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HK1080455A - Benzophenones as inhibitors of reverse transcriptase - Google Patents

Benzophenones as inhibitors of reverse transcriptase Download PDF

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Publication number
HK1080455A
HK1080455A HK05111885.0A HK05111885A HK1080455A HK 1080455 A HK1080455 A HK 1080455A HK 05111885 A HK05111885 A HK 05111885A HK 1080455 A HK1080455 A HK 1080455A
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Hong Kong
Prior art keywords
alkyl
compound
halogen
group
aryl
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HK05111885.0A
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Chinese (zh)
Inventor
Clarence Webster Andrews
Joseph Howing Chan
George Andrew Freeman
Karen Rene Romines
Jeffrey H. Tidwell
Pascal Maurice Charles Pianetti
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Glaxo Group Limited
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Publication of HK1080455A publication Critical patent/HK1080455A/en

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Benzophenones as reverse transcriptase inhibitors
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The present application is a divisional application of the application having the title "benzophenone as a reverse transcriptase inhibitor", filed on 31/8/2000 and having the application number 00815249.7(PCT/EP 00/08487).
Background
The human immunodeficiency virus ("HIV") is the causative agent of acquired immunodeficiency syndrome ("AIDS"), which is characterized by the immune system, particularly CD4+The destruction of T-cells, with concomitant susceptibility to opportunistic infections, and the precursor aids-related complex ("ARC") of the disease, a syndrome characterized by conditions such as persistent generalized lymphadenopathy, fever, and weight loss. HIV is a retrovirus; its conversion of RNA into DNA is effected by the action of reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit HIV replication in infected cells. Such compounds are useful for the prevention or treatment of HIV infection in humans.
In addition to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have also gained a position in the treatment of HIV-1 infections. NNRTIs interact with specific sites of HIV-1 reverse transcriptase, which is closely related to, but a distinct site from, the NRTI binding site. However, it is well known that NNRTIs rapidly cause resistance due to mutations in the amino acids surrounding the NNRTI-binding site (E.De Clercq, IlFamaco 54, 26-45, 1999). Failure of the long-term effects of NNRTIs is often associated with the emergence of resistant strains (j. balzarini, Biochemical Pharmacology, vol 58, 1-27, 1999). However, this mutation occurring in reverse transcriptase often causes reduced sensitivity to other reverse transcriptase inhibitors, which results in cross-resistance.
JP 59181246 discloses certain benzophenones useful as anticancer agents. Wyatt et al (J.Med.chem.38: 1657-1665, 1995) disclose certain benzophenone derivatives as inhibitors of HIV-1 reverse transcriptase. However, these compounds are mainly active against wild-type HIV-1 reverse transcriptase, but rapidly produce resistant viruses and are therefore inactive against commonly resistant strains.
We now disclose that the compounds of the present invention are useful as both types of inhibitors of wild type HIV-1 reverse transcriptase and mutants of HIV reverse transcriptase.
Brief description of the invention
A first aspect of the invention features compounds of formulas I, IA, IB, IC, ID, II, III and IV. These compounds, either as individual compounds, pharmaceutically acceptable salts, or as components of pharmaceutical compositions, are useful for inhibiting HIV reverse transcriptase, particularly drug resistant variants thereof, preventing infection by HIV, treating infection by HIV, and treating AIDS and/or ARC. A second aspect of the invention features a method of treating AIDS as monotherapy or in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines, a method of preventing infection by HIV, and a method of treating infection by HIV. A third aspect of the invention features pharmaceutical compositions containing the above compounds, which compositions are suitable for use in the prevention or treatment of HIV infection. A fourth aspect of the invention features a method of making the above compound.
Detailed Description
The present invention relates to compounds of formula I, IA, IB, IC, ID, II, III and IV and combinations thereof, or pharmaceutically acceptable salts thereof, that inhibit HIV reverse transcriptase and drug-resistant variants thereof, prevent or treat HIV infection and treat the resulting Acquired Immune Deficiency Syndrome (AIDS).
