳基,5-10員雜芳基,C 1-6鹵代烷基,C 2-8烷氧基烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-N(R 9a)C(O)-O-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-O-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,-CH 2CH(N(R 9a) 2)C(O)OR 9b,C 1-6烷基-雜環基,C 1-6烷基-芳基或C 1-6烷基-(5-10員)雜芳基,其中所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個R 5a和R 5b獨立地是H,C 1-6烷基,C 1-6烷氧基,C 1-6鹵代烷基,C 2-6烷氧基烷基,鹵素,C 3-10環烷基,雜環基,-C 1-6烷基-N(R 9a)(R 9b),-CN,-OR 5a1,或-N(R 5a1)(R 5a2);或者,R 5a和R 5b與它們所連接的原子組合成C 3-10環烷基或雜環基,它們各自可選地被1至4個R 5a3地取代;每個R 5a1和R 5a2獨立地是H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、C 6-10芳基或5-10員雜芳基,其中,環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個鹵素取代; 每個R 3d和R 5a3獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO 2R 3e,-NO 2,或-C(O)N(R 2a)(R 2b),其中,所述雜環基或5-10員雜芳基各自可選地被C 1-6烷基、C 1-6鹵代烷基或C 1-6鹵代烷氧基取代; 每個R 8獨立地是C 1-9烷基,C 1-8鹵代烷基,C 2-6烯烴基,C 2-6炔烴基,鹵素,氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基); 每個R 9a和R 9b獨立地是H,C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3;或R 9a和R 9b融合形成一個3-10員雜環基,其可選性地被C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3取代; 每個Z 1獨立地是C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1a取代; 每個Z 1a獨立地是C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個Z 1b獨立地是H,C 1-9烷基,C 1-8鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 2-6烯基),-O(C 2-6炔基),-O(C 3-15環烷基),-O(雜環基),-O(C 6-10芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 2-6烯基),-NH(C 2-6炔基),-NH(C 3-15環烷基),-NH(雜環基),-NH(C 6-10芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基) 2,-N(C 2-6烯基) 2,-N(C 2-6炔基) 2,-N(C 3-15環烷基) 2,-N(雜環基) 2,-N(C 6-10芳基) 2,-N(5-10員雜芳基) 2,-N(C 1-9烷基)(C 1-8鹵代烷基),-N(C 1-9烷基)(C 2-6烯基),-N(C 1-9烷基)(C 2-6炔基),-N(C 1-9烷基)(C 3-15環烷基),-N(C 1-9烷基)(雜環基),-N(C 1-9烷基)(C 6-10芳基),-N(C 1-9烷基)(5-10員雜芳基),-C(O)(C 1-9烷基),-C(O)(C 1-8鹵代烷基),-C(O)(C 2-6烯基),-C(O)(C 2-6炔基),-C(O)(C 3-15環烷基),-C(O)(雜環基),-C(O)(C 6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C 1-9烷基),-C(O)O(C 1-8鹵代烷基),-C(O)O(C 2-6烯基),-C(O)O(C 2-6炔基),-C(O)O(C 3-15環烷基),-C(O)O(雜環基),-C(O)O(C 6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH 2,-C(O)NH(C 1-9烷基),-C(O)NH(C 1-8鹵代烷基),-C(O)NH(C 2-6烯基),-C(O)NH(C 2-6炔基),-C(O)NH(C 3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C 6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C 1-9烷基) 2,-C(O)N(C 1-8鹵代烷基) 2,-C(O)N(C 2-6烯基) 2,-C(O)N(C 2-6炔基) 2,-C(O)N(C 3-15環烷基) 2,-C(O)N(雜環基) 2,-C(O)N(C 6-10芳基) 2,-C(O)N(5-10員雜芳基) 