• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention provides a compound having the following structural formula or a specific enantiomer, a specific tautomer or a pharmaceutically acceptable salt thereof; Wherein X is O, S, CH 2 or NR 5 ; Y is O or S; R 1 is H, substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 8 alkylaryl, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6 ' OC (O) R 4 , -CR 6 R 6' OC (O) NHR 7 , -C (O) NR 10 R 11 , -C (O) NR 8 R 9 NR 8 R 9 , —N (R 5 ) C (O) NHR 5 or CH 2 R 4 ; R 2 is substituted or unsubstituted straight C 1 -C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; And R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl, Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl, -CH 2 -aryl, aryl-C 1 -C 30 alkyl, heteroaryl-C 1 -C 30 alkyl Or C 3 -C 10 cycloalkyl; R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl C 1 -C 30 alkyl, heteroarylalkyl or cycloalkyl; R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or C 3 -C 10 cycloalkyl or together form a 3-7 membered ring system; R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or C 3 -C 10 cycloalkyl; And R 8 and R 9 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylaryl or piperazine substituted with NR 8 R 9 Forms a piperidine ring or dihydro-1H-isoquinoline ring system; The present invention also relates to a method for treating diabetes or obesity by administering a therapeutically effective amount of the compound.
    公开号:KR20040068316A
    申请号:KR10-2004-7009797
    申请日:2002-12-20
    公开日:2004-07-30
    发明作者:데이빗 위터；앨린도엘. 캐스텔하노
    申请人:오에스아이 파마슈티컬스, 인코포레이티드；
    IPC主号:
    专利说明:

    Pancreatic Lipase Inhibitor Compound, Synthesis Method and Usage Method {PANCREATIC LIPASE INHIBITOR COMPOUNDS, THEIR SYNTHESIS AND USE}
    [3] Over the past two decades, obesity has become an increasingly common problem for the people of developed countries. The increase in obesity is due in part to the adoption of Western diets-diets containing foods with high and low fiber content in many developed countries, and partly due to the lifestyle of Western societies. Obesity is known to increase the risk of contractile diseases such as diabetes, cardiovascular disease and hypertension.
    [4] A pharmaceutical approach to the treatment of obesity is to try to increase the body's energy consumption to burn more fat or reduce the body's energy absorption. The latter promoted the development of various drugs to reduce the body's ability to absorb fat. These drugs target enzymes that counteract lipolysis in the human digestive cycle. The most important lipolytic enzymes are lipases, especially pancreatic lipases. Orlistat, a derivative of the lipase derivative lipstatin, has been disclosed as an anti-obesity drug in European patent application EP 129748. Other lipase inhibitors are also disclosed in PCT International Publications WO 00/40569 and WO 00/40247, respectively.
    [1] This application takes precedence over US Provisional Application No. 60 / 342,617, dated December 20, 2001 and US Provisional Application No. 60 / 357,015, dated February 13, 2002, the contents of which are incorporated herein by reference.
    [2] Various publications mentioned in the contents of the present application are cited, and are included for the purpose of introducing in detail related technologies that can be fully understood by those skilled in the art as of the filing date of the present invention.
    [5] Summary of the Invention
    [6] The present invention provides a compound having the following structural formula or a specific enantiomer, specific tautomer or a pharmaceutically acceptable salt thereof:
    [7]
    [8] Wherein X is O, S, CH 2 or NR 5 ;
    [9] Y is O or S;
    [10] R 1 is H, substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 8 alkylaryl, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6 ' OC (O) R 4 , -CR 6 R 6' OC (O) NHR 7 , -C (O) NR 10 R 11 , -C (O) NR 8 R 9 NR 8 R 9 , —N (R 5 ) C (O) NHR 5 or CH 2 R 4 ;
    [11] R 2 is substituted or unsubstituted straight C 1 -C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; And
    [12] R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl,
    [13] Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl, -CH 2 -aryl, aryl-C 1 -C 30 alkyl, heteroaryl-C 1 -C 30 alkyl Or C 3 -C 10 cycloalkyl;
    [14] R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl C 1 -C 30 alkyl, heteroarylalkyl or cycloalkyl;
    [15] R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or C 3 -C 10 cycloalkyl or together form a 3-7 membered ring system;
    [16] R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or C 3 -C 10 cycloalkyl; And
    [17] R 8 and R 9 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylaryl or piperazine substituted with NR 8 R 9 To form a piperidine ring or dihydro-1H-isoquinoline ring system.
    [18] The invention also provides a compound having the structure:
    [19]
    [20] Wherein R 10 is H or substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 15 alkylaryl or -C (O) R 14 ;
    [21] Wherein R 14 is hydroxyl or substituted or unsubstituted C 1 -C 30 alkyl, alkylamino, dialkylamino, alkoxy, benzyloxy, cycloalkyl, alkylheteroaryl, alkylaryl, or heterocycle, heteroaryl or aryl Ring;
    [22] R 11 is hydrogen or methyl;
    [23] R 12 is hydrogen or tert-butyl; And
    [24] R 13 is hydrogen or —C (O) ZR 15 ;
    [25] Wherein Z is CH 2 , O or N and R 15 is substituted or unsubstituted C 1 -C 15 alkyl or aryl.
    [26] The present invention also provides a method of treating obesity comprising treating obesity by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.
    [27] The present invention also provides a method for treating diabetes comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention to treat diabetes.
    [28] The invention also provides a method of inhibiting the hydrolytic activity of a pancreatic lipase enzyme comprising contacting a cell with an effective amount of a compound of the invention to inhibit the hydrolytic activity of the pancreatic lipase enzyme.
    [29] Detailed description of the invention
    [30] The present invention provides a compound having the following structural formula or a specific enantiomer, specific tautomer or a pharmaceutically acceptable salt thereof:
    [31]
    [32] Wherein X is O, S, CH 2 or NR 5 ;
    [33] Y is O or S;
    [34] R 1 is H, substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 8 alkylaryl, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6 ' OC (O) R 4 , -CR 6 R 6' OC (O) NHR 7 , -C (O) NR 10 R 11 , -C (O) NR 8 R 9 NR 8 R 9 , —N (R 5 ) C (O) NHR 5 or CH 2 R 4 ;
    [35] R 2 is substituted or unsubstituted straight C 1 -C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; And
    [36] R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl,
    [37] Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl, -CH 2 -aryl, aryl-C 1 -C 30 alkyl, heteroaryl-C 1 -C 30 alkyl Or C 3 -C 10 cycloalkyl;
    [38] R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl C 1 -C 30 alkyl, heteroarylalkyl or cycloalkyl;
    [39] R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or C 3 -C 10 cycloalkyl or together form a 3-7 membered ring system;
    [40] R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or C 3 -C 10 cycloalkyl; And
    [41] R 8 and R 9 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylaryl or piperazine substituted with NR 8 R 9 To form a piperidine ring or dihydro-1H-isoquinoline ring system.
    [42] In one embodiment, the compound has the structure
    [43]
    [44] Wherein X is O, S or NR 5 ;
    [45] Y is O or S;
    [46] R 1 is H, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6' OC (O) R 4 , -CR 6 R 6 'OC (O) NHR 7, or CH 2 R 4;
    [47] R 2 is substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [48] R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or cycloalkyl,
    [49] Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [50] R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [51] R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
    [52] R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or cycloalkyl.
    [53] In another embodiment, the compound has the structure
    [54]
    [55] Wherein X is O, S or NR 5 ;
    [56] R 1 is H, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6' OC (O) R 4 , -CR 6 R 6 'OC (O) NHR 7, or CH 2 R 4;
    [57] R 2 is substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [58] R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or cycloalkyl,
    [59] Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [60] R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [61] R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
    [62] R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or cycloalkyl.
    [63] In another embodiment of the compound,
    [64] X is O or NR 5 ;
    [65] R 1 is —C (O) O— (C 6 -C 30 ) alkyl, -C (O) NH— (C 6 -C 30 ) alkyl or —C (O) OCH 2 (C 6 H 5 );
    [66] R 2 is C 6 -C 30 alkyl; And
    [67] R 3 is C 1 -C 6 alkyl.
    [68] In another embodiment, R 3 is H or CH 3 .
    [69] In another embodiment, X is O.
    [70] In another embodiment, R 3 is methyl.
    [71] In another embodiment, X is N.
    [72] In another embodiment, R 3 is methyl.
    [73] In another embodiment, the compound has the structure
    [74]
    [75] here,
    [76] Y is O or S;
    [77] R 1 is H,-(CH 2 ) r CH 3 , -CH (CH 3 ) 2 , -CH (CH 3 ) CH 2 C (CH 3 ) 3 , -CH (CH 3 ) (CH 2 ) 3 C ( = CH 2 ) CH 3 , -CH (CH 3 ) (CH 2 ) 3 C (CH 3 ) 2 OC (O) CH 3 , -CH (CH 3 ) [CH 2 ] 3 C (CH 3 ) 2 OCH 3 , -CH S (C 6 H 5 ), -C (O) OH, -C (O) NH (CH 2 ) t CH 3 , -C (O) O (CH 2 ) u CH 3 , -C (O ) OCH [(CH 2 ) 3 CH 3 ] 2 , -C (O) NH (CH 2 ) v CH 3 , -C (O) N (CH 3 ) 2 , -C (0) NHCH 2 (C 6 H 5 ), -C (O) NHCH 2 (C 5 H 4 N), -C (O) N [(CH 2 ) 3 CH 3 ] 2 , -C (O) N [(CH 2 ) 5 CH 3 ] 2 , -C (O) N [(CH 2 ) 7 CH 3 ] 2 , -C (O) NH (C 6 H 11 ), -C (O) (NC 4 H 8 N) CH 2 (C 6 H 5 ), -C (O) (NC 5 H 9 ) CH 2 (C 6 H 5 ), -C (O) NH (CH 2 ) 3 O (C 6 H 5 ), -C (O) NHCH [( CH 2 ) 3 CH 3 ] 2 , -C (O) NH (CH 2 ) 3 N (CH 3 ) 2 , -C (O) NHCH 2 C (O) CH 2 (C 6 H 5 ), -C ( O) N (CH 3 ) CH 2 (C 5 H 3 N [CH 3 ]), -C (O) NH (CH 2 ) 2 (C 5 H 4 N), -C (O) N (CH 2 CH 3 ) (CH 2 ) 2 (C 5 H 4 N), -C (O) NHCH 2 (C 4 H 3 O), -C (O) (NC 4 H 8 N) [CH 2 ] 2 (NC 5 H 10 ), -C (O) NHCH 2 CH (CH 3 ) 2 , -C (O) NHCH 2 (C 5 H 4 N), -C (O) NHCH 2 C (CH 3 ) 3 , -C ( O) (NC 4 H 8 N) CH 2 C (O) NHCH (CH 3 ) 2 , -C (O) (NC 9 H 8 ) [OCH 3 ] 2 , -C (O) NHCH 2 (C 6 H 3 [OCH 3 ] 2 ), -C (O) NHCH 2 (C 7 H 5 O 2 ), -C (O) NH (CH 2 ) 2 O (C 6 H 5 ), -C (O) NH (CH 2 ) 2 OCH 3 , -C (O) NH (CH 2 ) 3 OCH 3 , -C (O) NH (CH 2 ) 4 (C 6 H 5 ) Or -C (O) NH (CH 2 ) 3 (C 6 H 5 );
    [78] r is an integer from 1 to 15;
    [79] s is an integer of 0 to 6;
    [80] t is an integer from 0 to 6;
    [81] u is an integer from 3 to 8;
    [82] v is an integer from 5 to 15;
    [83] XR 2 is-(CH 2 ) n CH 3 , -O (CH 2 ) m CH 3 , -OCH (CH 3 ) 2 , -OCH (CH 3 ) (CH 2 ) 5 CH 3 , -OCH 2 CH (CH 3 ) 2 , -O (CH 2 ) 2 OCH 3 , -O (CH 2 ) 2 OCH 2 (C 6 H 5 ), -O (CH 2 ) p (C 6 H 5 ), -OCH 2 ([C 6 H 4 (CH 2 ) 3 CH 3 ]), -O (C 6 H 4 [(CH 2 ) 3 CH 3 ]), -O (CH 2 ) 2 (C 6 H 4 [CH 3 ]),- O (CH 2 ) 3 OCH 2 (C 6 H 5 ), -O (CH 2 ) 4 OCH 2 (C 6 H 5 ), -N ([CH 2 ] 7 CH 3 ) C (O) NH (CH 2 ) 7 CH 3 , -N ([CH 2 ] 6 CH 3 ) C (O) NH (CH 2 ) 6 CH 3 , -NH (CH 2 ) q CH 3 , -NH (C 6 H 4 ) O (C 6 H 5 ), -N (CH 3 ) (CH 2 ) 5 CH 3 , -NHCH [(CH 2 ) 3 CH 3 ] 2 , -NHCH (CH 3 ) [CH 2 ] 5 CH 3 , or -N ( [CH 2 ] 7 CH 3 ) 2 ;
    [84] n is an integer from 6 to 15;
    [85] m is an integer from 1 to 15;
    [86] p is an integer from 0 to 6;
    [87] q is an integer from 6 to 15; And
    [88] R 3 is H, —CH 3 or —CH 2 OCH 3 .
    [89] In another embodiment, the compound has the structure
    [90]
    [91] here,
    [92] Y is O or S;
    [93] R 1 is H,-(CH 2 ) 3 CH 3 ,-(CH 2 ) 5 CH 3 ,-(CH 2 ) 6 CH 3 ,-(CH 2 ) 7 CH 3 ,-(CH 2 ) 9 CH 3 , -(CH 2 ) 11 CH 3 , -CH (CH 3 ) 2 , -CH (CH 3 ) CH 2 C (CH 3 ) 3 , -CH (CH 3 ) (CH 2 ) 3 C (= CH 2 ) CH 3 , -CH (CH 3 ) (CH 2 ) 3 C (CH 3 ) 2 OC (O) CH 3 , -CH (CH 3 ) [CH 2 ] 3 C (CH 3 ) 2 OCH 3 , -CH 2 ( C 6 H 5 ),-(CH 2 ) 2 (C 6 H 5 ),-(CH 2 ) 3 (C 6 H 5 ),-(CH 2 ) 4 (C 6 H 5 ),-(CH 2 ) 5 (C 6 H 5 ), -C (O) OH, -C (O) NHCH 3 , -C (O) NHCH 2 CH 3 , -C (O) NH (CH 2 ) 3 CH 3 , -C ( O) OCH 2 (C 6 H 5 ), -C (O) O (CH 2 ) 5 CH 3 , -C (O) O (CH 2 ) 6 CH 3 , -C (O) O (CH 2 ) 7 CH 3 , -C (O) OCH [(CH 2 ) 3 CH 3 ] 2 , -C (O) NH (CH 2 ) 5 CH 3 , -C (O) NH (CH 2 ) 7 CH 3 , -C (O) NH (CH 2 ) 9 CH 3 , -C (O) NH (CH 2 ) 11 CH 3 , -C (O) NH (CH 2 ) 15 CH 3 , -C (O) N (CH 3 ) 2 , -C (O) NHCH 2 (C 6 H 5 ), -C (O) NHCH 2 (C 5 H 4 N), -C (O) N [(CH 2 ) 3 CH 3 ] 2 , -C (O) N [(CH 2 ) 5 CH 3 ] 2 , -C (O) N [(CH 2 ) 7 CH 3 ] 2 , -C (O) NH (C 6 H 11 ), -C (O) (NC 4 H 8 N) CH 2 (C 6 H 5 ), -C (O) (NC 5 H 9 ) CH 2 (C 6 H 5 ), -C (O) NH (CH 2 ) 3 O (C 6 H 5 ), -C (O) NHCH [(CH 2 ) 3 CH 3 ] 2 ,- C (O) NH (CH 2 ) 3 N (CH 3 ) 2 , -C (O) NHCH 2 C (O) OCH 2 (C 6 H 5 ), -C (O) N (CH 3 ) CH 2 [ C 5 H 3 N [CH 3 ]), -C (O) NH (CH 2 ) 2 (C 5 H 4 N), -C (O) N (CH 2 CH 3 ) (CH 2 ) 2 (C 5 H 4 N), -C (O) NHCH 2 (C 4 H 3 O), -C (O) (NC 4 H 8 N) [CH 2 ] 2 (NC 5 H 10 ), -C (O) NHCH 2 CH (CH 3 ) 2 , -C (O) NHCH 2 (C 5 H 4 N), -C (O) NHCH 2 C (CH 3 ) 3 , -C (O) (NC 4 H 8 N) CH 2 C (O) NHCH (CH 3 ) 2 , -C (O) (NC 9 H 8 ) [OCH 3 ] 2 , -C (O) NHCH 2 (C 6 H 3 [OCH 3 ] 2 ), -C (O) NHCH 2 (C 7 H 5 O 2 ), -C (O) NH (CH 2 ) 2 O (C 6 H 5 ), -C (O) NH (CH 2 ) 2 OCH 3 , C (O ) NH (CH 2 ) 3 OCH 3 , —C (O) NH (CH 2 ) 4 (C 6 H 5 ), or —C (O) NH (CH 2 ) 3 (C 6 H 5 );
    [94] XR 2 is-(CH 2 ) 6 CH 3 ,-(CH 2 ) 10 CH 3 ,-(CH 2 ) 14 CH 3 , -O (CH 2 ) 3 CH 3 , -O (CH 2 ) 5 CH 3 , -O (CH 2 ) 6 CH 3 , -O (CH 2 ) 7 CH 3 , -O (CH 2 ) 9 CH 3 , -O (CH 2 ) 11 CH 3 , -O (CH 2 ) 15 CH 3 , -OCH (CH 3 ) 2 , OCH (CH 3 ) (CH 2 ) 5 CH 3 , -OCH 2 CH (CH 3 ) 2 , -O (CH 2 ) 2 OCH 3 , -O (CH 2 ) 2 OCH 2 (C 6 H 5 ), -O (CH 2 ) 4 (C 6 H 5 ), -O (CH 2 ) 3 (C 6 H 5 ), -O (CH 2 ) 2 (C 6 H 5 ),- O (C 6 H 5 ), -OCH 2 (C 6 H 5 ), -OCH 2 (C 6 H 4 [(CH 2 ) 3 CH 3 ]), -O (C 6 H 4 [(CH 2 ) 3 CH 3 ]), -O (CH 2 ) 2 (C 6 H 4 [CH 3 ]), -O (CH 2 ) 3 OCH 2 (C 6 H 5 ), -O (CH 2 ) 4 OCH 2 (C 6 H 5 ), -N ([CH 2 ] 7 CH 3 ) C (O) NH (CH 2 ) 7 CH 3 , -N ([CH 2 ] 6 CH 3 ) C (O) NH (CH 2 ) 6 CH 3 , -NH (CH 2 ) 6 CH 3 , -NH (CH 2 ) 7 CH 3 , -NH (CH 2 ) 11 CH 3 , -NH (CH 2 ) 13 CH 3 , -NH (CH 2 ) 15 CH 3 , -NH (C 6 H 4 ) O (C 6 H 5 ), -N (CH 3 ) (CH 2 ) 5 CH 3 , -NHCH [(CH 2 ) 3 CH 3 ] 2 , -NHCH (CH 3 ) [CH 2 ] 5 CH 3 , or —N ([CH 2 ] 7 CH 3 ) 2 ; And
    [95] R 3 is H, —CH 3 or —CH 2 OCH 3 .
    [96] In another embodiment, the compound is:
    [97] 6-heptyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [98] 6-hexyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [99] 2-octyloxy-6- (1,3,3-trimethyl-butyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    [100] 6-butyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [101] 6-heptyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one;
    [102] 6-butyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one;
    [103] 6-benzyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one;
    [104] 6-heptyl-2-undecyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [105] 6- (5-methoxy-1,5-dimethyl-hexyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [106] 6- (1,5-dimethyl-hex-4-enyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [107] 6- (1,5-dimethyl-hex-5-enyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [108] Trifluoro-acetic acid 1,1-dimethyl-5- (2-octyloxy-4-oxo-4H-thieno [2,3-d] [1,3] oxazin-6-yl) -hexyl ester;
    [109] 2- (2-benzyloxy-ethoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [110] 6-heptyl-5-methyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [111] 6-methyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [112] 2-octyloxy-6-phenethyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [113] 2-octyloxy-6- (3-phenyl-propyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    [114] 2-octyloxy-6- (4-phenyl-butyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    [115] 2-octyloxy-6- (5-phenyl-pentyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    [116] 6-decyl-2- (2-methoxy-ethoxy) -thieno [2,3-d] [1,3] oxazin-4-one;
    [117] 2- (4-butyl-phenoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [118] 2- (3-benzyloxy-propoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [119] 2- (3-benzyloxy-butyloxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [120] 6-isopropyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [121] 6-octyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [122] 6-dodecyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [123] 2-benzyloxy-6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [124] 2- (4-butylbenzyloxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    [125] 6-decyl-2- (2-p-tolyl-ethoxy) -thieno [2,3-d] [1,3] oxazin-4-one;
    [126] 6-decyl-2-phenethyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    [127] 3-methyl-6-octyl-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    [128] 2-butoxy-6-octyl-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    [129] 2-hexyloxy-6-octyl-5H-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    [130] 2-dodecyloxy-6-octyl-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    [131] 6-decyl-2-phenoxy-5H-thieno [2,3-b] pyridin-4-one;
    [132] 2-decyloxy-6-octyl-5H-thieno [2,3-b] pyridin-4-one;
    [133] 6-benzyl-2-oxylthieno [2,3-d] oxazin-4-one;
    [134] 6-decyl-2-octyloxythieno [2,3-d] oxazin-4-one;
    [135] 6-decyl-2- (1-methylheptyloxy) thieno [2,3-d] [1,3] oxazin-4-one;
    [136] 6-heptyl-2- (1-methylheptyloxy) thieno [2,3-d] [1,3] oxazin-4-one;
    [137] 6-decyl-2- (4-phenylpropoxy) thieno [2,3-d] [1,3] oxazin-4-one; And
    [138] 6-decyl-2- (4-phenylbutoxy) thieno [2,3-d] [1,3] oxazin-4-one.
    [139] The present invention also provides a compound having the structure
    [140]
    [141] Wherein R 10 is H or substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 15 alkylaryl or -C (O) R 14 ,
    [142] Wherein R 14 is hydroxyl or substituted or unsubstituted C 1 -C 30 alkyl, alkylamino, dialkylamino, alkoxy, benzyloxy, cycloalkyl, alkylheteroaryl, alkylaryl, or heterocyclic, heteroaryl or Aryl ring;
    [143] R 11 is hydrogen or methyl;
    [144] R 12 is hydrogen or tert-butyl; And
    [145] R 13 is hydrogen or —C (0) ZR 15 ;
    [146] Wherein Z is CH 2 , O or N and R 15 is substituted or unsubstituted C 1 -C 15 alkyl or aryl.
    [147] The invention also provides a method of treating obesity, comprising treating a subject's obesity by administering to the subject in need thereof a therapeutically effective amount of a compound of the present invention.
    [148] The present invention also provides a method for treating diabetes comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention to treat diabetes in the subject.
    [149] The present invention also provides a method for inhibiting the hydrolytic activity of an intracellular pancreatic lipase enzyme, which comprises contacting a cell of the compound of the present invention effective to inhibit the hydrolytic activity of the pancreatic lipase enzyme.
    [150] The method described above is for contacting cells in vitro or in vivo .
    [151] The invention also provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.
    [152] In one embodiment, the pharmaceutical compositions are formulated in oral, topical, parenteral or nasal dosage forms.
    [153] The invention also provides a process for the preparation of a pharmaceutical composition comprising mixing a compound of the invention with a pharmaceutically acceptable carrier.
    [154] The present invention also provides a packaging material;
    [155] The pharmaceutical composition described above; And
    [156] Also provided are products comprising instructions on the use of the pharmaceutical compositions in the treatment of obesity.
    [157] The present invention also provides a method for preparing a compound of the structure
    [158]
    [159] Wherein X is O, S, CH 2 or NR 5 ;
    [160] R 1 is H, substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 8 alkylaryl, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6 ' OC (0) R 4 , -CR 6 R 6' OC (O) NHR 7 , -C (0) NR 8 R 9 , -C (O) NR 8 R 9 NR 8 R 9 , -N (R 5 ) C (O) NHR 5 , or CH 2 R 4 ;
    [161] R 2 is substituted or unsubstituted straight C 1 -C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [162] R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or cycloalkyl;
    [163] R 4 is H or substituted or unsubstituted, straight or branched C 6 -C 30 alkyl, aryl, -CH 2 -aryl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [164] R 5 is H or substituted or unsubstituted, straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    [165] R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
    [166] R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or cycloalkyl;
    [167] R 8 and R 9 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylaryl, or NR 8 R 9 is a piperazine substituted together Forms a piperidine ring or dihydro-1H-isoquinoline ring system,
    [168] (a)
    [169]
    [170] Is reacted in the presence of sulfur, base and solvent:
    [171]
    [172] Preparing a;
    [173] (b) the product of step (a)
    [174]
    [175] By reaction in the presence of a base:
    [176]
    [177] Preparing a;
    [178] (c) reacting the product of step (b) with trifluoroacetic acid (TFA) in the presence of a solvent:
    [179]
    [180] Preparing a;
    [181] (d) providing a method of preparing the compound of the present invention by reacting the product of step (c) with SOCl 2 in the presence of a solvent.
    [182] In one embodiment of the method, the base of step (a) is triethyl amine and the solvent is dimethylformamide (DMF).
    [183] In another embodiment, the solvent of step (c) is dichloromethane.
    [184] In another embodiment, the solvent of step (d) is pyridine: CH 2 Cl 2 .
    [185] The present invention also provides a compound prepared by the above method.
    [186] The invention also provides the use of a compound of the invention for the manufacture of a medicament useful for treating obesity in a subject.
    [187] The invention also provides the use of a compound of the invention for the preparation of a medicament useful for inhibiting the hydrolytic activity of intracellular pancreatic lipase enzymes.
    [188] Inhibition of cells can be effective in vitro or in vivo .
    [189] The present invention also provides heterocyclic or heteroaryl rings in the presence of piperazine, piperidine, (1,4) diazepane, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azede Thidine, pyrrole, benzothiazole, benzodioxolane, dithiolane, oxatiin, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro [4.5] decane, mor The compound is characterized in that it is a Pauline, furan or isothiazole ring.
    [190] The present invention also provides that any substituents, when present, are halogen, hydroxyl, straight chain (C 1 -C 30 ) alkyl, branched (C 3 -C 30 ) alkyl, (C 3 -C 10 ) cycloalkyl, straight chain (C 1- C 10 ) alkylcarbonyloxy, branched chain (C 3 -C 30 ) alkylcarbonyloxy, arylcarbonyloxy, straight chain (C 1 -C 30 ) alkoxycarbonyloxy, branched chain (C 3 -C 30 ) alkoxycarbonyl Oxy, aryloxycarbonyloxy, carboxylate, straight chain (C 1 -C 30 ) alkylcarbonyl, branched (C 3 -C 30 ) alkylcarbonyl, straight chain (C 1 -C 30 ) alkoxycarbonyl, side chain (C 3 -C 30 ) alkoxycarbonyl, aminocarbonyl, straight chain (C 1 -C 30 ) alkylthiocarbonyl, branched (C 3 -C 30 ) alkylthiocarbonyl, straight chain (C 1 -C 30 ) alkoxy, Side chain (C 1 -C 30 ) alkoxy, phosphate, phosphonato, cyano, amino, straight chain (C 1 -C 30 ) alkylamino, side chain (C 3 -C 30 ) alkylamino, straight chain (C 1 -C 30) dialkylamino, branched chain (C 3 -C 30) dialkylamino, arylamino, diarylamino, straight chain (C 1 -C 30) alkyl aryl amino, branched (C 3 -C 30 ) alkylarylamino, acylamino, straight chain (C 1 -C 30 ) alkylcarbonylamino, branched chain (C 3 -C 30 ) alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino , Imino, sulfhydryl, straight chain (C 1 -C 30 ) alkylthio, branched chain (C 3 -C 30 ) alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro , Trifluoromethyl, azido, 4-10 membered heterocyclic, straight chain (C 1 -C 30 ) alkylaryl, branched (C 3 -C 30 ) alkylaryl, benzo (1,3) dioxol, or aromatic Or as a 5-6 membered heteroaromatic moiety, a substituent may be further substituted by any of the foregoing.
    [191] The carbon number represented by "(C 1 -C 30 )" or "(C 3 -C 30 )" is a natural number between 1 and 3 and 30, e.g. 1, 2, 3, 4, 5 .... 30 means.
    [192] Another embodiment of the compound of the present invention is as follows.
    [193]
    [194]
    [195]
    [196]
    [197]
    [198]
    [199]
    [200]
    [201]
    [202]
    [203]
    [204]
    [205]
    [206] In the above table, "k" and "Ymax" are the same as the values of the formula shown in the present specification p159. All compounds listed as oils were oil at room temperature.
    [207] A "therapeutically effective amount" described below for a compound of the present invention refers to an amount of therapeutic compound necessary or sufficient to perform the desired function in the mammalian body. The effective amount of the therapeutic composition can vary depending on such factors as the amount, age, sex, weight of the causative drug already present in the mammalian body and the ability of the therapeutic compound of the invention to be effective in achieving the desired result in the mammal. Those skilled in the art will be able to study these variables to make decisions about the effective amount of therapeutic compound without undue experimentation. In vitro or in vivo assays can also be used to determine the “effective amount” of the therapeutic compound described below. Those skilled in the art will be able to select the appropriate amount of therapeutic compound used in the analytical or therapeutic treatment described above.
    [208] The therapeutically effective amount is preferably at least about 20% (more preferably at least 40%, more preferably at least about 60%, and even more preferred when comparing the at least one indication or effect associated with the disease to be treated to an untreated subject. Preferably at least about 80%). Assays can be designed by those skilled in the art to determine the reduction of the above signs and / or effects. Known assays capable of measuring these parameters are also included as part of the present invention.
    [209] "Animal" includes any organism having an adenosine receptor. Examples of such animals include yeast, mammals, reptiles and birds. It also includes transgenic animals.
    [210] "Mammals" is a known term and preferably includes warm-blooded animals, more preferably cattle, sheep, pigs, horses, dogs, cats, mice, mice, humans, and the like. Mammals susceptible to obesity-related diseases are included as part of the present invention.
    [211] "Alkyl" refers to the radical of a saturated aliphatic group including a straight alkyl group, branched alkyl group, cycloalkyl (alicyclic) group, alkyl substituted cycloalkyl group, and cycloalkyl substituted alkyl group. In a preferred embodiment, the straight or branched chain alkyl has up to 30 carbon atoms in the backbone (e.g. C 1 -C 30 for straight chains, C 3 -C 30 for side chains), and more preferably 20 or less It has a carbon atom of. Likewise, preferred cycloalkyls are those having 4-10 carbon atoms in the ring structure, more preferably those having 5, 6 or 7 carbon atoms.
    [212] "Substituted alkyl" refers to an alkyl moiety having a substituent replacing hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents are, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthio Carbonyl, alkoxy, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (alkylcarbonylamino, Arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfamoyl, sulfonamido, nitro, tri Fluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that the moieties substituted on the hydrocarbon chain may be substituted for one another as appropriate. Cycloalkyls can be further substituted, for example, by the substituents described above. “Alkylaryl” moiety is alkyl substituted with aryl (eg phenylmethyl (benzyl)). "Alkyl" also includes unsaturated aliphatic groups of similar length and possible substituents for the foregoing alkyls, but each contains at least one double or triple bond.
    [213] "Aryl" refers to the radical of an aryl group including 5- and 6-membered monocyclic aromatic groups containing 0 to 4 heteroatoms, for example benzene, pyrrole, furan, thiophene, imidazole, benzoxazole , Benzothiazole, thiazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine and the like. Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl and the like. These aryl groups having a hetero atom in the ring structure may also be referred to as "aryl heterocycles", "heteroaryls" or "heteroaromatics" and the like. The aromatic ring may be substituted with the substituents described above and with the substituents described above at one or more ring positions, for example halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl Latex, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (alkylamino, dialkylamino, arylamino, diarylamino and alkylamyl Amino)), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate It may be substituted by substituents such as sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl or aromatic or heteroaromatic moieties. . Aryl groups can also be fused or bridged with non-aromatic alicyclic or heterocyclic rings to form a polycycle (eg, tetralin).
    [214] "Alkenyl" and "alkynyl" are substituents which are similar in length to unsaturated aliphatic groups and the above-mentioned alkyl, and each contain at least one double bond or triple bond. For example, the present invention contemplates cyano and propargyl groups.
    [215] The number of carbons is unless otherwise indicated, where "lower alkyl" is an alkyl group as defined above, but in the framework structure 1 to 10 carbons, preferably 1 to 6 carbons, more preferably 1 to 3 It has one carbon atom. Likewise, "lower alkenyl" and "lower aquinyl" have similar chain lengths.
    [216] "Alkoxyalkyl", "polyaminoalkyl" and "thioalkoxyalkyl" further include an alkyl group as described above, but an oxygen, nitrogen or sulfur atom that substitutes for one or more carbons of the hydrocarbon backbone.
    [217] "Polycyclyl" or "polycyclic radical" means a radical of two or more cyclic rings in which two or more atoms are common to two bond rings (eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or Heterocyclyl), and this ring is referred to as the "fused ring". Rings joined by nonadjacent atoms are referred to as "crosslinked" rings. Each ring of the polycycle is substituted with a substituent as described above, for example halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, Alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, forfonato, phosphinato, cyano, amino (alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino Acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato , Sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl or aromatic or heteroaromatic moieties.
    [218] Here, the "heteroatom" refers to an atom of an element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
    [219] "Heteroatom" or "heterocyclic system" refers to a saturated, partially unsaturated, stable 5, 6 or 7-membered monocyclic or 7, 8, 9, 10 or 11-membered bicyclic heterocyclic ring.
    [220] "Carboxylic" or "heterocyclic" also includes spiro compounds which refer to bicyclic compounds in which the two rings have one atom in common and the atoms are carbon or heteroatoms.
    [221] "Amino acids" are in proteins such as glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, proline, hiscithin, phenylalanine, tyrosine and tryptophan Contains naturally occurring and artificially occurring amino acids found in Amino acid homologs also include amino acids that have been lengthened or shortened by side chains or modified side chains with appropriate functionalities. Amino acids also include the D and L stereoisomers of amino acids when the amino acid structure takes stereoisomeric forms. "Dipeptide" includes two or more amino acids linked together. Preferably, the dipeptide is two amino acids linked via two peptide bonds. Particularly preferred dipeptides include, for example, alanine-alanine and glycine-alanine.
    [222] Some of the compounds of the present invention contain asymmetric carbon atoms in the structure and are therefore due to the fact that a single enantiomer, a diastereomer mixture and individual diastereomers occur as racemate racemate mixtures. Be careful. All of these isomeric compounds are included in the present invention. Each stereo genotype carbon may be in R or S structure. Therefore, isomers resulting from such asymmetry (eg, both enantiomers and diastereomers) are included within the scope of the present invention unless otherwise noted. Such isomers may be obtained in substantially pure form by conventional separation techniques and stereochemically controlled synthesis methods.