The invention features compounds of formula (I) or a pharmaceutically acceptable derivative thereof
Wherein:
x is C, O or N;
R1is C1-8An alkyl group; c3-6A cycloalkyl group; c which may be optionally substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl radical, C1-8Alkylamino, alkoxy, C3-6Cycloalkyl radical C2-6Alkenyl radical, C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl, and from the group consisting of hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group; or a heterocycle optionally substituted with one or more substituents selected from: halogen, C1-8Alkyl, -CN, C6-14Aryl radical C1-8Alkyl and heterocyclic;
R6is selected from hydroxy, halogen, -CF3C optionally substituted by one or more substituents of aryl and heterocycle1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C 3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R2is hydrogen, halogen or C1-8An alkyl group;
R3and R4Independently is hydrogen; a hydroxyl group; heterocycle optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy C1-8Alkyl, halogen, C1-8Alkyl, -OR11、-S(O)2NR8R9and-SR10N(R10)2(ii) a Or C substituted by one or more substituents selected from the group consisting of6-14Aryl: hydroxy, halogen, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、C1-8Alkylamino, heterocyclic C1-8Alkyl, -C (O) NH2、-S(O)R7、-S(O)2R7、-C(O)R7、-NS(O)2R7、-S(O)2NR8R9、-S(O)2NHR11、-S(O)2R11、-S(O)2NR7COR11、-S(O)2NHCOR11、-S(O)2[COR11]nWherein n is 1, 2 OR 3, -OR11、-OR11OR11、-C(O)R11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11C, heterocycle2-6Alkenyl, optionally substituted by one or more groups selected from oxo, C1-8Alkyl and C (O) OR11And a heterocycle which may be substituted by one or more substituents selected from the group consisting of-CN and by-C (O) R11Optionally substituted heterocyclic substituent optionally substituted C1-8An alkyl group; provided that R is3And R4Cannot be simultaneously hydrogen or hydroxyl;
R8and R9Independently selected from hydrogen, C3-6Cycloalkyl, C optionally substituted with one or more substituents selected from the group consisting of1-8Alkyl groups: oxo, heterocycle, CN and substituted alkoxy, C1-8Alkylamino radical, C1-8Alkyl heterocycles, heterocycles C1-8Alkyl radical, C3-6Cycloalkyl radical C1-8Alkyl and C3-6Cycloalkyl optionally substituted C6-14An aryl group;
R10is C1-8An alkyl group;
R11is C optionally substituted by one or more substituents selected from the group consisting of 1-8Alkyl groups: hydrogen, hydroxy, halogen, C1-8Alkyl radical, C3-6Cycloalkyl, alkoxy, -S (O)2NR8R9、NCONH2And is selected from one or more of oxo, hydroxy and
C1-8a heterocycle optionally substituted with a substituent of alkyl; from a heterocyclic ring C1-8An alkyl optionally substituted heterocycle; or from alkoxy groupsSubstituted C6-14An aryl group;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group;
provided that
(a) When X is N; r1Is C substituted by halogen6-14An aryl group; r2And R3Is hydrogen; r5When is halogen; r4Can not be composed of C1-8An alkyl-substituted heterocycle;
(b) when X is C; r2Is hydrogen, halogen or C1-8An alkyl group; r3Is hydrogen; r4Is selected from halogen, hydroxy or C1-8Alkyl substituted C6-14An aryl group; r5Is hydrogen, halogen, C1-8Alkyl or alkoxy groups; then R is1Can not be C1-8Alkyl radical, C3-6Cycloalkyl radicals or radicals derived from halogen, C1-8Alkyl, alkoxy or C6-14Aryl radical C2-6Alkenyl-substituted C6-14An aryl group; and
(c) when X is C; r2Is hydrogen or alkyl; r3Is hydrogen; r4Is selected from halogen, CN, C1- 8Alkyl or-NO2Substituted C6-14An aryl group; r5Is hydrogen, -NO2Or NH2When the current is over; then R is1Not being C substituted by alkoxy10-14And (4) an aryl group.
Preferred compounds of formula (I) are those wherein X is O.
More preferred compounds of formula (I) are those wherein X is O; r 1Is C substituted by one or more substituents selected from the group consisting of6- 14Aryl: halogen, -CF3、C1-8Alkyl, -CN, -SR6、-S(O)2R6(ii) a Or a heterocycle optionally substituted with one or more substituents selected from: c1-8Alkyl, -CN and C6-14Aryl radical C1-8An alkyl group; r6Is C optionally substituted by halogen1-8An alkyl group; r7Is C optionally substituted by one or more substituents selected from hydroxy1-8An alkyl group; -NH2Or a heterocycle; r2Is hydrogen; r3Is hydrogen or C1-8An alkyl group; r4Is a heterocycle optionally substituted with one or more substituents selected from the group consisting of: oxo, halogen, C1-8Alkyl, -OR11、-SR10N(R10)2and-S (O)2NR8R9(ii) a Or C substituted by one or more substituents selected from the group consisting of6-14Aryl: hydroxy, halogen, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、-C(O)NH2、-S(O)R7、-S(O)2R7、-S(O)2NR8R9、-OR11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11And may be substituted by one or more groups selected from oxo, C1-8Alkyl and heterocycle C1-8A heterocycle optionally substituted with a substituent of alkyl; r8And R9Can be the same or different and is selected from hydrogen and C1-8Alkyl radical, C1-8Alkyl heterocycles, heterocycles and C3-6A cycloalkyl group; r10Is C1-8An alkyl group; r11Is prepared from-SO2NR8R9Optionally substituted C1-8An alkyl group; and R5Is halogen or-NO2。
More preferred compounds of formula (I) are those wherein X is O; r1Is C substituted by one or more substituents selected from the group consisting of 6- 14Aryl: halogen, -CF3、C1-8Alkyl and-CN; r2And R3Is hydrogen; r4Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, C1-8Alkyl, -CN, -NO2、-S(O)R7、-S(O)2R7、-NS(O)2R7Wherein R is7is-NH2(ii) a And R5Is halogen.