2,-NHC(O)(C 1-9烷基),-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 2-6烯基),-NHC(O)(C 2-6炔基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C 6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6烯基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C 6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C 1-9烷基),-NHC(O)NH(C 1-8鹵代烷基),-NHC(O)NH(C 2-6烯基),-NHC(O)NH(C 2-6炔基),-NHC(O)NH(C 3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C 6-10芳基),或者-NHC(O)NH(5-10員雜芳基),其中,烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團取代:C 1-9烷基,C 1-8鹵代烷基,鹵素,-OH,-NH 2,CO 2H-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 3-15環烷基) 2,-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),或者-NHC(O)NH(C 1-9烷基); 每個R 1b,R 1c,R 2a,R 2b,R 4c,R 9c,R 12a,R 12b和R 12c獨立地是H,OH,C 1-9烷基,C 2-6烯基,C 2-6炔基,C 3-15環烷基,雜環基,C 6-10芳基,或5-10員雜芳基,其中烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 並且 每個R 3e獨立地是H,C 1-6烷基,C 1-6鹵代烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基,-C 1-4烷基-O-C(O)-O-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基;其中烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1-4個Z 1b取代;其中每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;並且其中每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子; 較佳地,每個R 5a和R 5b獨立地是H,C 1-9烷基,或者C 2-6烷氧基烷基並且其中C 1-9烷基或C 2-6烷氧基烷基各自可地被一個或多個鹵素取代; 較佳地,環C為選自由以下組成的組的C 6-10芳基或5-10員雜芳基: 上述基團各自可選地被1至4個取代基取代,所述取代基各自獨立地選自由以下組成的組:H、OH、氧代、鹵素、C 1-6烷基、C 1-6鹵代烷基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 2-6烷氧基烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、-NO 2、-N 3、-CN、-O-C 1-6烷基、-C(O)-C 1-6烷基、-C(O)-N(C 0-6烷基)(C 0-6烷基),和-N(C 0-6烷基)(C 0-6烷基), 其中,所述1至4個取代基各自可選地被一個或多個鹵素取代。
- 如請求項1所述之化合物、或其藥學上可接受的鹽,其中所述化合物是具有式I-A-4或式I-A-5的化合物, 其中C環是C 3-10環烷基,雜環基,C 6-10的芳基或5-10員雜芳基,其各自可選地被1至4個Z 1取代; Y 1-V是N-CH 2,N-CH(CH 3),N-CF 2,CH-CH 2,CH-CF 2,CH-NH,N-S(O),N-S(O) 2,N-C(O),CH-C(O)或環丙烷基; Y 2是C,CH或N; R 2是H,C 1-6烷基,C 1-6烷基-烷氧基,C 1-6烷基-環烷氧基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-OR 2a,-S-R 2a,-S(O)R 2a,-S(O)(NH)R 2a,-S(O) 2R 2a,-S(O) 2N(R 2a)(R 2b),或-S(O)(NR 2a)R 2b,其中,烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1取代並且其中任何兩個Z 1可以與它們所連接的原子結合以形成C 3-10環烷基或雜環基或C 6-10芳基或5-10員雜芳基; X各自獨立地為-N=,-C(H)=,或-C(R 8)=; 每個R 3和R 3’各自獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-NO 2,-OR 3a,-C(O)R 3a,-CH 2C(O)OR 3a,-C(O)OR 3a,-C(O)N(R 3a)(R 3b),-N(R 3a)C(O)R 3b,-N(R 3a)C(O)OR 3b,-N(R 3a)C(O)N(R 