    [223] The invention also provides pharmaceutical compositions for the treatment of obesity and obesity related diseases in animals. Pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. It is understood that all compounds described below are included in the therapeutic treatment. It is also understood that the compounds of the present invention may be used alone or in combination with other compounds of the present invention or in combination with separate therapeutic compounds such as, for example, antibiotics, anti-inflammatory or anticancer agents.
    [224] The term "antibiotic" is recognized in the art and is produced by the proliferation of microorganisms which eliminate or inhibit the growth of pathogens and which are selectively toxic to the pathogens with minimal or no deleterious effects on the infected host and their Synthetic derivatives. Suitable examples of antibiotics include, but are not limited to, the major classes of aminoglycosides, cephalosporins, chloramphenicols, fusidic acids, macrolides, penicillins, polymyxins, tetracyclines and streptomycin.
    [225] The term “anti-inflammatory” is known in the art and includes agents that act on the body's mechanisms without directly opposing the causative agent of inflammation, such as glycocorticoids, aspirin, ibuprofen, NSAIDS, and the like.
    [226] The term "anticancer agent" is recognized in the art and preferably includes agents that reduce, eradicate or prevent the proliferation of cancer cells without adversely affecting other physiological functions. Representative examples are cisplatin and cyclophosphamide.
    [227] When the compounds of the invention are administered to humans and mammals as medicaments, they are administered on their own or, for example, from 0.1 to 99.5% (more preferably from 0.5 to 90%) of the active ingredient together with a pharmaceutically acceptable carrier. It can provide as a pharmaceutical composition containing.
    [228] As used herein, the term "pharmaceutically acceptable carrier" is a pharmaceutically acceptable compound involving the transport or transport of a compound (s) of the present invention into or to a patient to perform its desired function. Possible materials, compositions or vehicles, for example liquid or solid fillers, diluents, excipients, solvents or encapsulating materials. Typically, such compounds are transported or transported from one organ or part of the body to another organ or part of the body. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose and sucrose; Starch such as corn starch and potato starch; Cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; malt; gelatin; talc; Excipients such as cocoa butter and suppository waxes; Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soy milk; Glycols such as propylene glycol; Polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; Esters such as ethyl oleate and ethyl laurate; Baby; Buffers such as magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; Ethyl alcohol; Phosphate buffers; And other nontoxic miscible materials used in pharmaceutical formulations.
    [229] As listed above, some embodiments of the present invention may contain basic functional groups, such as amino or alkylamino, and thus may form pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in this respect refers to the relatively nontoxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the purified compounds of the invention separately in a free base form with a suitable organic or inorganic acid and isolating the salts formed thereby. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate , Maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate salts and the like (see, eg, Berge et al. (1977) " Pharmaceutical Salts ", J. Pharm. Sci. 66: 1-19).
    [230] In other cases, the compounds of the present invention may contain one or more acidic functionalities and thus may form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In this case the term "pharmaceutically acceptable salts" refers to the relatively nontoxic inorganic and organic base addition salts of the compounds of the invention. These salts are likewise subjected to in situ in the final isolation and purification of the compounds, or to the purified compounds in free acid form with a suitable base such as hydroxides, carbonates or bicarbonates, ammonia of pharmaceutically acceptable metal cations Or by reacting separately with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Typical alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts. Typical organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
    [231] The term "pharmaceutically acceptable ester" refers to a relatively nontoxic esterified product of a compound of the invention. These esters can be prepared in situ during the final isolation and purification of the compounds, or by reacting the purified compounds separately with suitable esterifying agents in their free acid form or hydroxyl. The carboxylic acid can be converted into an ester via treatment with alcohol in the presence of a catalyst. The hydroxyl containing derivatives can be converted to esters by treatment with esterifying agents, for example alkanoyl halides. The term also includes lower hydrocarbon groups, such as alkyl esters, methyl, ethyl and propyl esters, which may be solvated under physiological conditions (see, eg, Berg et al., Supra).
    [232] The present invention also contemplates the use of prodrugs that are converted in vivo to the therapeutic compounds of the invention (see, eg, RB Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chapter 8). ]. Such prodrugs may be used to alter the biodistribution of the therapeutic compound (eg to allow compounds that do not typically enter the reactive sites of the protease) or pharmacokinetics. For example, carboxylic acid groups can be esterified, for example with methyl groups or ethyl groups, to obtain esters. When the ester is administered to a patient, the ester is cleaved by enzymes or non-enzymatically, reductively or by hydrolysis to reveal anionic groups. Anionic groups can be esterified with residues (eg acyloxymethyl esters) that are cleaved to reveal the intermediate compound and subsequently degraded to give the active compound. In another embodiment, the prodrug is a reduced form of sulfate or sulfonate, such as thiol, which is oxidized to a therapeutic compound in vivo. Furthermore, anionic moieties can be esterified into groups that are actively transported in vivo or selectively absorbed by the target organ. The ester may be selected such that the therapeutic moiety is specifically targeted to a specific reactive site, as described below for the carrier moiety.
    [233] The compounds of the present invention may comprise water soluble prodrugs disclosed in WO 99/33815 (International Application No. PCT / US98 / 04595, filed March 9, 1998, published July 8, 1999). The entire contents of WO 99/33815 are incorporated by reference. Water-soluble prodrugs are metabolized into the body via esterase catalyzed hydrolysis to become active drugs.
    [234] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coatings, sweeteners, flavors and flavors, preservatives and antioxidants may also be present in the composition.
    [235] Examples of pharmaceutically acceptable antioxidants include water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; And metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
    [236] Formulations of the present invention include those suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and / or nasal oral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, the amount in 100% will range from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%.
    [237] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the invention with a carrier and optionally one or more accessory ingredients. Generally, such formulations are prepared by uniformly and intimately associating a compound of the present invention with a liquid carrier or finely divided solid carrier or both, and then optionally molding the product.
    [238] Formulations of the invention suitable for oral administration may be presented in capsules, cachets, pills, pills, tablets, lozenges (using flavor bases such as sucrose and acacia or tragacanth), powders, granules, or aqueous or non-aqueous liquids. As a solution or suspension, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastel (using an inert base such as gelatin and glycerin, or sucrose and acacia) and / or mouthwash It may be in the form of, each of which contains a predetermined amount of the compound of the present invention as an active ingredient. The compounds of the present invention may also be administered as large pills, soft pills or pastes.
    [239] In solid dosage forms of the present invention (capsules, tablets, pills, dragees, powders, granules, etc.) for oral administration, the active ingredient is added to one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or Mix with any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; Binders such as carboxymethylcellulose, alginate, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; Diluents such as glycerol; Disintegrants such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; Dissolution retardants such as paraffin; Absorption accelerators such as quaternary ammonium compounds; Wetting agents such as cetyl alcohol and glycerol monostearate; Absorbents such as kaolin and bentonite clay; Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; And colorants. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise a buffer. Solid compositions of a similar type may also use high molecular weight polyethylene glycols and the like, as well as excipients such as lactose or lactose as fillers in soft and hard filled gelatin capsules.
    [240] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets use binders (e.g. gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (e.g. sodium starch glycolate or crosslinked sodium carboxymethyl cellulose), surface active or dispersants Can be prepared. Molded tablets can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.
    [241] Tablets of the pharmaceutical compositions of the present invention, and other solid dosage forms, such as dragees, capsules, pills and granules, can optionally be coated with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical-formulation. Can be obtained or manufactured. They may also be formulated to provide slow or controlled release of the active ingredient therein, eg using varying proportions of hydroxypropylmethyl cellulose, other polymeric substrates, liposomes and / or microspheres to provide the desired release profile. It may be. They can be sterilized, for example, by filtration through a bacterial maintenance filter or by incorporation of the sterilizing agent in the form of a sterile solid composition which can be dissolved in sterile water or some other sterile infusion medium immediately before use. These compositions may also optionally contain an opaque agent and may have a composition that releases the active ingredient (s) only or preferentially to a particular portion of the gastrointestinal tract, in an optionally delayed manner. Examples of investment compositions that can be used are polymeric substances and waxes. The active ingredient may also be in microencapsulated form, optionally with one or more of the excipients described above.
    [242] Liquid dosage forms for oral administration of a compound of this invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms are inert diluents commonly used in the art, for example water or other solvents, solubilizers and emulsifiers, for example ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl Alcohols, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and Fatty acid esters of sorbitan, and mixtures thereof.
    [243] In addition to inert diluents, the oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, flavoring agents and preservatives.
    [244] Suspensions in addition to the active compounds may be suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and these It may contain a mixture of.
    [245] A pharmaceutical composition formulation of the present invention may be provided as a suppository for rectal or vaginal administration, which provides one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycols, suppository waxes or sali It can be prepared by mixing with silates and will melt in the rectum or vaginal cavity, which is solid at room temperature but liquid at body temperature and will therefore release the active compound.
    [246] Formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing carriers known to be suitable in the art.
    [247] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers or optionally propellants.
    [248] The ointments, pastes, creams and gels are excipients in addition to the active compounds of the invention, for example animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc And zinc oxide, or mixtures thereof.
    [249] Powders and sprays may contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these materials. The spray may further contain conventional propellants such as chlorofluorohydrocarbons and volatile non-substituted hydrocarbons such as butane and propane.
    [250] Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. Such flow rates can be controlled by providing a rate controlling membrane or by dispersing the active compound in a polymer matrix or gel.
    [251] Suitable buffer systems (eg sodium phosphate, sodium acetate or sodium borate) can be added to prevent the pH from shifting under storage conditions.
    [252] Pharmaceutical compositions of the present invention suitable for non-oral administration may be prepared by admixing one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile injectable solutions or dispersions immediately prior to use. Together with sterile powders, which may be reconstituted, which may contain antioxidants, buffers, bacteriostatic agents, solutes or suspensions or thickeners that make the formulation isotonic with the blood of the intended recipient.
    [253] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (eg glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, And injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of surfactants, by means of coating materials, for example lecithin, by maintaining the desired particle size in the case of dispersions.
    [254] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. The incorporation of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc., can reliably prevent the action of microorganisms. It may also be desirable to include isotonic reagents, such as sugars, sodium chloride, and the like into the compositions. Prolonged absorption of the injectable drug form can also be achieved by incorporating agents that delay absorption, such as aluminum monostearate and gelatin.
    [255] In some cases, to prolong the effect of the drug, it may be desirable to retard the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug varies with its rate of dissolution which, in turn, may vary with crystal size and crystal form. On the one hand, delayed absorption of drug forms administered orally is achieved by dissolving or suspending the drug in an oil vehicle.
    [256] Injectable depot forms are made by forming microcapsule substrates of the subject compounds with biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers are poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
    [257] The formulations of the invention can be provided orally, orally, topically or rectally. These are, of course, provided in a form suitable for the respective route of administration. For example, in the form of tablets or capsules, by injection, inhalation, eye lotion, ointment, suppositories, etc. administered by injection, infusion or inhalation; Topically by lotion or ointment; And rectally by suppository. Oral administration is preferred.
    [258] As used herein, the expressions "non-oral administration" and "non-orally administered" refer to a mode of administration, usually by infusion, in addition to oral and topical administration, including but not limited to intravenous, intramuscular, arterial Intracardiac, intracapsular, intracapsular, orbital, intracardiac, intradermal, intraperitoneal, intranasal, subcutaneous, subcutaneous, intraarticular, subcapsular, subretinal, intrathecal and intrasternal injections and injections.
    [259] As used herein, the expressions "systemic administration", "systemically administered", "peripheral administration" and "peripherally administered" refer to a compound, drug or other substance in a manner other than directly to the central nervous system, for example. Administration by subcutaneous administration means that it enters the patient's whole body and thus metabolism and other similar processes are applied.
    [260] These compounds may be administered by any suitable route of administration for treatment, including oral, nasal, eg, spray, rectal, intravaginal, non-oral, in reservoir and topically, eg, oral and sublingual. It can be administered to humans and other animals by, powder, ointment or drops.
    [261] Regardless of the route of administration chosen, the compounds of the invention and / or the pharmaceutical compositions of the invention, which can be used in a suitable hydrated form, are formulated in a pharmaceutically acceptable dosage form by conventional methods known to those skilled in the art. Make up.
    [262] The actual level of administration of the active ingredients in the compositions of the invention can be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response without being toxic to the patient for the particular patient, composition, and mode of administration.
    [263] The dosage level chosen is based on a variety of factors, such as the activity of the specific compound of the invention or ester, salt or amide thereof used, route of administration, time of administration, rate of secretion of the specific compound used, duration of treatment, specific compound used And other drugs, compounds and / or substances used in conjunction with, the age, sex, weight, disease, general health and history of the patient to be treated, and similar factors well known in the medical arts.
    [264] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may use a dose of a compound of the present invention in a pharmaceutical composition, starting at a lower level than necessary to achieve the desired therapeutic effect and gradually increasing the dose until the desired effect is achieved. You can.
    [265] In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such effective dose will generally vary depending on the factors described above. In general, when used for the indicated analgesic effect, the intravenous and subcutaneous doses of the compounds of the present invention to a patient range from about 0.0001 to about 200 mg, more preferably from about 0.01 to about 150 mg / kg body weight per day, Even more preferably from about 0.2 to about 140 mg.
    [266] Optionally, the daily effective dose of the active compound is administered at appropriate intervals throughout the day, optionally in unit dosage form, in two, three, four, five, six or more sub doses administered separately. May be administered.
    [267] It is also possible to administer the compounds of the invention alone, but it is preferred to administer the compounds as pharmaceutical compositions.
    [268] The invention also relates to pharmaceutical compositions packaged for the treatment of unit obesity or obesity related diseases in mammals. The packaged pharmaceutical composition comprises a container holding a therapeutically effective amount of at least one compound of the present invention; Instructions for use of said compound for treating unit obesity or obesity-related diseases in mammals.
    [269] Features and details of the present invention will be described in more detail. Particular embodiments of the invention are illustrative only and the invention is not limited thereby. The main features of the invention can be applied to various embodiments without departing from the scope of the invention.
    [270] The invention is illustrated in the following non-limiting examples. All references cited herein, the contents of ongoing and published applications, are incorporated by reference. The model used in the examples is the model being accommodated and the effect is expected for humans.
    [271] The invention can be better understood from the following detailed description of the experiment. However, it will be understood by those skilled in the art that specific methods and examination results are only for illustrating the present invention and the present invention is limited by the appended claims.
    [272] The compounds in the examples are represented by the integers shown in the table above and X, Y to X are the example numbers and Y is the index starting from 1 in each example, if the compound is not in the table above.
    [273] Detailed description of the experiment
    [274] Non-aqueous reactions requiring anhydrous conditions were all conducted under positive pressure of nitrogen (N 2 ) in an oven dried glass vessel and cooled under N 2 . All solvents for anhydrous reactions were purchased from Aldrich. Solvent removal refers to vaporization under vacuum in a rotary evaporator followed by reduced pressure (<0.1 mmHg) to a predetermined sample weight. The solvent used in the chromatography purchased HPLC grade. The reagents used were all American Chemical Society (ACS) grades or higher. Air sensitive reagents were handled under anhydrous N 2 atmosphere.
    [275] All possible reactions were followed by thin layer chromatography (TLC) treatment and visualized using UV fluorescence, 3% KMnO 4 (aqueous) staining and / or dodecamolibidophosphoric acid. Commercially available thin film and prepared layer chromatography plates were Si250F and Si500F, respectively manufactured by JTBaker. Flash chromatography was performed using JT Baker's 40 μm 'Baker' silica gel. All solvents are expressed in volume ratio.
    [276] Melting points were measured with open capillaries on Mel-Temp II (Laboratory Device, USA) without correction. Mass spectra (MS) were recorded on a Platform 2 micromass instrument. Nuclear magnetic resonance (NMR) spectra were measured on a Varian 200 instrument in a specific solvent with tetramethylsilane (TMS) as the internal standard for 1 H NMR. In the 13 C NMR spectrum, the double solvent peak was used as the reference with the position set for TMS.
    [277] LCMS method: A method = LC1 method; Method B = polarization method, method C = polarization_short method; D method = strong_polarization method.
    [278] General Procedure: Amide / Ester
    [279] a. A path
    [280] Aminothiophenes were synthesized according to known protocols (McKibben, BP, Cartwell, CH Castelhano, AL Tetrahedron Lett . 1999, 40, 5471-5474). Amide protection results from amide protection with trifluoroacetic anhydride followed by treatment with TFA deprotection and sodium carbonate. Attempts to deprotect TFA without amide protection result in decarboxylation. The amino acids react with various acid chlorides and chloroformates to provide thienoxazinone in the proper yield (Scheme 1).
    [281] Scheme 1
    [282]
    [283] b. B path
    [284] In general, the reaction of t- Bu protected amino acids directly with chloroformate or isocyanate followed by TFA deprotection of t- Bu esters and thionyl chloride yields the corresponding thienoxazinone in high yield (Scheme 2). .
    [285] Scheme 2
    [286]
    [287] In addition, the 5-position change was achieved through transesterification of ethyl acetoacetate with various alcohols or benzyl deprotection of diester prior to thiophene formation, followed by esterification by EDC coupling with various alcohols and amines. Or amides are produced respectively.
    [288] Example 1 : General Procedure for Amino-thiophene Formation
    [289]
    [290] 5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- Level 3 -Butyl ester. (1.1)
    [291] Diethylamine was added dropwise to a suspension of benzyl acetoacetate (20.0 g, 104.1 mmol), t-butyl cyanoacetate (14.7 g, 104.1 mmol), sulfur (3.5 g, 109.3 mmol) and pyridine (120 ml). After 2 days, the black solution was concentrated under reduced pressure, which was dissolved in Et 2 0 and filtered through silica. The eluate was concentrated. Chromatography (silica, 7: 1 hexanes / EtOAc) yielded 25.58 g (71%) of orange oil, which crystallized slowly upon standing: 1 H-NMR (CDCl 3 ) 1.58 (s, 9H), 2.70 (s , 3H), 5.27 (s, 2H), 7.38 (m, 5H). 1 H-NMR was the same as known data.
    [292]
    [293] 5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-heptyl ester 4- Level 3 -Butyl ester. (1.2)
    [294] The same method as for preparing 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- tert -butyl ester was used. By this, tert -butyl cyanoacetate (10.3 mL, 72.0 mmol), heptyl acetoacetate (13.7 g, 68.0 mmol) and sulfur (4.4 g, 0.14 mol) were added to diethylamine (7.1 mL in pyridine (80 mL). , 68.0 mmol) was cyclized to give 18.4 g of thiophene (76%) after column chromatography (10: 1, hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ 6.47 (bs, 2H), 4.19 (t, 2H, J = 6.6 Hz), 2.67 (s, 3H), 1.80-1.50 (m, 2H), 1.57 (s, 9H) , 1.30 (bs, 8H), 0.89 (t, 3H, J = 6.6 Hz).
    [295]
    [296] 5-Amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester 4- Level 3 -Butyl ester. (1.3)
    [297] The same method as for preparing 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- tert -butyl ester was used. Thus, tert -butyl cyanoacetate (6.2 mL, 43.0 mmol), octyl acetoacetate (8.5 g, 41.0 mmol) and sulfur (2.6 g, 82.0 mmol) were diluted in pyridine (50 mL) in diethylamine (4.3 mL, 41.0 mmol) was cyclized to give 10.3 g of thiophene (68%) after column chromatography (10: 1, hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ 6.63 (s, 2H), 4.14 (t, 2H, J = 6.6 Hz), 2.63 (s, 3H), 1.72-1.50 (m, 2H), 1.52 (s, 9H) , 1.22 (bs, 10 H), 0.83 (t, 3 H, J = 6.8 Hz). 13 C-NMR (CDCl 3 ) δ 165.9, 165.4, 163.0, 147.9, 109.6, 108.0, 81.0, 64.4, 31.7, 29.1, 28.6, 28.4, 25.9, 22.5, 16.2, 14.0.
    [298] Example 2 : General procedure for cyclization from chloroformate and amino acids
    [299]
    [300] 2-dodecyloxy-5-methyl-4-oxo-4 H -Thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester (6)
    [301] Dodecyl chloroformate (2.80 mL, 2.56 g) was added to the stirred solution of 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester (1.00 g, 3.43 mmol) in pyridine (20 mL). 10.3 mmol) was added. The reaction was stirred at 0 ° C. for 0.5 h and then the solvent was removed under reduced pressure. The product was purified by column chromatography (10: 1 hexanes / EtOAc) to give 169 mg (10%) of solids. 1 H-NMR (CDCl 3 ) δ7.50-7.25 (m, 5H), 5.35 (s, 2H), 4.17 (t, 2H, J = 6.6Hz), 2.87 (s, 3H), 1.72-1.40 (m , 2H), 1.40-1.00 (m, 18H), 0.88 (t, 3H, J = 6.4 Hz). MS (EI): 486.4 (m + + H).
    [302]
    [303] 5-Methyl-2-octyloxy-4-oxo-4H-thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester (5)
    [304] The same method as in 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester was used: 1 H- NMR (CDCl 3 ) δ7.53-7.25 (m, 5H), 5.33 (s, 2H), 4.44 (t, 2H, J = 6.6Hz), 2.83 (s, 3H), 1.80 (quint, 2H, J = 6.6 Hz), 1.26 (bs, 10 H), 0.88 (t, 3 H, J = 6.6 Hz).
    [305]
    [306] 2-hexadecyloxy-5-methyl-4-oxo-4 H -Thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester (7)
    [307] The same method as in 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester was used: 1 H- NMR (CDCl 3 ) δ7.50-7.25 (m, 5H), 5.34 (s, 2H), 4.44 (t, 2H, J = 6.6Hz), 2.83 (s, 3H), 1.80 (quint, 2H, J = 6.6 Hz), 1.26 (bs, 26H), 0.88 (t, 3H, J = 6.6 Hz).
    [308] Example 3 : General Procedure for Cyclization from Acyl Chloride and Amino Acids
    [309]
    [310] 2-heptyl-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (1)
    [311] 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester (200 mg, 0.69 mmol) was added to pyridine (5 mL) and octanoyl chloride (352 μL, 2.56 g, 10.3 mmol) was added to the stirred solution. Was added. The reaction was stirred at 0 ° C. for 0.5 h and then left at RT to stir for 3.5 h. The solvent was removed under reduced pressure. The mixture was diluted with EtOAc and washed with H 2 0. The organic portion was dried (MgSO 4 ) and concentrated under reduced pressure. The product was purified by column chromatography (9: 1 hexanes / EtOAc) to give 48 mg (18%) of solids. 1 H-NMR (CDCl 3 ) δ 7.32-7.48 (m, 5H), 5.35 (s, 2H), 2.86 (s, 3H), 2.69 (t, 2H, J = 7.2 Hz), 1.90-1.70 (m , 2H), 1.45-1.20 (m, 8H), 0.98-0.80 (m, 3H).
    [312]
    [313] 5-Methyl-4-oxo-2-pentadecyl-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (3)
    [314] The same method as in 2-heptyl-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester was used. Cyclization with hexadecanoyl chloride (476 mL, 2.06 mmol) afforded 56 mg (16%) of oily product after column chromatography (9: 1 hexanes / EtOAc). 1 H-NMR (CDCl 3 ) δ7.30-7.55 (m, 5H), 5.35 (s, 2H), 2.86 (s, 3H), 2.69 (t, 2H, J = 7.2Hz), 2.00-1.70 (m , 2H), 1.50-1.0 (m, 24H), 1.00-0.90 (m, 3H).
    [315]
    [316] 2-Undecyl-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (2)
    [317] The same method as in 2-heptyl-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester was used. Cyclization with dodecanoyl chloride (476 mL, 2.06 mmol) afforded 77 mg (24%) of an oily product after column chromatography (9: 1 hexanes / EtOAc). 1 H-NMR (CDCl 3 ) δ7.30-7.50 (m, 5H), 5.35 (s, 2H), 2.86 (s, 3H), 2.69 (t, 2H, J = 7.2Hz), 1.90-1.70 (m , 2H), 1.50-1.20 (m, 16H), 1.00-0.90 (m, 3H).
    [318] Example 4 : General Procedure of Acylation Reaction with Chloroformate of Diester
    [319]
    [320] 3-methoxymethyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- Level 3 -Butyl ester (4.1)
    [321] 5-Amino-3-methoxymethyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- tert -butyl ester (1.16 mg, 3.06 mmol) was added to pyridine (15 mL) and stirred in octyl chloroform. Acid salt (0.9 mL, 886 mg, 4.6 mmol) was added. The reaction was stirred at 0 ° C. for 1 hour and then the solvent was removed under reduced pressure. The product was purified by column chromatography (10: 1 hexanes / EtOAc) to yield 1.27 g (78%) of solids. 1 H-NMR (CDCl 3 ) δ10.51 (s, 1H), 7.32 (m, 5H), 5.12 (s, 2H), 4.19 (t, 2H, J = 6.6 Hz), 3.81 (s, 3H), 3.76 (s, 2H), 1.68 (quint, 2H, J = 6.6 Hz), 1.45 (s, 9H), 1.44-1.21 (m, 10h), 0.89 (t, 3H, J = 5.8 Hz). MS (EI): 533.9 (m + )
    [322]
    [323] 3-Methyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester 2-octyl ester (4.2)
    [324] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- tert -butyl ester was used. Acylation with octyl chloroformate (0.171 mL, 168 mg, 0.87 mmol) afforded 80 mg (26%) of solid after column chromatography (9: 1 hexane / EtOAc) treatment. 1 H-NMR (CDCl 3 ) δ10.86 (s, 1H), 4.23 (t, 2H, J = 6.6 Hz), 2.67 (s, 3H), 1.80-1.40 (m, 4H), 1.57 (s, 9H ), 1.42-1.08 (m, 20H), 0.89 (t, 3H, J = 6.6 Hz). MS (EI): 526.0 (m + )
    [325]
    [326] 3-Methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester 2-heptyl ester (4.3)
    [327] 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-heptyl ester 4- tert -butyl ester (5.0 g, 14.0 mmol) was added to a stirred solution in which CH 2 Cl 2 (100 mL) was mixed. Chloroformate (5.0 ml, 5.0 g, 28.0 mmol) was added. The reaction was stirred at room temperature for 20 hours and then the solvent was removed under reduced pressure. The product was purified by column chromatography (9: 1 hexanes / EtOAc) to give 3.1 g (45%) of solids. 1 H-NMR (CDCl 3 ) δ10.86 (s, 1H), 4.23 (t, 2H, J = 6.6 Hz), 2.67 (s, 3H), 1.80-1.40 (m, 4H), 1.57 (s, 9H ), 1.42-1.08 (m, 20H), 0.89 (t, 3H, J = 6.6 Hz).
    [328]
    [329] 5-benzoyloxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester 2-octyl ester (4.4)
    [330] The same method as in 3-methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-heptyl ester was used. Acylation with benzyl chloroformate (0.154 mL, 185 mg, 1.1 mmol) afforded 138 mg (52%) of solid after column chromatography (10: 1 hexanes / EtOAc) treatment. 1 H-NMR (CDCl 3 ) δ10.97 (s, 1H), 7.50-7.30 (m, 5H), 5.28 (d, 2H, J = 4.8Hz), 4.23 (t, 2H, J = 6.6Hz), 2.72 (s, 3H), 1.80-1.55 (m, 2H), 1.58 (s, 9H), 1.28 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz)
    [331]
    [332] 4-Methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid ethyl ester (4.5)
    [333] The same method as in 3-methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-heptyl ester was used. Acylation with octyl chloroformate (1.06 mL, 1.04 g, 5.4 mmol) afforded 254 mg (28%) of solid after column chromatography (9: 1 hexanes / EtOAc). 1 H-NMR (CDCl 3 ) δ10.53 (s, 1H), 6.31 (s, 1H), 4.34 (q, 2H, J = 6.8Hz), 4.12 (t, 2H, J = 6.6Hz), 2.34 ( s, 3H), 1.67 (bs, 10H), 1.37 (quint, 3H, J = 6.8 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 6.6 Hz). MS (EI): 341.9 (m &lt; + &gt;).
    [334]
    [335] 5- Iso Propoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester 2-octyl ester (4.6)
    [336] The same method as in 3-methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-heptyl ester was used. Acylation with iso- propyl chloroformate (0.54 mL, 0.54 mmol) in toluene gave 117 mg (95%) of solid after column chromatography (9: 1 hexane / EtOAc) treatment. 1 H-NMR (CDCl 3 ) δ10.82 (s, 1H), 5.30 (s, 1H), 5.08 (sept, 1H, J = 6.2Hz), 4.23 (t, 2H, J = 6.6Hz), 2.73 ( s, 3H), 1.80-1.60 (m, 2H), 1.60 (s, 9H), 1.34 (d, 6H, J = 6.2 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 6.6 Hz ).
    [337]
    [338] 5- Iso -Butoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester 2-octyl ester (4.7)
    [339] The same method as in 3-methyl-5-heptyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-heptyl ester was used. Acylation with iso- butyl chloroformate (0.07 mL, 74.0 mg, 0.54 mmol) afforded 98 mg (77%) of solid after column chromatography (9: 1 hexane / EtOAc). 1 H-NMR (CDCl 3 ) δ 10.86 (s, 1 H), 4.23 (q, 2H, J = 6.6 Hz), 4.02 (d, 2H, J = 6.6 Hz), 2.73 (s, 3H), 2.02 ( nonet, 1H, J = 6.6 Hz, 1.80-1.50 (m, 2H), 1.06 (s, 9H), 1.28 (bs, 10H), 1.00 (d, 6H, J = 6.6 Hz), 0.88 (t, 3H , J = 6.6 Hz).
    [340] Example 5 : General Procedure of Acylation Reaction with Isocyanate in Diester Reaction
    [341]
    [342] 3-Methyl-5 (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester 2-octyl ester (5.1)
    [343] 5-amino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester 4- tert -butyl ester (348 mg, 0.94 mmol) and DBU (0.35 mL, 360 mg, 2.4 mmol) were converted to CH 2 Cl 2 Octyl isocyanate (0.166 mL, 146 mg, 0.94 mmol) was added to the stirred solution dissolved in (10 mL). The reaction was stirred at RT for 16 h and then the solvent was removed under reduced pressure. The product was purified by column chromatography (5: 1, hexanes: EtOAc) to give 431 mg (87%) of solids: Mp 92.0-94.0 ° C .; 1 H-NMR (CDCl 3 ) δ12.30 (s, 1H), 8.64 (s, 1H), 5.30 (t, 1H, J = 6.0Hz), 4.25 (t, 2H, J = 6.4Hz), 3.29 ( q, 2H, J = 6.0 Hz), 2.74 (s, 3H), 1.90-1.50 (m, 4H), 1.61 (s, 9H), 1.28 (bs, 20H), 0.88 (m, 6H). MS (EI): 525.1 (m + ).
    [344]
    [345] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- Level 3 -Butyl ester (5.2)
    [346] The same method as in 3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-octyl ester was used. Acylation with octyl isocyanate (3.83 mL, 3.37 g, 21.7 mmol) afforded 3.42 g (38%) of solid after column chromatography (9: 1 hexanes / EtOAc). Mp 119.0-120.0 ° C .; 1 H-NMR (CDCl 3 ) δ11.03 (s, 1H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.03 (vt, 1H), 3.29 (q, 2H, J = 6.6Hz ), 2.71 (s, 3H), 1.63-1.40 (m, 2H), 1.57 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz). MS (EI): 502.8 (m + )
    [347]
    [348] 3-Methyl-5 (3-tetradecyl-ureido) -thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- Level 3 -Butyl ester (5.3)
    [349] The same method as in 3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-octyl ester was used. Acylation with tetradecyl isocyanate (0.33 mL, 287 mg, 1.2 mmol) afforded 253 mg (36%) of solid after column chromatography (9: 1 hexane / EtOAc) treatment. Mp 104.5-106.0 ° C .; 1 H-NMR (CDCl 3 ) δ11.04 (s, 1H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.14 (t, 1H, J = 6.2Hz), 3.29 (q, 2H , J = 6.2 Hz), 2.71 (s, 3H), 1.65-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 22H), 0.88 (t, 3H, J = 6.0 Hz). MS (EI): 587.1 (m + )
    [350]
    [351] 5- (3-hexadecyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- Level 3 -Butyl ester (5.4)
    [352] The same method as in 3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-octyl ester was used. Acylation with hexadecyl isocyanate (0.37 mL, 321 mg, 1.2 mmol) afforded 218 mg (30%) of solid after column chromatography (9: 1 hexane / EtOAc) treatment. Mp 104.0-105.0 ° C .; 1 H-NMR (CDCl 3 ) δ11.04 (s, 1H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.14 (t, 1H, J = 6.2Hz), 3.29 (q, 2H , J = 6.2 Hz), 2.71 (s, 3H), 1.65-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 26H), 0.88 (t, 3H, J = 6.0 Hz). MS (EI): 615.1 (m + )
    [353]
    [354] 5- (3-Dodecyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- Level 3 -Butyl ester (5.5)
    [355] The same method as in 3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- tert -butyl ester 2-octyl ester was used. Acylation with decyl isocyanate (0.29 mL, 254 mg, 1.2 mmol) afforded 265 mg (40%) of solid after column chromatography (9: 1 hexane / EtOAc) treatment. Mp 106.8-108.0 ° C .; 1 H-NMR (CDCl 3 ) δ11.04 (s, 1H), 7.45-7.26 (m, 5H), 5.27 (s, 2H), 5.24 (t, 1H, J = 5.6Hz), 3.28 (q, 2H , J = 6.6 Hz), 2.72 (s, 3H), 1.60-1.40 (m, 2H), 1.57 (s, 9H), 1.25 (bs, 22H), 0.88 (t, 3H, J = 6.4 Hz). MS (EI): 559.0 (m + )
    [356] Example 6 : General Procedure for TFA Deprotection in C-2
    [357]
    [358] 3-methoxymethyl-5-octyloxycarbonylamino-thiophene [2,4] dicarboxylic acid 2-benzyl ester (6.1)
    [359] 3-methoxymethyl-5-octyloxycarbonylamino-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4- tert -butyl ester (0.60 mg, 0.11 mmol) was CH 2 Cl 2 (1.0 mL) TFA (1.0 mL) was added to the stirred solution. The reaction was stirred at room temperature for 12 hours and then the solvent was removed under reduced pressure to give a solid. The product was taken without further purification. 1 H-NMR (CDCl 3 ) δ 11.98 (s, 1H), 10.09 (s, 1H), 7.45-7.20 (m, 3H), 5.14 (s, 2H), 4.22 (t, 2H, J = 6.6Hz ), 3.85 (s, 3H), 3.82 (s, 2H), 1.70 (quint, 2H, J = 6.6 Hz), 3.85 (s, 3H), 3.82 (s, 2H), 1.70 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10 H), 0.88 (t, 3 H, J = 5.6 Hz).