More preferred compounds of formula (I) are those wherein X is O; r1Is C which may be optionally substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, C1-8Alkyl, CF3、-CN；R2And R3Is hydrogen; r4Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: c1-8Alkyl and S (O)2NR8R9Wherein R is8And R9Independently selected from hydrogen, C3-6Cycloalkyl, C optionally substituted with one or more substituents selected from the group consisting of1-8Alkyl groups: oxo, heterocycle, CN and substituted alkoxy, C1-8Alkylamino radical, C1-8Alkyl heterocycles, heterocycles C1-8Alkyl radical, C3-6Cycloalkyl radical C1-8Alkyl and C3-6Cycloalkyl optionally substituted C6-14And (4) an aryl group.
Other preferred compounds of formula (I) are those wherein R is1Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl and-CN; r2And R3Is hydrogen; r4Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, C1-8Alkyl, -CN, -NO 2、-S(O)R7、-S(O)2R7、-NS(O)2R7Wherein R is7is-NH2(ii) a And R5Is halogen; provided that when X is C; r2And R3Is hydrogen; r4Is selected from halogen, CN, C1-8Alkyl, -NO2Substituted C6-14An aryl group; and R5When is halogen; then R is1Not being C substituted by alkoxy6-10And (4) an aryl group.
In another aspect of the invention, compounds of formula (IA) or a pharmaceutically acceptable derivative thereof are disclosed:
wherein:
x is C, O or N;
R1is C which may be optionally substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl radical, C1-8Alkylamino, alkoxy, C3-6Cycloalkyl radical C2-6Alkenyl radical, C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl and may be selected from hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group;
R6is selected from hydroxy, halogen, -CF3C optionally substituted by one or more substituents of aryl and heterocycle1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R2is hydrogen, halogen or C1-8An alkyl group;
R3is hydrogen;
R4is C substituted by one or more substituents selected from the group consisting of 6-14Aryl: hydroxy, halogen, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、C1-8Alkylamino, heterocyclic C1-8Alkyl, -C (O) NH2、-S(O)R7、-S(O)2R7、-C(O)R7、-NS(O)2R7、-S(O)2NR8R9、-S(O)2NHR11、-S(O)2R11、-S(O)2NR7COR11、-S(O)2NHCOR11、-S(O)2[COR11]nWherein n is 1, 2 OR 3, -OR11、-OR11OR11、-C(O)R11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11C, heterocycle2-6Alkenyl, optionally substituted by one or more groups selected from oxo, C1-8Alkyl and C (O) OR11And a heterocycle which may be substituted by one or more substituents selected from the group consisting of-CN and by-C (O) R11Optionally substituted heterocyclic substituent optionally substituted C1-8An alkyl group;
R8and R9Independently selected from hydrogen, C3-6Cycloalkyl, C optionally substituted with one or more substituents selected from the group consisting of1-8Alkyl groups: oxo, heterocycle, CN and substituted alkoxy, C1-8Alkylamino radical, C1-8Alkyl heterocycles, heterocycles C1-8Alkyl radical, C3-6Cycloalkyl radical C1-8Alkyl and C3-6Cycloalkyl optionally substituted C6-14An aryl group;
R11is C optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: hydrogen, hydroxy, halogen, C1-8Alkyl radical, C3-6Cycloalkyl, alkoxy, -S (O)2NR8R9、NCONH2And is selected from one or more of oxo, hydroxy and C1-8A heterocycle optionally substituted with a substituent of alkyl; from a heterocyclic ring C1-8An alkyl optionally substituted heterocycle; or C optionally substituted by alkoxy6-14An aryl group;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group; provided that
(a) When X is C; r2Is hydrogen, halogen or C 1-8An alkyl group; r3Is hydrogen; r4Is selected from halogen, hydroxy or C1-8Alkyl radicalSubstituted C6-14An aryl group; r5Is hydrogen, halogen, C1-8Alkyl or alkoxy groups; then R is1Can not be C1-8Alkyl radical, C3-6Cycloalkyl radicals or radicals derived from halogen, C1-8Alkyl or C6- 14Aryl radical C2-6Alkenyl-substituted C6-14An aryl group; and
(b) when X is C; r2Is hydrogen or alkyl; r3Is hydrogen; r4Is selected from halogen, CN, alkyl or-NO2Substituted C6-14An aryl group; r5Is hydrogen, -NO2Or NH2When the current is over; then R is1Not being C substituted by alkoxy10-14And (4) an aryl group.
Preferred compounds of formula (IA) are those wherein X is O.
More preferred compounds of formula (IA) are those wherein X is O; r1Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl, -CN, C optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl and may be selected from hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group; r2And R3Is hydrogen; r4Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: c1-8Alkyl, -S (O)2R7、-S(O)2NR8R9、-OR11C, heterocycle2-6Alkenyl, and heterocycle which may be optionally substituted by oxo; and R5Is halogen.