3b) 2,-C(O)NHS(O) 2R 3a,-C(O)NR 3aS(O) 2R 3b,-C(O)NR 3aS(O) 2NR 3bR 3c,-C(O)NR 3a-S(O)(=NR 3b)R 3c,-S(O) 2R 3a,-S(O) 2OR 3a,-S(O) 2N(R 3a)(R 3b),-N(R 3a)S(O) 2R 3b,-S(O) 2NHC(O)R 3a,-S(O)(=NR 3a)R 3b,-S(O)(=NR 3a)NR 3b,-S(=NR 3a)(=NR 3b)R 3c,-P(O)(OR 3a)(R 3b),-P(O)(OR 3a)(OR 3b),-B(OR 3a)(OR 3b),或-O-C 1-6烷基-C(O)OR 3a,其中,所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R 3d取代; 每個R 3a,R 3b和R 3c獨立地是H,C 1-6烷基,C 6-10芳基,5-10員雜芳基,C 1-6鹵代烷基,C 2-8烷氧基烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-N(R 9a)C(O)-O-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-O-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,-CH 2CH(N(R 9a) 2)C(O)OR 9b,C 1-6烷基-雜環基,C 1-6烷基-芳基或C 1-6烷基-(5-10員)雜芳基,其中,所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個R 5a獨立地選自H,C 1-6烷基,C 1-6烷氧基,C 1-6鹵代烷基,C 2-6烷氧基烷基,鹵素,C 3-10環烷基,雜環基,-C 1-6烷基-N(R 9a)(R 9b),-CN,-OR 5a1,或-N(R 5a1)(R 5a2); 每個R 5a1和R 5a2獨立地是H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、C 6-10芳基或5-10員雜芳基,其中,環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個鹵素取代; 每個R 3d獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO 2R 3e,-NO 2,或-C(O)N(R 2a)(R 2b),其中,所述雜環基或5-10員雜芳基可選地被C 1-6烷基、C 1-6鹵代烷基或C 1-6鹵代烷氧基取代; 每個R 8獨立地是C 1-9烷基,C 1-8鹵代烷基,C 2-6烯烴基,C 2-6炔烴基,鹵素,氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基) 2; 每個R 9a和R 9b獨立地是H,C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3;或R 9a和R 9b融合形成一個3-10員雜環基,其可選地被以下基團取代:C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3; 每個Z 1獨立地是C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1a取代; 每個Z 1a獨立地是H、C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個Z 1b獨立地是C 1-9烷基,C 1-8鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 2-6烯基),-O(C 2-6炔基),-O(C 3-15環烷基),-O(雜環基),-O(C 6-10芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 2-6烯基),-NH(C 2-6炔基),-NH(C 3-15環烷基),-NH(雜環基),-NH(C 6-10芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基) 2,-N(C 2-6烯基) 2,-N(C 2-6炔基) 2,-N(C 3-15環烷基) 2,-N(雜環基) 2,-N(C 6-10芳基) 2,-N(5-10員雜芳基) 2,-N(C 1-9烷基)(C 1-8鹵代烷基),-N(C 1-9烷基)(C 2-6烯基),-N(C 1-9烷基)(C 2-6炔基),-N(C 1-9烷基)(C 3-15環烷基),-N(C 1-9烷基)(雜環基),-N(C 1-9烷基)(C 6-10芳基),-N(C 1-9烷基)(5-10員雜芳基),-C(O)(C 1-9烷基),-C(O)(C 1-8鹵代烷基),-C(O)(C 2-6烯基),-C(O)(C 2-6炔基),-C(O)(C 3-15環烷基),-C(O)(雜環基),-C(O)(C 6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C 1-9烷基),-C(O)O(C 1-8鹵代烷基),-C(O)O(C 2-6烯基),-C(O)O(C 2-6炔基),-C(O)O(C 3-15環烷基),-C(O)O(雜環基),-C(O)O(C 