    [360]
    [361] 3-methoxymethyl-5-octylcarbonylamino-thiophene-2,4-dicarboxylic acid 2-octyl ester (6.2)
    [362] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. Deprotection with TFA afforded 64 mg (68%) of solid after column chromatography (5: 1 hexanes / EtOAc). 1 H-NMR (CDCl 3 ) δ 10.56 (s, 1H), 4.27 (t, 2H, J = 6.5 Hz), 4.25 (t, 2H, J = 6.5 Hz), 2.81 (s, 3H), 1.80- 1.53 (m, 4H), 1.50-1.15 (m, 20H), 0.89 (t, 3H, J = 6.5 Hz). MS (EI): 469.9 (m + )
    [363]
    [364] 5-heptyloxycarbonylamino-3-methoxymethyl-thiophene-2,4-dicarboxylic acid 2-octyl ester (6.3)
    [365] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. Deprotection with TFA gave 2.7 g (96%) of solid after titration with hexane. 1 H-NMR (CDCl 3 ) δ10.53 (s, 1H), 4.26 (t, 4H, J = 6.6 Hz), 2.81 (s, 3H), 1.90-1.58 (m, 4H), 1.6-1.12 (m , 16H), 0.89 (t, 3H, J = 6.6 Hz). MS (EI): 441.9 (m + )
    [366]
    [367] 5-benzyloxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester (6.4)
    [368] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. Deprotection treatment with TFA gave a solid which was used without purification. MP 148.0-149.5 ° C. 1 H-NMR (CDCl 3 ) δ10.56 (bs, 2H), 7.50-7.30 (m, 5H), 5.30 (d, 2H, J = 4.8 Hz), 4.25 (t, 2H, J = 6.6 Hz), 2.79 (s, 3H), 1.83-1.60 (m, 2H), 1.83-1.60 (m, 2H), 1.29 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz).
    [369]
    [370] 5- Iso -Propoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester (6.5)
    [371] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The solid obtained as a result of deprotection with TFA was taken without further purification. MP 152.0-153.0 ° C. 1 H-NMR (CDCl 3 ) δ10.45 (s, 1H), 5.12 (sept, 1H, J = 6.6 Hz), 4.25 (t, 2H, J = 6.6 Hz), 2.82 (s, 3H), 1.73 (quint, 2H, J = 6.6 Hz), 1.38 (d, 6H, J = 6.6 Hz), 1.28 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz).
    [372]
    [373] 5- Iso -Butoxycarbonylamino-3-methyl-thiophene-2,4-dicarboxylic acid 2-octyl ester (6.6)
    [374] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification. 1 H-NMR (CDCl 3 ) δ 10.53 (bs, 2H), 4.2 (t, 2H, J = 6.2 Hz), 4.08 (d, 2H, J = 6.6 Hz), 2.82 (s, 3H), 2.06 ( nonet, 1H, J = 6.6 Hz, 1.71 (quint, 2H, J = 6.6 Hz), 1.29 (bs, 10H), 1.00 (d, 6H, J = 6.6 Hz), 0.89 (t, 3H, J = 6.6 Hz).
    [375]
    [376] 4-Methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (6.7)
    [377] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The solid resulting from deprotection with TFA was used without further purification. 1 H-NMR (CDCl 3 ) δ10.90 (bs, 2H), 5.82-5.62 (m, 1H), 5.78-5.60 (m, 1H), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s , 3H), 1.70-1.40 (m, 4H), 1.27 (bs, 20H), 0.88 (m, 6H).
    [378]
    [379] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 2-octyl ester (6.8)
    [380] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification. 1 H-NMR (CDCl 3 ) δ12.30 (s, 1H), 10.91 (bs, 2H), 5.30 (t, 1H, J = 6.0 Hz), 4.25 (t, 2H, J = 6.4 Hz), 3.29 ( q, 2H, J = 6.0 Hz), 2.74 (s, 3H), 1.90-1.50 (m, 4H), 1.28 (bs, 20H), 0.88 (m, 6H). MS (EI): 468.9 (m + )
    [381]
    [382] 5-Benzylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (6.9)
    [383] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification. 1 H-NMR (CDCl 3 ) δ 11.16 (s, 1H), 7.40-7.10 (m, 5H), 6.19 (t, 1H, J = 5.4 Hz), 4.56 (d, 2H, J = 5.4 Hz), 3.25 (q, 2H, J = 6.6 Hz), 2.63 (s, 3H), 1.60-1.40 (m, 4H), 1.26 (bs, 10H), 0.86 (t, 3H, J = 6.2 Hz). MS (EI): 445.9 (m + )
    [384]
    [385] 5-Dimethylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (6.10)
    [386] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification. 1 H-NMR (CDCl 3 ) δ 10.89 (s, 2H), 5.39 (t, 1H, J = 6.6 Hz), 3.27 (q, 2H, J = 6.6 Hz), 3.05 (s, 6H), 2.28 ( s, 3H), 1.65-1.45 (m, 2H), 1.26 (s, 10H), 0.87 (t, 3H, J = 6.2 Hz). MS (EI): 383.9 (m + )
    [387]
    [388] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 2-benzyl ester (6.11)
    [389] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification. 1 H-NMR (CDCl 3 ) δ10.57 (s, 1H), 7.45-7.25 (m, 5H), 5.30 (s, 1H), 4.26 (t, 2H, J = 6.6Hz), 2.81 (s, 3H ), 1.72 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10 H), 0.88 (t, 3H, J = 6.6 Hz).
    [390]
    [391] 4-Methyl-5-octylcarbamoyl-2- (3-tetradecyl-ureido) -thiophene-3-carboxylic acid (6.12)
    [392] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification.
    [393]
    [394] 2- (3-hexadecyl-ureido) -4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid (6.13)
    [395] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification. MS (EI): 580.2 (m + )
    [396]
    [397] 2- (3-Dodecyl-ureido) -4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid (6.14)
    [398] The same method as in 3-methoxymethyl-5-octyloxycarbonylamino-thiophene- [2,4] dicarboxylic acid 2-benzyl ester was used. The resulting solid, deprotected with TFA, was used without purification.
    [399] MS (EI): 524.1 (m + )
    [400] Example 7 : Additional TFA Deprotection Treatment
    [401]
    [402] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid (7.1)
    [403] 3-methoxymethyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- tert -butyl ester (50.0 mg, 0.13 mmol) was added to CH 2 Cl 2 (1 mL). TFA (1 mL) was added to the stirred solution. The reaction was stirred at RT for 2 h and then the solvent was removed under reduced pressure to give a solid. The product was dissolved in EtOAc and washed with saturated NaHCO 3 (aq.) And brine. The organic layer was dried over MgSO 4 , filtered and concentrated under reduced pressure to yield 10.0 mg of solid (22%). 1 H-NMR (CDCl 3 ) δ10.45 (bs, 1H), 6.27 (bs, 1H), 5.00 (bs, 1H), 3.50-3.20 (m, 2H), 2.37 (m, 2H), 1.70-1.40 (m, 2H), 1.26 (bs, 10H), 0.88 (t, 3H, J = 6.2 Hz). MS (EI): 312.9 (m + -COOH).
    [404] Example 8 : Ethyl ester hydrolysis
    [405]
    [406] 4-Methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (8.1)
    [407] 4-Methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid ethyl ester (254 mg, 0.74 mmol) was added to ethanol (2 mL) and THF (2 mL) and stirred into LiOH-H 2 O (31 mg, 0.74 mmol) was added. The reaction was stirred at RT for 5 days and then the solvent was removed under reduced pressure to give a solid. The product was taken without further purification. 1 H-NMR (CDCl 3 ) δ6.02 (s, 1H), 4.07 (t, 2H, J = 6.6 Hz), 2,32 (s, 3H), 1.60-1.40 (m, 2H), 1.27 (bs , 10H), 0.86 (t, 3H, J = 6.6 Hz).
    [408] Example 9 : General Procedure for Hydrolysis in C-6
    [409]
    [410] 5-Methyl-2-octyloxy-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid (11)
    [411] 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester (50 mg, 0.10 mmol) in EtOAc (2 mL) 10% Pd / C (5 mg, 10% by weight) was added to the stirred solution. The reaction was charged with H 2 and stirred at RT for 1 hour. The reaction slurry was filtered through a plug of celite and then the solvent was removed under reduced pressure . The product was taken without further purification. 1 H-NMR (CDCl 3 ) δ4.47 (t, 2H, J = 6.2 Hz), 4.19 (bs, 1H), 2.85 (s, 3H), 1.80 (quint, 2H, J = 6.2 Hz), 1.27 ( bs, 18H), 0.88 (t, 3H, J = 6.6 Hz). MS (EI): 395.4 (m + )
    [412]
    [413] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester (9.1)
    [414] The same method as the preparation of 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid was used. Hydrolysis resulted in a solid which was used without purification. 1 H-NMR (CDCl 3 ) δ11.06 (s, 1H), 5.14 (vt, 1H), 3.30 (q, 2H, J = 6.0Hz), 2.71 (s, 3H), 1.70-1.40 (m, 2H ), 1.59 (s, 9H), 1.27 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz). MS (EI): 412.8 (m + )
    [415]
    [416] 5- (3-Dodecyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester (9.2)
    [417] The same method as the preparation of 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid was used. Hydrolysis resulted in 0.198 g of solid (98%) which was used without purification. MP 187.0-188.50 ° C .; 1 H-NMR (CDCl 3 ) δ11.06 (s, 1H), 5.21 (s, 1H), 5.21 (bs, 1H), 3.31 (q, 2H, J = 5.8 Hz), 2.72 (s, 3H), 1.65-1.40 (m, 2H), 1.60 (s, 9H), 1.26 (bs, 18H), 0.88 (t, 3H, J = 6.6 Hz). MS (EI): 469.0 (m + )
    [418]
    [419] 3-Methyl-5- (3-tetradecyl-ureido) -thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester (9.3)
    [420] The same method as the preparation of 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid was used. Hydrolysis resulted in 123 mg of solid (58%) which was used without purification. MP 176.0-178.0 ° C. 1 H-NMR (CDCl 3 ) δ11.06 (s, 1H), 7.35 (t, 1H, J = 6.2 Hz), 5.20 (bs, 1H), 3.30 (q, 2H, J = 6.2 Hz), 2.72 (s, 3H), 1.70-1.45 (m, 2H), 1.59 (s, 9H), 1.26 (bs, 22H), 0.88 (t, 3H, J = 6.6 Hz). MS (EI): 497.0 (m + )
    [421]
    [422] 5- (3-hexadecyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 4- Level 3 -Butyl ester (9.4)
    [423] The same method as the preparation of 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid was used. Hydrolysis resulted in a solid which was used without purification. MP 187.5-189.0 ° C. 1 H-NMR (CDCl 3 ) δ11.07 (s, 1H), 5.18 (bs, 1H), 3.29 (q, 2H, J = 6.2Hz), 2.72 (s, 3H), 1.70- 1.45 (m, 2H), 1.60 (s, 9H), 1.25 (bs, 26H), 0.88 (t, 3H, J = 6.6 Hz). MS (EI): 525.0 (m + )
    [424] Example 10 : General Procedure for Amide / Ester Formation at C-6
    [425]
    [426] 4-Methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid Level 3 -Butyl ester (10.1)
    [427] 3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- tert -butyl ester (185 mg, 0.46 mmol) and octylamine (0.112 mL, 87.3 mg, 0.69 mmol) Was added to CH 2 Cl 2 (10 mL) and EDC (133 mg, 0.69 mmol) and DMAP (2.8 mg, 0.02 mmol) were added to the stirred solution. The reaction was stirred at RT for 16 h and washed with H 2 O, 0.5N citric acid, saturated NaHCO 3 and brine. The organic portion was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (9: 1; hexanes: EtOAc) to give 290 mg of solid (99%). 1 H-NMR (CDCl 3 ) δ 10.89 (s, 1H), 5.82-5.62 (m, 1H), 5.78-5.60 (m, 1H), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s , 3H), 1.70-1.40 (m, 4H), 1.27 (bs, 20H), 0.88 (m, 6H), MS (EI): 524.1 (m + )
    [428]
    [429] 5-benzylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid Level 3 -Butyl ester (10.2)
    [430] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert -butyl ester was used. Coupling with benzylamine (0.061 mL, 60 mg, 0.56 mmol) gave 202 mg of solids (99%) after column chromatography (95: 5; CHCl 3 : MeOH) treatment. 1 H-NMR (CDCl 3 ) δ10.90 (s, 1H), 7.40-7.20 (m, 5H), 6.05 (t, 1H, J = 5.4 Hz), 5.33 (t, 1H, J = 6.6 Hz) 4.55 (d, 2H, J = 5.4 Hz), 3.26 (q, 2H, J = 6.6 Hz), 2.63 (s, 3H), 1.65-1.40 (m, 2H), 1.56 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J = 6.2 Hz). MS (EI): 502.0 (m + )
    [431]
    [432] 5-Dimethylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid Level 3 -Butyl ester (10.3)
    [433] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert -butyl ester was used. Coupling with 40% dimethylamine solution (0.063 mL, 0.56 mmol) dissolved in H 2 O afforded 174 mg of solid (99%) after column chromatography (95: 5; CHCl 3 : MeOH) treatment. 1 H-NMR (CDCl 3 ) δ 10.78 (s, 1H), 5.39 (t, 1H, J = 6.6 Hz), 3.27 (q, 2H, J = 6.6 Hz) 3.5 (s, 6H), 2.28 (s , 3H), 1.65-1.45 (m, 2H), 1.56 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J = 6.2 Hz). MS (EI): 440.0 (m + )
    [434]
    [435] 2- (3-Dodecyl-ureido) -4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid Level 3 -Butyl ester (10.4)
    [436] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert -butyl ester was used. Coupling with octylamine (0.111 mL, 87.0 mg, 0.69 mmol) yielded 205 mg of solid (81%) after column chromatography (9: 1; hexanes: EtOAc) treatment. 1 H-NMR (CDCl 3 ) δ10.90 (s, 1H), 5.74 (t, 1H, J = 5.4 Hz), 5.47 (t, 1H, J = 6.2 Hz) 3.32 (vsext, 4H, J = 6.6 Hz ), 2.61 (s, 3H), 1.70-1.40 (m, 4H), 1.55 (s, 9H), 1.26 (bs, 28H), 0.88 (t, 6H, J = 6.6 Hz). MS (EI): 580.2 (m + )
    [437]
    [438] 4-Methyl-5-octylcarbamoyl-2- (3-tetradecyl-ureido) -thiophene-3-carboxylic acid Level 3 -Butyl ester (10.5)
    [439] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert -butyl ester was used. Coupling with octylamine (0.112 mL, 87.3 mg, 0.69 mmol) gave 290 mg of solid (99%) after column chromatography (9: 1; hexanes: EtOAc) treatment. 1 H-NMR (CDCl 3 ) δ10.90 (s, 1H), 5.74 (t, 1H, J = 5.4 Hz), 5.44 (bs, 1H), 3.33 (vsext, 4H, J = 6.2 Hz), 2.61 ( s, 3H), 1.60-1.40 (m, 4H), 1.56 (s, 9H), 1.26 (bs, 32H), 0.88 (t, 6H, J = 6.6 Hz). MS (EI): 608.1 (m + )
    [440]
    [441] 2- (3-hexadecyl-ureido) -4-methyl-5-octylcarbamoyl-thiophene-3-carboxylic acid Level 3 -Butyl ester (10.6)
    [442] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert -butyl ester was used. Coupling with octylamine (0.080 mL, 62.0 mg, 0.50 mmol) gave 195 mg of solid (93%) after column chromatography (9: 1; hexanes: EtOAc) treatment. 1 H-NMR (CDCl 3 ) δ10.90 (s, 1H), 5.73 (t, 1H, J = 5.4 Hz), 5.35 (bs, 1H), 3.33 (vsext, 4H, J = 6.2 Hz), 2.61 ( s, 3H), 1.65-1.40 (m, 4H), 1.56 (s, 9H), 1.26 (bs, 36H), 0.88 (t, 6H, J = 6.6 Hz). MS (EI): 636.2 (m + )
    [443]
    [444] 2-heptyl-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid hexyl ester (4)
    [445] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert -butyl ester was used. Coupling with octyl alcohol (0.125 mL, 1.50 mmol), Prep. 20 mg of solid (21%) were obtained after TLC (9: 1; hexanes: EtOAc) treatment. 1 H-NMR (CDCl 3 ) δ4.29 (t, 2H, J = 6.6 Hz), 2.84 (s, 3H), 2.87 (t, 2H, J = 7.2 Hz), 2.00-1.60 (m, 4H), 1.15-1.60 (m, 24H), 1.15-0.70 (m, 6H).
    [446] Example 11 : General Procedure for Cyclization Using EDCI
    [447]
    [448] 5-methoxy-2-octyloxy-4-oxo-4 H -Thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (112)
    [449] 3-methoxymethyl-5-octyloxycarbonylamino-thiophene [2,4] dicarboxylic acid 2-benzyl ester (27 mg, 0.056 mmol) was added to CH 2 Cl 2 (1.0 mL) and stirred in a solution. 16.0 mg, 0.084 mmol) was added. The reaction was stirred at RT for 16 h and washed with H 2 O and brine. The organic portion was dried (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (5: 1; hexanes: EtOAc) to give 7.0 mg of solid (27%). 1 H-NMR (CDCl 3 ) δ 7.42-7.27 (m, 5H), 5.16 (s, 2H), 4.38 (t, 2H, J = 6.6 Hz), 3.89 (s, 3H), 3.85 (s, 2H ), 1.78 (quint, 2H, J = 6.6 Hz), 1.55-1.10 (m, 10H), 0.89 (t, 3H, J = 6.6 Hz). MS (EI): 461.9 (m + H + )
    [450]
    [451] 5-methyl-2-octyloxy-4-oxo-4 H -Thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid octyl ester (9)
    [452] The same method as the preparation of 5-methoxy-2-octyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester was used. As a result of the cyclization reaction, 15 mg of solid (24%) was obtained after column chromatography (9: 1; hexanes: EtOAc). 1 H-NMR (CDCl 3 ) δ4.45 (t, 2H, J = 6.6 Hz), 4.29 (t, 2H, J = 6.6 Hz), 2.80 (s, 3H), 1.88-1.70 (m, 4H), 1.29 (bs, 20 H), 0.89 (t, 6 H, J = 6.6 Hz). MS (EI): 451.8 (m + )
    [453] Example 12 SOCl 2 Procedure for Cyclization Reaction
    [454]
    [455] 5-methoxy-2-heptyloxy-4-oxo-4 H -Thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester (10)
    [456] 5-heptyloxycarbonylamino-3-methoxymethyl-thiophene-2,4-dicarboxylic acid 2-heptyl ester (2.7 mg, 6.1 mmol) was added to pyridine (65 mL) and thienyl chloride (0.88) was added to the stirred solution. mL, 1.4 g, 12.0 mmol) was added. The reaction was stirred at RT for 0.5 h and concentrated under reduced pressure. The residue was dissolved in CHCl 3 and washed with H 2 O, 0.5N citric acid, saturated NaHHCO 3 and brine. The organic portion was dried (MgSO 4 ), filtered and concentrated under reduced pressure. Purification by residue column chromatography (20: 1; hexanes: EtOAc) yielded 2.6 mg of solid (99%). 1 H-NMR (CDCl 3 ) δ4.45 (t, 2H, J = 6.6 Hz), 4,29 (t, 2h, J = 6.6 Hz), 2.80 (s, 3H), 1.78 (dquint, 4H, J) = 13.2, 6.6 Hz), 1.58-1.18 (bs, 16H), 0.90 (t, 6H, J = 7.0 Hz). 13 C NMR (CDCl 3 ) δ 168.9, 162.1, 158.3, 154.0, 144.1, 121.4, 113.9, 71.1, 65.4, 31.6, 31.6, 28.8, 28.7, 28.6, 28.2, 25.9, 25.5, 22.5, 14.6, 14.0; MS (EI): 423.9 (m + )
    [457]
    [458] 2-benzyloxy-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octyl ester (113)
    [459] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 11.0 mg of a solid (10%) was obtained after column chromatography (20: 1; hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ7.55-7.30 (m, 5H), 5.48 (s, 2H), 4.29 (t, 2H, J = 6.6Hz), 2.82 (s, 3H), 1.75 (dquint, 2H , J = 6.6 Hz), 1.29 (bs, 10H), 0.89 (t, 3H, J = 6.6 Hz).
    [460]
    [461] 2- Iso -Propoxy-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octyl ester (12)
    [462] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 108 mg of solid (98%) was obtained after column chromatography (20: 1; hexane: EtOAc). MP 47.5-48.0 ° C. 1 H-NMR (CDCl 3 ) δ5.31 (sept, 1H, J = 6.2 Hz), 4.29 (t, 2H, J = 6.6 Hz), 2.81 (s, 3H), 1.75 (quint, 2H, J = 6.6 Hz), 1.44 (d, 6H, J = 6.2 Hz), 1.29 (bs, 10H), 0.89 (t, 3H, J = 6.4 Hz). MS (EI): 482.9 (m + )
    [463]
    [464] 2- Iso -Butoxy-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octyl ester (114)
    [465] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 15 mg of solid (25%) was obtained after column chromatography (20: 1; hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ4.31 (q, 2H, J = 6.6 Hz), 4023 (d, 2H, J = 6.6 Hz), 2.82 (s, 3H), 2.13 (nonet, 1H, J = 6.6 Hz), 1.73 (quint, 2H, J = 6.6 Hz), 1.29 (bs, 10H), 1.03 (d, 6H, J = 6.6 Hz), 0.89 (t, 3H, J = 6.6 Hz). MS (EI): 395.9 (m + )
    [466]
    [467] 5-Methyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (23)
    [468] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 44 mg of oil (20%) was obtained after column chromatography (20: 1; hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ6.59 (s, 1H), 4.4 (t, 2H, J = 6.6 Hz), 2.46 (s, 3H), 1.80 (quint, 2H, J = 6.6 Hz), 1.29 ( bs, 10H), 0.89 (t, 3H, J = 6.6 Hz). MS (EI): 295.9 (m + )
    [469]
    [470] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octylamide (18)
    [471] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 106 mg of solid (4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3- after column chromatography (95: 5; CHCl 3 : MeOH) treatment 52%) from carboxylic acid tert-butyl ester). Mp 152.0-152.8 ° C. 1 H-NMR (CDCl 3 ) δ5.70 (bs, 1H), 5.06 (bs, 1H), 3.42 (q, 6H, J = 6.2Hz), 2.71 (s, 3H), 1.70- 1.42 (m, 4H), 1.54 (s, 9H), 1.28 (bs, 20H), 0.89 (t, 6H, J = 6.6 Hz). MS (EI): 450.5 (m + )
    [472]
    [473] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octyl ester (20)
    [474] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 229 mg of solid (67% from t-Bu ester) was obtained after column chromatography (20: 1; hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ 5.20 (bs, 1H), 4.26 (t, 2H, J = 6.6 Hz), 3.51-3.40 (m, 2H), 2.78 (s, 3H), 1.85-1.48 (m , 4H), 1.28 (bs, 20H), 1.00-0.80 (m, 6H). MS (EI): 451.0 (m + )
    [475]
    [476] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl amide (21)
    [477] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, after column chromatography (95: 5; CHCl 3 : MeOH), 75.0 mg of solid (3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4 49% from -tert-butyl ester). 1 H-NMR (CDCl 3 ) δ 7.40-7.26 (m, 5H), 6.03 (t, 1H, J = 5.4 Hz), 5.20 (bs, 1H), 4.62 (d, 2H, J = 5.4 Hz), 3.50-3.30 (m, 2H), 2.72 (s, 3H), 1.73-1.43 (m, 2H), 1.28 (bs, 10H), 0.88 (t, 3H, J = 6.6 Hz). MS (EI): 427,9 (m + )
    [478]
    [479] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid dimethylamide (22)
    [480] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 17.0 mg of solid (3-methyl-5- (3-octyl-ureido) -thiophene-2,4- after column chromatography (1: 1 to 1: 5; hexanes: EtOAc) was treated. 13%) was obtained from dicarboxylic acid 4-tert-butyl ester. 1 H-NMR (CDCl 3 ) δ5.22 (bs, 1H), 3.41 (q, 2H, J = 5.4 Hz), 3.08 (s, 6H), 2.41 (s, 3H), 1.62 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10 H), 0.88 (t, 3 H, J = 6.2 Hz). MS (EI): 365.9 (m + )
    [481]
    [482] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (16)
    [483] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 229 mg of solid (3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4-3 after column chromatography (9: 1; hexane: EtOAc) was treated. 63%) was obtained from a tert-butyl ester. Mp 153.5-154.0 ° C. 1 H-NMR (CDCl 3 ) δ7.50-7.30 (m, 5H), 5.44 (bs, 1H), 5.32 (s, 2H), 3.42 (q, 2H, J = 6.2Hz), 2.79 (s, 3H), 1.78-1.50 (m, 2H), 1.27 (bs, 10H), 0.88 (t, 3H, J = 6.4 Hz). MS (EI): 428.9 (m + )
    [484]
    [485] 5-heptylamino-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (17)
    [486] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 12 mg of a solid was obtained. 1 H-NMR (CDCl 3 ) δ7.50-7.30 (m, 5H), 5.32 (s, 2H), 5.24 (bs, 1H), 3.42 (q, 2H, J = 6.2Hz), 2.79 (s, 3H ), 1.78-1.50 (m, 2H), 1.27 (bs, 8H), 0.88 (t, 3H, J = 6.4 Hz). MS (EI): 414.8 (m + )
    [487]
    [488] 2-dodecylamino-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octylamide (24)
    [489] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 56 mg of solid (2- (3-decyl-ureido) -4-methyl-5-octylcarbamoyl-thiophene after column chromatography (9: 1 to 5: 1; hexanes: EtOAc) was treated. 32%) from 3- carboxylic acid tert -butyl ester) were obtained. Mp 137.1-138.0 ° C. 1 H-NMR (CDCl 3 ) δ5.74 (bs, 1H), 5.30 (bs, 1H), 3.42 (q, 4H, J = 6.6 Hz), 2.71 (s, 3H), 1.75- 1.45 (m, 4H), 1.27 (bs, 28H), 0.89 (t, 6H, J = 6.0 Hz). MS (EI): 506.1 (m + )
    [490]
    [491] 5-Methyl-4-oxo-2-tetradecylamino-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octylamide (25)
    [492] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 25 mg of solid (4-methyl-5-octylcarbamoyl-2- (3-tetradecyl-ureido) -thiophene-3- after column chromatography (5: 1; hexane: EtOAc) was treated. 19% from carboxylic acid tert -butyl ester). Mp 145.0-145.8 ° C. 1 H-NMR (CDCl 3 ) δ5.74 (bs, 1H), 5.30 (bs, 1H), 3.42 (q, 4H, J = 6.6 Hz), 2.71 (s, 3H), 1.75- 1.45 (m, 4H), 1.27 (bs, 32H), 0.89 (t, 6H, J = 6.0 Hz). MS (EI): 534.1 (m + )
    [493]
    [494] 2-hexadecylamino-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octylamide (26)
    [495] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of cyclization, 24 mg of solid (2- (3-hexadecyl-ureido) -4-methyl-5-octylcarbamoyl-thiophene-3- after column chromatography (5: 1; hexanes: EtOAc) was treated. 14% from carboxylic acid tert -butyl ester). Mp 146.3-147.0 ° C. 1 H-NMR (CDCl 3 ) δ5.74 (bs, 1H), 5.30 (bs, 1H), 3.42 (q, 4H, J = 6.6 Hz), 2.71 (s, 3H), 1.75- 1.45 (m, 4H), 1.27 (bs, 36H), 0.89 (t, 6H, J = 6.0 Hz). MS (EI): 562.1 (m + )
    [496]
    [497] 5-Methyl-4-oxo-2- (4-phenoxy-phenylamino) -4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octyl ester (19)
    [498] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. The result of the cyclization reaction gave a solid, which was purified by EtOAc / hexane recrystallization to give 25 mg of solid (24%). 1 H-NMR (CDCl 3 ) δ7.50 (d, 2H, J = 8.8 Hz), 7.25-7.45 (m, 2H), 7.40-6.90 (m, 5H), 4.27 (t, 2H, J = 6.6 Hz ), 2.81 (s, 3H), 1.73 (dt, 2H, J = 6.6 Hz), 1.27 (bs, 10H), 0.89 (t, 3H, J = 6.0 Hz).
    [499]
    [500] 2-heptyloxy-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (8)
    [501] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 116 mg of solid (63%) was obtained after column chromatography (4: 1; hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ7.50-7.30 (m, 5H), 5.33 (s, 2H), 4.44 (t, 2H, J = 6.2Hz), 1.90-1.70 (m, 2H), 1.45-1.15 (m, 10 H), 1.00-0.80 (m, 3 H).
    [502]
    [503] 5-Methyl-2-octyloxy-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid octylamide (15)
    [504] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was used. As a result of the cyclization reaction, 44.0 mg of a solid (44%) was obtained after column chromatography (4: 1; hexane: EtOAc). 1 H-NMR (CDCl 3 ) δ 5.90-5.70 (m, 1H), 4.43 (t, 2H, J = 6.6 Hz), 3.42 (q, 2H, J = 6.6 Hz), 2.72 (s, 3H), 1.90-1.70 (m, 2H), 1.70-1.50 (m, 2H), 1.50-1.15 (m, 20H), 0.95-0.80 (m, 6H).
    [505] Example 13 : Carbamate / Urea Intermediates
    [506] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-4-ylmethyl) -carbamoyl] -thiophene-3-carboxylic acid tert-butyl ester (13.1)
    [507] Purification of the compound by column chromatography (100% EtOAc) gave 175 mg (70%) of a white foam. : (70%) 1 H NMR (CDCl 3 , 200 MHz) δ 0.86 (m, 3H), 1.25 (brs, 10H), 1.56 (brs, 11H), 2.64 (s, 3H), 3.28 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 4.56 (d, 2H, J = 5.8 Hz), 5.16 (t, 1H, J = 5.4 Hz), 6.17 (t, 1H, J = 5.8 Hz), 7.24 (d , 2H, J = 5.8 Hz, 8.54 (d, 2H, J = 5.8 Hz), 10.94 (s, 1H)
    [508] 4-Methyl-5- [methyl- (6-methyl-pyridin-2-ylmethyl) -carbamoyl] -2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.2 ): (84%). 1 H NMR (CDCl 3 , 200 MHz) δ 0.87 (m, 3H), 1.25 (brs, 10H), 1.56 (brs, 11H), 2.32 (s, 3H), 2.52 (s, 3H), 3.01 (s, 3H), 3.28 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 4.74 (s, 2H), 4.95 (t, 1H, J = 5.4 Hz), 7.03 (d, 2H, J = 7.8 Hz) , 7.55 (d, 1H, J = 7.6 Hz), 10.75 (s, 1H)
    [509] 5- [Ethyl- (2-pyridin-2-yl-ethyl) -carbamoyl] -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.3) : (99%). 1 H NMR (CDCl 3 , 200 MHz) δ 0.87 (m, 3H), 1.11 (t, 3H, J = 7.0 Hz) 1.25 (brs, 10H), 1.56 (brs, 11H), 2.20 (s, 3H), 3.09 (t, 2H, J = 7.0 kPa), 3.26 (m, 4H), 3.80 (t, 2H, J = 7.0 kPa), 5.08 (t, 1H, J = 5.0 kPa), 7.15 (m, 2H), 7.59 (ddd, 1H, J = 7.6 Hz, J = 7.6 Hz, J = 1.4 Hz), 8.51 (d, 1H, J = 4.4 Hz), 10.76 (s, 1H)
    [510] 5- (Benzoyloxycarbonylmethyl-carbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.4): (95%). 1 H NMR (CDCl 3 , 200 MHz) δ 0.86 (m, 3H), 1.25 (brs, 10H), 1.58 (brs, 11H), 2.56 (s, 3H), 3.25 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 4.21 (t, 2H, J = 5.4 Hz), 5.21 (s, 2H), 5.49 (brs, 1H), 6.51 (t, 1H, J = 5.6 Hz), 7.36 (s, 5H) , 10.71 (s, 1H)
    [511] 5- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid 3 Tert-butyl ester (13.5): (97%). 1 H NMR (CDCl 3 , 200 MHz) δ 0.87 (brs, 3H), 1.27 (brs, 10H), 1.57 (s, 11H), 2.30 (s, 3H), 2.83 (t, 2H, J = 5.8 Hz) , 3.29 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 3.80 (m, 8H), 4.69 (s, 2H), 4.87 (t, 1H, J = 5.6 Hz), 6.55 (s, 1H) , 6.60 (s, 1H), 10.83 (s, 1H)
    [512] 5- (3,4) -Dimethoxy-benzylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.6): (97%) . 1 H NMR (CDCl 3 , 200 MHz) δ 0.86 (brs, 3H), 1.25 (brs, 10H), 1.56 (s, 11H), 2.63 (s, 3H), 3.25 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 3.86 (m, 6H), 4.47 (d, 2H, J = 5.6 Hz), 5.05 (t, 1H, J = 5.8 Hz), 5.95 (t, 1H, J = 5.0 Hz), 6.84 (m, 3 H), 10.90 (s, 1 H)
    [513] 5- (2-Acetylamino-ethylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.7): (58%). 1 H NMR (CDCl 3 , 200 MHz) δ 0.87 (s, 3H), 1.27 (brs, 10H), 1.57 (s, 11H), 2.04 (s, 3H), 2.60 (s, 3H), 3.29 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 3.50 (m, 4H), 4.90 (brs, 1H), 6.29 (brm, 2H), 10.92 (s, 1H)
    [514] 5- [4- (Isopropylcarbamoyl-methyl) -piperazin-1-carbonyl] -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester ( 13.8): (61%). 1 H NMR (CDCl 3 , 200 MHz) δ 0.86 (brs, 3H), 1.10-1.28 (m, 16H), 1.56 (s, 11H), 2.29 (s, 3H), 2.51 (s, 4H), 2.99 ( s, 3H), 3.27 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 3.63 (s, 4H), 4.10 (m, 1H), 5.05 (brs, 1H), 6.81 (d, 1H, J = 8.0 μs), 10.79 (s, 1H)
    [515] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 2-benzyl ester quaternary-butyl ester (13.9): 1 H NMR (CDCl 3 , 200 MHz) δ 0.88 ((m, 3H), 1.28 (brs, 10H), 1.59 (m, 11H), 2.72 (s, 3H), 3.47 (m, 2H), 5.30 (b, 2H), 6.31 (brs, 1H), 7.36 (m, 5 H).
    [516] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-3-yl-methyl) -carbamoyl] -thiophene-3-carboxylic acid tert-butyl ester (13.10). The reaction proceeded through a plug of silica gel with ethyl acetate to yield 13.10, 3.42 g (crude yield 94%) of a grayish white solid.