In another aspect of the invention there is provided a compound of formula (IB):
Wherein:
x is C, O or N;
R1is C which may be substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl radical, C1-8Alkylamino, alkoxy, C3-6Cycloalkyl radical C2-6Alkenyl radical, C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl and may be selected from hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group;
R6is selected from hydroxy, halogen, -CF3C optionally substituted by one or more substituents of aryl and heterocycle1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R2is hydrogen, halogen or C1-8An alkyl group;
R3is hydrogen;
R4is a heterocycle optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy C1-8Alkyl, halogen, C1-8Alkyl, -OR11、-SR10N(R10)2and-S (O)2NR8R9；
R8And R9Independently selected from hydrogen, C3-6Cycloalkyl, C optionally substituted with one or more substituents selected from the group consisting of1-8Alkyl groups: oxo, heterocycle, CN and substituted alkoxy, C1-8Alkylamino radical, C1-8Alkyl heterocycles, heterocycles C1-8Alkyl radical, C3-6Cycloalkyl radical C1-8Alkyl and C 3-6Cycloalkyl optionally substituted C6-14An aryl group;
R10is C1-8An alkyl group;
R11is C optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: hydrogen, hydroxy, halogen, C1-8Alkyl radical, C3-6Cycloalkyl, alkoxy, -S (O)2NR8R9、NCONH2And is selected from one or more of oxo, hydroxy and C1-8A heterocycle optionally substituted with a substituent of alkyl; from a heterocyclic ring C1-8An alkyl optionally substituted heterocycle; or C optionally substituted by alkoxy6-14An aryl group;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group;
provided that when X is N; r1Is C substituted by halogen6-14An aryl group; r2And R3Is hydrogen; r5When is halogen; r4Can not be composed of C1-8Alkyl-substituted heterocycles.
Preferred compounds of formula (IB) are those wherein X is O.
More preferred compounds of formula (IB) are those wherein X is O; r1Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3and-CN; r2Is hydrogen; r3Is hydrogen; r4Is a heterocycle, and R5Is halogen.
In another aspect of the invention there is provided a compound of formula (IC) or a pharmaceutically acceptable derivative thereof
Wherein:
x is C, O or N;
R1is a heterocycle optionally substituted with one or more substituents selected from the group consisting of: c 1-8Alkyl, halogen, -CN, C6-14Aryl radical C1-8Alkyl and heterocyclic;
R2is hydrogen, halogen or C1-8An alkyl group;
R3is hydrogen;
R4is C substituted by one or more substituents selected from the group consisting of6-14Aryl: hydroxy, halogen, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、C1-8Alkylamino, heterocyclic C1-8Alkyl, -C (O) NH2、-S(O)R7、-S(O)2R7、-C(O)R7、-NS(O)2R7、-S(O)2NR8R9、-S(O)2NHR11、-S(O)2R11、-S(O)2NR7COR11、-S(O)2NHCOR11、-S(O)2[COR11]nWherein n is 1, 2 OR 3, -OR11、-OR11OR11、-C(O)R11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11C, heterocycle2-6Alkenyl, optionally substituted by one or more groups selected from oxo, C1-8Alkyl and C (O) OR11And a heterocycle which may be substituted by one or more substituents selected from the group consisting of-CN and by-C (O) R11Optionally substituted heterocyclic substituent optionally substituted C1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R8and R9Independently selected from hydrogen, C3-6Cycloalkyl radicals formed from one or moreC optionally substituted with a substituent selected from the group consisting of1-8Alkyl groups: oxo, heterocycle, CN and substituted alkoxy, C1-8Alkylamino radical, C1-8Alkyl heterocycles, heterocycles C1-8Alkyl radical, C3-6Cycloalkyl radical C1-8Alkyl and C3-6Cycloalkyl optionally substituted C6-14An aryl group;
R11is C optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: hydrogen, C1-8Alkyl, alkoxy, -S (O)2NR8R9、-NR8R9And from one or more radicals selected from oxo and C 1-8A heterocycle optionally substituted with a substituent of alkyl;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group.
Preferred compounds of formula (IC) are those wherein X is O.
More preferred compounds of formula (IC) are those wherein X is O; r1Is a heterocycle optionally substituted by-CN; r2And R3Is hydrogen; r4Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: c1-8Alkyl, -S (O)2NR8R9、-OR11And a heterocycle which may be optionally substituted by one or more substituents selected from oxo; and R5Is halogen.
The invention also features a compound of formula (ID) or a pharmaceutically acceptable derivative thereof:
wherein:
x is C, O or N;
R1to select from one or moreA heterocycle optionally substituted with substituents selected from: c1-8Alkyl, halogen, -CN, C6-14Aryl radical C1-8Alkyl and heterocyclic;
R2is hydrogen, halogen or C1-8An alkyl group;
R3and R4Independently is hydrogen; a hydroxyl group; heterocycle optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy C1-8Alkyl, halogen, C1-8Alkyl, -OR11、-S(O)2NR8R9and-SR10N(R10)2(ii) a Or R3And R4Together with the nitrogen atom to which they are attached form a compound which may be composed of C6-14Aryl optionally substituted heterocycle, said C 6-14The aryl group may be substituted by one or more groups selected from C1-8Alkyl and-NO2The substituent(s) is optionally substituted; provided that R is3And R4Cannot be simultaneously hydrogen or hydroxyl;
R8and R9Independently selected from hydrogen, C3-6Cycloalkyl, C optionally substituted with one or more substituents selected from the group consisting of1-8Alkyl groups: oxo, heterocycle, CN and substituted alkoxy, C1-8Alkylamino radical, C1-8Alkyl heterocycles, heterocycles C1-8Alkyl radical, C3-6Cycloalkyl radical C1-8Alkyl and C3-6Cycloalkyl optionally substituted C6-14An aryl group;
R10is C1-8An alkyl group;
R11is C optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: hydrogen, C1-8Alkyl, -S (O)2NR8R9And from one or more radicals selected from oxo and C1-8A heterocycle optionally substituted with a substituent of alkyl;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group.