6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH 2,-C(O)NH(C 1-9烷基),-C(O)NH(C 1-8鹵代烷基),-C(O)NH(C 2-6烯基),-C(O)NH(C 2-6炔基),-C(O)NH(C 3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C 6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C 1-9烷基) 2,-C(O)N(C 1-8鹵代烷基) 2,-C(O)N(C 2-6烯基) 2,-C(O)N(C 2-6炔基) 2,-C(O)N(C 3-15環烷基) 2,-C(O)N(雜環基) 2,-C(O)N(C 6-10芳基) 2,-C(O)N(5-10員雜芳基) 2,-NHC(O)(C 1-9烷基),-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 2-6烯基),-NHC(O)(C 2-6炔基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C 6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6烯基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C 6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C 1-9烷基),-NHC(O)NH(C 1-8鹵代烷基),-NHC(O)NH(C 2-6烯基),-NHC(O)NH(C 2-6炔基),-NHC(O)NH(C 3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C 6-10芳基),-NHC(O)NH(5-10員雜芳基),其中,烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團取代:C 1-9烷基,C 1-8鹵代烷基,鹵素,-OH,-NH 2,CO 2H-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 3-15環烷基) 2,-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),或者-NHC(O)NH(C 1-9烷基); 每個R 1b,R 1c,R 2a,R 2b,R 4c,R 9c,R 12a,R 12b,和R 12c獨立地是H,OH,C 1-9烷基,C 2-6烯基,C 2-6炔基,C 3-15環烷基,雜環基,C 6-10芳基,或5-10員雜芳基,其中烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個R 3e獨立地是H,C 1-6烷基,C 1-6鹵代烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基,-C 1-4烷基-O-C(O)-O-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,其中烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1-4個Z 1b取代;其中每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子;並且其中每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子; 較佳地,其中R 5a各自獨立選自H,C 1-9烷基或C 2-6烷氧基烷基,並且其中C 1-9烷基或C 2-6烷氧基烷基各自可選地被一個或多個鹵素取代; 較佳地,其中環C為選自由以下組成的組的C 6-10芳基或5-10員雜芳基: 上述基團各自可選地被1至4個取代基取代,所述取代基各自獨立地選自由以下組成的組:H、OH、氧代、鹵素、C 1-6烷基、C 1-6鹵代烷基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 2-6烷氧基烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、-NO 2、-N 3、-CN、-O-C 1-6烷基、-C(O)-C 1-6烷基、-C(O)-N(C 0-6烷基)(C 0-6烷基)和-N(C 0-6烷基)(C 0-6烷基), 其中,所述1至4個取代基各自可選地被一個或多個鹵素取代。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其中所述化合物是具有式I-A-6或式I-A-7的化合物, 其中C環是C 3-10環烷基,雜環基,C 6-10芳基或5-10員雜芳基,其各自可選地被1-4個Z 1取代; V是CH 2、CH(CH 3)、NH、C(O)、S(O)、S(O) 2; n=0,1,2,3,或4; R 2是H,C 1-6烷基,-C 1-6烷基-烷氧基,-C 1-6烷基-環烷氧基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-OR 2a,-S-R 2a,-S(O)R 2a,-S(O)(NH)R 2a,-S(O) 2R 2a,-S(O) 2N(R 2a)(R 2b),或-S(O)(NR 2a)R 