    [517] 5- (Furan-2-ylmethyl) -carbamoyl] -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.11): white solid (yield 97 %). 1 H NMR (CDCl 3 , 200 MHz) δ 0.86 (t, 3H, J = 6.6 Hz), 1.24-1.27 (m, 10H), 1.54 (bs, 11H), 2.61 (s, 3H), 3.26 (dt, 2H, J = 6.4, 5.8 Hz), 4.54 (d, 2H, J = 5.4 Hz), 5.31 (bs, 11H), 6.02 (t, 1H, J = 5.3 Hz), 6.27 (1H, dd, J = 11.4 , 3.2 μs), 6.30 (d, 1H, J = 3.2 μs), 7.34 (s, 1H), 10.89 (bs, 1H), 13 C NMR (CDCl 3 ) δ 14.0, 16.0, 22.6, 26.8, 28.4, 29.1 , 29.2, 29.9, 31.7, 36.9, 40.8, 82.3, 107.6, 110.4, 112.9, 118.7, 140.5, 142.3, 151.0, 152.7, 153.6, 163.2, 166.4, MS (ES +) 491.95 (M + 1), 493.00 (M + 2)
    [518] 4-Methyl-2- (3-octyl-ureido) -5-[(2-pyridin-3-yl-ethyl) -carbamoyl] -thiophene-3-carboxylic acid tert-butyl ester (13.12). White solid (yield 73%) 1 H NMR (CDCl 3 , 200 MHz) δ 0.85 (t, 3H, J = 6.6 Hz), 1.21-1.28 (m, 10H), 1.52 (bs, 11H), 2.54 (s, 3H), 2.89 (t, 2H, J = 6.9 Hz), 3.27 (dt, 2H, J = 6.4, 6.2 Hz), 3.61 (dt, 2H, J = 6.6, 6.2 Hz), 5.69 (bs, 1H), 5.92 (t, 1H, J = 5.9 Hz), 7.23 (dd, 1H, J = 6.2, 5.2 Hz), 7.55 (ddd, 1H, J = 7.6, 1.8, 1.8 Hz), 8.46 (d, 1H, J = 4.8 Hz), 8.47 (s, 1 H), 10.81 (bs, 1 H). 13 C NMR (CDCl 3 ) δ 14.0, 15.9, 22.6, 26.8, 28.3, 29.1, 29.2, 29.9, 31.7, 33.0, 40.7, 40.9, 82.2, 112.7, 118.9, 123.5, 134.4, 136.3, 139.9, 147.9, 150.1, 152.6, 153.6, 163.7, 166.3, MS (ES +) 516.98 (M + 1), 518.05 (M + 2).
    [519] 4-Methyl-2- (3-octyl-ureido) -5- [4- (2-pyridin-1-yl-ethyl) -piperazin-1-carbonyl] -thiophene-3-carboxylic acid tertiary- Butyl ester (13.13). Yellow oil (Yield 80%) 1 H NMR (CDCl 3 , 200 MHz) δ 0.84 (t, 3H, J = 6.4 Hz), 1.22 (bs, 12H), 1.53 (m, 15H), 2.25 (s, 3H) , 2.33-2.52 (m, 8H), 3.23 (dt, 2H, J = 6.6, 6.4 Hz), 3.57 (bs, 2H), 5.63 (bs, 1H), 10.73 (bs, 1H), ms (ES +) 592.07 (M + 1), 593.13 (M + 2).
    [520] 5- (3-hexyl-3-methyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (13.14): 1 H NMR (CDCl 3 , 200 MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.25-1.32 (m, 6H), 1.58 (s, 11H), 2.72 (s, 3H), 3.04 (S, 3H), 3.36 (t, 2H, J = 7.7 Hz), 5.26 (s, 2H), 7.27-7.43 (m, 5H), 11.53 (bs, 1H), 13 C NMR (CDCl 3 ) δ 13.9, 15.8, 22.5, 26.3, 27.7, 28.3 , 31.4, 34.4, 49.3, 65.8, 82.3, 113.1, 115.2, 127.9, 128.4, 136.1, 145.5, 153.6, 156.6 163.0, 166.7, MS (ES +) 557 (M + 68)
    [521] 5- [3- (1-Butyl-pentyl) -ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (13.15): 1 H NMR (CDCl 3 , 200 MHz) δ 0.86 (t, 6H, J = 6.6 Hz), 1.25-1.31 (m, 12H), 1.55 (s, 9H), 2.70 (s, 3H), 3.58-3.78 (m, 1H), 5.04 (bd, 1H, J = 8.8 Hz), 5.25 (s, 2H), 7.27-7.41 (m, 5H), 10.98 (bs, 1H), 13 C NMR (CDCl 3 ) δ 13.9, 14.0, 15.8, 22.6 , 22.7, 28.0, 28.1, 28.3, 35.1,35.6, 65.9, 82.3, 112.8, 115.2, 127.9, 128.4, 136.1, 145.5, 153.1, 156.3 163.0, 166.4, 186.4 MS (ES +) 585 (M + 68).
    [522] 5- (3,3-Dioctyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (13.16): 1 H NMR (CDCl 3 , 200 MHz) δ 0.87 (t, 6H, J = 6.6 Hz), 1.26-1.30 (m, 20H), 1.58 (bs, 13H), 2.72 (s, 3H), 3.32 (t, 4H, 7.7 Hz), 5.25 ( s, 2H), 7.28-7.43 (m, 5H), 11.58 (bs, 1H). 13 C NMR (CDCl 3 ) δ 14.0, 15.8, 22.6, 26.9, 28.3, 28.5, 29.2, 29.3, 31.8, 47.9, 65.9, 82.3, 113.0, 115.1, 127.9, 128.0, 128.5, 136.1, 145.6, 153.3, 163.0, 166.7.
    [523] 5-isobutylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.17). MS (ES): m / z 467.9 [M−H + ]: 1 H NMR (CDCl 3 , 200 MHz): δ = 0.83 (m, 9H), 1.26-1.57 (m, 20H), 1.87 (m, 1H, 6.6 Hz), 2.62 (s, 3H), 3.16-3.30 (m, 4H), 5.11 (brs, 1H), 5.64 (m, 1H).
    [524] 5- (2, 2-Dimethyl-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.18). MS (ES): m / z 481.7 [M−H + ]: 1 H NMR (CDCl 3 , 200 MHz): δ = 0.83 (m, 9H), 1.26-1.57 (m, 23H), 2.62 (s, 3H), 3.16-3.30 (m, 4 H), 5.11 (brs, 1 H), 5.64 (m, 1 H).
    [525] 5-[(2,3-Dihydro-benzofuran-5-ylmethyl) -carbamoyl] -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.19) MS (ES): m / z 543.87 [M−H + ]
    [526]
    [527] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-2-ylmethyl) -carbamoyl] -thiophene-3-carboxylic acid tert-butyl ester (13.20):
    [528] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, binding to 2- (aminomethyl) pyridine (31.5 mg, 0.36 mmol) after column chromatography yielded 86.9 mg of solid (71%) (EtOAc): 1 H NMR (CDCl 3 ) δ 0.87 (m , 3H), 1.45-1.20 (m, 10H), 1.70-1.45 (m, 11H), 2.64 (s, 3H), 3.29 (dt, 4H, J = 6.7, 6.6 Hz), 4.68 (d, 2H, J = 5.8 Hz), 4.91 (m, 1H), 7.02 (m, 1H), 7.35-7.10 (m, 1H), 7.65 (t, 1H, J = 8.0 Hz), 8.53 (d, 1H, J = 5.0 Hz ), 10.92 (s, 1 H), MS (EI): cal'd 502.86, exp 502.94 (MH + ).
    [529]
    [530] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-3-ylmethyl) -carbamoyl] -thiophene-3-carboxylic acid tert-butyl ester (13.21):
    [531] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, binding to 3- (aminomethyl) pyridine (31.5 mg, 0.36 mmol) after column chromatography yielded 93.1 mg of solid (76%) (EtOAc): 1 H NMR (CDCl 3 ) δ 0.87 (m , 3H), 1.45-1.20 (m, 10H), 1.70-1.45 (m, 11H), 2.65 (s, 3H), 3.29 (dt, 4H, J = 6.7, 6.6 Hz), 4.57 (d, 2H, J = 5.6 Hz), 4.89 (m, 1H), 6.05 (t, 1H, J = 7.0, 5.0 Hz), 7.68 (d, 1H, J = 7.0 Hz), 8.53 (d, 1H, J = 5.0 Hz), 8.58 (s, 1 H), 10.92 (s, 1 H); MS (EI): cal'd 502.86, exp 502.94 (MH + ).
    [532]
    [533] 5-Dibutylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.22):
    [534] The same method as the preparation of 4-methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester was employed. Thus, binding to dibutylamine (37.6 mg, 0.36 mmol) after column chromatography yielded 56.9 mg of solid (45%) (8: 2; hexanes: EtOAc): 1 H NMR (CDCl 3 ) δ 0.87 (m, 9H), 1.18-1.40 (m, 14H), 1.45-1.68 (m, 15H), 2.23 (s, 3H), 3.20-3.46 (m, 6H), 5.11 (m, 1H), 10.74 (s , 1H), MS (EI): cal'd 523.77, exp 524.02 (MH + ).
    [535] 5- (4-Benzyl-piperidine-1-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.23): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (s, 3H), 1.26 (brs, 11H), 1.56 (brs, 15H), 2.27 (s, 3H), 2.54 (d, 2H, J = 6.6 Hz), 2.80 ( m, 2H), 3.27 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 4.20 (m, 2H), 5.06 (t, 1H, J = 5.2 Hz), 7.05-7.30 (m, 5H), 10.77 (s, 1 H); MS (ES): MS (ES) 570.1 (M + 1)
    [536] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2- (1-butyl-pentyl) ester (13.24): (60%). 1 H NMR (CD 3 OD , 200 MHz) δ 0.89 (s, 9H), 1.32 (s, 18H), 1.60 (s, 15H), 2.69 (s, 3H) 3.19 (t, 2H, J = 6.4 Hz) , 5.00 (p, 1H, J = 6 Hz), 10.95 (s, 1H); MS (ES) 539.2 (M + 1)
    [537] 4-Methyl-2- (3-octyl-ureido) -5- (3-phenoxy-propylcarbamoyl) -thiophene-3-carboxylic acid tert-butyl ester (13.25): (55%). 1 H NMR (CDCl 3, 400 MHz) δ 0.88 (m, 3H), 1.27 (m, 10H), 1.55 (m, 11H), 2.07 (m, 2H), 2.62 (s, 3H), 3.30 (dt, 2H, J = 5.6 Hz, J = 7.2 Hz), 3.59 (dt, 2H, J = 5.6 Hz, J = 6.4 Hz), 4.07 (t, 2H, J = 5.6 Hz), 4.82 (brs, 1H), 6.14 (brs, 1 H), 6.95 (m, 3 H), 7.25 (m, 2 H), 10.95 (s, 1 H); MS (ES) 545.95 (M)
    [538] 5- (1-Butyl-pentylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.26): (92%). 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (s, 9H), 1.29 (m, 18H), 1.56 (s, 11H), 2.61 (s, 3H), 3.29 (dt, 2H, J = 6.6 Hz, J = 6.6 Hz), 4.02 (brs, 1H), 5.04 (t, 1H, J = 5.6 Hz), 5.40 (d, 1H, J = 8.8 Hz), 10.91 (s, 1H)
    [539] 5-[(furan-2-ylmethyl) -carbamoyl] -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.27): MS (ES +) 491.88 (M + 1).
    [540] 4-Methyl-2- (3-octyl-ureido) -5- (thiazol-2-ylcarbamoyl) -thiophene-3-carboxylic acid tert-butyl ester (13.28): MS (ES &lt; + &gt;) 494.84 (M +1).
    [541] 4-Methyl-2- (3-octyl-ureido) -5- (2-pyridin-3-yl-ethylcarbamoyl) -thiophene-3-carboxylic acid tert-butyl ester (13.29): MS (ES +) 516.93 (M + 1).
    [542] 4-Methyl-2- (3-octyl-ureido) -5- [4- (2-pyridin-1-yl-ethyl) -piperazin-1-carbonyl] -thiophene-3-carboxylic acid tertiary- Butyl ester (13.30): MS (ES &lt; + &gt;) 592.04 (M + 1).
    [543] 4-Methyl-2- (3-octyl-ureido) -5- (4-phenyl-piperazine-1-carbonyl) -thiophene-3-carboxylic acid tert-butyl ester (13.31): MS (ES +) 556.94 (M + 1).
    [544] 5-([1,4 '] bipyridinyl-1'-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.32) : MS (ES +) 563.01 (M + l).
    [545] 5- (3-Imidazol-1-yl-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.33): MS (ES + 519.95 (M + 1).
    [546] 5-Dihexylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.34): (40%). 1 H NMR (CD 3 Cl , 200 MHz) δ 0.85 (s, 9H), 1.24 (s, 22H), 1.56 (s, 15H), 2.24 (s, 3H), 3.31 (m, 6H), 4.83 (t , 1H, J = 5.2 Hz), 10.76 (s, 1H); MS (ES) 580.21 (M + 1)
    [547] 5-Dioctylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.35): (65%). 1 H NMR (CD 3 Cl , 200 MHz) δ 0.86 (m, 9H), 1.23 (s, 32H), 1.56 (s, 15H), 2.25 (s, 3H), 3.31 (m, 6H), 4.80 (t , 1H, J = 5.6 Hz), 10.77 (s, 1H); MS (ES) 637.00 (M + 1)
    [548] 5-cyclohexylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.36): (75%). 1 H NMR (CD 3 Cl , 200 MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.26 (m, 16H), 1.56 (m, 15H), 2.60 (s, 3H), 3.28 (dt, 2H , J = 6.6 Hz, J = 6.2 Hz), 3.88 (m, 1H), 4.97 (t, 1H, J = 5.4 Hz), 5.57 (d, 1H, J = 7.2 Hz), 10.78 (s, 1H); MS (ES) 494.12 (M + 1)
    [549] 5- (4-Benzyl-piperazin-1-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.37): (72%) . 1 H NMR (CD 3 Cl , 200 MHz) δ 0.87 (m, 3H), 1.26 (brs, 10H), 1.56 (brs, 11H), 2.28 (s, 3H), 2.44 (brs, 4H), 3.27 (dt , 2H, J = 6.6 Hz, J = 6.6 Hz), 3.52 (s, 2H), 3.60 (brs, 4H), 4.88 (t, 1H, J = 5.0 Hz), 7.30 (brs, 5H), 10.78 (s , 1H); MS (ES) 571.16 (M + l)
    [550] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-3-ylmethyl) -carbamoyl] -thiophene-3-carboxylic acid tert-butyl ester (13.38):
    [551] The crude solid was then colored through a plug of silica gel with ethyl acetate to give 13.38, 3.84 g (crude yield 98%) of a tan solid.
    [552] 5- (3-Dimethylamino-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.39): MS (ES &lt; + &gt;) 496.95 (M +1)
    [553] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (13.40): Mp 119.0-120.0 ° C .: 1 H NMR (CDCl 3 ) δ 11.03 (s, 1H), 7.50-7.20 (m, 5H), 5.27 (s, 2H), 5.03 (vt, 1H), 3.29 (q, 2H, J = 6.6 Hz), 2.71 (s, 3H ), 1.63-1.40 (m, 2H), 1.57 (s, 9H), 1.26 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz). MS (EI): 502.8 (M &lt; + &gt;).
    [554] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4-tert-butyl ester 2-octyl ester (13.41): Mp 92.0-94.0 ° C .: 1 H NMR (CDCl 3 ) δ 12.30 (s, 1H), 8.64 (s, 1H), 5.30 (t, 1H, J = 6.0Hz), 4.25 (t, 2H, J = 6.4Hz), 3.29 (q, 2H, J = 6.0 Hz), 2.74 (s, 3H), 1.90-1.50 (m, 4H), 1.61 (s, 9H), 1.28 (bs, 20H), 0.88 (m, 6H), MS (EI): 525.1 (M + ) .
    [555] 4-Methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.42): 1 H NMR (CDCl 3 ) δ 10.89 (s, 1H) , 5.82-5.62 (m, 1H), 5.78-5.60 (m, 1H), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s, 3H), 1.70-1.40 (m, 4H), 1.55 (s , 9H), 1.27 (bs, 20H), 0.88 (m, 6H), MS (EI): 524.1 (M + ).
    [556] 4-Methyl-2- (3-octyl-ureido) -5- (4-phenyl-butylcarbamoyl) -thiophene-3-carboxylic acid tert-butyl ester (13.43): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.21-1.43 (m, 10H), 1.57 (s, 15H), 2.60 (m, 5H), 3.24-3.43 (m, 4H), 5.22 (brs, 1H), 5.70 (t, 1H, J = 5.0 Hz), 7.25 (m, 5H), 10.90 (s, 1H).
    [557] 4-Methyl-2- (3-octyl-ureido) -5- (3-phenyl-propylcarbamoyl) -thiophene-3-carboxylic acid tert-butyl ester (13.44): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.21-1.43 (m, 10H), 1.57 (s, 11H), 1.89 (tt, 2H, J = 7.4 Hz, J = 7.6 Hz), 2.65 (m, 5H), 3.24-3.45 (m, 4H), 5.14 (brs, 1H), 5.73 (t, 1H, J = 5.2 Hz), 7.17-7.31 (m, 5H), 10.90 (s, 1H).
    [558] 4-Methyl-2- (3-octyl-ureido) -5- (2-phenoxy-ethylcarbamoyl) -thiophene-3-carboxylic acid tert-butyl ester (13.45): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.22-1.49 (m, 10H), 1.56 (s, 11H), 2.61 (s, 3H), 3.28 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz) , 3.78 (dt, 2H, J = 5.2 Hz, J = 5.4 Hz), 4.09 (t, 2H, J = 5.2 Hz), 5.08 (t, 1H, J = 5.0 Hz), 6.21 (t, 1H, J = 5.4 Hz), 6.29 (m, 3H), 7.28 (m, 2H) 10.91 (s, 1H).
    [559] 5- (2-Methoxy-ethylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.46): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.22-1.45 (m, 10H), 1.57 (brs, 11H), 2.60 (s, 3H), 3.24-3.37 (m, 5H), 3.54 (m, 4H), 5.05 (t, 1H, J = 5.2 Hz), 6.12 (brs, 1H) 10.88 (s, 1H).
    [560] 5- (3-methoxy-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (13.47): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.21-1.49 (m, 10H), 1.57 (brs, 11H), 1.83 (tt, 2H, J = 5.8 Hz, J = 6.2 Hz), 2.60 (s, 3H) , 3.24-3.35 (m, 5H), 3.49 (m, 4H), 5.13 (t, 1H, J = 5.6 Hz), 6.31 (t, 1H, J = 5.6 Hz), 10.90 (s, 1H).
    [561] 5-((benzo (1,3) dioxol-5-ylmethyl) -carbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester ( 13.48): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.26-1.43 (brs, 10H), 1.57 (brs, 11H), 2.63 (s, 3H), 3.27 (dt, 2H, J = 6.2Hz, J = 6.6Hz), 4.44 (d, 2H, J = 5.6Hz), 4.92 (t, 1H, J = 5.6Hz), 5.94 (s, 2H), 6.76 (s, 2H), 6.81 (s, 1 H), 10.91 (s, 1 H).
    [562]
    [563] 3-Methyl-5- (1-methylheptyloxycarbonylamino) thiophene-2,4-dicarboxylic acid 2-benzyl ester 4-tert-butyl ester (13.49):
    [564] Light brownish oil 1 H NMR (CDCl 3, 200 MHz) with a yield of 82% as a mixture of two rotamers (ratio 2: 1): δ 7.35-7.40 (m, 5H), 6.49 (brs, 1H) ), 5.25 and 5.28 (s, 2H), 4.70-4.80 and 4.80-5.05 (m, 1H), 2.68 and 2.73 (s, 3H), 1.50-1.61 (m, 9H), 1.20-1.40 (m, 8H) , 0.87 (m, 3 H).
    [565]
    [566] 3-Methyl-5- [3- (1methylheptyl) ureido] -thiophene-2,4-carboxylic acid 2-benzyl ester 4-tert-butyl ester (13.50):
    [567] Yield 99% light yellow oil 1 H NMR (CDCl 3, 200 MHz) as two rotamer mixtures (proportion 2: 1): δ 11.00 (brs, 1H), 7.29-7.43 (m, 5H), 5.24 and 5. 26 (s, 2H), 4.60and4.68 (brs, 1H), 3.80-3.95 (brs, 1H), 3.45-3.90 (m, 1H), 2.65and2.70 (s, 3H), 1.55and1.57 ( s, 9H), 1.40-1.50 (m, 2H), 1.20-1.40 (m, 8H), 1.17 (d, 2H, J = 6.6 Hz), 1.09 (d, 1H, J = 6.2 Hz), 0.80-0.95 (m, 3 H).
    [568] Example 14 Acid Intermediates
    [569] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-4-ylmethyl) -carbamoyl) -thiophene-3-carboxylic acid (14.1): (99%). 1 H NMR (CD 3 OD , 200 MHz): δ 0.86 (M, 3H), 1.25 (brs, 10H), 1.56 (m, 2H), 2.64 (s, 3H), 3.28 (m, 2H), 4.56 ( d, 2H, J = 5.8 Hz, 7.24 (d, 2H, J = 5.8 Hz), 8.54 (d, 2H, J = 5.8 Hz)
    [570] 4-Methyl-5- [methyl- (6-methyl-pyridin-2-ylmethyl) -carbamoyl] -2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.2): (99% ). 1 H NMR (CD 3 OD , 200 MHz): δ 0.86 (m, 3H), 1.28 (brs, 10H), 1.50 (brs, 2H), 2.38 (s, 3H), 2.50 (s, 3H), 3.04 ( s, 3H), 3.17 (brs, 2H), 4.74 (s, 2H), 7.15 (m, 2H), 7.55 (t, 1H, J = 7.6 Hz)
    [571] 5- [Ethyl- (2-pyridin-2-yl-ethyl) -carbamoyl] -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.3): (99%) . 1 H NMR (CD 3 OD , 200 MHz): δ 0.85 (m, 3H), 1.20 (brs, 13H), 1.49 (brs, 2H), 2.20 (s, 3H), 3.19 (m, 4H), 3.41 ( m, 2H), 3.83 (brs, 2H), 7.38 (m, 2H), 7.84 (t, 1H, J = 7.2 Hz), 8.49 (d, 1H, J = 3.6 Hz)
    [572] 5- (Benzyloxycarbonylmethyl-carbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.4): (99%). 1 H NMR (CD 3 OD , 200 MHz): δ 0.86 (m, 3H). 1.28 (brs, 10H), 1.50 (brs, 2H), 2.57 (s, 3H), 3.18 (m, 2H), 4.09 (s, 2H), 7.31 (brs, 5H).
    [573] 3-Methyl-5- (3-octyl-thioureido) -thiophene-2,4-dicarboxylic acid 2-benzyl ester (14.5): (99%). 1 H NMR (CD 3 OD , 200 MHz): δ 0.99 (brs, 3H), 1.29 (brs, 10H), 1.61 (brs, 2H), 2.74 (s, 3H), 3.48 (brs, 2H), 5.29 (s, 2H), 7.38 (m, 5H),
    [574] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-3-yl-methyl) -carbamoyl] -thiophene-3-carboxylic acid (14.6)
    [575] Thiophene (3.42 g, 6.8 mmol) was dissolved in 40 mL of CH 2 CL 2 . Trifluoroacetic acid (10 mL) was added slowly and the reaction stirred at rt for 4 h. The reaction was concentrated in vacuo. The residue was dissolved in methanol and saturated NaHCO 3 was added to PH-7. The solution was concentrated in vacuo and the filtrate was concentrated in vacuo to yield 2.19 g (crude yield 72%) of a tan solid in 14.6.
    [576] 5-[(furan-2-yl-methyl) carbamoyl] -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.7) white solid (yield 73%): 1 H NMR (CD 3 OD , 200 MHz): δ 0.90 (t, 3H, J = 6.4 Hz), 1.30-1.39 (m, 10H), 1.50-1.60 (m, 2H), 2.56 (s, 3H), 3.20 ( t, 2H, J = 6.9 Hz), 4.49 (s, 2H), 6.27 (1H, d, J = 3.0 Hz), 6.35 (dd, 1H, J = 3.2, 1.8 Hz), 7.34 (d, 1H, J = 1.8 Hz). MS (ES +) 435.76 (M + 1), 436.66 (M + 2).
    [577] 4-Methyl-2- (3-octyl-ureido) -5-[(2-pyridin-3-yl-ethyl) -carbamoyl] -thiophene-3-carboxylic acid (14.8) Light plunk solid (yield 100 %): 1 H NMR (CD 3 OD , 200 MHz): δ 0.90 (t, 3H, J = 9.9 Hz), 1.32 (bs, 10H), 1.51-1.60 (m, 2H), 2.58 (s, 3H) , 2.96 (t, 2H, J = 7.0 Hz), 3.20 (t, 2H, J = 6.7 Hz), 3.59 (t, 2H, J = 7.0 Hz), 7.39 (dd, 1H, J = 7.8, 4.8 Hz) , 7.78 (d, 1H, J = 7.8 Hz), 8.39 (d, 1H, J = 4.8 Hz), 8.46 (s, 1H), MS (ES−) 458.92 (M-1).
    [578] 4-Methyl-2- (3-octyl-ureido) -5- [4- (2-pyridin-1-yl-ethyl) -piperazin-1-carbonyl] -thiophene-3-carboxylic acid (14.9) Peach solid (yield 80%): MS (ES-) 534.04 (M-1)
    [579] 5- (3-hexyl-3-methyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid 2-benzyl ester (14.10) light pink solid (yield 100%): 1 H NMR (CDCl 3 , 200 MHz): δ 0.87 (t, 3H, J = 6.4 Hz), 1.25-1.31 (m, 6H), 1.58-1.62 (m, 2H), 2.78 (s, 3H), 3.05 (s, 3H), 3.36 (t, 2H, J = 7.5 Hz), 5.29 (s, 2H), 7.29-7.44 (m, 5H), 10.39 (bs, 1H), 11.18 (bs, 1H), 13 C NMR (CDCl 3 ) δ 13.9, 15.4, 22.4, 26.3, 27.7, 31.4, 34.7, 49.7, 66.4, 110.8, 116.4, 127.9, 128.1, 128.5, 135.7, 146.1, 153.5, 158.6 162.9, 171.3, MS (ES +) 432.74 (M + 1).
    [580] 5- (3,3-Dioctyl-ureido) -3-methyl-thiophene-2,4-dicarboxylic acid benzyl ester (14.11) light pink solid (yield 84%): 1 H NMR (CDCl 3, 200 MHz ): δ 0.86 (t, 6H, J = 6.6 Hz), 1.26-1.30 (m, 20H), 1.63 (bs, 4H), 2.80 (s, 3H), 3.33 (t, 4H, J = 7.0 Hz), 5.28 (s, 2H), 7.30-7.43 (m, 5H), 11.20 (s, 1H), 11.92 (bs, 1H).
    [581] 5-Isobutylcarbamoyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.12). MS (ES): m / z 411.8 [M−H + ].
    [582] 5- (2,2-Dioctyl-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.13). MS (ES): m / z 425.8 [M−H + ]: 1 H NMR (CDCl 3, 200 MHz): δ = 1.26-1.57 (m, 23H), 2.62 (s, 3H), 3.16-3.30 (m, 4H ), 5.11 (brs, 1 H), 5.64 (m, 1 H).
    [583]
    [584] 4-Methyl-2- (3-octyl-ureido) -5- [yridin-2-ylmethyl) -carbamoyl] -thiophene-3-carboxylic acid (14.14)
    [585] The same method as the preparation of 3-methoxymethyl-5-octyloxycarbonylamino-thiophene [2,4] dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection treatment with TFA gave a solid that was used without purification: 1 H NMR (CDCl 3 + 1 drop of CD 3 OD) δ 0.86 (m, 3H), 1.32-1.20 (m, 10H), 1.60 -1.32 (m, 2H), 2.59 (s, 3H), 3.22 (dt, 4H, J = 6.7, 6.6 Hz), 4.76 (s, 2H), 7.40-7.15 (m, 2H), 7.76 (t, 1H , J = 7.9 Hz), 8.53 (d, 1H, J = 5.0 Hz)
    [586]
    [587] 4-Methyl-2- (3-octyl-ureido) -5-[(pyridin-3-ylmethyl) -carbamoyl] -thiophene-3-carboxylic acid (14.15)
    [588] The same method as the preparation of 3-methoxymethyl-5-octyloxycarbonylamino-thiophene [2,4] dicarboxylic acid 2-benzyl ester was employed. Thus, deprotection treatment with TFA gave a solid that was used without purification: 1 H NMR (CDCl 3 + 1 drop of CD 3 OD) δ 0.82 (m, 3H), 1.45-1.20 (m, 10H), 1.70 -1.45 (m, 2H), 2.02 (m, 3H), 2.92 (m, 2H), 4.39 (m, 1H), 7.11 (m, 1H), 7.55 (m, 1H), 8.31 (m, 1H), 8.49 (m, 1 H)
    [589] 5- (4-Benzyl-piperidine-1-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.16): (100%) 1 H NMR ( CD 3 OD, 200 MHz) δ 0.87 (s, 3H), 1.26 (brs, 11H), 1.56 (brs, 6H), 2.27 (s, 3H), 2.54 (d, 2H, J = 6.6 Hz), 2.90 ( m, 2H), 3.27 (t, 2H, J = 6.6 Hz), 4.20 (brs, 2H), 7.05-7.30 (m, 5H)
    [590] 3-Methyl-5- (3-octyl-ureido) -thiophene-3-carboxylic acid 2- (1-butyl-pentyl) ester (14.17): (95%) 1 H NMR (CD 3 OD, 400 MHz) δ 0.89 (s, 9H), 1.33 (m, 18H), 1.50-1.70 (m, 6H), 2.73 (s, 3H), 3.19 (t, 2H, J = 6.6 Hz), 5.02 (m, 1H)
    [591] 5- (1-Butyl-pentylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.18): (100%). 1 H NMR (CD 3 OD, 200 MHz) δ 0.87 (s, 9H), 1.29 (m, 18H), 1.56 (s, 6H), 2.52 (s, 3H), 3.35 (t, 2H, J = 6.6 Hz ), 3.90 (brs, 1 H).
    [592] 4-Methyl-2- (3-octyl-ureido) -5- (3-phenoxy-propylcarbamoyl) -thiophene-3-carboxylic acid (14.19): (100%). 1 H NMR (CD 3 OD, 200 MHz) δ 0.89 (m, 3H), 1.32 (s, 10H), 1.55 (brs, 2H), 2.06 (tt, 2H, J = 6.0 Hz, J = 6.0 Hz), 2.55 (s, 3H), 3.19 (t, 2H, J = 7.0 Hz), 3.51 (t, 2H, J = 6.8 Hz), 6.90 (m, 3H), 7.24 (m, 2H)
    [593] 4-Methyl-2- (3-octyl-ureido) -5- (pyridin-3-ylmethyl) -carbamoyl) -thiophene-3-carboxylic acid (14.20): 110 mg (crude yield 100%) tan solid.
    [594] 5- (3-Dimethylamino-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.21). MS (ES-) 438.70 (M-1).
    [595] 5-[(Furan-2-ylmethyl) -carbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.22). MS (ES-) 434.03 (M-1).
    [596] 4-Methyl-2- (3-octyl-ureido) -5- (thiazol-2-ylcarbamoyl) -thiophene-3-carboxylic acid (14.23). MS (ES−) 436.23 (M-1).
    [597] 4-Methyl-2- (3-octyl-ureido) -5- (2-pyridin-3-yl-ethylcarbamoyl) -thiophene-3-carboxylic acid (14.24). MS (ES-) 459.03 (M-1).
    [598] 4-Methyl-2- (3-octyl-ureido) -5- [4- (2-pyridin-1-yl-ethyl) -piperazin-1-carbonyl] -thiophene-3-carboxylic acid (14.25) . MS (ES−) 534.20 (M-1).
    [599] 4-Methyl-2- (3-octyl-ureido) -5- (4-phenyl-piperazine-1-carbonyl) -thiophene-3-carboxylic acid (14.26). MS (ES-) 499.03 (M-1).
    [600] 5-([1,4 '] Bifireridinyl-1'-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.27). MS (ES−) 505.08 (M-1).
    [601] 5- (3-Imidazol-1-yl-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.28). MS (ES−) 462.09 (M-1).
    [602] 3-Methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid 4- tert -butyl ester (14.29). 1 H NMR (CDCl 3 ) δ 11.6 (s, 1H), 5.14 (vt, 1H), 3.30 (q, 2H, J = 6.0Hz), 2.71 (s, 3H), 1.70-1.40 (m, 2H), 1.59 (s, 9H), 1.27 (bs, 10H), 0.87 (t, 3H, J = 6.6 Hz), MS (EI): 412.8 (M + ).
    [603] 2-dodecyloxy-5-methyl-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid (14.30). 1 H NMR (CDCl 3 ) δ 4.47 (t, 2H, J = 6.2 Hz), 4.19 (bs, 1H), 2.85 (s, 3H), 1.80 (quint, 2H, J = 6.2 Hz), 1.27 (bs, 18H), 0.88 (t, 3H, J = 6.6 Hz), MS (EI): 395.4 (M + ).
    [604] 4-Methyl-5-octylcarbamoyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.31). 1 H NMR (CDCl 3 ) δ 10.90 (bs, 2H), 5.82-5.62 (m, 1H), 5.78-5.60 (m, 1H), 3.33 (q, 4H, J = 6.6 Hz), 2.61 (s, 3H ), 1.70-1.40 (m, 4H), 1.27 (bs, 20H), 0.88 (m, 6H).
    [605] 3-methoxymethyl-5-octyloxycarbonylamino-thiophene [2,4] dicarboxylic acid 2-benzyl ester (14.32). 1 H NMR (CDCl 3 ) δ 11.98 (s, 1H), 10.09 (s, 1H), 7.45 -7.20 (m, 5H), 5.14 (s, 2H), 4.22 (t, 2H, J = 6.6 Hz), 3.85 (s, 3H), 3.82 (s, 2H), 1.70 (quint, 2H, J = 6.6 Hz), 1.28 (bs, 10H), 0.88 (t, 3H, J = 5.6 Hz).
    [606] 5- (4- (Isopropylcarbamoyl-methyl) -piperazine-1-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.33). 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (brs, 3H), 1.15-1.34 (m, 16H), 1.56 (m, 2H), 2.37 (s, 3H), 3.05-3.49 (m, 10H), 3.95 (m, 1 H).
    [607] 5-((Benzo (1,3) dioxol-5-ylmethyl) -carbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.34). 1 H NMR (CDCl 3, 200 MHz) δ 0.86 (m, 3H), 1.32-1.45 (m, 10H), 1.53 (m, 2H), 2.56 (s, 3H), 3.19 (m, 2H), 4.4 ( d, 2H, J = 6.0 Hz), 5.91 (s, 2H), 6.80 (m, 3H).
    [608] 5- (3,4-Dimethoxy-benzylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.35). 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (brs, 3H), 1.31-1.45 (m, 10H), 1.56 (m, 2H), 2.56 (s, 3H), 3.18 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 3.80 (s, 3H), 3.82 (s, 3H), 4.43 (s, 2H), 6.89 (s, 2H), 6.97 (s, 1H).
    [609] 5- (6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid ( 14.36): 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (m, 3H), 1.31-1.45 (m, 10H), 1.51 (brs, 2H), 2.31 (s, 3H), 2.85 (t, 2H, J = 6.0 Hz), 3.18 (t, 2H, J = 7.0 Hz), 3.79 (m, 8H), 6.71 (s, 1H), 6.74 (s, 1H).