Preferred compounds of formula (ID) are those wherein X is O.
More preferred compounds of formula (ID) are those wherein X is O; r1Is a heterocycle; r2And R3Is hydrogen; r4Is a heterocycle; and R5Is halogen.
In another aspect of the invention there is provided a compound of formula (II) or a pharmaceutically acceptable derivative thereof:
wherein:
R1is C which may be optionally substituted by one or more substituents selected from the group consisting of 6-14Aryl: halogen, -CF3、C1-8Alkyl radical, C1-8Alkylamino, alkoxy, C3-6Cycloalkyl radical C2-6Alkenyl radical, C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl and may be selected from hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group;
R6is selected from hydroxy, halogen, -CF3C optionally substituted by one or more substituents of aryl and heterocycle1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R2is hydrogen, halogen or C1-8An alkyl group;
R3and R4Can be formed of C6-14Aryl optionally substituted heterocycle, said C6-14The aryl group may be substituted by one or more groups selected from C1-8Alkyl and-NO2The substituent(s) is optionally substituted;
provided that when R is1Is unsubstituted C6-14When aryl is present, then R3R4Is substituted;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group.
Preferred compounds of formula (II) are those wherein R is1Is C substituted by halogen6-14An aryl group; r2Is hydrogen; r3And R4Can be formed of C6-14Aryl optionally substituted heterocycle, said C 6-14The aryl group may be substituted by one or more groups selected from C1-8Alkyl and-NO2The substituent(s) is optionally substituted; r5Is halogen.
Another aspect of the invention features a compound of formula (III):
wherein:
R1is C which may be optionally substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl radical, C1-8Alkylamino, alkoxy, C3-6Cycloalkyl radical C2-6Alkenyl radical, C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl andcan be selected from hydroxyl, halogen, aryl and C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group; or a heterocycle optionally substituted with one or more substituents selected from: c1-8Alkyl, -CN, C6-14Aryl radical C1-8Alkyl and heterocyclic;
R6is selected from hydroxy, halogen, -CF3C optionally substituted by one or more substituents of aryl and heterocycle1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R4is a heterocycle optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy C1-8Alkyl, halogen, C 1-8Alkyl, -OR11and-SR10N(R10)2(ii) a Or C substituted by one or more substituents selected from the group consisting of6-14Aryl: hydroxy, halogen, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、C1-8Alkylamino, heterocyclic C1-8Alkyl, -C (O) NH2、-S(O)R7、-S(O)2R7、-C(O)R7、-NS(O)2R7、-S(O)2NR8R9、-OR11、-S(O)2NHR11、S(O)2R11、OR11OR11、-C(O)R11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11C, heterocycle2-6Alkenyl, optionally substituted by one or more groups selected from oxo, C1-8Alkyl and-C (O) OR11And a heterocycle which may be substituted by one or more substituents selected from the group consisting of-CN and by-C (O) R11Optionally substituted heterocyclic substituent optionally substituted C1-8An alkyl group;
R8and R9Independently selected from hydrogen; c3-6A cycloalkyl group; c optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: oxo, heterocycle, CN and substituted alkoxy, C1-8Alkylamino radical, C1-8Alkyl heterocycles, heterocycles C1-8Alkyl radical, C3-6Cycloalkyl radical C1-8Alkyl and C3-6A cycloalkyl group; or-C (O) NH2；
R10Is C1-8An alkyl group;
R11is C optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: hydrogen, C1-8Alkyl, alkoxy, -S (O)2NR8R9、-NR8R9And is prepared from one or
Plural is selected from oxo and C1-8A heterocycle optionally substituted with a substituent of alkyl;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group;
provided that
(a) When R is4Is made of OR11Substituted C6-14Aryl, wherein R11Is NR8R9Wherein R is8And R9Is C1-8Alkyl radical, R1Is C 6-14When aryl is present, then R1Cannot be substituted in the para position, and
(b)R1and R4Cannot be simultaneously unsubstituted.