2b,其中,烷基、烷氧基、環烷氧基、鹵代烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1取代並且其中任何兩個Z 1可以與它們所連接的原子結合以形成C 3-10環烷基或雜環基或C 6-10芳基或5-10員雜芳基; X各自獨立地是-N=,-C(H)=,或-C(R 8)=; 每個R 3和R 3’各自獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CN,-NO 2,-OR 3a,-C(O)R 3a,-CH 2C(O)OR 3a,-C(O)OR 3a,-C(O)N(R 3a)(R 3b),-N(R 3a)C(O)R 3b,-N(R 3a)C(O)OR 3b,-N(R 3a)C(O)N(R 3b) 2,-C(O)NHS(O) 2R 3a,-C(O)NR 3aS(O) 2R 3b,-C(O)NR 3aS(O) 2NR 3bR 3c,-C(O)NR 3a-S(O)(=NR 3b)R 3c,-S(O) 2R 3a,-S(O) 2OR 3a,-S(O) 2N(R 3a)(R 3b),-N(R 3a)S(O) 2R 3b,-S(O) 2NHC(O)R 3a,-S(O)(=NR 3a)R 3b,-S(O)(=NR 3a)NR 3b,-S(=NR 3a)(=NR 3b)R 3c,-P(O)(OR 3a)(R 3b),-P(O)(OR 3a)(OR 3b),-B(OR 3a)(OR 3b),或-O-C 1-6烷基-C(O)OR 3a,其中,所述烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個R 3d取代; 每個R 3a,R 3b,和R 3c獨立地是H,C 1-6烷基,C 6-10芳基,5-10員雜芳基,C 1-6鹵代烷基,C 2-8烷氧基烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-N(R 9a)C(O)-O-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-O-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基-OP(O)(OR 9c) 2,-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,-CH 2CH(N(R 9a) 2)C(O)OR 9b,C 1-6烷基-雜環基,C 1-6烷基-芳基或C 1-6烷基-(5-10員)雜芳基;其中,所述烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個R 4獨立地是H、-OH、CH 2OH、C 1-9烷基,C 1-8鹵代烷基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 4a,-C(O)R 4a,-C(O)O-R 4a,-C(O)N(R 4a)(R 4b),-N(R 4a)(R 4b),-N(R 4a) 2(R 4b) +,-N(R 4a)-C(O)R 4b,-N(R 4a)C(O)O(R 4b),-N(R 4a)C(O)N(R 4b)(R 4c),-N(R 4a)S(O) 2(R 4b),-N(R 4a)S(O) 2-N(R 4b)(R 4c),-N(R 4a)S(O) 2O(R 4b),-OC(O)R 4a,-OC(O)OR 4a,-OC(O)-N(R 4a)(R 4b),-S-R 4a,-S(O)R 4a,-S(O)(NH)R 4a,-S(O) 2R 4a,-S(O) 2N(R 4a)(R 4b),-S(O)(NR 4a)R 4b,或-Si(R 4a) 3,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代;或者,兩個連接在相鄰環原子上的R 4基團與它們所連接的原子結合以形成C 5-10環烷基或雜環基,它們各自可選地被1至4個Z 1b取代; 每個R 5a和R 5b獨立地是H,C 1-6烷基,C 1-6烷氧基,C 1-6鹵代烷基,C 2-6烷氧基烷基,鹵素,C 3-10環烷基,雜環基,-C 1-6烷基-N(R 9a)(R 9b),-CN,-OR 5a1,或-N(R 5a1)(R 5a2);或者,R 5a和R 5b與它們所連接的原子組合以形成C 3-10環烷基或雜環基,它們各自可選地被1至4個R 5a3取代; 或者,R 5a或R 5b與環A上的任意取代基環合組合以形成C 3-10環烷基或雜環基,它們各自可選地被1至4個R 5a3取代; 每個R 5a1和R 5a2獨立地是H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、C 6-10芳基或5-10員雜芳基,其中,環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個鹵素取代; 每個R 3d和R 5a3獨立地是H,C 1-6烷基,C 1-6鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,-CO 2R 3e,-NO 2,或-C(O)N(R 2a)(R 2b),其中,所述雜環基或5-10員雜芳基各自可選地被C 1-6烷基、C 1-6鹵代烷基或C 1-6鹵代烷氧基取代; 每個R 8獨立地是C 1-9烷基,C 1-8鹵代烷基,C 2-6烯烴基,C 