    [610] 4-Methyl-2- (3-octyl-ureido) -5- (4-phenyl-butylcarbamoyl) -thiophene-3-carboxylic acid (14.37): 1 H NMR (CDCl 3, 200 MHz) δ 0.89 ( brs, 3H), 1.26-1.45 (m, 10H), 1.59 (m, 6H), 2.54 (s, 3H), 2.65 (t, 2H, J = 7.0 Hz), 3.19 (m, 4H), 7.21 (m , 5H).
    [611] 4-Methyl-2- (3-octyl-ureido) -5- (3-phenyl-propylcarbamoyl) -thiophene-3-carboxylic acid (14.38). 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (m, 3H), 1.25-1.45 (m, 10H), 1.57 (brs, 2H), 1.89 (tt, 2H, J = 7.4 Hz, J = 7.6 Hz) , 2.55 (s, 3H), 3.17-3.39 (m, 4H), 7.23 (m, 5H)
    [612] 4-Methyl-2- (3-octyl-ureido) -5- (2-phenoxy-ethylcarbamoyl) -thiophene-3-carboxylic acid (14.39). 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.25-1.41 (m, 10H), 1.56 (brs, 2H), 2.56 (s, 3H), 3.19 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz, 3.71 (dt, 2H, J = 5.2 Hz, J = 5.4 Hz), 4.12 (t, 2H, J = 5.2 Hz), 6.95 (m, 3H), 7.25 (m, 2H) .
    [613] 5- (2-Methoxy-ethylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.40). 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (brs, 3H), 1.25-1.43 (m, 10H), 1.53 (m, 2H), 2.56 (s, 3H), 3.19 (t, 2H, J = 7.0 Hz), 3.37 (s, 3 H), 3.51 (m, 4 H).
    [614] 5- (3-Methoxy-propylcarbamoyl) -4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (14.41). 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (brs, 3H), 1.27-1.44 (m, 10H), 1.51 (brs, 2H), 1.84 (tt, 2H, J = 6.2 Hz, J = 6.6 Hz) , 2.56 (s, 3H), 3.19 (t, 2H, J = 7.0 Hz), 3.34 (s, 3H), 3.39 (t, 2H, J = 7.0 Hz), 3.49 (t, 2H, J = 6.2 Hz) .
    [615]
    [616] 5-methyl-2- (1-methylheptyloxy) -4-oxo-4 H -Thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid benzyl ester (14.42).
    [617] Light yellow oil in 32% yield
    [618] 1 H NMR (CDCl 3, 200 MHz) δ 10.70 (brs, 1H), 8.31 (brs, 2H), 7.29-7.43 (m, 5H), 5.27 (s, 2H), 3.45-3.90 (m, 1H), 2.75 (s, 3H), 1.40 -1.60 (m, 2H), 1.10-1.40 (m, 11H), 0.85 (t, 3H, J = 6.6 Hz)
    [619]
    [620] 3-methyl-5- [3- (1-methylheptyl) ureido] thiophene-2,4-dicarboxylic acid 2-benzyl ester (14.43).
    [621] Light brownish solid in 99% yield.
    [622] 1 H NMR (CDCl 3, 200 MHz): δ 10.52 (s, 1H), 9.00 (brs, 1H), 7.35-7.39 (m, 5H), 5.28 (s, 2H), 4.70-5.05 (m, 1H) , 2.79 (s, 3H), 1.42-1.62 (m, 2H), 1.10-1.40 (m, 8H), 0.87 (t, 3H, J = 6.6 Hz), MS (ES) [M-1] 444.96.
    [623]
    [624] 5- (4-Benzyl-piperazin-1-carbonyl) -4-methyl-2- (3-octyl-ureido] -thiophene-3-carboxylic acid (37). 1 H NMR (DMSO , 200 MHz) δ 0.83 (brm, 3H), 1.18-1.41 (brm, 12H), 2.26 (s, 3H), 2.33 (brs, 4H), 2.99 (dt, 2H, J = 5.8 Hz, J = 5.8 Hz), 3.29 ( s, 2H), 3.43 (brm, 4H), 7.21-7.41 (m. 5H).
    [625] Example 15 : Tien Oxazinone
    [626]
    [627] [(5-methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carbonyl) -amino] -acetic acid benzyl ester (48): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (m, 3H), 1.30 (brs, 10H), 1.61 (m, 2H), 2.74 (s, 3H), 3.42 (dt, 2H, J = 6.2 Hz, J = 7.0 Hz), 4.25 (d, 2H, J = 5.0 Hz), 5.08 (brs, 1H), 5.23 (s, 2H), 6.29 (brs. 1H), 7.37 (s, 5H).
    [628]
    [629] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid (pyridin-4-ylmethyl) -amino (55): ( 15%). 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (brs, 3H), 1.25 (brs, 10H), 1.55 (brs, 2H), 2.75 (s, 3H), 3.38 (dt, 2H, J = 6.4 Hz, J = 6.6 Hz), 4.60 (d, 2H, J = 5.8 Hz), 6.17 (s, 1H), 7.24 (s, 2H), 8.54 (d, 2H, J = 5.8 Hz).
    [630]
    [631] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-methyl carboxy- (6-methyl-pyridin-2-ylmethyl)- Amino (49): (20%). 1 H NMR (CDCl 3, 200 MHz) δ 0.86 (m, 3H), 1.26 (brs, 10H), 1.58 (m, 2H), 2.45 (s, 3H), 2.52 (s, 3H), 3.06 (s, 3H), 3.38 (dt, 2H, J = 6.4 Hz, J = 6.6 Hz), 4.73 (s, 2H) 5.28 (brs, 1H), 7.05 (d, 2H, J = 7.6 Hz), 7.56 (t, 1H , J = 7.8 Hz).
    [632]
    [633] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid ethyl- (2-pyridin-2-yl-ethyl) -amino (51): (58%). 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (m, 3H), 1.14 (t, 3H, J = 7.0 Hz), 1.26 (brs, 10H), 1.59 (m, 2H), 2.31 (s, 3H) , 3.10 (t, 2H, J = 7.0 MHz), 3.38 (dt, 4H, J = 6.2 Hz, J = 7.0 Hz), 3.84 (t, 2H, J = 7.6 Hz) 5.26 (brs, 1H), 7.14 ( m, 2H), 7.59 (ddd, 1H, J = 7.4 Hz, J = 7.6 Hz, J = 1.6 Hz), 8.52 (d, 1H, J = 4.4 Hz).
    [634]
    [635] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] thiazine-6-carboxylic acid benzyl ester (56): 1 H NMR (CD 3 OD, 200 MHz) δ 0.87 (brs, 3H), 1.27 (brs, 10H), 1.61 (m, 2H), 2.82 (s, 3H), 3.45 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 5.31 ( s, 2H), 5.42 (brs, 1H), 7.35 (m, 5H)
    [636]
    [637] 2- (hexyl-methyl-amino) -5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (57): 1 H NMR ( CDCl 3, 200 MHz) δ 0.99 (t, 3H, J = 6.6 Hz), 1.30 (bs, 6H), 1.58-1.64 (m, 2H), 2.77 (s, 3H), 3.11 (s, 3H), 3.47-3.50 (m, 2H), 5.29 (s, 2H), 7.30-7.44 (m, 5H). MS (ES &lt; + &gt;) 414.70. (M + l).
    [638]
    [639] 2- (1-Butyl-pentylamino) -5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (59): 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (t, 6H, J = 6.4 Hz), 1.22-1.40 (bs, 8H), 1.48-1.66 (m, 4H), 2.79 (s, 3H), 3.90-4.00 (m , 1H), 5.32 (s, 2H), 5.77 (d, J = 8.4 Hz), 7.31-7.45 (m, 5H).
    [640]
    [641] 2-dioctylamino-5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (60): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 6H, J = 6.6 Hz), 1.26-1.37 (m, 20H), 1.58-1.64 (m, 4H), 2.79 (s, 3H), 3.39-3.53 (m, 4H), 5.31 (s, 2H), 7.29-7.45 (m, 5H).
    [642]
    [643] 5-Methyl-2-octylamino-6- [4- (2-piperidin-1-yl-ethyl) -piperazin-1-carbonyl] -thieno [2,3-d] [1,3 ] Oxazine -4-one (53) MS (ES): m / z 517.9 [M−H + ]. 1 H NMR (CDCl 3, 200 MHz): δ 0.87-1.59 (m, 9H), 1.18-1.59 (m, 14H), 2.54 (s, 3H), 2.23-2.51 (m, 4H), 3.34 (dt , 2H, J = 7Hz), 3.61 (m, 3H), 5.21 (brs, 1H)
    [644]
    [645] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid (furan-2-ylmethyl) -amino (52) MS ( ES): m / z 417.3 [M−H + ].
    [646] 1 H NMR (CDCl 3, 200 MHz) δ 1.18-1.41 (m, 14H), 2.67 (s, 3H), 3.43 (t, 2H, J = 8.4 Hz), 4.48 (m, 2H, J = 5.6 Hz) , 5.12 (brs, 1 H), 6.02-6.57 (m, 3 H).
    [647]
    [648] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid (2-pyridin-3-yl-ethyl) -amino (50 ) MS (ES): m / z 443.5 [M−H + ]. 1 H NMR (CDCl 3, 200 MHz): δ 1.25-1.68 (m, 14H), 2.60 (s, 3H), 2.99 (t, 2H, J = 7.4 Hz), 3.39 (dt, 2H, J = 6.6 Hz ), 5.25 (brs, 1H), 5.77 (s, 1H), 7.25 (m, 2H), 7.61 (d, 1H, J = 19.4 Hz), 8.51 (m, 1H).
    [649]
    [650] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid isobutyl-amino (54) MS (ES): m / z 393.8 [M−H + ].
    [651] 1 H NMR (CDCl 3, 200 MHz): δ 0.84-0.88 (m, 20H), 0.95-0.99 (d, 6H), 1.41 (m, 14H), 2.67 (s, 3H), 3.43 (t, 2H, J = 8.4 Hz), 4.48 (m, 2H, J = 5.6 Hz), 5.12 (brs, 1H).
    [652]
    [653] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [l, 3] oxazine-6-carboxylic acid (2, 2-dimethyl-propyl-amino (58). MS (ES): m / z 407.66 [M−H + ].
    [654] 1 H NMR (CDCl 3, 200 MHz): δ 0.84-0.93 (m, 14H), 0.96 (s, 9H), 2.72 (s, 3H), 3.24 (s, 2H), 3.42 (m, 2H, J = 6.2 Hz), 5.12 (brs, 1 H), 5.76 (brs, 1 H).
    [655]
    [656] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid dibutylamino (36).
    [657] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was employed. Thus, 20 mg of solid was obtained after column chromatography (7: 3; hexanes: EtOAc) (40% from tert-butyl ester): 1 H NMR (CDCl 3 ) δ 0.88 (m, 9H), 1.18- 1.40 (m, 14H), 1.45-1.68 (m, 6H), 2.37 (s, 3H), 3.30-3.46 (m, 6H), 5.19 (brs, 1H); MS (EI): cal'd 449. 66, exp 449.95 (MH + ).
    [658]
    [659] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [l, 3] oxazine-6-carboxylic acid (pyridin-3-ylmethyl) amino (35).
    [660] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was employed. Thus, 46 mg of solid was obtained after tritration (36.6% from tert-butyl ester): 1 H NMR (CDCl 3 ) δ 0.87 (m, 3H), 1.42-1.20 (m, 10H), 1.68-1.45 (m, 2H), 2.72 (s, 3H), 3.41 (dt, 4H, J = 6.7, 6.6 Hz), 4.62 (d, 2H, J = 6.0 Hz), 5.15 (m, 1H), 6.07 (m, 1 H), 7.38-7.20 (m, 1 H), 7.70 (d, 1 H, J = 8.6 Hz), 8.65-8.52 (m, 2H); MS (EI): cal'd 428.56, exp 428.88 (MH + ).
    [661]
    [662] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid (pyridin-2-ylmethyl) amide (34)
    [663] The same method as the preparation of 5-methyl-2-heptyloxy-4-oxo- 4H -thieno [2,3- d ] [1,3] oxazine-6-carboxylic acid heptyl ester was employed. Thus, 46 mg of solid was obtained after tritration (36.6% from tert-butyl ester): 1 H NMR (CDCl 3 ) δ 0.87 (m, 3H), 1.45-1.20 (m, 10H), 1.80-1.50 (m, 2H), 2.79 (s, 3H), 3.41 (dt, 4H, J = 6.7, 6.6 Hz), 4.72 (d, 2H, J = 4.4 Hz), 5.25 (m, 1H), 7.45 -7.18 (m, 2H), 7.69 (t, 1H, J = 7.6 Hz), 8.55 (d, 1H, J = 4.6 Hz); MS (EI): cal'd 428.56, exp 428.88 (MH + ).
    [664]
    [665] 6- (4-benzyl-piperidine-1-carbonyl) -5-methyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one (43)
    [666] 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (brs, 3H), 1.27 (brs, 11H), 1.54-1.70 (m, 6H), 2.40 (s, 3H), 2.57 (d, 2H, J = 7.0 Hz), 2.86 (m, 2H), 3.40 (dt, 2H, J = 6.4 Hz, J = 6.4 Hz), 4.20 (brs, 2H), 5.09 (s, 1H), 7.11-7.35 (m, 5H); MS (ES) 496.69 (M + l).
    [667]
    [668] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [l, 3] oxazine-6-carboxylic acid 1-butyl-pentyl ester (39):(73%). OneH NMR (CDCl3,200 MHz) δ 0.89 (s, 9H), 1.31 (s, 18H), 1.61 (m, 6H), 2.78 (s, 3H), 3.42 (dt, 2H, J = 6.2 Hz, J = 6.6 Hz), 5.00 -5.20 (m, 2H); MS (ES) 465.67 (M + 1)
    [669]
    [670] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid (1-butyl-pentyl) -amide (45):(28%). OneH NMR (CDCl3,200 MHz) δ 0.87 (m, 9H), 1.29 (m, 18H), 1.56 (s, 2H), 2.65 (s, 3H), 3.40 (dt, 2H, J = 6.6 Hz, J = 6.6 Hz), 4.02 (brs, 1 H), 5.04 (brs, 1 H), 5.40 (d, 1 H, J = 8.8 Hz); MS (ES) 464.6 (M + 1)
    [671]
    [672] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid (3-phenoxy-propyl) -amide (44)(22%). OneH NMR (CDCl3,200 MHz) δ 0.88 (m, 3H), 1.27 (m, 10H), 1.55 (m, 2H), 2.07 (m, 2H), 2.62 (s, 3H), 3.40 (dt, 2H, J = 5.6 Hz, J = 7.2 Hz), 3.65 (dt, 2H, J = 5.6 Hz, J = 6.4 Hz), 4.12 (t, 2H, J = 5.6 Hz), 5.05 (brs, 1H), 6.30 (brs, 1H), 6.95 (m, 3 H), 7.25 (m, 2 H); MS (ES) 471.81 (M + 1)
    [673]
    [674] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid cyclohexylamide (38):(21%) OneH NMR (CDCl3,400 MHz) δ 0.87 (s, 3H), 1.26 (m, 16H), 1.56 (m, 6H), 2.60 (s, 3H), 3.40 (dt, 2H, J = 6.6 Hz, J = 6.2 Hz), 3.88 (m, 1 H), 5.07 (br s, 1 H), 5.57 (d, 1 H, J = 7.2 Hz); MS (ES) 420.12 (M + 1)
    [675]
    [676] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid dioctylamide (41): (61%) 1 H NMR ( CDCl 3, 400 MHz) δ 0.87 (m, 9H), 1.25 (brs, 30H), 1.58 (m, 6H), 2.38 (s, 3H), 3.39 (m, 6H), 5.12 (brs, 1H); MS (ES) 562.15 (M + 1)
    [677]
    [678] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid dihexylamide (42): (56%) 1 H NMR ( CDCl 3, 200 MHz) δ 0.87 (m, 9H), 1.27 (brs, 22H), 1.56 (m, 6H), 2.38 (s, 3H), 3.40 (m, 6H), 5.05 (brs, 1H); MS (ES) 506.03 (M + l).
    [679]
    [680] 6- (4-benzyl-piperazine-1-carbonyl) -5-methyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one (40): ( 67%) 1 H NMR (CDCl 3, 400 MHz) δ 0.87 (t, 3H, J = 5 Hz), 1.27 (brs, 10H), 1.58 (brs, 2H), 2.40 (s, 3H), 2.46 (t, 4H, J = 4.8 Hz, 3.39 (dt, 2H, J = 6.6 Hz, J = 6.6 Hz), 3.52 (s, 2H), 3.62 (brs, 4H), 5.19 (brs, 1H), 7.30 (s, 5H); MS (ES) 497.11 (M + 1)
    [681]
    [682] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid methylamide (31): (70% grayish white solid) . 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (m, 3H), 1.25-1.4 (m), 1.59-1.65 (m), 2.71 (s, 3H), 2.99 (d, 3H, (J = 5.2) ), 3.41 (q, 2H, J = 7 Hz), 5.32 (bs, 1H), 5.76 (bs, 1H). MS (ES &lt; + &gt;) 351.93 (M + 1), 352.99 (M + 2).
    [683]
    [684] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid ethylamide (33): (greyish white solid). 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.5 Hz), 1.21-1.31 (m, 13H), 1.59-1.65 (m, 2H), 2.71 (s, 3H), 3.36- 3.53 (m, 4 H), 5.27 (bs, 1 H), 5.72 (bs, 1 H). MS (ES &lt; + &gt;) 365.95 (M + 1), 367.01 (M + 2).
    [685]
    [686] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid butylamide (32): (greyish white solid). 1 H NMR (CDCl 3, 200 MHz) δ 0.85-1.00 (m, 6H), 1.28-1.50 (m, 12H), 1.53-1.63 (m, 4H), 2.70 (s, 3H), 3.41-3.43 (m , 4H), 5.53 (bs, 1 H), 5.78 (bs, 1 H). MS (ES &lt; + &gt;) 393.98 (M + 1), 395.05 (M + 2).
    [687]
    [688] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid hexylamide (27): (greyish white solid). 1 H NMR (CDCl 3, 200 MHz) δ 0.88-0.89 (m, 6H), 1.27-1.32 (m, 16H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.44 (bs, 1 H), 5.76 (bs, 1 H). MS (ES &lt; + &gt;) 422.05 (M + 1), 423.13 (M + 2).
    [689]
    [690] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [l, 3] oxazine-6-carboxylic acid decylamide (28): (greyish white solid). 1 H NMR (CDCl 3, 200 MHz) δ 0.85-0.88 (m, 6H), 1.26-1.31 (m, 24H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.27 (bs, 1 H), 5.73 (bs, 1 H). MS (ES &lt; + &gt;) 478.08 (M + 1), 479.10 (M + 2).
    [691]
    [692] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid dodecylamide (29): (greyish white solid) 1 H NMR (CDCl 3, 200 MHz) δ 0.85-0.91 (m, 6H), 1.26-1.31 (m, 24H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.30 (bs, 1 H), 5.73 (bs, 1 H). MS (ES &lt; + &gt;) 506.14 (M + 1), 507.14 (M + 2).
    [693]
    [694] 5-Methyl-2-octylamino-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid hexadecylamide (30): (greyish white solid) 1 H NMR (CDCl 3, 200 MHz) δ 0.8 4-0. 91 (m, 6H), 1.26-1.32 (m, 34H), 1.61 (bs, 4H), 2.70 (s, 3H), 3.41 (2xdt, 4H), 5.21 (bs, 1H), 5.72 (bs, 1H) . MS (ES &lt; + &gt;) 562.19 (M + 1), 563.22 (M + 2).
    [695]
    [696] 6- (6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl) -5-methyl-2-octylamino-thieno (2,3-d) (1,3 Oxazine -4-one (65): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (brs, 3H), 1.28-1.45 (m, 10H), 1.62 (m, 2H), 2.43 (s, 3H) ), 2.85 (t, 2H, J = 5.6 Hz), 3.41 (dt, 2H, J = 6.6 Hz, J = 6.6 Hz), 3.84 (m, 8H), 4.69 (s, 2H). 5.20 (brs, 1 H), 6.56 (s, 1 H), 6.63 (s, 1 H).
    [697]
    [698] 5-Methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-4-carboxylic acid (2- (3,4-dimethoxy-phenyl) -methyl ) -Amide (66): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (brs, 3H), 1.28-1.43 (m, 10H), 1.59 (m, 2H), 2.71 (s, 3H), 3.41 ( dt, 2H, J = 6.6 Hz, J = 6.6 Hz), 3.88 (m, 6H), 4.55 (d, 2H, J = 5.4 Hz). 5.10 (brs, 1 H), 5.96 (brs, 1 H), 6.88 (m, 3 H).
    [699]
    [700] N-isopropyl-2- (4- (5-methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-6-carbonyl-piperazine -1-yl) -acetamide (64): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (m, 3H), 1.28-1.45 (m, 16H), 1.60 (m, 2H), 2.41 (s, 3H), 2.54 (m, 4H), 3.25 (s, 2H), 3.40 (dt, 2H, J = 6.6 Hz, J = 6.6 Hz), 3.59 (m, 4H), 4.61 (m, 1H), 5.08 ( brs, 1H).
    [701]
    [702] 5-Methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-6-carboxylic acid (2-benzo (1,3) dioxol-5-yl -Methyl) -amide (69): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 7.0 Hz), 1.27-1.45 (m, 10H), 1.60 (m, 2H), 2.71 ( s, 3H), 3.44 (dt, 2H, J = 6.4 Hz, J = 6.4 Hz), 4.51 (d, 2H, J = 5.6 Hz), 5.08 (brs, 1H), 5.96 (s, 3H), 6.79 ( m, 3H).
    [703]
    [704] 5-Methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-6-carboxylic acid (2-phenoxy-ethyl) -amide (70): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 7.0 Hz), 1.27-1.42 (m, 10H), 1.60 (m, 2H), 2.72 (s, 3H), 3.41 (dt, 2H , J = 6.6 Hz, J = 6.6 Hz), 3.84 (dt, 2H, J = 5.0 Hz, J = 5.2 Hz), 4.15 (t, 2H, J = 5.0 Hz), 5.08 (brs, 1H), 6.25 ( brs, 1 H), 6.93 (m, 3 H), 7.30 (m, 2 H).
    [705]
    [706] 5-Methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-6-carboxylic acid (2-methoxy-ethyl) -amide (72): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.28-1.45 (m, 10H), 1.61 (m, 2H), 2.71 (s, 3H), 3.93 (m, 5H ), 3.58 (m, 4H), 5.08 (brs, 1 H), 6.15 (brs, 1 H).
    [707]
    [708] 5-Methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-6-carboxylic acid (3-methoxy-propyl) -amide (73): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.28-1.44 (m, 10H), 1.61 (m, 2H), 1.87 (tt, 2H, J = 5.8 Hz, J = 6.0 Hz), 2.70 (s, 3H), 3.40 (m, 5H), 3.57 (m, 4H), 5.09 (brs, 1H), 6.77 (brs, 1H).
    [709]
    [710] 5-Methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-6-carboxylic acid (4-phenyl-butyl) -amide (79): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.28-1.45 (m, 10H), 1.66 (m, 6H), 2.69 (m, 5H), 3.43 (m, 4H) , 5.07 (brs, 1 H), 5.68 (brs, 1 H), 7.20 (m, 5 H).
    [711]
    [712] 5-Methyl-2-octylamino-4-oxo-4H-thieno (2,3-d) (1,3) oxazine-6-carboxylic acid (3-phenyl-propyl) -amide (80): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.27-1.44 (m, 10H), 1.58 (m, 2H), 1.96 (tt, 2H, J = 7.0 Hz, J = 7.4 Hz), 2.72 (m, 5H), 3.43 (m, 4H), 5.71 (brs, 1H), 7.22 (m, 5H).
    [713]
    [714] 5-methyl-2- (1-methylheptyloxy) -4-oxo- 4H -Thieno (2,3- d ) (1,3) oxazine-6-carboxylic acid benzyl ester (89):
    [715] Light yellow oil in 22% yield.
    [716] 1 H NMR (CDCl 3, 200 MHz) δ 7.31-7.50 (m, 5H), 5.34 (s, 2H), 5.18 (tq, 1H, J = 6.2, 6.2 Hz), 2.82 (s, 3H), 1.58- 1.83 (m, 2H), 1.40 (d, 3H, J = 6.2 Hz), 1.10-1.34 (m, 8H), 0.88 (t, 3H, J = 6.6 Hz).
    [717]
    [718] 5-Methyl-2- (1-methylheptylamino) -4-oxo- 4H -Thieno (2,3- d ) (1,3) oxazine-6-carboxylic acid benzyl ester (71):
    [719] Light yellow oil in 40% yield.
    [720] 1 H NMR (CDCl 3, 200 MHz): δ 7.31-7.43 (m, 5H), 5.32 (s, 2H), 5.13 (d, 1H, J = 6.2 Hz), 400 (m, 1H), 2.79 ( s, 3H), 1.42-1.62 (m, 2H), 1.10-1.40 (m, 8H), 0.87 (t, 3H, J = 6.6 Hz). MS (ES) [M ++ 1] 429.10.
    [721]
    [722] 2- (1,3-Dioctyl-ureido) -5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (13): 1 H NMR (CDCl 3, 200 MHz): δ 9.25 (m, 1H), 7.31-7.43 (m, 5H), 5.32 (s, 2H), 3.99 (m, 2H), 3.35 (dt, 2H, J = 5.6, 5.6Hz), 2.83 (s, 3H), 1.70-1.5 (m, 4H), 1.50-1.20 (m, 20H), 0.87 (m, 6H, J = 6.6Hz) .MS (ES) [M + +1] 583.99.
    [723]
    [724] 2- (1,3-Dioctyl-ureido) -5-methyl-4-oxo-4H-thieno [2,3-d] [1,3] oxazine-6-carboxylic acid benzyl ester (14): 1 H NMR (CDCl 3, 200 MHz): δ 9.25 (m, 1H), 7.31-7.43 (m, 5H), 5.32 (s, 2H), 3.99 (m, 2H), 3.35 (dt, 2H, J = 5.6, 5.6Hz), 2.83 (s, 3H), 1.70-1.5 (m, 4H), 1.50-1.20 (m, 16H), 0.87 (m, 6H, J = 6.6Hz) .MS (ES) [M + +1] 555.97.
    [725]
    [726] 5-Methyl-3-octyl-1H-thieno [2,3-d] pyridine-2,4-dione-6-carboxylic acid octylamide (47):
    [727] Compound 18 (100 mg, 0.22 mmol) was dissolved in 1.8 ml of pure alcohol. Sodium ethoxylated (21% by weight of ethanol, 1.1 mL, 2.9 mmol) was added and the solution was refluxed for 1 hour. Once cooled to room temperature, the solution was poured into 10 ml of 1N HCl solution. The resulting precipitate was filtered to give 47 (116 mg) as a grayish white solid (yield 100%). 1 H NMR (CDCl 3, 200 MHz): δ 0.87 (m, 6H), 1.27-1.32 (m, 20H), 1.54-1.70 (m, 4H), 2.78 (s, 3H), 3.44 (dt, 2H, J = 7.0, 6.2 Hz), 3.97 (t, 2H, J = 7.7 Hz), 5.86 (t, 1H, J = 5.4 Hz), 10.39 (s, 1H).
    [728] Example 16 Reduction Procedure of Carboxylic Acid: 5-hydroxymethyl-4-methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (2)
    [729] 3-methyl-5- (3-octyl-ureido) -thiophene-2,4-dicarboxylic acid quaternary ester (1.0 g, 2.40 mmol) was added to 25 mL of CH 2 Cl 2 and 0.25 mL of DMF. Dissolved. Thionyl chloride was added to CH 2 Cl 2 as a 2M solution and the solution was stirred for 2 hours. Sodium borohydride (910 mg, 24.0 mmol) was added and the reaction stirred for 2 hours. The reaction was poured into 100 mL of H 2 O and extracted with EtOAc. The organic layer was washed with 1N HCL (aq), H 2 O, dried over MgSO 4 , and the solvent was rotary degassed. The residue was recrystallized from EtOAc / hexanes to give 600 mg of the title compound: (62%). 1 H NMR (CDCl 3, 200 MHz): δ 0.87 (m, 3H), 1.26 (brs, 20H), 1.57 (brs, 11H), 2.30 (s, 3H), 3.28 (dt, 2H, J = 6.2 Hz , J = 6.6 Hz), 4.64 (s, 2H), 4.74 (t, 2H, J = 5.6 Hz), 10.77 (s, 1H).
    [730] Scheme 3
    [731]
    [732] Example 17 Aldehyde Intermediates
    [733] General procedures for the synthesis of non-commercial aldehydes 17.1-17.4 are described in Yoshisuke, Tsuda et al. Chem. Pharm. Bull. See 1991, 39 (1), 18-22.
    [734]
    [735] 4-phenyl-butylaldehyde (17.1) clear solution (860 mg, yield 87%) 1 H NMR (CDCl 3, 200 MHz): δ 1.99 (tt, 2H, J = 7.8, 7.4 Hz), 2.45 (dt, 2H, J = 7.0, 1.2 Hz, 2.67 (t, 2H, J = 7.4H z), 7.26 (m, 5H), 9.76 (t, 1H, J = 1.4 Hz).
    [736]
    [737] 5-phenyl-pentanol (17.2) clear solution (470 mg, yield 48%) 1 H NMR (CDCl 3, 200 MHz): δ 1.67 (m, 4H), 2.45 (dt, 2H, J = 4.8, 1.8 Hz), 2.64 (brs, 2H), 7.25 (m, 5H), 9.75 (t, 1H, J = 1.8 Hz).
    [738]
    [739] 6-phenyl- hexanol (17.3) pale yellow oil (2.49 g, yield 84%) 1 H NMR (CDCl 3, 200 MHz): δ 1.20-1.43 (m, 4H), 1.44-1.76 (m, 4H), 2.41 (dt, 2H, J = 7.0, 7.6 Hz), 2.60 (t, 2H, J = 7.2 Hz), 7.06-7.35 (m, 5H), 9.75 (t, 1H, J = 1.8 Hz); MS (ES ) No ionization and no LC found.
    [740]
    [741] 5-phenyl-heptanol (17.4) light yellow oil (401 mg, yield 81%) 1 H NMR (CDCl 3, 200 MHz): δ 1.20-1.50 (m, 2H), 1.50-1.80 (m, 4H), 2.41 (dt, 2H, J = 7.0, 7.4 Hz), 2.61 (t, 2H, J = 7.4 Hz), 7.00-7.20 (m, 5H), 9.75 (t, 1H, 2 Hz), MS (ES) No ionization and no LC was found.
    [742]
    [743] Example 18 : Aminothiophene
    [744]
    [745] 2-Amino-5-methyl-thiophene-3-carboxylic acid tert-butyl ester (18.1): 1 H NMR (CDCl 3, 200 MHz): δ1.54 (s, 9H), 2.24 (s, 3H), 5.65 (brd, 2 H), 7.25 (s, 1 H); MS (ES): cal 'd213.70, exp 213.96 (MH + ).
    [746]
    [747] 2-Amino-5-heptyl-thiophene-3-carboxylic acid tert-butyl ester (18.2) yellow oil (5.808 g, 46% yield) : 0.88 (t, 3H, J = 6.4 Hz), 1.24-1.32 (m , 8H), 1.54-1.57 (m, 11H), 2.56 (t, 2H, J = 7.5 Hz), 5.69 (bs, 2H), 6.56 (s, 1H). MS (ES +) 297.
    [748] General procedures for the synthesis of 2-amino-5-alkyl-thiophene-3-carboxylic acid tert-butyl esters from aldehydes are described in J. Med. Chem. See 1981, 24, 878-882.
    [749]
    [750] 2-Amino-5-butyl-thiophene-3-carboxylic acid tert-butyl ester (18.3) yellow oil (372 mg, 41% yield) : 1 H NMR (CDCl 3, 200 MHz): δ 0.91 (t, 3H, J = 7.1 Hz), 1.26-1.41 (m, 4H), 1.53 (bs, 9H), 2.56 (t, 2H, J = 7.3 Hz), 5.77 (bs, 2H), 6.56 (t, 1H, J = 1.1 Hz). 13 C NMR (CDCl 3 , 50 MHz) δ 13.7, 22.0, 28.4, 29.3, 29.9, 33.2, 79.7, 107.7, 121.8, 126.3, 160.4, 164.9 MS (ES +) 340.4 (M + 1).
    [751]
    [752] 2-Amino-5-decyl-thiophene-3-carboxylic acid tert-butyl ester (18.4) yellow oil (11.32 g, yield 79%): 1 H NMR (CDCl 3, 400 MHz): δ 0.98 (t, 3H, J = 6.8 Hz), 1.26 -1.30 (m, 14H), 1.52-1.55 (m, 11H), 2.56 (t, 2H, J = 7.4 Hz), 5.68 (bs, 2H), 6.56 (s, 1H ).
    [753]
    [754] 2-Amino-5-benzyl-thiophene-3-carboxylic acid tert-butyl ester (18.5) yellow oil (520 mg, yield 51%): 1 H NMR (CDCl 3, 200 MHz): δ 1.53 (s, 9H), 3.89 (s, 2H), 5.71 (bs, 2H), 6.66 (t, 1H, J = 1.1 Hz), 7.16-7.33 (m, 5H). 13 C NMR (CDCl 3, 50 MHz) δ 28.4, 35.9, 79.9, 107.8, 123.4, 124.7, 126.5, 128.4, 128.5, 140.0, 161.3, 164.9.MS (ES +) 289.9 (M + 1).
    [755]
    [756] 2-Amino-5- (l, 3,3-trimethyl-butyl) -thiophene-3-carboxylic acid tert-butylester (18.6) yellow oil (846 mg, yield 79%): 1 H NMR (CDCl 3, 200 MHz): δ 0.99 (s, 9H), 1.22 (d, 3H, J = 7.0 Hz), 1.39 (dd, 1H, J = 13.8, 4.6 Hz), 1.54 (s, 9H), 1.59 (dd, 1H, J = 14.0, 7.0 Hz), 2.80-2.96 (m, 1H), 5.67 (bs, 2H), 6.55 (s, 1H).
    [757]
    [758] 2-Amino-5- (5-methoxy-l, 5-dimethyl-hexyl) -thiophene-3-carboxylic acid tert-butyl ester (18.7) yellow oil (2.328 mg, yield 80%): 1 H NMR ( CDCl 3, 200 MHz): δ 1.12 (s, 6H), 1.22 (d, 3H, J = 6.8 Hz), 1.22-1.54 (m, 18H), 2.74 (dq, 1H, J = 7.0, 6.2 Hz) , 3.16 (s, 3 H), 5.70 (bs, 2 H), 6.57 (s, 1 H). MS (ES &lt; + &gt;) 341.93 (M + 1).