Preferred compounds of formula (III) are those wherein R is1Is C which may be substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl, -CN, -SR6、-S(O)2R6(ii) a Or a heterocycle optionally substituted with one or more substituents selected from: c1-8Alkyl, -CN and C6-14Aryl radical C1-8An alkyl group; r6Is C optionally substituted by halogen1-8An alkyl group; r7Is selected from hydroxyl, -NH2Or C optionally substituted by one or more substituents of the heterocycle1-8An alkyl group; r4Is a heterocycle optionally substituted with one or more substituents selected from the group consisting of: oxo, halogen, C1-8Alkyl, -OR11and-SR10N(R10)2(ii) a Or C substituted by one or more substituents selected from the group consisting of6-14Aryl: hydroxy, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、-C(O)NH2、-S(O)2R7、-S(O)2NR8R9、-OR11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11May be selected from one or more of oxo and C1-8A heterocycle optionally substituted with a substituent of alkyl; r8And R9Can be the same or different and is selected from hydrogen and C1-8Alkyl radical, C1-8Alkyl heterocycles, heterocycles and C3-6A cycloalkyl group; r10Is C1-8An alkyl group; r11Is composed of-S (O)2NR8R9Optionally substituted C1-8An alkyl group; r5Is halogen or-NO2。
More preferred compounds of formula (III) are those wherein R is 1Is C which may be substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl and-CN; r4Is C substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, C1-8Alkyl, -CN, -NO2、-S(O)R7、-S(O)2R7、-NS(O)2R7Wherein R is7is-NH2(ii) a And R5Is halogen.
The invention also features a compound of formula (I) or a pharmaceutically acceptable derivative thereof, wherein
R1Is composed ofPhenyl substituted in the meta position with one or more substituents selected from the group consisting of: halogen, -CF3、C1-xAlkyl radical, C1-8Alkylamino, alkoxy, C3-6Cycloalkyl radical C2-6Alkenyl radical, C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl and may be selected from hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group;
R2is hydrogen;
R3is hydrogen;
R4is phenyl substituted at the ortho position by a substituent selected from the group consisting of: hydroxy, halogen, -CF3Or C1-8Alkyl and phenyl substituted at the para-position with a substituent selected from the group consisting of: hydroxy, halogen, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、C1-8Alkylamino, heterocyclic C1-8Alkyl, -C (O) NH2、-S(O)R7、-S(O)2R7、-C(O)R7、-NS(O)2R7、-S(O)2NR8R9、-S(O)2NHR11、-SO2R11、-OR11、-C(O)R11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11C, heterocycle2-6Alkenyl, optionally substituted by one or more groups selected from oxo, C1-8Alkyl and C (O) OR 11And a heterocycle which may be substituted by one or more substituents selected from the group consisting of-CN and by-C (O) R11Optionally substituted heterocyclic substituent optionally substituted C1-8An alkyl group;
R5is a substituent at the para position relative to X and is selected from halogen and C1-8Alkyl, -NO2、-NH2、
C1-8Alkylamino radical, CF3Or an alkoxy group;
R11is C optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: hydrogen, C1-8Alkyl, -S (O)2NR8R9、-NR8R9And from one or more radicals selected from oxo and C1-8A heterocycle optionally substituted with a substituent for an alkyl group.
The invention also features a compound of formula (IV):
wherein:
x is C, O or N;
y is a heterocycle optionally substituted with one or more substituents selected from the group consisting of: halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino, -CF3Or an alkoxy group;
R1is C1-8An alkyl group; c3-6A cycloalkyl group; c which may be optionally substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl radical, C1-8Alkylamino radical, C3-6Cycloalkyl radical C2-6Alkenyl radical, C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl, and from the group consisting of hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C 2-6An alkynyl group; or a heterocycle optionally substituted with one or more substituents selected from: c1-8Alkyl, -CN、C6-14Aryl radical C1-8Alkyl and heterocyclic;
R6is selected from hydroxy, halogen, -CF3C optionally substituted by one or more substituents of aryl and heterocycle1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R2is hydrogen, halogen or C1-8An alkyl group;
R3and R4Independently is hydrogen; a hydroxyl group; heterocycle optionally substituted with one or more substituents selected from the group consisting of: oxo, hydroxy C1-8Alkyl, halogen, C1-8Alkyl, OR11and-SR10N(R10)2(ii) a Or C substituted by one or more substituents selected from the group consisting of6-14Aryl: hydroxy, halogen, -CF3、C1-8Alkyl, hydroxy C1-8Alkyl, -CN, -NO2、C1-8Alkylamino, heterocyclic C1-8Alkyl, -C (O) NH2、-S(O)R7、-S(O)2R7、-C(O)R7、-NSO2R7、-S(O)2NR8R9、-OR11、-C(O)R11、-C(O)NR11、-C(O)OR11、-NR11、-NC(O)R11C, heterocycle2-6Alkenyl, optionally substituted by one or more groups selected from oxo, C1-8Alkyl and C (O) OR11And a heterocycle which may be substituted by one or more substituents selected from the group consisting of-CN and by-C (O) R11Optionally substituted heterocyclic substituent optionally substituted C1-8An alkyl group; provided that R is3And R4Cannot be simultaneously hydrogen or hydroxyl;
R8and R9Independently selected from hydrogen, C1-8Alkyl radical, C1-8Alkylamino radical, C 1-8Alkyl heterocycles, heterocycles and C3-6A cycloalkyl group;
R10is C1-8An alkyl group;
R11is C optionally substituted by one or more substituents selected from the group consisting of1-8Alkyl groups: hydrogen, C1-8Alkyl, -SO2NR8R9And from one or more radicals selected from oxo and C1-8A heterocycle optionally substituted with a substituent of alkyl;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group.