2-6炔烴基,鹵素氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基) 2; 每個R 9a和R 9b獨立地是H,C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3;或R 9a和R 9b融合形成一個3-10員雜環基,其可選地被以下基團所取代:C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3; 每個Z 1獨立地是C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1a取代; 每個Z 1a獨立地是H、C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-R 12a,-C(O)R 12a,-C(O)O-R 12a,-C(O)N(R 12a)(R 12b),-N(R 12a)(R 12b),-N(R 12a) 2(R 12b) +,-N(R 12a)-C(O)R 12b,-N(R 12a)C(O)O(R 12b),-N(R 12a)C(O)N(R 12b)(R 12c),-N(R 12a)S(O) 2(R 12b),-N(R 12a)S(O) 2-N(R 12b)(R 12c),-N(R 12a)S(O) 2O(R 12b),-OC(O)R 12a,-OC(O)OR 12a,-OC(O)-N(R 12a)(R 12b),-S-R 12a,-S(O)R 12a,-S(O)(NH)R 12a,-S(O) 2R 12a,-S(O) 2N(R 12a)(R 12b),-S(O)(NR 12a)R 12b,或-Si(R 12a) 3,其中,烷基、鹵代烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 每個Z 1b獨立地是H、C 1-9烷基,C 1-8鹵代烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-OH,-CN,CO 2R 3e,-NO 2,-NH 2,-N 3,-SH,-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 2-6烯基),-O(C 2-6炔基),-O(C 3-15環烷基),-O(雜環基),-O(C 6-10芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 2-6烯基),-NH(C 2-6炔基),-NH(C 3-15環烷基),-NH(雜環基),-NH(C 6-10芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 1-8鹵代烷基) 2,-N(C 2-6烯基) 2,-N(C 2-6炔基) 2,-N(C 3-15環烷基) 2,-N(雜環基) 2,-N(C 6-10芳基) 2,-N(5-10員雜芳基) 2,-N(C 1-9烷基)(C 1-8鹵代烷基),-N(C 1-9烷基)(C 2-6烯基),-N(C 1-9烷基)(C 2-6炔基),-N(C 1-9烷基)(C 3-15環烷基),-N(C 1-9烷基)(雜環基),-N(C 1-9烷基)(C 6-10芳基),-N(C 1-9烷基)(5-10員雜芳基),-C(O)(C 1-9烷基),-C(O)(C 1-8鹵代烷基),-C(O)(C 2-6烯基),-C(O)(C 2-6炔基),-C(O)(C 3-15環烷基),-C(O)(雜環基),-C(O)(C 6-10芳基),-C(O)(5-10員雜芳基),-C(O)O(C 1-9烷基),-C(O)O(C 1-8鹵代烷基),-C(O)O(C 2-6烯基),-C(O)O(C 2-6炔基),-C(O)O(C 3-15環烷基),-C(O)O(雜環基),-C(O)O(C 6-10芳基),-C(O)O(5-10員雜芳基),-C(O)NH 2,-C(O)NH(C 1-9烷基),-C(O)NH(C 1-8鹵代烷基),-C(O)NH(C 2-6烯基),-C(O)NH(C 2-6炔基),-C(O)NH(C 3-15環烷基),-C(O)NH(雜環基),-C(O)NH(C 6-10芳基),-C(O)NH(5-10員雜芳基),-C(O)N(C 1-9烷基) 2,-C(O)N(C 1-8鹵代烷基) 2,-C(O)N(C 2-6烯基) 2,-C(O)N(C 2-6炔基) 2,-C(O)N(C 3-15環烷基) 2,-C(O)N(雜環基) 2,-C(O)N(C 6-10芳基) 2,-C(O)N(5-10員雜芳基) 2,-NHC(O)(C 1-9烷基),-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 2-6烯基),-NHC(O)(C 2-6炔基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(C 6-10芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6烯基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(C 6-10芳基),-NHC(O)O(5-10員雜芳基),-NHC(O)NH(C 1-9烷基),-NHC(O)NH(C 1-8鹵代烷基),-NHC(O)NH(C 2-6烯基),-NHC(O)NH(C 2-6炔基),-NHC(O)NH(C 