    [759]
    [760] 2-Amino-5- (1, 5-dimethyl-hex-4-enyl) -thiophene-3-carboxylic acid tert-butyl ester (18.8) yellow oil (2.029 mg, yield 77%): 1 H NMR (CDCl 3, 200 MHz): δ1.21 (d, 3H, J = 6.6 Hz), 1.51-1.54 (m, 11H), 1.57 (s, 3H), 1.68 (s, 3H), 1.96 (dt, 2H, J = 7 .2, 7.0 Hz), 2.75 (tq, 1H, J = 7.0, 6.6 Hz), 5.08 (t, 1H, J = 6.4 Hz), 5.69 (bs, 2H), 6.56 (s, 1H). MS (ES &lt; + &gt;) 309.9 (M + 1).
    [761]
    [762] 2-Amino-5-phenethyl-thiophene-3-carboxylic acid tert-butyl ester (18.9) yellow oil (1.5 mg, yield 85%): 1 H NMR (CDCl 3, 200 MHz): δ 1.53 (s , 9H), 2.88 (s, 4H), 5.70 (s, 2H), 6.59 (s, 1H), 7.26 (m, 5H).
    [763]
    [764] 2-Amino-5- (3-phenyl-propyl) -thiophene-3-carboxylic acid tert-butyl ester (18.10) yellow oil (440 mg, yield 48%): 1 H NMR (CDCl 3, 200 MHz): δ 1.54 (s, 9H), 1.90 (tt, 2H, J = 7.8, 7.2 Hz), 2.62 (m, 4H), 5.70 (s, 2H), 6.58 (s, 1H), 7.26 (m, 5H)
    [765]
    [766] 2-Amino-5- (4-phenyl-butyl) -thiophene-3-carboxylic acid tert-butyl ester (18.11) yellow oil (1.22 g, yield 67%): 1 H NMR (CDCl 3, 200 MHz): δ 0.98 (bt, 2H, J = 6.6 Hz), 1.16-1.31 (m, 2H), 1.54 (s, 9H), 1.57-1.74 (m, 2H), 2.52-2.70 (m, 2H), 5.69 ( bs, 2H), 6.56 (t, 1H, J = 1.2 Hz), 7.11-7.22 (m, 3H), 7.22-7.34 (m, 2H); MS (ES) no ionization. (M + 1), t R (method D) = 9.11 min.
    [767]
    [768] 2-Amino-5- (5-phenyl-pentyl) -thiophene-3-carboxylic acid tert-butyl ester (18.12) yellow oil (638 mg, yield 36%): 1 H NMR (CDCl 3, 200 MHz): δ 1.21-1.50 (m, 2H), 1.50-1.76 (m, 14H), 2.44-2.72 (m, 4H), 5.69 (bs, 2H), 6.56 (t, 1H, J = 1.2 Hz), 7.07- 7.3 7 (m, 5H); MS (ES) no ionization. (M + 1), t R (Method D) = LC effect not observed.
    [769]
    [770] 2-Amino-5-butyl-thiophene-3-carboxylic acid tert-butyl ester (18.13) 1 H NMR (CDCl 3, 200 MHz): δ = 0.91 (t, J = 7.1 Hz, 3H), 1.10-1.80 (m, 13H), 2.56 (td, J = 0.8, 7.4 Hz, 2H), 5.68 (brs, 2H), 6.56 (t, J = 1.1 Hz, 1H).
    [771]
    [772] 2-amino-5-isopropyl-thiophene-3-carboxylic acid tert-butyl ester (18.14) 1 H NMR (CDCl 3, 200 MHz): δ = 1.23 (dd, J = 2.2, 6.8 Hz, 6H), 1.54 (s, 9H), 2.78-3.02 (m, 1H), 5.68 (brs, 2H), 6.57 (d, J = 1.2 Hz, 1H).
    [773]
    [774] 2-Amino-5-octyl-thiophene-3-carboxylic acid tert-butyl ester (18.15) 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.14-1.43 (m, 10H), 1.44-1.68 (m, 11H), 2.56 (t, 2H, J = 7.1 Hz), 5.67 (brs, 2H), 6.56 (s, 1H).
    [775]
    [776] 2-Amino-5-dodecyl-thiophene-3-carboxylic acid tert-butyl ester (18.16) 1 H NMR (CDCl 3, 200 MHz): δ 0.88 (t, J = 6.6 Hz, 3H), 1.16-1.42 (m, 18H), 1.46-1.68 (m, 11H), 2.55 (t, J = 7.5 Hz, 2H), 5.68 (brs, 2H), 6.55 (t, J = 1.2 Hz, 1H).
    [777]
    [778] 2-Amino-5-heptyl-4-methyl-thiophene-3-carboxylic acid tert-butyl ester (18.17):9.561 g (61%) OneH NMR (CDCl3,200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 1.16-1.40 (m, 10H), 1.55 (s, 9H), 2.12 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H ).
    [779]
    [780] 2-Amino-5-octyl-4-methyl-thiophene-3-carboxylic acid tert-butyl ester (18.18):10.202 g (63%) OneH NMR (CDCl3,200 MHz): δ 0.87 (t, J = 6.8 Hz, 3H), 1.20-1.38 (m, 12H), 1.55 (s, 9H), 2.12 (s, 3H), 2.41 (t, J = 7.2 Hz, 2H ).
    [781]
    [782] 2-Amino-6-benzylthiophene-3-carboxylic acid t-butyl ester (18.19)
    [783] Light yellow oil with 62% yield
    [784] OneH NMR (CDCl3,200 MHz): δ 7.18-7.38 (m, 5H), 6.66 (t, 1H, J = 1.0 Hz), 5.70 (brs, 2H), 3.90 (s, 2H), 1.54 (s, 9 H).
    [785]
    [786] 2-Amino-6-decylthiophene-3-carboxylic acid t-butyl ester (18.20)
    [787] Dark brown oil in 74% yield
    [788] 1 H NMR (CDCl 3, 200 MHz): δ 6.56 (t, J = 1.2 Hz, 1H), 5.68 (brs, 2H), 2.56 (dt, 2H, J = 7.6, 1.2 Hz), 1.54 (s, 9H ), 1.20-1.40 (m, 8H), 0.89 (t, J = 7.6 Hz, 3H).
    [789]
    [790] 2-Amino-6-hexylthiophene-3-carboxylic acid t-butyl ester (18.21)
    [791] Dark brown oil in 99% yield
    [792] 1 H NMR (CDCl 3, 200 MHz): δ 6.56 (t, J = 1.2 Hz, 1H), 5.68 (brs, 2H), 2.55 (dt, 2H, J = 8.0, 1.2 Hz), 1.54 (s, 9H ), 1.20-1.40 (m, 16HO, 0.88 (t, J = 7.0 Hz, 3H).
    [793] Example 19 : Carbamate / Urea Intermediates
    [794]
    [795] 5-heptyl-4-methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (19.1): 1 H NMR (CDCl 3 ) δ 0.83-0.92 (m, 6H), 1.20- 1.40 (m, 18H), 1.50-1.60 (m, 11H), 1.64-1.72 (m, 2H), 2.20 (s, 3H), 2.62 (t, 2H, J = 7.6 Hz), 4.19 (t, 2H, J = 7.2 Hz); MS (EI): cal'd 467.72, exp, not ionized.
    [796]
    [797] 5-Methyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (19.2): 1 H NMR (CDCl 3 ) δ 0.87 (t, 3H, J = 7.2 Hz), 1.20-1.42 (m, 10H), 1.45-1.68 (m, 11H), 2.32 (s, 3H), 3.27 (dt, 2H, J = 7.2, 7.2 Hz), 4.79 (m, 1H), 6.70 (s, 1H), 10.2 (brs, 1H) MS (EI): cal'd 368.5, exp 368.87 (MH + ).
    [798]
    [799] 5-Methyl-2-octylcarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (19.3): 1 H NMR (CDCl 3 ) δ 0.88 (t, 3H, J = 7.2 Hz), 1.20-1.42 ( m, 10H), 1.55 (s, 9H), 1.62-1.72 (m, 2H), 2.34 (s, 3H), 4.19 (t, 2H, J = 6.8 Hz), 6.74 (s, 1H), 10.12 (brs MS (EI): cal'd 369.5, exp, not ionized.
    [800]
    [801] General procedure for forming the element (19.4-19.6)
    [802] 5-heptyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (19.4)
    [803] Amino thiophene 18.2 (200 mg, 0.67 mmol) was dissolved in 3 mL CH 2 Cl 2 and cooled to 0 ° C. Under the N 2 atmosphere, DBU (0.25 mL, 1.68 mmol) was added slowly and octyl isocyanate (104 mg, 0.67 mmol) was added. The reaction was slowly heated to room temperature and stirred at room temperature for 5 hours. The reaction was then dried over MgSO 4 and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (15: 1 hexanes: ethyl acetate) to give 19.4, 73 mg (yield 24%) of a grayish white solid: 1 H NMR (CDCl 3, 200 MHz): δ 0 .88 (t, 6H, J = 6.4 Hz), 1.27-1.29 (m, 18H), 1.54-1.58 (m, 13H), 2.64 (t, 2H, J = 7.5 Hz), 3.26 (dt, 2H, J = 7.0, 5.8 Hz), 4.85 (t, 1 H, J = 5.7 Hz), 6.69 (s, 1 H), 10.25 (s, 1 H). MS (ES &lt; + &gt;) 453.1 (M + 1).
    [804]
    [805] 5-Butyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (19.5) greyish white solid (353 mg, yield 59%): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, 3H, J = 7.1 Hz), 0.09 (t, 3H, J = 7.1 Hz), 1.25-1.41 (m, 12H), 1.53-1.64 (m, 13H), 2.64 (t, 2H, J = 7.5 Hz), 3.27 (dt, 2H, J = 7.0, 6.2 Hz), 5.29 (t, 1H, J = 5.7 Hz), 6.69 (s, 1H), 10.27 (bs, 1H). 13 C NMR (CDCl 3, 50 MHz) δ 13.7, 14.0, 22.1, 22.6 26.8, 28.3, 29.1, 29.2, 29.3, 30.0, 31.7, 33.4, 40.8, 80.7, 110.7, 119.8, 133.0, 149.9, 153.7, 165.6.
    [806]
    [807] 5-benzyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid tert-butyl ester (19.6) pale yellow solid (394 mg, yield 49%): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.27 (bs, 10H), 1.54 (s, 11H), 3.25 (dt, 2H, J = 7.0, 5.8 Hz), 3.97 (s, 2H), 4.88 (t, 1H, J = 5.6 Hz), 6.48 (t, 1H, J = 1.0 Hz), 7.16-7.32 (m, 5H), 10.26 (bs, 1H).
    [808]
    [809] General procedure for the formation of amides and carbamate (19.7-19.17):
    [810] 5-dodecanoylamino-5-heptyl-thiophene-3-carboxylic acid tert-butyl ester (19.7)
    [811] Amino thiophene 18.2 (171 mg, 0.57 mmol) was dissolved in 3 ml CH 2 Cl 2 and 2 ml pyridine. Under N 2 atmosphere, lauroyl chloride (126 mg, 0.57 mmol) was added and the reaction stirred at rt for 6 h. The reaction was then diluted with 10 mL CH 2 Cl 2 and washed with water, 5% citric acid, and brine. The organic solution was then dried over MgSO 4 and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (40: 1 hexanes: ethyl acetate) to give 19.7, 175 mg (yield 63%) of a grayish white solid: 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, 6H, J = 6.4 Hz), 1.25-1.44 (m, 24H), 1.51-1.73 (m, 13H), 2.45 (t, 2H, J = 7.5 Hz), 2.67 (t, 2H, J = 7.5 Hz), 6.77 (s, 1 H), 10.94 (bs, 1 H). 13 C NMR (CDCl 3, 50 MHz) δ 14.0, 14.1, 22.5, 22.6, 25.3, 28.3, 28.8, 29.0, 29.2, 29.3, 29.4, 29.5, 29.6, 31.3, 31.7, 31.9, 36.7, 81.2, 113.3, 120.1 , 134.8, 146.3, 165.1, 169.9.
    [812]
    [813] 2-Octyloxycarbonylamino-5-heptyl- (1,3,3-trimethyl-butyl) -thiophene-3-carboxylic acid tert-butyl ester (19.8) yellow oil (185 mg, yield 34%): 1 H NMR (CDCl 3, 200 MHz) δ 0.85-0.91 (m, 12H), 1.26-1.76 (m, 26H), 2.90-3.03 (m, 1H), 4.20 (t, 2H, J = 6.8 Hz), 6.73 (s, 1 H), 10.15 (bs, 1 H). 13 C NMR (CDCl 3, 50 MHz) δ 14.0, 22.6, 25.8, 26.3, 28.3, 28.8, 29.1, 29.2, 29.8, 31.2,31.8, 32.0, 52.6, 66.3, 81.2, 112.3, 118.9, 142.1, 147.7, 153.3 , 164.9.
    [814]
    [815] 5- (5-methoxy-1, 5-methyl-hexyl) -2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (19.9) pale yellow oil: 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (t, 3H, J = 6.4 Hz), 1.11 (s, 6H), 1.26-1.48 (m, 19H), 1.50-1.71 (m, 11H), 2.74 (dq, 1H, J = 7.0 , 7.0 Hz), 3.15 (s, 3H), 4.20 (t, 2H, J = 6.6 Hz), 6.74 (s, 1H) 10. 17 (s, 1H). 13 C NMR (CDCl 3, 50 MHz) δ 14.0, 21.5, 22.5, 22.6, 24.9, 25.7, 28.2, 28.7, 29.1, 31.7, 35.1, 39.3, 39.5, 48.9, 60.2, 66.2, 74.3, 81.1, 112.2, 119.3 , 139.7, 147.9, 153.1, 164.8.
    [816]
    [817] 5- (1,5-Dimethyl-hex-4-enyl) -2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (19.10) brownish oil (630 mg, 90% yield) : 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.26-1.42 (m, 13H), 1.55-1.73 (m, 19H), 1.96 (dt, 2 H, J = 7.8, 7.2 Hz), 2.86 (tq, 1H, J = 7.2, 6.6 Hz), 4.20 (t, 3H, J = 6.6 Hz), 5.08 (t, 1H, J = 7.2 Hz), 6.74 (s, 1H ), 10.16 (bs, 1 H).
    [818]
    [819] 2-Octyloxycarbonylamino-5-phenethyl-thiophene-3-carboxylic acid tert-butylester (19.11) White oil (740 mg, yield 98%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.28 (brs, 10H), 1.56 (s, 9H), 1.68 (m, 2H), 2.96 (s, 4H), 4.20 (t, 2H, J = 6.6 Hz) , 6.75 (s, 1H), 7.26 (m, 5H), 10.15 (s, 1H)
    [820]
    [821] 2-Octyloxycarbonylamino-5- (3-phenyl-propyl) -thiophene-3-carboxylic acid tert-butyl ester (19.12) yellow oil (720 mg, yield 90%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.28 (brs, 10H), 1.6 (brs, 11H), 1.97 (tt, 2H, J = 7.8, 7.2 Hz), 2.69 (m, 4H) , 4.20 (t, 2H, J = 6.6 Hz), 6.76 (s, 1H), 7.26 (m, 5H), 10.15 (s, 1H)
    [822]
    [823] 2-Octyloxycarbonylamino-5- (4-phenyl-butyl) -thiophene-3-carboxylic acid tert-butyl ester (19.13) clear colorless oil (401 mg, yield 88%): 1 H NMR (CDCl 3 , 200 MHz) δ 0.88 (bt, 3H, J = 6.2 Hz), 1.15-1.42 (m, 11H), 1.56 (s, 9H), 1.61-1.80 (m, 6H), 2.52-2.8 0 (m, 4H ), 4.20 (t, 2H, J = 6.6 Hz), 6.74 (s, 1H), 7.09-7.35 (m, 5H), 10.15 (s, 1H); MS (ES) No ionization or no LC observed.
    [824]
    [825] 2-octyloxycarbonylamino-5- (5-phenyl-pentyl) -thiophene-3-carboxylic acid tert-butyl ester (19.14) clear / colorless oil (331 mg, yield 75%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (bt, 3H, J = 6.2 Hz), 1.20-1.50 (m, 14H), 1.50-1.75 (m, 15H), 2.50-2.75 (m, 4H), 4.19 (t, 2H , J = 7.0Hz), 6.74 (t, 1H, J = 1.0Hz), 7.08-7.36 (m, 5H); No influence of MS (ES) LC and no ionization.
    [826]
    [827] 5-decyl-2- (2-methoxy-ethoxycarbonylamino) -thiophene-3-carboxylic acid tert-butyl ester (19.15) pale yellow oil (307 mg, yield 76%): 1 H NMR (CDCl 3 , 200 MHz): δ 0.88 (bt, 3H, J = 6.2 Hz), 1.16-1.43 (m, 14H), 1.55 (s, 9H), 1.57-1.73 (m, 2H), 2.66 (t, 2H, J = 7.8 Hz), 3.41 (s, 3H), 3.58-3.70 (m, 2H), 4.25-4.44 (m, 2H), 6.74 (s, 1H), 10.27 (bs, 1H); MS (ES) 442.64 ( M + 1), t R (method D) = 12.9 min.
    [828]
    [829] 2- (4-Butyl-phenoxycarbonylamino) -5-decyl-thiophene-3-carboxylic acid tert-butyl ester (19.16)
    [830] Amino thiophene 18.4 (300 mg, 0.92 mmol) was dissolved in anhydro THF (4 mL). Under N 2 atmosphere, 4-chloroformate nitrophenyl (184 mg, 0.92 mmol) was added and stirred overnight at room temperature. Without isolation of the 4-nitrophenyl carbamate intermediate, 4-butyl phenol sodium salt (200 mg, 1.26 mmol) was added dropwise to the solution of the intermediate and the solution of the intermediate was stirred at room temperature for 2 hours and further up to 40 ° C. Followed by heating. Sodium salt of phenol was prepared by dissolving 4-butyl phenol (174 mg, 1.16 mmol) in anhydro THF (3 mL) and cooling to 0 ° C. NaH (60% diffusion in mineral oil) was then added to the reaction mixture and stirred at 0 ° C. for 1/2 hour to use as described above. The reaction mixture was separated by partitioning between CHCl 3 and H 2 O. The H 2 O layer was separated by re-extraction with CHCl 3 ( 3 ×). The combined CHCl 3 layer was washed with 2M NaOH (1 ×), 1M HCl (1 ×), brine (1 ×), dried over Na 2 SO 4 and concentrated to give 490 mg of a dark orange oil. The crude material was further purified by flash silica chromatography (2% EtOAc in hexanes) to give 241 mg of yellow oil (yield 50%). 1 H NMR (CDCl 3, 200 MHz): δ 0.83-0.93 (m, 6H), 1.19-1.45 (m, 18H), 1.47-1.72 (m, 14H), 2.55-2.75 (m, 4H), 6.80 ( s, 1H), 7.11 (d, 2H, J = 8.8 Hz), 7.19 (d, 2H, J = 8.8 Hz), 10.58 (s, 1H).
    [831]
    [832] 5-decyl-2- (4-phenyl-butoxycarbonylamino) -thiophene-3-carboxylic acid tert-butyl ester (19.17) pale yellow oil (241 mg, yield 89%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.26-1.38 (m, 14H), 1.56-1.70 (m, 11H), 1.99 (tt, 2H, J = 12.6, 6.2 Hz), 2.66 ( t, 2H, J = 7.5 Hz), 3.58 (t, 2H, J = 6.2 Hz), 4.34 (t, 2H, J = 6.2 Hz), 4.50 (s, 2H), 6.75 (s, 1H), 7.24- 7.34 (m, 5 H), 10.16 (s, 1 H). 13 C NMR (CDCl 3, 50 MHz) δ 14.04, 22.60, 28.26, 28.97, 29.19, 29.23, 29.27, 29.45, 29.48, 29.51,31.25, 31.82, 63.35, 66.35, 72.96, 81.09, 112.53, 120.60, 127.48, 127.53 , 128.28, 133.87, 138.21, 147.97, 152.97, 164.77.
    [833] Example 20 : Tert-butyl ester intermediate
    [834]
    [835] 5-Butyl-2-octylcarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.1): 1 H NMR (CDCl 3, 200 MHz): δ = 0.88-1.00 (m, 6H), 1.18- 1.49 (m, 12H), 1.50-1.79 (m, 13H), 2.67 (t, J = 7.3 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 6.74 (t, J = 0.9 Hz, 1H ), 10.14 (brs, 1 H).
    [836]
    [837] 5-isopropyl-2-octylcarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.2): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.16-1.46 (m, 16H), 1.50-1.76 (m, 11H), 2.90-3.16 (m, 1H), 4.20 (t, J = 6.6 Hz, 2H), 6.75 (d, J = 1.0 Hz, 1H) , 10.16 (brs, 1 H).
    [838]
    [839] 5-Octyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.3): 1 H NMR (CDCl 3, 200 MHz) δ 0.79-0.88 (m, 6H), 1.18-1.46 (m, 20H), 1.51-1.78 (m, 13H), 2.66 (td, J = 0.8, 7.5 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 6.74 (t, J = 1.1 Hz, 1H), 10.14 (brs, 1H).
    [840]
    [841] 5-dodecyl-2-octylcarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.4): 1 H NMR (CDCl 3, 200 MHz) δ 0.80-0.98 (m, 6H), 1.15-1.46 (m, 28H), 1.52-1.78 (m, 13H), 2.66 (t, J = 7.3 Hz, 2H), 4.20 (t, J = 6.8 Hz, 2H), 6.74 (s, 1H), 10.14 (brs, 1H).
    [842]
    [843] 2-benzyloxycarbonylamino-5-decyl-thiophene-3-carboxylic acid tert-butyl ester (20.5): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.4 Hz), 1.18-1.42 (m, 14H), 1.48 -1.72 (m, 11H), 2.66 (t, J = 7.5 Hz, 2H), 5.24 (s, 2H), 6.74 (s, 1H), 7.31-7.47 (m, 5H), 10.25 (brs, 1 H).
    [844] General procedure for the preparation of tert-butyl ester 20.6-20.8 and the corresponding commercially available alcohols from aminothiophene 18.4:
    [845] A solution of 4-butylbenzyl alcohol (0.30 mL, 1.76 mmol) added to CH 2 Cl 2 (10 mL) is impregnated with NaHCO 3 (10 mL), followed by dropping diphosgene (0.25 mL, 2.07 mmol). . The mixture was allowed to stir vigorously at room temperature for 45 minutes and aminothiophene 18.4 (283 mg, 0.83 mmol) was added in one portion. After vigorously stirring for 2 hours, the reaction mixture was diluted with Et 2 O (100 mL) and washed with NaHCO 3 (2 × 20 mL) and brine (40 mL) impregnated with the organic layer. The organic layer was dried over Na 2 S0 4 and filtered. The filtrate was concentrated and the resulting residue was purified by flash column chromatography (40: 1 hexanes / EtOAc) to give tert-butyl ester 20.6 as a light yellow oil (416 mg, 95%).
    [846]
    [847] 2- (4-Butylbenzyloxycarbonylamino) -5-decyl-thiophene-3-carboxylic acid tert-butylester (20.6): 1 H NMR (CDCl 3, 200 MHz) δ 0.82-1.00 (m, 6H ), 1.18-1.46 (m, 16H), 1.48-1.72 (m, 13H), 2.54-2.73 (m, 4H), 5.20 (s, 2H), 6.73 (s, 1H), 7.13-7.38 (m, 4H) ), 10.23 (brs, 1 H).
    [848]
    [849] 5-decyl-2- (2-p-tolyl-ethoxycarbonylamino) -thiophene-3-carboxylic acid tert-butyl ester (20.7): 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 ( t, J = 6.4 Hz, 3H), 1.17-1.42 (m, 14H), 1.49-1.72 (m, 11H), 2.32 (s, 3H), 2.66 (t, J = 7.3 Hz, 2H), 2.96 (t , J = 7.1 Hz, 2H,), 4.39 (t, J = 7.3 Hz, 2H), 6.74 (s, 1H), 7.08-7.19 (m, 4H), 10.14 (brs, 1H).
    [850]
    [851] 5-decyl-2-phenethyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.8): 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t, 3H, J = 6.4) Hz), 1.18-1.42 (m, 14H), 1.50-1.72 (m, 11H), 2.66 (t, 2H, J = 7.3 Hz), 3.01 (t, 2H, J = 7.5 Hz), 4.42 (t, 2H , J = 7.3 Hz), 6.74 (s, 1 H), 7.18-7.40 (m, 5 H), 10.15 (brs, 1 H).
    [852]
    [853] 4-Methyl-5-octyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.9): 2.35 g 3%) 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t , J = 6.6 Hz, 3H), 0.88 (t, J = 7.6 Hz, 3H), 1.30-1.72 (m, 24H), 1.57 (s, 9H), 2.61 (t, J = 7.8 Hz, 2H), 4.18 (t, J = 6.6 Hz, 2H), 10.26 (s, 1H). 13 C NMR (CDCl 3, 75 MHz): δ 12.3, 12.9, 20.9, 24.0, 24.1, 25.4, 26.7, 27.1, 27.3, 27.4, 27.5, 27.6, 29.6, 30.1, 30.1, 64.5, 79.7, 111.2, 126.2, 127.1, 146.7, 151.5, 164.0.
    [854]
    [855] 2- Butyloxycarbonylamino -5-octyl-thiophene-3-carboxylic acid tert-butyl ester (20.10): 693 mg (92%). 1 H NMR (CDCl 3, 200 MHz): δ 0.83 (t, J = 6.6 Hz, 3H), 0.94 (t, J = 7.0 Hz, 3H), 1.20-1.48 (m, 12H), 1.55 (s, 9H ), 1.52-1.75 (m, 4H), 2.65 (t, J = 7.0 Hz, 2H), 4.20 (t, J = 6.6 Hz, 2H), 6.73 (s, 1H), 10.14 (s, 1H).
    [856]
    [857] 2-hexyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid tert-butyl ester (20.11): 760 mg (98%). 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, J = 6.6 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H), 1.18-1.44 (m, 14H), 1.55 (s, 9H) , 1.54-1.76 (m, 4H), 2.65 (t, J = 7.0 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 6.73 (s, 1H), 10.14 (s, 1H).
    [858]
    [859] 2- Dodecyloxycarbonylamino -5-octyl-thiophene-3-carboxylic acid tert-butylester (20.12): 831 mg (88%). 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, J = 6.6 Hz, 6H), 1.051-1.50 (m, 28H), 1.55 (s, 9H), 1.50-1.75 (m, 4H), 2.65 ( t, J = 7.2 Hz, 2H), 4.19 (t, J = 6.6 Hz, 2H), 6.73 (t, J = 1.2 Hz, 1H), 10.14 (s, 1H).
    [860]
    [861] 5-decyl-2-phenyloxycarbonylamino-thiophene-3-carboxylic acid tert-butyl ester (20.13): 696 mg (84%). 1 H NMR (CDCl 3, 200 MHz): δ 0.88 (t, J = 7.0 Hz, 3H), 1.20-1.36 (m, 14H), 1.52-1.66 (m, 2H), 1.59 (s, 9H), 2.67 (dt, J = 7.4, 1.2 Hz, 2H), 6.78 (t, J = 1.2 Hz, 1H), 7.14-7.48 (m, 5H), 10.55 (s, 1H).
    [862]
    [863] 2-dodecyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid tert-butyl ester (20.14): 863 mg (91%). 1 H NMR (CDCl 3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 6H), 1.44 (m, 24H), 1.55 (s, 9H), 1.52-1.76 (m, 4H), 2.65 (t , J = 7.2 Hz, 2H), 4.19 (t, J = 0.6 Hz, 2H), 6.73 (s, 1H), 10.14 (s, 1H).
    [864]
    [865] 6-benzyl-2- (octyloxycarbonylamino) thiophene-3-carboxylic acid tert-butyl ester (20.15)
    [866] Light yellow oil with 77% yield
    [867] 1 H NMR (CDCl 3, 200 MHz): δ 10.14 (s, 1H), 7.20-7.40 (m, 5H), 6.82 (s, 1H), 4.17 (t, J = 6.6 Hz, 2H), 3.99 ( s, 2H), 1.64 (q, 2H, J = 6.6 Hz), 1.55 (s, 9H), 1.10-1.50 (m, 10H), 0.88 (t, 3H, J = 6.6 Hz).
    [868]
    [869] 6-hexyl-2- (octyloxycarbonylamino) thiophene-3-carboxylic acid tert-butyl ester (20.16)
    [870] Light yellow oil in 86% yield
    [871] 1 H NMR (CDCl 3, 200 MHz): δ 10.14 (brs, 1H), 6.74 (s, 1H), 4.19 (t, 2H, J = 6.6 Hz), 2.66 (t, 2H, J = 7.6 Hz) , 1.60-1.75 (m, 2H), 1.56 (s, 9H), 1.10-1.40 (m, 18H), 0.80-0.95 (m, 6H).
    [872]
    [873] 6-decyl-2- (octyloxycarbonylamino) thiophene-3-carboxylic acid tert-butyl ester (20.17)
    [874] Light yellow oil with 99% yield
    [875] 1 H NMR (CDCl 3, 200 MHz): δ 10.14 (brs, 1H), 6.74 (s, 1H), 4.19 (t, 2H, J = 6.6 Hz), 2.66 (t, 2H, J = 8.0 Hz) , 1.60-1.75 (m, 2H), 1.56 (s, 9H), 1.08-1.40 (m, 26H), 0.80-0.95 (m, 6H).
    [876]
    [877] 6-decyl-2- (1-methylheptyloxycarbonylamino) thiophene-3-carboxylic acid tert-butyl ester (20.18)
    [878] Light yellow oil with 99% yield
    [879] 1 H NMR (CDCl 3, 200 MHz): δ 10.10 (brs, 1H), 6.73 (s, 1H), 4.82-5.00 (m, 1H), 2.65 (t, 2H, J = 7.4 Hz), 1.50- 1.83 (m, 15 H), 1.08-1.50 (m, 23 H), 0.80-1.00 (m, 6H).
    [880]
    [881] 6-heptyl-2- (1-methylheptyloxycarbonylamino) thiophene-3-carboxylic acid tert-butyl ester (20.19)
    [882] Light yellow oil with 99% yield
    [883] 1 H NMR (CDCl 3, 200 MHz): δ 10.01 (brs, 1H), 6.73 (s, 1H), 4.80-5.00 (m, 1H), 2.65 (t, 2H, J = 7.4 Hz), 1.50- 1.83 (m, 13 H), 1.08-1.50 (m, 17 H), 0.80-1.00 (m, 6H).
    [884]
    [885] 5-decyl-2- (4-phenylbutoxycarbonylamino) thiophene-3-carboxylic acid tert-butyl ester (20.20)
    [886] Light brownish oil in 99% yield
    [887] 1 H NMR (CDCl 3, 200 MHz): δ 10.12 (s, 1H), 7.26-7.31 (m, 2H), 7.19-7.26 (m, 3H), 6.75 (s, 1H), 4.23 (t, 2H , J = 6.4 Hz, 2.73 (t, 2H, J = 7.6 Hz), 2.66 (q, 2H, J = 7.2 Hz), 1.98-2.07 (m, 2H), 1.59-1.65 (m, 2H), 1.52 -1.57 (m, 11H), 1.26-1.30 (m, 12H), 0.88 (t, 3H, J = 6.4 Hz).
    [888]
    [889] 5-decyl-2- (4-phenylbutoxycarbonylamino) thiophene-3-carboxylic acid tert-butyl ester (20.21)
    [890] Light brownish oil with 98% yield
    [891] 1 H NMR (CDCl 3, 400 MHz): δ 10.11 (s, 1H), 7.26-7.31 (m, 2H), 7.18-7.26 (m, 3H), 6.74 (s, 1H), 4.26 (brs, 2H ), 2.67-2.70 (m, 4H), 1.70-1.80 (m, 4H), 1.50-1.70 (m, 11H), 1.18-1.40 (m, 16H), 0.88 (t, 3H, J = 6.8 Hz).
    [892] Example 21 Acid Intermediates
    [893]
    [894] 5-heptyl-4-methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.1):
    [895] Can contain 10% other isomers;OneH NMR (CDCl3) δ 0.82-0.94 (m, 6H), 1.20-1.46 (m, 18H), 1.50-1.66 (m, 2H), 1.62-1.80 (m, 2H), 2.28 (s, 3H), 2.64 (t, 2H) , J = 7.2 Hz), 4.22 (t, 2H, J = 7.2 Hz). There were other peaks at 2.79 (t, J = 7.0 Hz), which may be from different isomers; MS (EI): cal 'd 411 .61, exp, Not ionized.
    [896]
    [897] 5-Methyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.2): 1 H NMR (CD Cl 3 ) δ 0.88 (t, 3H, J = 7.2 Hz), 1.20-1.45 (m, 10H ), 1.65-1.75 (m, 2H), 2.37 (s, 3H), 4.23 (t, 2H, J = 6.8 Hz), 6.84 (s, 1H), 9.89 (s, 1H); MS (EI): cal'd 313.41, exp.
    [898]
    [899] 5-heptyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (21.3) tan solid (51 mg, yield 80%): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, 6H, J = 5.7 Hz), 1.26 (bs, 18H), 1.54-1.61 (m, 4H), 2.63 (t, 2H, J = 7.5 Hz), 3.26 (dt, 2H, J = 7.0, 7.0 Hz), 5.95 (bs, 1 H), 6.77 (s, 1 H), 10.10 (s, 1 H). 11.36 (bs, 1 H). 13 C NMR (CDCl 3, 50 MHz) δ 14.0, 22.6, 26.8, 29.2, 29.3, 29.4, 29.7, 31.1, 31.7, 31.8, 41.0, 88.4, 108.9, 119.6, 134.2, 151.9, 154.1, 169.9.
    [900]
    [901] 5-Butyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (21.4) Purple oil (308 mg, yield 100%): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, 6H, J = 5.7 Hz), 1.26 (bs, 18H), 1.54-1.61 (m, 4H), 2.63 (t, 2H, J = 7.5 Hz), 3.26 (dt, 2H, J = 7.0, 7.0 Hz), 5.95 (bs, 1 H), 6.77 (s, 1 H), 10.10 (s, 1 H). 11.36 (bs, 1 H).
    [902]
    [903] 5-Benzyl-2- (3-octyl-ureido) -thiophene-3-carboxylic acid (21.5) tan solid (450 mg): 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, 3H, J = 6.4 Hz, 1.26 (bs, 10H), 1.51 (tt, 2H, J = 12.2, 6.5 Hz), 3.21 (dt, 2H, J = 6.6, 6.0 Hz), 3.96 (s, 2H), 6.33 (bs, 1H), 6.82 (s, 1H), 7.14-7.32 (m, 5H), 10.16 (bs, 1H).
    [904]
    [905] 2-dodecanoylamino-5-heptyl-thiophene-3-carboxylic acid (21.6) Dark brown solid (185 mg, yield 100%): 1 H NMR (CDCl 3, 200 MHz) δ 0.85-0.91 (m, 6H ), 1.26-1.40 (m, 24H), 1.54-1.79 (m, 4H), 2.52 (t, 2H, J = 7.5 Hz), 2.71 (t, 2H, J = 7.5 Hz), 6.91 (s, 1H) , 10.53 (bs, 1 H), 10.75 (s, 1 H). MS (ES−) 421.86 (M-1).