Preferred compounds of formula (IV) are those compounds, or pharmaceutically acceptable derivatives thereof, wherein Y is a heterocycle substituted with one or more substituents selected from the group consisting of: halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino, -CF3Or an alkoxy group. More preferred compounds of formula (IV) are those wherein X is O. The most preferred compounds of formula (IV) are those wherein X is O and Y is a heterocycle substituted with one or more substituents selected from the group consisting of: halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino, -CF3Or an alkoxy group; or a pharmaceutically acceptable derivative thereof.
Preferred compounds of the invention include:
2- [2- (1-benzothien-2-ylcarbonyl) -4-chlorophenoxy ] -N-phenylacetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (1H-imidazol-1-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (2-thienylcarbonyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (1H-1, 2, 4-triazol-1-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (4-morpholino) phenyl ] acetamide;
n- [4- (aminosulfonyl) phenyl ] -2- (2-benzoyl-4-chlorophenoxy) acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- {4- [ (1, 3-thiazol-2-ylamino) sulfonyl ] phenyl } acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (4-methyl-1-piperazinyl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (hydroxymethyl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- {4- [ (methylamino) sulfonyl ] phenyl } acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (1, 1-dioxo-1 λ -6-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [ 2-methyl-4- (4-morpholino) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- {4- [3- (dimethylamino) propoxy ] -2-methylphenyl } acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (1-hydroxyethyl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (1-hydroxyethyl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [ 2-methyl-4- (1-oxo-1 λ -4, 4-thiazinan-4-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- { 2-methyl-4- [3- (1-pyrrolidinyl) propoxy ] phenyl } acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- (1H-indazol-5-yl) acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- { 2-methyl-4- [3- (4-morpholino) propoxy ] phenyl } acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- {4- [3- (1H-imidazol-1-yl) propoxy ] -2-methylphenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- (1H-indazol-6-yl) acetamide;
2- [ 4-chloro-2- (2-thienylcarbonyl) phenoxy ] -N- (1H-indazol-5-yl) acetamide;
2- [ 4-chloro-2- (2-furoyl) phenoxy ] -N- (1H-indazol-5-yl) acetamide;
2- [ 4-chloro-2- (3-thienylcarbonyl) phenoxy ] -N- (1H-indazol-5-yl) acetamide;
2- [ 4-chloro-2- (2-thienylcarbonyl) phenoxy ] -N- { 2-methyl-4- [3- (4-morpholino) propoxy ] phenyl } acetamide;
2- [ 4-chloro-2- (2-thienylcarbonyl) phenoxy ] -N- [4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- { 2-methyl-4- [3- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) propoxy ] phenyl } acetamide;
2- [ 4-chloro-2- (2-furoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (sulfamoyl) -2-methylphenyl ] -acetamide;
2- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (2-thienylcarbonyl) phenoxy ] acetamide;
2- [2- (1-benzofuran-2-ylcarbonyl) -4-chlorophenoxy ] -N-phenylacetamide;
2- [ 4-chloro-2- (1, 3-thiazol-2-ylcarbonyl) phenoxy ] -N-phenylacetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (2-furoyl) phenoxy ] acetamide;
2- [ 4-chloro-2- (2-furoyl) phenoxy ] -N- (1H-indazol-6-yl) acetamide;
2- [ 4-chloro-2- (3-furoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-thienylcarbonyl) phenoxy ] -N- [4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-thienylcarbonyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- { 4-chloro-2- [ (1-methyl-1H-pyrrol-2-yl) carbonyl ] phenoxy } -N-phenylacetamide;
2- (4-chloro-2- { [5- (2-pyridinyl) -2-thienyl ] carbonyl } phenoxy) -N-phenylacetamide;
2- [ 4-chloro-2- (1, 3-thiazol-2-ylcarbonyl) phenoxy ] -N- (1H-indazol-5-yl) acetamide;
2- [ 4-chloro-2- (1, 3-thiazol-2-ylcarbonyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-pyridylcarbonyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [2- (2-bromobenzoyl) -4-chlorophenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [2- (4-bromobenzoyl) -4-chlorophenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [2- (2-bromo-benzoyl) -4-chlorophenoxy ] -N- [4- (sulfamoyl) -2-methylphenyl ] -acetamide;
2- { 4-chloro-2- [ (5-methyl-3-isoxazolyl) carbonyl ] phenoxy } -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-fluorobenzoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-chlorobenzoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-fluorobenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-chlorobenzoyl) phenoxy ] acetamide;
2- { 4-chloro-2- [ (4-cyano-2-thienyl) carbonyl ] phenoxy } -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- { 4-chloro-2- [ (4-cyano-2-thienyl) carbonyl ] phenoxy } acetamide;
2- { 4-chloro-2- [3- (trifluoromethyl) benzoyl ] phenoxy } -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [2- (3-bromobenzoyl) -4-chlorophenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [2- (3-bromo-benzoyl) -4-chlorophenoxy ] -N- [4- (sulfamoyl) -2-methylphenyl ] -acetamide;