3-15環烷基),-NHC(O)NH(雜環基),-NHC(O)NH(C 6-10芳基),-NHC(O)NH(5-10員雜芳基),其中,烷基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至3個以下基團所取代:C 1-9烷基,C 1-8鹵代烷基,鹵素,-OH,-NH 2,CO 2H-O(C 1-9烷基),-O(C 1-8鹵代烷基),-O(C 3-15環烷基),-O(雜環基),-O(芳基),-O(5-10員雜芳基),-NH(C 1-9烷基),-NH(C 1-8鹵代烷基),-NH(C 3-15環烷基),-NH(雜環基),-NH(芳基),-NH(5-10員雜芳基),-N(C 1-9烷基) 2,-N(C 3-15環烷基) 2,-NHC(O)(C 1-8鹵代烷基),-NHC(O)(C 3-15環烷基),-NHC(O)(雜環基),-NHC(O)(芳基),-NHC(O)(5-10員雜芳基),-NHC(O)O(C 1-9烷基),-NHC(O)O(C 1-8鹵代烷基),-NHC(O)O(C 2-6炔基),-NHC(O)O(C 3-15環烷基),-NHC(O)O(雜環基),-NHC(O)O(芳基),-NHC(O)O(5-10員雜芳基),或者-NHC(O)NH(C 1-9烷基); 每個R 1b,R 1c,R 2a,R 2b,R 4a,R 4b,R 4c,R 9c,R 12a,R 12b,和R 12c獨立地是H,OH,C 1-9烷基,C 2-6烯基,C 2-6炔基,C 3-15環烷基,雜環基,C 6-10芳基,或5-10員雜芳基,其中烷基、烯基、炔基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代;並且 每個R 3e獨立地是H,C 1-6烷基,C 1-6鹵代烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,其中烷基、烯基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1-4個Z 1b取代; 其中每個5-10員雜芳基具有5至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子; 並且其中每個雜環基具有3至12員結構,並且具有1至4個各自獨立地是N、O或S的雜原子; 較佳地,其中每個R 5a和R 5b獨立地是H,C 1-9烷基或C 2-6烷氧基烷基,並且其中C 1-9烷基或C 2-6烷氧基烷基各自可選地被一個或多個鹵素取代; 較佳地,其中環C為選自由以下組成的組的C 6-10芳基或5-10員雜芳基: 上述基團各自可選地被1至4個取代基取代,所述取代基各自獨立地選自由以下組成的組:H、OH、氧代、鹵素、C 1-6烷基、C 1-6鹵代烷基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 2-6烷氧基烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、-NO 2、-N 3、-CN、-O-C 1-6烷基、-C(O)-C 1-6烷基、-C(O)-N(C 0-6烷基)(C 0-6烷基)和-N(C 0-6烷基)(C 0-6烷基), 其中所述1至4個取代基各自可選地被一個或多個鹵素取代。
- 如請求項1所述之化合物、或其藥學上可接受的鹽,其中環A選自由以下組成的組: 上述基團各自可選地被1至4個Z 1a取代; 較佳地,其中1至4個Z 1a中的每一個獨立地選自H、鹵素、C 1-9烷基、C 1-6烷氧基、C 2-6烷氧基烷基、C 2-6烯基、C 2-6炔基、C 3-15環烷基或雜環基,上述基團各自獨立地被一個或多個鹵素取代; 較佳地,其中R 2是C 1-6烷基、C 1-6烷基-烷氧基、C 1-6烷基-環烷氧基、C 1-6鹵代烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、C 6-10芳基、或者5-10員雜芳基;上述基團各自可選地被1至4個Z 1取代; 更佳地,其中R 2選自由以下組成的組: 上述基團可選地被1至4個Z 1取代; 其中,R 2’是H,C 1-6烷基,C 1-6鹵代烷基,或者-C 1-6烷基-環烷氧,上述基團各自可選地被一個或多個鹵素取代; 較佳地,其中每個R 3和R 3’獨立地選自H,C 6-10芳基,5-10員雜芳基,-C(O)R 3a,-CH 2C(O)OR 3a,-C(O)N(R 3a)(R 3b),-N(R 3a)C(O)R 3b,-N(R 3a)C(O)OR 3b,-N(R 3a)C(O)N(R 3b) 2,-C(O)NHS(O) 2R 3a,-C(O)NR 3aS(O) 2R 3b,-C(O)NR 3aS(O) 2NR 3bR 3c,-C(O)NR 3a-S(O)(=NR 3b)R 3c,-S(O) 2N(R 3a)(R 3b),-N(R 3a)S(O) 2R 3b,-S(O) 2NHC(O)R 3a,或者-O-C 1-6烷基-C(O)OR 3a,上述基團各自可選地被1至4個R 3d取代; 較佳地,=,其中每個R 3和R 3’獨立地選自H,C(O)NR 3a(CH 2) mR 3b,C(O)NR 3a(CH 2) mC(O)R 3b,NR 3aC(O)(CH 2) mR 3b,NR 3a(CH 2) mR 3b,NR 3a(CH 2) mC(O)R 3b,C(O)NR 3aR 3b,或者NR 3aC(O)R 3b,上述基團各自可選地被1至4個R 3d取代,其中m是0,1,2或3; 