    [906] 5-heptyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.7) pale yellow solid (76 mg, yield 54%): 1 H NMR (CDCl 3, 200 MHz) δ 0.85-0.90 (m, 6H ), 1.30 (bs, 18H), 1.5-1.75 (m, 4H), 2.69 (t, 2H, J = 7.5 Hz), 4.24 (t, 2H, J = 6.6 Hz), 6.86 (s, 1H), 9.90 (s, 1 H). MS (ES-) 395.93 (M-1).
    [907]
    [908] 2-octyloxycarbonylamino-5- (1,3,3-trimethyl-butyl) -thiophene-3-carboxylic acid (21.8) light tan solid (190 mg, yield 100%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88-0.89 (m, 12H), 1.28-1.76 (m, 17H), 2.90-3.09 (m, 1H), 4.24 (t, 2H, J = 6.6 Hz), 6.87 (s, 1H), 9.85 (s, 1 H), 10.34 (bs, 1 H).
    [909] 2- (2-benzyloxy-ethoxycarbonylamino) -5-decyl-thiophene-3-carboxylic acid (21.9) tan solid (142 mg): 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (t, 3H, J = 6.5 Hz), 1.23-1.27 (m, 14H), 1.58-1.69 (m, 2H), 2.69 (t, 2H, J = 7.3 Hz), 3.76 (t, 2H, J = 4.6 Hz), 4.43 (t, 2H, J = 4.6 Hz), 4.61 (s, 2H), 6.88 (s, 1H). 7.28-7.38 (m, 5H), 9.99 (s, 1H), 10.48 (bs, 1H) .MS (ES-) 460.06 (M-1).
    [910]
    [911] 2- Octyloxycarbonylamino -5-phenethyl-thiophene-3-carboxylic acid (21.10) White solid (203 mg, yield 97%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.28 (brs, 10H), 2.98 (s, 4H), 4.23 (t, 2H, J = 7.0 Hz), 6.84 (s, 1H) .7.22 (m, 5H), 9.96 (s, 1H)
    [912]
    [913] 2- Octyloxycarbonylamino -5- (3-phenyl-propyl) -thiophene-3-carboxylic acid (21.11) Yellow solid (175 mg, yield 99%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.28 (brs, 10H), 1.68 (m, 2H), 1.98 (tt, 2H, J = 7.8, 7.2 Hz), 4.23 (t, 2H, J = 7.0 Hz) , 6.87 (s, 1 H), 7.26 (m, 5 H), 9.93 (1 H)
    [914]
    [915] 2-Octyloxycarbonylamino-5- (4-phenyl-butyl) -thiophene-3-carboxylic acid (21.12) Light white solid (303 mg, yield 92%): 1 H NMR (CD 3 OD , 400 MHz) : δ 0.90 (bt, 3H, J = 6.8 Hz), 1.21-1.48 (m, 12H), 1.57-1.7 (m, 6H), 2.57-2.77 (m, 4H), 4.20 (t, 2H, J = 6.4 Hz), 6.82 (s, 1 H), 7.08-7.32 (m, 5H); MS (ES) 430.35 (M-1), t R (method D) = 7.74 min.
    [916]
    [917] 2-Octyloxycarbonylamino-5- (5-phenyl-pentyl) -thiophene-3-carboxylic acid (21.13) greyish white solid (331 mg, yield 90%): 1 H NMR (CD 3 OD , 400 MHz): δ 0.90 (bt, 3H, J = 6.4 Hz), 1.23-1.45 (m, 14H), 1.58-1.75 (m, 6H), 2.59 (t, 2H, J = 7.6 Hz), 2.68 (t , 2H, J = 7.2 Hz), 4.20 (t, 2H, J = 6.8 Hz), 6.81 (bs, 1H), 7.07-7.18 (m, 3H), 7.19-7.27 (m, 2H) .MS (ES ) 443.58 (M-1), t R (method D) = 8.58 min.
    [918]
    [919] 5-decyl-2- (2-methoxy-ethoxycarbonylamino) -thiophene-3-carboxylic acid (21.14) greyish white solid (256 mg, yield 95%): 1 H NMR (CDCl 3, 200 MHz): δ 0.98 (bt, 3H, J = 6.2 Hz), 1.11-1.44 (m, 14H), 1.47-1.73 (m, 2H), 2.69 (t, 2H, J = 7.8 Hz), 3.43 (s , 3H), 3.62-3.75 (m, 2H), 4.31-4.47 (m, 2H), 6.86 (s, 1H), 10.00 (s, 1H) .MS (ES) 384.52 (M-1), t R ( Method D) = 6.28 min.
    [920]
    [921] 2- (4-Butyl-phenoxycarbonylamino) -5-decyl-thiophene-3-carboxylic acid (21.15) tan solid (214 mg, yield 97%) 1 H NMR (CD 3 OD , 400 MHz) δ 0. 891 (bt, 3H, J = 6.8 Hz), 0.949 (t, 3H, J = 7.2 Hz), 1.21-1.43 (m, 16H), 1.54-1.71 (m, 4H), 2.63 (t, 2H, J = 7.6 Hz), 2.70 (t, 2H, J = 7.2 Hz), 6.87 (s, 1H), 7.12 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.8 Hz); MS (ES) no ionization (M-1), t R (method D) = no peak
    [922]
    [923] 2- (3-Phenoxy-propoxycarbonylamino) -5-decyl-thiophene-3-carboxylic acid (21.16) A grayish white solid (137 mg, yield 80%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.4 Hz), 1.26-1.38 (m, 14H), 1.64 (tt, 2H, J = 12.4, 7.0 Hz), 2.02 (tt, 2H, J = 12.4, 6.2 Hz ), 2.68 (t, 2H, J = 7.3 Hz), 3.60 (t, 3H, J = 6.2 Hz), 4.37 (t, 2H, J = 6.2 Hz), 4.53 (s, 2H), 6.87 (s, 1 H), 7.25-7.34 (m, 5H), 9.88 (s, 1H), 10.85 (bs, 1H).
    [924] 2- (4-Benzyloxy-butoxycarbonylamino) -5-decyl-thiophene-3-carboxylic acid (21.17) greyish white solid (55 mg, yield 55%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.3 Hz), 1.26-1.38 (m, 14H), 1.61-1.82 (m, 6H), 2.68 (t, 2H, J = 7.4, Hz), 3.53 (t, 2 H, J = 5.8Hz), 4.27 (t, 2H, J = 5.8Hz), 4.50 (s, 2H), 6.86 (s, 1H), 7.25-7.33 (m, 5H), 9.92 (s, 1H) .
    [925]
    [926] 2-pentyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.18) : 1 H NMR (CDCl 3, 200 MHz): δ 0.78-1.02 (m, 6H), 1.14-1.50 (m, 12H), 1.52-1.82 (m, 4H), 2.69 (t, J = 7.5 Hz, 2H), 4.23 (t, J = 6.8 Hz, 2H), 6.59 (s, 1H), 9.88 (brs, 1H).
    [927]
    [928] 5-Isopropyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.19) : 1 H NMR (CDCl 3, 200 MHz): δ 0.98 (t, J = 6.4 Hz, 3H), 1.16- 1.50 (m, 16H), 1.60-1.82 (m, 2H), 2. 90-3.18 (m, 1H), 4.24 (t, J = 6.8 Hz, 2H), 6.87 (d, J = 1.2 Hz, 1H) , 9.81 (brs, 1 H) .9.86 (brs, 1 H)
    [929]
    [930] 5-Octyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.20) : 1 H NMR (CDCl 3, 200 MHz): δ = 0.78-1.00 (m, 6H), 1.12-1.49 (m, 20H), 1.54-1.82 (m, 4H), 2. 68 (t, J = 7.3 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 6.86 (s, 1H), 9.89 (brs, 1H ).
    [931]
    [932] 5-Dodecyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.21) : 1 H NMR (CDCl 3, 200 MHz): δ = 0.78-0.96 (m, 6H), 1.12-1.46 (m , 28H), 1.52-1.78 (m, 4H), 2. 68 (t, J = 7.3 Hz, 2H), 4.23 (t, J = 6.8 Hz, 2H), 6.85 (s, 1H), 9.90 (brs, 1H).
    [933]
    [934] 2-benzyloxycarbonylamino-5-decyl-thiophene-3-carboxylic acid (21.22) : 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.14-1.44 (m, 14H), 1.50-1.74 (m, 2H), 2. 68 (t, J = 7.1 Hz, 2H), 5.26 (s, 2H), 6.85 (s, 1H), 7.33-7.49 (m, 5H ), 9.95 (brs, 1 H).
    [935]
    [936] 2- (4-Butylbenzyloxycarbonylamino) -5-decyl-thiophene-3-carboxylic acid (21.23) : 1 H NMR (CDCl 3, 200 MHz): δ = 0.78-1.02 (m, 6H), 1.10 -1.46 (m, 16H), 1.48-1.76 (m, 4H), 2. 52-2.80 (m, 4H), 5.23 (s, 2H), 6.84 (s, 1H), 7.13-7.40 (m, 4H) , 9.93 (brs, 1 H).
    [937]
    [938] 5-decyl-2- (2-p-tolyl-ethoxycarbonylamino) -thiophene-3-carboxylic acid (21.24) : 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.16-1.46 (m, 14H), 1.52-1.78 (m, 2H), 2.33 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H), 3.00 (t, J = 7.3 Hz , 2H), 4.43 (t, J = 7.3 Hz, 2H), 6.87 (s, 1H), 7.08-7.22 (m, 4H), 9.91 (brs, 1H).
    [939]
    [940] 5-decyl-2-phenethyloxycarbonylamino-thiophene-3-carboxylic acid (21.25) : 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t, J = 6.4 Hz, 3H), 1.16- 1.46 (m, 14H), 1.52-1.76 (m, 2H), 2. 69 (t, J = 7.3 Hz, 2H), 3.05 (t, J = 7.3 Hz, 2H), 4.46 (t, J = 7.5 Hz , 2H), 6.87 (s, 1H), 7.18-7.42 (m, 5H), 9.92 (brs, 1H).
    [941]
    [942] 4-Methyl-5octyl-2-octyloxycarbonylamino-thiophene-3-carboxylic acid (21.26) : 520 mg (69%) 1 H NMR (CDCl 3, 200 MHz): δ = 0.87 (t, J = 6.6 Hz, 6H), 1.16-1.62 (m, 24H), 2.28 (s, 3H), 2.64 (t, J = 7.2 Hz, 2H), 4.18 (t, J = 6.6 Hz, 2H), 10.26 (s, 1H).
    [943]
    [944] 2-Butyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid (21.27) : 366 mg (67%). 1 H NMR (CDCl 3, 200 MHz): δ = 0.87 (t, J = 6.6 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H), 1.14-1.82 (m, 16H), 2.67 (t, J = 7.4 Hz, 2H), 4.24 (t, J = 6.6 Hz, 2H), 6.8 5 (s, 1H), 9.89 (s, 1H).
    [945]
    [946] 2-hexyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid (21.28) : 395 mg (60%). 1 HNMR (CDCl 3, 200 MHz): δ = 0.87 (t, J = 7.0 Hz, 3H), 0.90 (t, J = 6.4 Hz, 3H), 1.12-1.52 (m, 16H), 1.50-1.82 (m , 4H), 2.68 (t, J = 7.2 Hz, 2H), 4.23 (t, J = 7.0 Hz, 2H), 6.68 (s, 1H), 9.88 (s, 1H).
    [947]
    [948] 2-Dodecyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid (21.29) : 541 mg (80%). 1 H NMR (CDCl 3, 200 MHz): δ = 0.87 (t, J = 6.4 Hz, 6H), 1.12-1.50 (m, 28H), 1.50-1.80 (m, 4H), 2.68 (t, J = 7.4 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 6.85 (s, 1H), 9.89 (s, 1H).
    [949]
    [950] 5-decyl-2-phenyloxycarbonylamino-thiophene-3-carboxylic acid (21.30) : 469 mg (80%). 1 H NMR (CDCl 3, 200 MHz): δ = 0.87 (t, J = 6.6 Hz, 3H), 1.18-1.44 (m, 14H), 1.54-1.76 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H), 6.91 (s, 2H), 7.17-7.48 (m, 5H), 10.27 (s, 1H).
    [951]
    [952] 2-decyloxycarbonylamino-5-octyl-thiophene-3-carboxylic acid (21.31) : 603 mg (86%). 1 H NMR (CDCl 3, 200 MHz): δ = 0.87 (t, J = 6.2 Hz, 6H), 1.32-1.50 (m, 24H), 1.52-1.82 (m, 4H), 2.67 (t, J = 7.4 Hz, 2H), 4.23 (t, J = 6.6 Hz, 2H), 6.85 (s, 1H), 9.89 (s, 1H).
    [953]
    [954] 6-benzyl-2- (octyloxycarbonylamino) thiophene-3-carboxylic acid (21.32)
    [955] Light yellow solid in 100% yield.
    [956] 1 H NMR (CDCl 3, 200 MHz): δ = 9.86 (s, 1H), 7.22-7.34 (m, 5H), 7.00 (brs, 1H), 6.87 (t, 1H, J = 1.0 Hz), 4.21 ( t, 2H, J = 6.6 Hz, 4.01 (s, 2H), 1.67 (q, 2H, J = 7.0 Hz), 1.15 -1.45 (m, 10H), 0.88 (t, 3H, J = 7.0 Hz).
    [957]
    [958] 6-hexyl-2- (octyloxycarbonylamino) thiophene-3-carboxylic acid (21.33)
    [959] Light yellow oil in 74% yield.
    [960] 1 H NMR (CDCl 3, 200 MHz): δ = 10.87 (brs, 1H), 9.83 (s, 1H), 6.86 (s, 1H), 4.24 (t, 2H, J = 6.6 Hz), 2.68 (t, 2H, J = 7.2 Hz), 1.60-1.80 (m, 4H), 1.10-1.45 (m, 20H), 0.80-0.95 (m, 6H).
    [961]
    [962] 6-decyl-2- (octyloxycarbonylamino) thiophene-3-carboxylic acid (21.34)
    [963] Light yellow solid in 100% yield.
    [964] 1 H NMR (CDCl 3, 200 MHz): δ = 9.89 (brs, 1H), 8.00 (brs, 1H), 6.85 (s, 1H), 4.23 (t, 2H, J = 6.6 Hz), 2.68 (t, 2H, J = 7.0 Hz, 1.60-1.80 (m, 24H), 1.08-1.40 (m, 24H), 0.80-0.95 (m, 6H).
    [965]
    [966] 6-decyl-2- (1-methylheptyloxycarbonylamino) thiophene-3-carboxylic acid (21.35)
    [967] Light yellow solid in 98% yield.
    [968] 1 H NMR (CDCl 3, 200 MHz): δ = 9.80 (brs, 1H), 8.24 (brs, 1H), 6.73 (s, 1H), 4.82-5.00 (m, 1H), 2.65 (t, 2H, J) = 7.4 Hz), 1.50-1.83 (m, 15H), 1.08-1.50 (m, 23H), 0.80-1.00 (m, 6H).
    [969]
    [970] 6-heptyl-2- (1-methylheptyloxycarbonylamino) thiophene-3-carboxylic acid (21.36)
    [971] Light yellow oil in 100% yield.
    [972] 1 H NMR (CDCl 3, 200 MHz): δ = 9.80 (brs, 1H), 8.24 (brs, 1H), 6.85 (s, 1H), 4.90-5.00 (m, 1H), 2.68 (t, 2H, J = 7.6 Hz), 1.50-1.83 (m, 4H), 1.08-1.50 (m, 20H), 0.8 0-1.00 (m, 6H).
    [973]
    [974] 5-decyl-2- (4-phenylpropoxycarbonylamino) thiophene-3-carboxylic acid (21.37)
    [975] Light brownish solid in 100% yield.
    [976] 1 H NMR (CDCl 3, 200 MHz): δ 10.4 (brs, 1H), 9.88 (s, 1H), 7.26-7.31 (m, 1H), 7.18-7.21 (m, 3H), 6.87 (s , 1H), 4.27 (t, 2H, J = 6.4 Hz), 2.74 (t, 2H, J = 8.0 Hz), 2.68 (t, 2H, J = 7 Hz), 2.02-2.07 (m, 2H), 1.59-1.66 (m, 2H), 1.18-1.40 (m, 14H), 0.98 (m, 3H, J = 6.0 Hz).
    [977]
    [978] 5-decyl-2- (4-phenylbutoxycarbonylamino) thiophene-3-carboxylic acid (21.38)
    [979] Light brownish solid in 100% yield.
    [980] 1 H NMR (CDCl 3, 200 MHz): δ 12.0 (brs, 1H), 9.90 (s, 1H), 7.26-7.31 (m, 2H), 7.17-7.21 (m, 3H), 6.87 (s , 1H), 4.26 (t, 2H, J = 6.4 Hz), 2.67-2.70 (m, 4H), 1.70-1.80 (m, 4H), 1.50-1.70 (m, 2H), 1.18-1.40 (m, 16H ), 0.88 (t, 3H, J = 6.8 Hz).
    [981] Example 22 : Tien Oxazinone
    [982]
    [983] 6-heptyl-5-methyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (74) (may contain ˜10% other isomers); Mp 29-31 ° C .: 1 H NMR (CDCl 3 ) δ 0.82-0.96 (m, 6H), 1.20-1.50 (m, 18H), 1.50-1.68 (m, 2H), 1.68-1.86 (m, 2H), 2.36 (s, 3H), 2.70 (t, 2H, J = 6.8 Hz), 4.38 (t, 2H, J = 6.6 Hz) Other peaks that may be from other isomers at 2083 (t, J = 6.7 Hz); MS (EI): cal'd 393.59, exp, not ionized.
    [984]
    [985] 6-Methyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (22.1): 1 H NMR (CDCl 3 ) δ 0.88 (t, 3H, J = 7.2 Hz), 1.20-1.45 (m, 10H), 1.55 (s, 9H), 1.70-1.84 (m, 2H), 2.46 (s, 3H), 4.39 (t, 2H, J = 6.6 Hz), 6.93 (s , 1H); MS (EI): cal'd 295.5, exp.
    [986]
    [987] 6-heptyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one (61): greyish white solid (38 mg, 801% yield) 1 H NMR ( CDCl 3 200 MHz) δ 0.87 (t, 6H, J = 6.4 Hz), 1.27-1.30 (m, 18H), 1.58-1.67 (m, 4H), 2.71 (t, 2H, J = 7.3 Hz), 3.38 ( dt, 2H, J = 7.0, 6.2 Hz), 5.45 (bs, 1H), 6.84 (s, 1H)
    [988]
    [989] 6-butyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one (63): grayish white solid (162 mg, yield 55%): mp93.0 -94.0 ° C. 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.4 Hz), 0.93 (t, 3H, J = 7.3 Hz), 1.27-1.48 (m, 12H), 1.56-1.71 (m, 4H), 2.72 (t, 2H, J = 7.5 Hz), 3.39 (dt, 2H, J = 7.0, 6.2 Hz), 5.73 (bs, 1H), 6.85 (t, 1H, J = 1.1 Hz). MS (ES &lt; + &gt;) 337.23 (M + 1).
    [990]
    [991] 6-benzyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one (62): greyish white solid (182 mg, two-step yield 55%): mp 123.0-124.0 ° C. 1 H NMR (CDCl 3, 200 MHz) δ 0.87 (t, 3H, J = 6.4 Hz), 1.26-1.28 (m, 10H), 1.51 (tt, 2H, J = 13.6, 6.5 Hz), 3.36 (dt, 2H, J = 7.0, 6.6 Hz, 4.02 (s, 2H), 5.81 (bs, 1H), 6.85 (s, 1H), 7.20-7.35 (m, 5H). MS (ES &lt; + &gt;) 371.18 (M + 1).
    [992]
    [993] 6-heptyl-2-undecyl-thieno [2,3-d] [1,3] oxazin-4-one (67): yellow oil (97 mg, yield 55%): 1 H NMR (CDCl 3 , 200 MHz) δ 0.85-0.91 (m, 6H), 1.26-1.32 (m, 24H), 1.66-1.83 (m, 4H), 2.69 (t, 2H, J = 7.7 Hz), 2.82 (t, 2H, J = 7.5 Hz), 7.06 (s, 1 H). 13 C NMR (CDCl 3, 50 MHz) δ 14.0, 14.1, 22.5, 22.6, 26.2, 28.8, 28.9, 29.0, 29.2, 29.3, 29.4, 29.5, 30.4, 31.0, 31.7, 31.9, 34.7, 117.8, 118.6, 144.3 , 155.6, 162.2, 165.2.
    [994]
    [995] 6-heptyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (68): yellow oil (36 mg, yield 50%): 1 H NMR (CDCl 3 , 200 MHz) δ 0.85-0.93 (m, 6H), 1.29-1.48 (m, 18H), 1.61-1.87 (m, 4H), 2.77 (t, 2H, J = 7.5 Hz), 4.41 (t, 2H, J = 6.6 Hz), 6.97 (t, 1H, J = 1.1 Hz).
    [996]
    [997] 6-octyloxy-6- (1,3,3-trimethyl-butyl) -thieno [2,3-d] [1,3] oxazin-4-one (78):Colorless Oil (92 mg, 51% yield):OneH NMR (CDCl3,200 MHz) δ 0.88-0.89 (m, 12H), 1.30-1.83 (m, 17H), 3.04-3.13 (m, 1H), 4.41 (t, 2H, J = 6.6 Hz), 6.98 (s, 1H).13C NMR (CDCl3,50 MHz) δ 14.0, 22.6, 25.6, 26.2, 28.3, 29.8, 31.3, 31.7, 32.8, 52.6, 70.5, 113.2, 116.5, 149.4, 154.5, 156.9, 165.3.
    [998]
    [999] 6- (5-methoxy-1, 5-dimethyl-hexyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (83): pale yellow oil (3 Mg): 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.11 (s, 6H), 1.26-1.67 (m, 19H), 1.77 (dt, 2H, J = 7.0, 6.6 Hz), 2.96 (dq, 1H, J = 7.2, 7.0 Hz), 3.15 (s, 3H), 4.40 (t, 2H, J = 6.6 Hz), 6.98 (s, 1H). MS (ES &lt; + &gt;) 424.03 (M + 1).
    [1000]
    [1001] 6- (1,5-dimethyl-hex-4-enyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-oneAnd6- (1,5-dimethyl-hex-5-enyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one(2: 1 mixture of isomers)(81):Colorless Oil (16 mg): MS (ES &lt; + &gt;) 391.95, 391.97 (M + l).
    [1002]
    [1003] Tripulouro-acetic acid 1,1-dimethyl-5- (2-octyloxy-4-oxo-4H-thieno [2,3-d] [1,3] oxazin-6-yl) -hexyl ester (82): Colorless oil (61 mg): 1 H NMR (CDCl 3, 200 MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.26-1.69 (m, 8H), 1.76-1.88 (m, 4H ), 2.97 (dq, 1H, J = 7.0, 6.8 Hz), 4.41 (t, 2H, J = 6.6 Hz), 6.98 (s, 1H). 13 C NMR (CDCl 3, 100 MHz) δ 14.2, 21.5, 22.7, 22.8, 25.7, 25.8, 28.5, 29.3, 31.9, 35.8, 38,7 40.3, 70.8, 89.1, 113.6, 114.6 (q, CF3, J = 285.9 Hz), 117.3, 117.4, 146.8, 154.7, 156.4 (q, COCF 3 , J = 40.9 Hz), 157.3, 165.8. MS (ES &lt; + &gt;) 505.93 (M + 1).
    [1004]
    [1005] 2- (2-benzyloxy-ethoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one (97): yellow oil (68 mg, yield 50%) : 1 H NMR (CDCl 3, 400 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.26-1.32 (m, 14H), 1.66 (tt, 2H, J = 14, 7.6 Hz), 2.76 (t , 2H, J = 7.6Hz), 3.81 (t, 2H, J = 4.4Hz), 4.57 (t, 2H, J = 4.6Hz), 4.60 (s, 2H), 6.95 (s, 1H), 7.25-7.34 (m, 5H) 13 C NMR (CDCl 3, 100 MHz) δ 14.0, 22.6, 28.8, 29.2, 29.3, 29.4, 29.5, 30.2, 30.9, 31.8, 67.1, 69.3, 73.3, 113.7, 118.2, 127.6, 127.7, 128.4, 137.6, 141.3, 154.2, 156.7, 165.2.
    [1006]
    [1007] 2-octyloxy-6-phenylethyl-thieno [2,3-d] [1,3] oxazin-4-one (103):Transparency Oil (84 mg, yield 88%):OneH NMR (CDCl3,200 MHz) δ 0.89 (t, 3H, J = 6.8 Hz), 1.28 -1.43 (m, 10H), 1.79 (tt, 2H, J = 7.6 Hz, 7.2 Hz), 2.98 (t, 2H, J = 7.2 Hz ), 3.10 (t, 2H, J = 7.6 Hz), 4.39 (t, 2H, J = 6.8 Hz), 6.95 (s, 1H). 7.17-7. 31 (m, 5 H).
    [1008]
    [1009] 2-octyloxy-6- (3-phenyl-propyl) -thieno [2,3-d] [1,3] oxazin-4-one (104): white solid (72 mg, yield 75%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.21-1.50 (m, 10H), 1.79 (tt, 2H, J = 7.0 Hz, J = 6.6 Hz), 2.01 (tt, 2H, J = 7.8Hz, J = 7.2Hz), 2.69 (t, 2H, J = 7.6Hz), 2.80J = (t, 2H, 7.2Hz), 4.40 (t, 2H, J = 6.6Hz ), 6.98 (s, 1H), 7.16-7.35 (m, 5H)
    [1010]
    [1011] 2-octyloxy-6- (4-phenyl-butyl) -thieno [2,3-d] [1,3] oxazin-4-one (92): pale yellow oil (218 mg, yield 78%): 1 H NMR (CDCl 3, 200 MHz): δ 0.887 (bt, 3H, J = 6.2 Hz), 1.08-1.52 (m, 10H), 1.60-190 (m, 6H), 2.54-2.72 (m, 2H ), 2.72-2.88 (m, 2H), 4.40 (t, 2H, J = 6.6 Hz), 6.95 (s, 1H), 7.09-7.38 (m, 5H); MS (ES) 414.59 (M + l), t R (method D) = 9.71 min.
    [1012]
    [1013] 2-octyloxy-6- (5-phenyl-pentyl) -thieno [2,3-d] [1,3] oxazin-4-one (93): pale yellow oil (223 mg, yield 94%): 1 H NMR (CDCl 3, 200 MHz): δ 0.887 (bt, 3H, J = 6.2 Hz), 1.20-1.50 (m, 12H), 1.57-1.88 (m, 6H), 2.61 (t, 2H, J = 7.4 Hz), 2.76 (t, 2H, J = 6.8 Hz), 4.40 (t, 2H, J = 6.6 Hz), 6.95 (t, 1H, J = 1 Hz), 7.08-7.35 (m, 5H); MS (ES) 428.62 (M + l), t R (method D) = 10.69 min.
    [1014]
    [1015] 2-decyl-2- (2-methoxy-ethoxy) -thieno [2,3-d] [1,3] oxazin-4-one (96): a grayish pale white solid (195 mg, Yield 83%) mp = 38-41 ° C .; 1 H NMR (CDCl 3, 200 MHz): δ 0.879 (bt, 3H, J = 6.2 Hz), 1.06-1.43 (m, 14H), 1.52-1.78 (m, 2H), 2.76 (t, 3H, J = 7.0 Hz), 3.43 (s, 3H), 3.62-3.82 (m, 2H), 4.44-4.64 (m, 1H), 6.96 (s, H); MS (ES) 368.52 (M + 1), t R (Method D) = 8.00 min.
    [1016]
    [1017] 2- (4-Butyl-phenoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one (102): light yellow solid (145 mg, yield 79%) mp = 55-58 ° C .: 1 H NMR (CDCl 3, 400 MHz): δ0.878 (t, 3H, J = 6.0 Hz), 0.946 (t, 3H, J = 7.6 Hz), 1.18-1.45 (m , 18H), 1.55-1.71 (m, 4H), 2.64 (t, 2H, J = 7.6 Hz), 2.76 (t, 2H, J = 7.6 Hz), 6.99 (s, 1H), 7.15 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J = 8.4 Hz); MS (ES) 442.64 (M + 1), t R (method D) = 12.19 min.
    [1018]
    [1019] 2- (3-benzyloxy-proxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one (109): colorless oil (115 mg, yield 87%): 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.6 Hz), 1.26-1.38 (m, 14H), 1.67 (tt, 2H, J = 14.4, 7.4 Hz), 2.09 (tt, 2H, J = 12.4, 6.2 Hz, 2.76 (t, 2H, J = 7.4 Hz), 3.62 (t, 2H, J = 6.2 Hz), 4.51 (s, 2H), 4.53 (t, 2H, J = 6.4 Hz), 6.96 (t, 1H, J = 1.1 Hz), 7.24-7.33 (m, 5H) 13 C NMR (CDCl 3, 100 MHz) δ 14.04, 22.61, 28.78, 28.83, 29.22, 29.23, 29.44, 29.50, 30.25, 31.82, 65.93, 67.46, 73.06, 113.59, 118.14, 127.60, 128.31, 138.09, 141.18, 154.30, 156.73, 165.54.
    [1020]
    [1021] 2- (3-benzyloxy-butyloxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one (111): colorless oil (19 mg, yield 36%) : 1 H NMR (CDCl 3, 200 MHz) δ 0.88 (t, 3H, J = 6.4 Hz), 1.26-1.38 (m, 14H), 1.63-1.99 (m, 14H), 2.76 (t, 2H, J = 7.7 Hz), 3.54 (t, 2H, J = 6.2 Hz), 4.44 (t, 2H, J = 6.2 Hz), 4.51 (s, 2H), 6.96 (t, 1H, J = 1.0 Hz), 7.28-7.35 (m, 5 H).
    [1022]
    [1023] 6-butyl-2-octyloxy) -thieno [2,3-d] [1,3] oxazin-4-one (75):m / z 338.49 [MH &lt; + &gt;] OneH NMR (CDCl3,200 MHz): δ 0.78-1.03 (m, 6H), 1.15-1.53 (m, 12H), 1.54-1.90 (m, 4H), 2.77 (t, 2H, J = 7.5 Hz), 4.40 (t, J = 6.6 Hz, 2H), 6.96 (t, J = 0.8 Hz, 1H).
    [1024]
    [1025] 6-isopropyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (76) MS (ES / SIR): m / z 324.46 [MH +] 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.18-1.52 (m, 16H), 1.70-1.88 (m, 2H), 2.98-3.22 (m, 1H), 4.40 (t, J = 6.6 Hz, 2H), 6.98 (d, J = 1.0 Hz, 1H).
    [1026]
    [1027] 6-octyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (85): 1 H NMR (CDCl 3, 200 MHz): δ = 0.80-1.00 ( m, 6H), 1.12-1.52 (m, 20H), 1.57-1.90 (m, 4H), 2.76 (td, J = 1.0, 7. 6 Hz, 2H), 4.40 (t, J = 6.6 Hz, 2H), 6.95 (t, J = 1.1 Hz, 1H).
    [1028]
    [1029] 6-dodecyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one (88): 1 H NMR (CDCl 3, 200 MHz) δ 0.80-0.98 (m , 6H), 1.16-1.52 (m, 28H), 1.58-1.88 (m, 4H), 2.76 (td, J = 7.2 Hz, 2H), 4.40 (t, J = 6.6 Hz, 2H), 6.95 (s, 1H).
    [1030]
    [1031] 6-benzyloxy-6-decyl-thieno [2,3-d] [1,3] oxazin-4-one (105): m / z 400.56 [MH +] 1 H NMR (CDCl 3, 400 MHz) : δ = 0.88 (t, J = 6.8 Hz, 3H), 1.17-1.42 (m, 14H), 1.67 (quint., J = 7.4 Hz, 2H), 2.77 (t, J = 7.1 Hz, 2H), 5.44 (s, 2H), 6.96 (s, 1H), 7.33-7.49 (m, 5H)
    [1032]
    [1033] 2- (4-butylbenzyloxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one (106): 1 H NMR (CDCl 3, 200 MHz) δ 0.78 -1.02 (m, 6H), 1.12-1.47 (m, 16H), 1.50-1.77 (m, 4H), 2.62 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 5.40 (s, 2H), 6.96 (s, 1H), 7.20 (d, J = 8.0 kPa, 2H), 7.36 (d, J = 8.2 kPa, 2H).
    [1034]
    [1035] 6-decyl-2- (2-p-tolyl-ethoxy) -thieno [2,3-d] [1,3] oxazin-4-one (107): 1 H NMR (CDCl 3, 200 MHz ): δ = 0.88 (t, J = 6.6 Hz, 3H), 1.14-1.46 (m, 14H), 1.56-1.78 (m, 2H), 2.32 (s, 3H), 2.6 (t, J = 7.4 Hz, 2H), 3.06 (t, J = 7.0 Hz, 2H), 4.58 (t, J = 7.0 Hz, 2H), 6.95 (t, J = 1.1 Hz, 1H), 7.07-722 (m, 4H)
    [1036]
    [1037] 6-decyl-2-phenethyloxy-thieno [2,3-d] [1,3] oxazin-4-one (108): 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t , J = 6.4 Hz, 3H), 1.14-1.46 (m, 14H), 1.56-1.76 (m, 2H), 2.76 (t, J = 7.2 Hz, 2H), 3.11 (t, J = 7.0 Hz, 2H) 4.60 (t, J = 7.0 Hz, 2H), 6.95 (s, 1H), 7.1 8-7.42 (m, 5H).
    [1038]
    [1039] 3-Methyl-6-octyl-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one (87): 51 mg (60%). Mp 36 ° C. 1 H NMR (CDCl 3, 200 MHz): δ = 0.88 (t, J = 6.6 Hz, 6HO, 1.10-1.94 (m, 24H), 2.35 (s, 3H), 2.69 (t, J = 7.2 Hz, 2H ), 4.38 (t, J = 7.0 Hz, 2H); 13 C NMR (CDCl 3, 75 MHz): δ 11.1, 12.3, 20.9, 23.9, 25.7, 26.6, 27.3, 27.4, 27.5, 27.6, 29.4, 30.0, 30.1, 68.6, 11.5, 126.9, 132.0, 153.1, 155.1, 162.9.
    [1040]
    [1041] 2-butoxy-6-octyl-5H-thieno [2,3-b] pyridin-4-one (95): 265 mg (93%). 1 H NMR (CDCl 3, 200 MHz): δ = 0.86 (t, J = 6.6 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H), 1.14-1.88 (m, 16H), 2.74 (t, J = 7.4 Hz, 2H), 4.39 (t, J = 6.6 Hz, 2H), 6.93 (s, 1H); 13 C NMR (CDCl 3, 75 MHz): δ 11.9, 12.3. 17.2, 20.9, 27.2, 27.4, 27.5, 28.6, 29.2, 30.1, 68.5, 101.9, 116.5, 139.4, 152.7, 155.2, 164.0; MS (SIR): 338.48 (M + 1).