更佳地,其中每個R 3和R 3’獨立地選自H,C(O)NHR 3b,或者NHC(O)R 3b; 更加較佳地,其中每個R 3b獨立地選自H,C 1-6烷基,C 1-6鹵代烷基,C 2-8烷氧基烷基,-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C(O)N(R 9a)(R 9b),-C 1-4烷基-O-C(O)-C 1-4烷基,-C 1-4烷基-O-C(O)-C 1-4烷基-N(R 9a)(R 9b),-C 1-4烷基-C 3-8環烷基,-C 1-4烷基-雜環基,C 2-6烯基,C 2-6炔基,C 3-10環烷基,雜環基,C 6-10芳基,5-10員雜芳基,-CH 2CH(N(R 9a) 2)C(O)OR 9b,C 1-6烷基-雜環基,C 1-6烷基-芳基和C 1-6烷基-(5-10員)雜芳基,其中所述烷基、烯烴基、環烷基、雜環基、芳基或5-10員雜芳基各自可選地被1至4個Z 1b取代; 更加較佳地,其中R 3b是C 6-10芳基或5-10員雜芳基,其中C 6-10芳基或5-10員雜芳基各自可選地被1至5個R 3f取代,其中 R 3f是H,OH,氧代、NH 2、鹵素、-NO 2、-N 3、-CN、C 1-6烷基、C 1-6鹵代烷基、C 1-6烷氧基、C 1-6鹵代烷氧基、C 2-6烷氧基烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、雜環基、-O-C 1-6烷基、-C(O)-C 1-6烷基、-C(O)-N(R 12a)(R 12b)、-N(R 12a)(R 12b)、C 6-10芳基、或者5-10員雜芳基,其中R 3f各自可選擇地被一個或多個鹵素、C 1-6烷基、C 1-6鹵代烷基、C 1-6烷氧基、或者C 1-6鹵代烷氧基取代; 又更加較佳地,其中在R 3b中的芳基或5-10員雜芳基選自由以下組成的組: , 上述基團各自可選地被1至5個R 3f取代; 較佳地,其中R 4獨立地選自H,-OH,-CH 2OH,C 1-9烷基,C 1-8鹵代烷基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-CN,-N 3,-O-C 1-9烷基,或者-C(O)C 1-9烷基,上述基團各自可選地被1至4個Z 1b取代,或者兩個連接到相鄰環原子上的R 4基團與其連接的原子結合以形成C 5-10環烷基或雜環基,每個環可選擇地被1至4個Z 1b取代; 更佳地,其中R 4獨立地選自H,鹵素,-CH 2OH,C 1-9烷基,C 1-8鹵代烷基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,或者C 3-15環烷基; 較佳地,其中Z 1獨立地選自C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,C 2-6烯基,C 2-6炔基,鹵素,C 3-15環烷基,雜環基,C 6-10芳基,5-10員雜芳基,氧代,-NO 2,-N 3,-CN,-O-R 12a,-C(O)-R 12a,-C(O)O-R 12a,-C(O)-N(R 12a)(R 12b),或者-N(R 12a)(R 12b); 較佳地,其中Z 1a獨立地選自H,-OH,C 1-9烷基,C 1-8鹵代烷基,C 1-6烷氧基,C 1-6鹵代烷氧基,C 2-6烷氧基烷基,或者鹵素; 較佳地,其中Z 1b獨立地選自H,C 1-9烷基,C 1-8鹵代烷基,鹵素,氧代,-OH,或者-CN; 較佳地,其中R 8獨立地選自H,氧代,OH,C 1-9烷基,C 1-8鹵代烷基,鹵素,-O(C 1-3烷基),或者-O(C 1-3鹵代烷基)。
- 如請求項1所述之化合物或其藥學上可接受的鹽,其具有選自由以下組成的組的結構: 。
- 一種藥物組合物,其包括如請求項1至6中任一項所述之化合物、或其藥學上可接受的鹽;以及藥學上可接受的輔料。
- 如請求項1至6中任一項所述之化合物、或其藥學上可接受的鹽,或者如請求項7所述之藥物組合物在製備用於治療GLP-1R介導的疾病或病症的藥物的用途,其中所述GLP-1R介導的疾病或病症選自由以下組成的組:T1D、T2DM、糖尿病前期、特發性T1D、LADA、EOD、YOAD、MODY、營養不良相關糖尿病、妊娠期糖尿病、高血糖、胰島素抵抗、肝臟胰島素抵抗、糖耐量受損、糖尿病神經病變、糖尿病腎病、腎病、糖尿病視網膜病變、脂肪細胞功能障礙、內臟脂肪沉積、睡眠呼吸暫停、肥胖症、進食障礙、使用其他藥物導致的體重增加、過度嗜糖、血脂異常、高胰島素血症、NAFLD、NASH、纖維化、肝硬化、肝細胞癌、心血管疾病、動脈粥樣硬化、冠狀動脈疾病、外周血管疾病、高血壓、內皮功能障礙、血管順應性受損、充血性心力衰竭、心肌梗死、中風、出血性中風、缺血性中風、創傷性腦損傷、肺動脈高壓、血管成形術後再狹窄、間歇性跛行、餐後脂血、代謝性酸中毒、酮症、關節炎、骨質疏鬆、帕金森病、左心室肥大,外周動脈疾病、黃斑變性、白內障、腎小球硬化、慢性腎衰竭、代謝綜合征、X綜合征、經前綜合征、心絞痛、血栓形成、動脈粥樣硬化、短暫性腦缺血發作、血管再狹窄、糖代謝受損、空腹血糖受損、高尿酸血症、痛風、勃起功能障礙,皮膚及結締組織疾病、銀屑病、足部潰瘍、潰瘍性結腸炎、高載脂蛋白B脂蛋白血症、阿爾茨海默病、精神分裂症、認知受損、炎症性腸病、短腸綜合征、克羅恩病、結腸炎、腸易激綜合征、多囊卵巢綜合征和物質成癮。
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