    [1042]
    [1043] 2-hexyloxy-6-octyl-5H-thieno [2,3-b] pyridin-4-one (94): 312 mg (94%). 1 H NMR (CDCl 3, 200 MHz): δ 0.86 (t, J = 6.6 Hz, 3H), 0.89 (t, J = 6.6 Hz, 3H), 1.15-1.54 (m, 16H), 1.54-1.88 (m , 4H), 2.74 (t, J = 7.0 Hz, 2H), 4.38 (t, J = 6.6 Hz, 2H), 6.94 (t, J = 1.2 Hz, 1H); 13 C NMR (CDCl 3, 75 MHz) δ 12.2. 12.3, 20.8, 20.9, 23.6, 26.6, 27.2, 27.4, 27.5, 28.6, 29.2, 29.6, 30.1, 68.8, 101.9, 116.5, 139.4, 152.7, 155.2, 164.0; MS (SIR): 366.55 (M + 1).
    [1044]
    [1045] 2-dodecyloxy-6-octyl-5H-thieno [2,3-b] pyridin-4-one (100): 322 mg (91%). 1 H NMR (CDCl 3, 200 MHz): δ 0.87 (t, J = 6.2 Hz, 6H), 1.04-1.52 (m, 28H), 1.52-1.90 (m, 4H), 2.75 (t, J = 7.0 Hz , 2H), 4.38 (t, J = 6.5 Hz, 2H), 6.94 (S, 1H); 13 C NMR (CDCl 3, 75 MHz): δ 12.3, 12.4, 20.9, 21.0, 23.9, 26.6, 27.2, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.6, 30.1, 30.2, 68.8, 11.9, 116.5, 139.4, 152.7, 155.2, 164.0; MS (SIR): 450.71 (M + l).
    [1046]
    [1047] 6-decyl-2-phenoxy-5H-thieno [2,3-b] pyridin-4-one (101): 322 mg (86%). 1 H NMR (CDCl 3, 200 MHz): δ 0.87 (t, J = 6.6 Hz, 3H), 1.15-1.45 (m, 14H), 1.55-1.75 (m, 2H), 2.75 (t, J = 7.0 Hz , 2H), 7.0 (t, J = 1 Hz, 1H), 7.22-7.51 (m, 5H); 13 C NMR (CDCl 3, 75 MHz) δ 12.4, 21.0, 27.2, 27.5, 27.6, 27.8, 28.6, 29.2,30.2, 97.7, 97.7, 102.5, 116.5, 119.4, 124.9, 128.0, 140.7, 149.5, 152.3, 154.5 , 163.1; MS (SIR): 358.48 (M + l).
    [1048]
    [1049] 2-decyloxy-6-octyl-5H-thieno [2,3-b] pyridin-4-one (110): 313 mg (69%). 1 H NMR (CDCl 3, 200 MHz): δ 0.85 (t, J = 6.4 Hz, 6H), 1.16-1.50 (m, 24H), 1.50-1.88 (m, 4H), 2.74 (t, J = 6.8 Hz , 2H), 4.38 (t, J = 6.6 Hz, 2H), 6.93 (s, 1H); 13 C NMR (CDCl 3, 75 MHz): δ 12.3, 20.9, 20.9, 23.9, 26.6, 27.2, 27.5, 27.6, 27.7, 27.8, 28.6,29.2,30.1,30.1, 68.8, 111.9, 116.5, 139.3, 152.6, 155.2, 164.0.
    [1050]
    [1051] 6-benzyl-2-octyloxythieno [2,3- d ] [1,3] oxazine-4-one (77)
    [1052] Light yellow oil with 53% yield
    [1053] 1 H NMR (CDCl 3, 200 MHz): δ 7.20-7.40 (m, 5H), 6.98 (t, 1H, J = 1.0 Hz), 4.38 (t, 2H, J = 6 Hz), 4.09 (s, 2H), 1.76 (q, 2H, J = 7.2 Hz), 1.10-1.50 (m, 10H), 0.88 (t, 3H, J = 7.0 Hz). MS (ES) [M + +1] 372.51.
    [1054]
    [1055] 6-hexyl-2-octyloxythieno [2,3- d ] [1,3] oxazine-4-one (84)
    [1056] Light yellow oil with 30% yield
    [1057] 1 H NMR (CDCl 3, 200 MHz): δ 6.94 (s, 1H), 4.39 (t, 2H, J = 6.6 Hz), 2.76 (t, 2H, J = 7.2 Hz),
    [1058] 1.76 (q, 2H, J = 7.4 Hz), 1.64 (q, 2H, J = 7.6 Hz), 1.08-1.50 (m, 14H), 0.80-0.95 (m, 6H). MS (ES) [M + +1] 366.55.
    [1059]
    [1060] 6-decyl-2-octyloxythieno [2,3- d ] [1,3] oxazine-4-one (86)
    [1061] Light yellow oil in 50% yield
    [1062] 1 H NMR (CDCl 3, 200 MHz): δ 6.94 (s, 1H), 4.39 (t, 2H, J = 6.6 Hz), 2.76 (t, 2H, J = 7.2 Hz),
    [1063] 1.76 (q, 2H, J = 7.4 Hz), 1.64 (q, 2H, J = 7.6 Hz), 1.08-1.50 (m, 20H), 0.80-0.95 (m, 6H). MS (ES) [M + +1] 422.56.
    [1064]
    [1065] 6-decyl-2- (1-methylheptyloxy) thieno [2,3- d ] [1,3] oxazine-4-one (90)
    [1066] Light yellow oil with 22% yield
    [1067] 1 H NMR (CDCl 3, 200 MHz): δ 6.96 (s, 1H), 5.13 (tq, 1H, J = 5.8, 6.2 Hz), 2.76 (t, 2H, J = 7.6 Hz), 1.58-1.83 (m , 4H), 1.08-1.50 (m, 26H), 0.80-1.00 (m, 6H). MS (ES) [M ++ 1] 380.57.
    [1068]
    [1069] 6-heptyl-2- (1-methylheptyloxy) thieno [2,3- d ] [1,3] oxazine-4-one (91)
    [1070] Light yellow oil with 28% yield
    [1071] 1 H NMR (CDCl 3, 200 MHz): δ 6.96 (s, 1H), 5.13 (tq, 1H, J = 6.2.6.6 Hz), 2.76 (t, 2H, J = 7. 6 Hz), 1.58-1.83 ( m, 4H), 1.08-1.50 (m, 20H), 0.80-1.00 (m, 6H). MS (ES) [M + +1] 422.65.
    [1072]
    [1073] 6-decyl-2- (4-phenylpropoxy) thieno [2,3- d ] [1,3] oxazine-4-one (99)
    [1074] Light yellow oil with 28% yield
    [1075] 1 H NMR (CDCl 3, 200 MHz): δ7.17-7.38 (m, 5H), 6.96 (s, 1H), 4.42 (t, 2H, J = 6.6 Hz), 2.72-2.85 (m, 4H), 2.05-2.20 (m, 2H), 1.50-1.75 (m, 2H), 1.20-1.40 (m, 16H). 0.88 (t, 3H, J = 6.6 Hz). MS (ES) [M + +1] 428.62.
    [1076]
    [1077] 6-decyl-2- (4-phenylbutoxy) thieno [2,3- d ] [1,3] oxazine-4-one (98)
    [1078] Light yellow oil in 25% yield
    [1079] 1 H NMR (CDCl 3, 200 MHz): δ 7.10-7.38 (m, 5H), 6.96 (s, 1H), 4.42 (t, 2H, J = 6.4 Hz), 2.60-2.80 (m, 4H), 1.75-1.83 (m, 4H), 1.50-1.70 (m, 2H), 1.18-1.40 (m, 16H). 0.88 (t, 3H, J = 6.4 Hz).
    [1080] Example 23 : Pancreatic Lipase Analysis
    [1081] The use of pancreatic lipase assays is known from Hadvary, P. et. Al. Biochem. J. (1988) 256: 357-361; Hadvary, P. et al. Biochem. J. (1991) 266: 2021-2027 Reference). The activity of pancrea lipase was measured by 718 type Stat Titrino (Brinkmann) programmed to maintain pH 8.0 using 0.1N NaOH. Substrate mixture (pH 8) contains 1 mM taurokenodeoxycholate (Sigma), 9 mM taurodeoxycholate (Sigma), 0.1 mM cholesterol (Sigma), 1 mM phosphatidylcholine (Sigma), 1.5% BSA, 2 mM Tris base, 100 mM NaCl , 10 mM CaCl 2 and 3% triolein (Sigma). The mixture (5 mL) was emulsified by sonication at room temperature and added to the titrator with rapid stirring. Stat Tytrino was switched on and lipase (7.0 nM VI-S Porcine Pancrea Lipase (Sigma) dissolved in PBS) was added to the titrator. After 10 minutes, an inhibitor (700 nM inhibitor dissolved in 100% DMSO) was added to the titrator and the reaction continued for 12.5 minutes. The k value was determined using the one-step exponential equation Y = Ymax * (1-exp (-k * X)) 12.5 minutes after the addition of the inhibitor. As a result, the k value for the lipase alone was 0.0004 ± 0.0001 seconds. The k value of the compounds described in the specification is> 0.0004 ± 0.0001 seconds.
    [1082] evaluation
    [1083] Those skilled in the art can understand that the present invention is not limited to the above-described embodiments without any prescriptive experiments and includes a number of equivalents, which are embodied within the claims of the present invention.
    权利要求:
    Claims (30)
    [1" claim-type="Currently amended] Compounds having the following structural formula or specific enantiomers, specific tautomers or pharmaceutically acceptable salt compounds thereof:

    Wherein X is O, S, CH 2 or NR 5 ;
    Y is O or S;
    R 1 is H, substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 8 alkylaryl, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6 ' OC (O) R 4 , -CR 6 R 6' OC (O) NHR 7 , -C (O) NR 10 R 11 , -C (O) NR 8 R 9 NR 8 R 9 , —N (R 5 ) C (O) NHR 5 or CH 2 R 4 ;
    R 2 is substituted or unsubstituted straight C 1 -C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl; And
    R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or C 3 -C 10 cycloalkyl,
    Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl, -CH 2 -aryl, aryl-C 1 -C 30 alkyl, heteroaryl-C 1 -C 30 alkyl Or C 3 -C 10 cycloalkyl;
    R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, aryl C 1 -C 30 alkyl, heteroarylalkyl or cycloalkyl;
    R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or C 3 -C 10 cycloalkyl or together form a 3-7 membered ring system;
    R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or C 3 -C 10 cycloalkyl; And
    R 8 and R 9 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylaryl or piperazine substituted with NR 8 R 9 To form a piperidine ring or dihydro-1H-isoquinoline ring system.
    [2" claim-type="Currently amended] The method of claim 1,
    Compounds having the following structural formula:

    Wherein X is O, S or NR 5 ;
    Y is O or S;
    R 1 is H, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6' OC (O) R 4 , -CR 6 R 6 'OC (O) NHR 7, or CH 2 R 4;
    R 2 is substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or cycloalkyl,
    Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
    R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or cycloalkyl.
    [3" claim-type="Currently amended] The method of claim 2,
    Compounds having the following structural formula:

    Wherein X is O, S or NR 5 ;
    R 1 is H, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6' OC (O) R 4 , -CR 6 R 6 'OC (O) NHR 7, or CH 2 R 4;
    R 2 is substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or cycloalkyl,
    Wherein R 4 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 5 is H or substituted or unsubstituted straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
    R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or cycloalkyl.
    [4" claim-type="Currently amended] The method of claim 3, wherein
    X is O or NR 5 ;
    R 1 is —C (O) O— (C 6 -C 30 ) alkyl, -C (O) NH— (C 6 -C 30 ) alkyl or —C (O) OCH 2 (C 6 H 5 );
    R 2 is C 6 -C 30 alkyl; And
    R 3 is C 1 -C 6 alkyl.
    [5" claim-type="Currently amended] The method of claim 3, wherein
    R 3 is H or CH 3 compound.
    [6" claim-type="Currently amended] The method of claim 5, wherein
    X is O;
    [7" claim-type="Currently amended] The method of claim 6,
    R 3 is methyl.
    [8" claim-type="Currently amended] The method of claim 5, wherein
    X is N;
    [9" claim-type="Currently amended] The method of claim 8,
    R 3 is methyl.
    [10" claim-type="Currently amended] The method of claim 1,
    Compounds having the following structural formula:

    here,
    Y is O or S;
    R 1 is H,-(CH 2 ) r CH 3 , -CH (CH 3 ) 2 , -CH (CH 3 ) CH 2 C (CH 3 ) 3 , -CH (CH 3 ) (CH 2 ) 3 C ( = CH 2 ) CH 3 , -CH (CH 3 ) (CH 2 ) 3 C (CH 3 ) 2 OC (O) CH 3 , -CH (CH 3 ) [CH 2 ] 3 C (CH 3 ) 2 OCH 3 , -CH S (C 6 H 5 ), -C (O) OH, -C (O) NH (CH 2 ) t CH 3 , -C (O) O (CH 2 ) u CH 3 , -C (O ) OCH [(CH 2 ) 3 CH 3 ] 2 , -C (O) NH (CH 2 ) v CH 3 , -C (O) N (CH 3 ) 2 , -C (0) NHCH 2 (C 6 H 5 ), -C (O) NHCH 2 (C 5 H 4 N), -C (O) N [(CH 2 ) 3 CH 3 ] 2 , -C (O) N [(CH 2 ) 5 CH 3 ] 2 , -C (O) N [(CH 2 ) 7 CH 3 ] 2 , -C (O) NH (C 6 H 11 ), -C (O) (NC 4 H 8 N) CH 2 (C 6 H 5 ), -C (O) (NC 5 H 9 ) CH 2 (C 6 H 5 ), -C (O) NH (CH 2 ) 3 O (C 6 H 5 ), -C (O) NHCH [( CH 2 ) 3 CH 3 ] 2 , -C (O) NH (CH 2 ) 3 N (CH 3 ) 2 , -C (O) NHCH 2 C (O) CH 2 (C 6 H 5 ), -C ( O) N (CH 3 ) CH 2 (C 5 H 3 N [CH 3 ]), -C (O) NH (CH 2 ) 2 (C 5 H 4 N), -C (O) N (CH 2 CH 3 ) (CH 2 ) 2 (C 5 H 4 N), -C (O) NHCH 2 (C 4 H 3 O), -C (O) (NC 4 H 8 N) [CH 2 ] 2 (NC 5 H 10 ), -C (O) NHCH 2 CH (CH 3 ) 2 , -C (O) NHCH 2 (C 5 H 4 N), -C (O) NHCH 2 C (CH 3 ) 3 , -C ( O) (NC 4 H 8 N) CH 2 C (O) NHCH (CH 3 ) 2 , -C (O) (NC 9 H 8 ) [OCH 3 ] 2 , -C (O) NHCH 2 (C 6 H 3 [OCH 3 ] 2 ), -C (O) NHCH 2 (C 7 H 5 O 2 ), -C (O) NH (CH 2 ) 2 O (C 6 H 5 ), -C (O) NH (CH 2 ) 2 OCH 3 , -C (O) NH (CH 2 ) 3 OCH 3 , -C (O) NH (CH 2 ) 4 (C 6 H 5 ) Or -C (O) NH (CH 2 ) 3 (C 6 H 5 );
    r is an integer from 1 to 15;
    s is an integer of 0 to 6;
    t is an integer from 0 to 6;
    u is an integer from 3 to 8;
    v is an integer from 5 to 15;
    XR 2 is-(CH 2 ) n CH 3 , -O (CH 2 ) m CH 3 , -OCH (CH 3 ) 2 , -OCH (CH 3 ) (CH 2 ) 5 CH 3 , -OCH 2 CH (CH 3 ) 2 , -O (CH 2 ) 2 OCH 3 , -O (CH 2 ) 2 OCH 2 (C 6 H 5 ), -O (CH 2 ) p (C 6 H 5 ), -OCH 2 ([C 6 H 4 (CH 2 ) 3 CH 3 ]), -O (C 6 H 4 [(CH 2 ) 3 CH 3 ]), -O (CH 2 ) 2 (C 6 H 4 [CH 3 ]),- O (CH 2 ) 3 OCH 2 (C 6 H 5 ), -O (CH 2 ) 4 OCH 2 (C 6 H 5 ), -N ([CH 2 ] 7 CH 3 ) C (O) NH (CH 2 ) 7 CH 3 , -N ([CH 2 ] 6 CH 3 ) C (O) NH (CH 2 ) 6 CH 3 , -NH (CH 2 ) q CH 3 , -NH (C 6 H 4 ) O (C 6 H 5 ), -N (CH 3 ) (CH 2 ) 5 CH 3 , -NHCH [(CH 2 ) 3 CH 3 ] 2 , -NHCH (CH 3 ) [CH 2 ] 5 CH 3 , or -N ( [CH 2 ] 7 CH 3 ) 2 ;
    n is an integer from 6 to 15;
    m is an integer from 1 to 15;
    p is an integer from 0 to 6;
    q is an integer from 6 to 15; And
    R 3 is H, —CH 3 or —CH 2 OCH 3 .
    [11" claim-type="Currently amended] The method of claim 10,
    Compounds having the following structural formula:

    here,
    Y is O or S;
    R 1 is H,-(CH 2 ) 3 CH 3 ,-(CH 2 ) 5 CH 3 ,-(CH 2 ) 6 CH 3 ,-(CH 2 ) 7 CH 3 ,-(CH 2 ) 9 CH 3 , -(CH 2 ) 11 CH 3 , -CH (CH 3 ) 2 , -CH (CH 3 ) CH 2 C (CH 3 ) 3 , -CH (CH 3 ) (CH 2 ) 3 C (= CH 2 ) CH 3 , -CH (CH 3 ) (CH 2 ) 3 C (CH 3 ) 2 OC (O) CH 3 , -CH (CH 3 ) [CH 2 ] 3 C (CH 3 ) 2 OCH 3 , -CH 2 ( C 6 H 5 ),-(CH 2 ) 2 (C 6 H 5 ),-(CH 2 ) 3 (C 6 H 5 ),-(CH 2 ) 4 (C 6 H 5 ),-(CH 2 ) 5 (C 6 H 5 ), -C (O) OH, -C (O) NHCH 3 , -C (O) NHCH 2 CH 3 , -C (O) NH (CH 2 ) 3 CH 3 , -C ( O) OCH 2 (C 6 H 5 ), -C (O) O (CH 2 ) 5 CH 3 , -C (O) O (CH 2 ) 6 CH 3 , -C (O) O (CH 2 ) 7 CH 3 , -C (O) OCH [(CH 2 ) 3 CH 3 ] 2 , -C (O) NH (CH 2 ) 5 CH 3 , -C (O) NH (CH 2 ) 7 CH 3 , -C (O) NH (CH 2 ) 9 CH 3 , -C (O) NH (CH 2 ) 11 CH 3 , -C (O) NH (CH 2 ) 15 CH 3 , -C (O) N (CH 3 ) 2 , -C (O) NHCH 2 (C 6 H 5 ), -C (O) NHCH 2 (C 5 H 4 N), -C (O) N [(CH 2 ) 3 CH 3 ] 2 , -C (O) N [(CH 2 ) 5 CH 3 ] 2 , -C (O) N [(CH 2 ) 7 CH 3 ] 2 , -C (O) NH (C 6 H 11 ), -C (O) (NC 4 H 8 N) CH 2 (C 6 H 5 ), -C (O) (NC 5 H 9 ) CH 2 (C 6 H 5 ), -C (O) NH (CH 2 ) 3 O (C 6 H 5 ), -C (O) NHCH [(CH 2 ) 3 CH 3 ] 2 ,- C (O) NH (CH 2 ) 3 N (CH 3 ) 2 , -C (O) NHCH 2 C (O) OCH 2 (C 6 H 5 ), -C (O) N (CH 3 ) CH 2 [ C 5 H 3 N [CH 3 ]), -C (O) NH (CH 2 ) 2 (C 5 H 4 N), -C (O) N (CH 2 CH 3 ) (CH 2 ) 2 (C 5 H 4 N), -C (O) NHCH 2 (C 4 H 3 O), -C (O) (NC 4 H 8 N) [CH 2 ] 2 (NC 5 H 10 ), -C (O) NHCH 2 CH (CH 3 ) 2 , -C (O) NHCH 2 (C 5 H 4 N), -C (O) NHCH 2 C (CH 3 ) 3 , -C (O) (NC 4 H 8 N) CH 2 C (O) NHCH (CH 3 ) 2 , -C (O) (NC 9 H 8 ) [OCH 3 ] 2 , -C (O) NHCH 2 (C 6 H 3 [OCH 3 ] 2 ), -C (O) NHCH 2 (C 7 H 5 O 2 ), -C (O) NH (CH 2 ) 2 O (C 6 H 5 ), -C (O) NH (CH 2 ) 2 OCH 3 , C (O ) NH (CH 2 ) 3 OCH 3 , —C (O) NH (CH 2 ) 4 (C 6 H 5 ), or —C (O) NH (CH 2 ) 3 (C 6 H 5 );
    XR 2 is-(CH 2 ) 6 CH 3 ,-(CH 2 ) 10 CH 3 ,-(CH 2 ) 14 CH 3 , -O (CH 2 ) 3 CH 3 , -O (CH 2 ) 5 CH 3 , -O (CH 2 ) 6 CH 3 , -O (CH 2 ) 7 CH 3 , -O (CH 2 ) 9 CH 3 , -O (CH 2 ) 11 CH 3 , -O (CH 2 ) 15 CH 3 , -OCH (CH 3 ) 2 , OCH (CH 3 ) (CH 2 ) 5 CH 3 , -OCH 2 CH (CH 3 ) 2 , -O (CH 2 ) 2 OCH 3 , -O (CH 2 ) 2 OCH 2 (C 6 H 5 ), -O (CH 2 ) 4 (C 6 H 5 ), -O (CH 2 ) 3 (C 6 H 5 ), -O (CH 2 ) 2 (C 6 H 5 ),- O (C 6 H 5 ), -OCH 2 (C 6 H 5 ), -OCH 2 (C 6 H 4 [(CH 2 ) 3 CH 3 ]), -O (C 6 H 4 [(CH 2 ) 3 CH 3 ]), -O (CH 2 ) 2 (C 6 H 4 [CH 3 ]), -O (CH 2 ) 3 OCH 2 (C 6 H 5 ), -O (CH 2 ) 4 OCH 2 (C 6 H 5 ), -N ([CH 2 ] 7 CH 3 ) C (O) NH (CH 2 ) 7 CH 3 , -N ([CH 2 ] 6 CH 3 ) C (O) NH (CH 2 ) 6 CH 3 , -NH (CH 2 ) 6 CH 3 , -NH (CH 2 ) 7 CH 3 , -NH (CH 2 ) 11 CH 3 , -NH (CH 2 ) 13 CH 3 , -NH (CH 2 ) 15 CH 3 , -NH (C 6 H 4 ) O (C 6 H 5 ), -N (CH 3 ) (CH 2 ) 5 CH 3 , -NHCH [(CH 2 ) 3 CH 3 ] 2 , -NHCH (CH 3 ) [CH 2 ] 5 CH 3 , or —N ([CH 2 ] 7 CH 3 ) 2 ; And
    R 3 is H, —CH 3 or —CH 2 OCH 3 .
    [12" claim-type="Currently amended] The method of claim 1,
    The compound is:
    6-heptyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    6-hexyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    2-octyloxy-6- (1,3,3-trimethyl-butyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    6-butyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    6-heptyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one;
    6-butyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one;
    6-benzyl-2-octylamino-thieno [2,3-d] [1,3] oxazin-4-one;
    6-heptyl-2-undecyl-thieno [2,3-d] [1,3] oxazin-4-one;
    6- (5-methoxy-1,5-dimethyl-hexyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    6- (1,5-dimethyl-hex-4-enyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    6- (1,5-dimethyl-hex-5-enyl) -2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    Trifluoro-acetic acid 1,1-dimethyl-5- (2-octyloxy-4-oxo-4H-thieno [2,3-d] [1,3] oxazin-6-yl) -hexyl ester;
    2- (2-benzyloxy-ethoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    6-heptyl-5-methyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    6-methyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    2-octyloxy-6-phenethyl-thieno [2,3-d] [1,3] oxazin-4-one;
    2-octyloxy-6- (3-phenyl-propyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    2-octyloxy-6- (4-phenyl-butyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    2-octyloxy-6- (5-phenyl-pentyl) -thieno [2,3-d] [1,3] oxazin-4-one;
    6-decyl-2- (2-methoxy-ethoxy) -thieno [2,3-d] [1,3] oxazin-4-one;
    2- (4-butyl-phenoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    2- (3-benzyloxy-propoxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    2- (3-benzyloxy-butyloxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    6-isopropyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    6-octyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    6-dodecyl-2-octyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    2-benzyloxy-6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    2- (4-butylbenzyloxy) -6-decyl-thieno [2,3-d] [1,3] oxazin-4-one;
    6-decyl-2- (2-p-tolyl-ethoxy) -thieno [2,3-d] [1,3] oxazin-4-one;
    6-decyl-2-phenethyloxy-thieno [2,3-d] [1,3] oxazin-4-one;
    3-methyl-6-octyl-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    2-butoxy-6-octyl-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    2-hexyloxy-6-octyl-5H-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    2-dodecyloxy-6-octyl-2-octyloxy-5H-thieno [2,3-b] pyridin-4-one;
    6-decyl-2-phenoxy-5H-thieno [2,3-b] pyridin-4-one;
    2-decyloxy-6-octyl-5H-thieno [2,3-b] pyridin-4-one;
    6-benzyl-2-oxylthieno [2,3-d] oxazin-4-one;
    6-decyl-2-octyloxythieno [2,3-d] oxazin-4-one;
    6-decyl-2- (1-methylheptyloxy) thieno [2,3-d] [1,3] oxazin-4-one;
    6-heptyl-2- (1-methylheptyloxy) thieno [2,3-d] [1,3] oxazin-4-one;
    6-decyl-2- (4-phenylpropoxy) thieno [2,3-d] [1,3] oxazin-4-one; And
    And 6-decyl-2- (4-phenylbutoxy) thieno [2,3-d] [1,3] oxazin-4-one.
    [13" claim-type="Currently amended] Compounds with the following structural formula:

    Wherein R 10 is H or substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 15 alkylaryl or -C (O) R 14 ,
    Wherein R 14 is hydroxyl or substituted or unsubstituted C 1 -C 30 alkyl, alkylamino, dialkylamino, alkoxy, benzyloxy, cycloalkyl, alkylheteroaryl, alkylaryl, or heterocyclic, heteroaryl or Aryl ring;
    R 11 is hydrogen or methyl;
    R 12 is hydrogen or tert-butyl; And
    R 13 is hydrogen or —C (0) ZR 15 ;
    Wherein Z is CH 2 , O or N and R 15 is substituted or unsubstituted C 1 -C 15 alkyl or aryl.
    [14" claim-type="Currently amended] A method of treating obesity, comprising treating a subject in need thereof with a therapeutically effective amount of a compound according to claim 1 in a therapeutically effective amount.
    [15" claim-type="Currently amended] A method for treating diabetes, comprising treating a subject's diabetes by administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1.
    [16" claim-type="Currently amended] A method for inhibiting the hydrolytic activity of an intracellular pancreatic lipase enzyme, comprising contacting a compound according to claim 1 with a cell in an amount effective to inhibit the hydrolytic activity of the pancreatic lipase enzyme.
    [17" claim-type="Currently amended] A pharmaceutical composition comprising the compound of claim 1, 2, 3, 10 or 11 and a pharmaceutically acceptable carrier.
    [18" claim-type="Currently amended] The method of claim 17,
    The pharmaceutical composition is a pharmaceutical composition, characterized in that formulated in oral, topical, parenteral or nasal dosage form.
    [19" claim-type="Currently amended] A method for preparing a pharmaceutical composition comprising mixing the compound of claim 1, 2, 3, 10 or 11 with a pharmaceutically acceptable carrier.
    [20" claim-type="Currently amended] Packaging material;
    A pharmaceutical composition according to claim 17; And
    A product comprising instructions for the use of said pharmaceutical composition in the treatment of obesity.
    [21" claim-type="Currently amended] By preparing a compound of the formula

    X is O, S, CH 2 or NR 5 ;
    R 1 is H, substituted or unsubstituted C 1 -C 15 alkyl, C 1 -C 8 alkylaryl, -C (O) OR 4 , -C (O) NR 4 R 5 , -CR 6 R 6 ' OR 4 , -CR 6 R 6 ' OC (0) R 4 , -CR 6 R 6' OC (O) NHR 7 , -C (0) NR 8 R 9 , -C (O) NR 8 R 9 NR 8 R 9 , -N (R 5 ) C (O) NHR 5 , or CH 2 R 4 ;
    R 2 is substituted or unsubstituted straight C 1 -C 30 alkyl or branched C 3 -C 30 alkyl, aryl, alkylaryl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 3 is H or substituted or unsubstituted C 1 -C 6 alkyl or cycloalkyl;
    R 4 is H or substituted or unsubstituted, straight or branched C 6 -C 30 alkyl, aryl, -CH 2 -aryl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 5 is H or substituted or unsubstituted, straight or branched C 6 -C 30 alkyl, arylalkyl, heteroarylalkyl or cycloalkyl;
    R 6 and R 6 ' are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, dialkyl or cycloalkyl or together form a 3-7 membered ring system;
    R 7 is H or substituted or unsubstituted C 1 -C 12 alkyl or cycloalkyl;
    R 8 and R 9 are each independently H, substituted or unsubstituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylaryl, or NR 8 R 9 is a piperazine substituted together Forms a piperidine ring or dihydro-1H-isoquinoline ring system,
    (a)

    Is reacted in the presence of sulfur, base and solvent:

    Preparing a;
    (b) the product of step (a)

    By reaction in the presence of a base:

    Preparing a;
    (c) reacting the product of step (b) with trifluoroacetic acid (TFA) in the presence of a solvent:

    Preparing a;
    (d) preparing the compound of the present invention by reacting the product of step (c) with SOCl 2 in the presence of a solvent.
    [22" claim-type="Currently amended] The method of claim 21,
    The base of step (a) is triethyl amine and the solvent is dimethylformamide (DMF).
    [23" claim-type="Currently amended] The method of claim 22,
    The solvent of step (c) is a production method, characterized in that dichloromethane.
    [24" claim-type="Currently amended] The method of claim 23, wherein
    The solvent of step (d) is pyridine: CH 2 Cl 2 characterized in that the production method.
    [25" claim-type="Currently amended] A compound prepared by the method of claim 21.
    [26" claim-type="Currently amended] Use of a compound according to claim 1 for the manufacture of a medicament useful for treating obesity in a subject.
    [27" claim-type="Currently amended] Use of a compound according to claim 1 for the manufacture of a medicament useful for treating diabetes in a subject.
    [28" claim-type="Currently amended] Use of a compound according to claim 1 for the preparation of a medicament useful for inhibiting the hydrolytic activity of intracellular pancreatic lipase enzymes.
    [29" claim-type="Currently amended] The method of claim 1,
    The compound is a heterocyclic or heteroaryl ring piperazine, piperidine, (1,4) diazepan, pyrazine, pyridine, pyrrolidine, pyrazole, pyrimidine, thiophene, imidazole, azetidine, Pyrrole, benzothiazole, benzodioxolane, dithiolane, oxatiin, imidazolidine, quinoline, isoquinoline, dihydroisoquinoline, indole, isoindole, triazaspiro [4.5] decane, morpholine, A compound characterized in that it is a furan or isothiazole ring.
    [30" claim-type="Currently amended] The method according to any one of claims 1, 2, 3, 5 to 9 or 13,
    If any substituent is present on the compound, the substituent is halogen, hydroxyl, straight chain (C 1 -C 30 ) alkyl, branched (C 3 -C 30 ) alkyl, (C 3 -C 10 ) cycloalkyl, straight chain ( C 1 -C 10 ) alkylcarbonyloxy, branched chain (C 3 -C 30 ) alkylcarbonyloxy, arylcarbonyloxy, straight chain (C 1 -C 30 ) alkoxycarbonyloxy, branched chain (C 3 -C 30 ) Alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, straight chain (C 1 -C 30 ) alkylcarbonyl, branched (C 3 -C 30 ) alkylcarbonyl, straight chain (C 1 -C 30 ) alkoxycarbonyl, Side chain (C 3 -C 30 ) alkoxycarbonyl, aminocarbonyl, straight chain (C 1 -C 30 ) alkylthiocarbonyl, side chain (C 3 -C 30 ) alkylthiocarbonyl, straight chain (C 1 -C 30 ) Alkoxyl, branched chain (C 1 -C 30 ) alkoxyl, phosphate, phosphonato, cyano, amino, straight chain (C 1 -C 30 ) alkylamino, side chain (C 3 -C 30 ) alkylamino, straight chain (C 1 -C 30 ) dialkylamino, branched (C 3 -C 30 ) dialkylamino, arylamino, diarylamino, straight chain (C 1 -C 30 ) alkyla Arylamino, branched (C 3 -C 30 ) alkylarylamino, acylamino, straight chain (C 1 -C 30 ) alkylcarbonylamino, branched (C 3 -C 30 ) alkylcarbonylamino, arylcarbonylamino, carba Moyl, ureido, amidino, imino, sulfhydryl, straight chain (C 1 -C 30 ) alkylthio, branched chain (C 3 -C 30 ) alkylthio, arylthio, thiocarboxylate, sulfate, sulfonato, sulfa Moyl, sulfonamido, nitro, trifluoromethyl, azido, 4-10 membered heterocyclic, straight chain (C 1 -C 30 ) alkylaryl, branched (C 3 -C 30 ) alkylaryl, benzo (1, 3) A diosol, or an aromatic or 5-6 membered heteroaromatic moiety wherein the substituents may be further substituted by any of the foregoing.
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    同族专利:
    公开号 | 公开日
    BR0215080A|2004-10-05|
    WO2003053944A1|2003-07-03|
    US7064122B2|2006-06-20|
    CA2471098A1|2003-07-03|
    EA200400831A1|2005-08-25|
    CN1620439A|2005-05-25|
    MXPA04005863A|2004-10-29|
    US20030195199A1|2003-10-16|
    AU2002366810A1|2003-07-09|
    JP2005518383A|2005-06-23|
    EA009368B1|2007-12-28|
    EP1467978A1|2004-10-20|
    EP1467978A4|2005-11-02|
    JP4668536B2|2011-04-13|
    AU2002366810B2|2009-06-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-12-20|Priority to US34261701P
    2001-12-20|Priority to US60/342,617
    2002-02-13|Priority to US35701502P
    2002-02-13|Priority to US60/357,015
    2002-12-20|Application filed by 오에스아이 파마슈티컬스, 인코포레이티드
    2002-12-20|Priority to PCT/US2002/041272
    2004-07-30|Publication of KR20040068316A
    优先权:
    申请号 | 申请日 | 专利标题
    US34261701P| true| 2001-12-20|2001-12-20|
    US60/342,617|2001-12-20|
    US35701502P| true| 2002-02-13|2002-02-13|
    US60/357,015|2002-02-13|
    PCT/US2002/041272|WO2003053944A1|2001-12-20|2002-12-20|Pancreatic lipase inhibitor compounds, their synthesis and use|
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