2- [ 4-chloro-2- (3-methylbenzoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] -N- (5-methyl-1H-indazol-6-yl) acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-pyridylcarbonyl) phenoxy ] acetamide;
2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] -N- { 2-methyl-4- [3- (1-pyrrolidinyl) propoxy ] phenyl } acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- { 4-chloro-2- [ (1-methyl-1H-imidazol-2-yl) carbonyl ] phenoxy } acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (1, 3-thiazol-2-ylcarbonyl) phenoxy ] acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- { 2-methyl-4- [3- (1-pyrrolidinyl) propoxy ] phenyl } acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- (1, 3-benzothiazol-6-yl) -acetamide;
2- (4-chloro-2- {3- [ (trifluoromethyl) thio (sulfanyl) ] benzoyl } phenoxy) -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-ethynylbenzoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3, 5-dichlorobenzoyl) phenoxy ] -N- [ 2-methyl-4- (1-oxo-1 λ -4-, 4-thiazinan-4-yl) phenyl ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-dichlorobenzoyl) phenoxy ] acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] N- (1, 3-benzothiazol-6-yl) -acetamide;
2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] -N- (2-methyl-1, 3-benzothiazol-5-yl) acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- (4-chloro-2- {3- [ (trifluoromethyl) sulfanyl ] benzoyl } phenoxy) acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-ethynylbenzoyl) phenoxy ] acetamide;
2- (2-benzoyl-4-chlorophenoxy) -N- [4- (methylsulfonyl) phenyl ] acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- { 4-chloro-2- [3- (2-cyclopentylethynyl) benzoyl ] phenoxy } acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- (5-methyl-1H-indazol-6-yl) acetamide;
2- [ 4-chloro-2- (3, 5-dichlorobenzoyl) phenoxy ] -N- (5-methyl-1H-indazol-6-yl) acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- { 4-chloro-2- [3- (2-phenylethynyl) benzoyl ] phenoxy } acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- (5-methyl-1H-indazol-6-yl) acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- [ 2-methyl-4- (methylsulfonyl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] N- (1, 2-benzisothiazol-5-yl) -acetamide;
2- [ 4-chloro-2- (3, 5-dichlorobenzoyl) phenoxy ] -N- (5-methyl-1H-benzoimidazol-6-yl) acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- (5-methyl-1H-benzimidazol-6-yl) acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- (5-methyl-1H-benzimidazol-6-yl) acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -1- (2, 3-dihydro-1H-indol-1-yl) -1-ethanone;
2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] -N- [ 2-methyl-4- (methylsulfonyl) phenyl ] acetamide;
2- [ 4-chloro-2- (3-ethynylbenzoyl) phenoxy ] -N- [ 2-methyl-4- (methylsulfonyl) phenyl ] acetamide;
n- {4- [3- (aminosulfonyl) propoxy ] -2-methylphenyl } -2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] acetamide;
2- {2- [3, 5-bis (trifluoromethyl) benzoyl ] -4-chlorophenoxy } -N- (5-methyl-1H-benzimidazol-6-yl) acetamide;
2- {2- [ (5-bromo-3-pyridinyl) carbonyl ] -4-chlorophenoxy } -N- (5-methyl-1H-benzimidazol-6-yl) acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- (6-methyl-1, 3-benzothiazol-5-yl) acetamide;
n- {4- [3- (aminosulfonyl) propoxy ] -2-methylphenyl } -2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- (4-chloro-2- {3- [ (trifluoromethyl) sulfonyl ] benzoyl } phenoxy) acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- [4- (1, 3-thiazol-2-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- [4- (1, 3-oxazol-2-yl) phenyl ] acetamide;
2- [ 4-chloro-2- (3, 5-difluorobenzoyl) phenoxy ] -N- {4- [ (3-hydroxypropyl) sulfonyl ] -2-methylphenyl } acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- (2-methyl-4- {3- [ (methylamino) sulfonyl ] propoxy } phenyl) acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- (4- {3- [ (dimethylamino) sulfonyl ] propoxy } -2-methylphenyl) acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- {2- [ (5-bromo-3-pyridinyl) carbonyl ] -4-chlorophenoxy } acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- {4- [3- (1H-imidazol-1-yl) propoxy ] -2-methylphenyl } acetamide;
2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } -N- { 2-methyl-4- [ (E) -4- (1-pyrrolidinyl) -1-butenyl ] phenyl } acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyano-5-fluorobenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] acetamide;
n- [6- (aminosulfonyl) -4-methyl-3-pyridinyl ] -2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-chloro-5-cyanobenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-dimethylbenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyano-5-ethylbenzoyl) phenoxy ] acetamide;
2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] -N- {4- [3- (2, 5-dihydro-1H-pyrrol-1-yl) propoxy ] -2-methylphenyl } acetamide hydrochloride;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-chloro-5-methylbenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-dichlorobenzoyl) phenoxy ] acetamide;
n- [4- (aminosulfonyl) -2-methylphenyl ] -2- { 4-chloro-2- [ (6-cyano-2-pyridinyl) carbonyl ] phenoxy } acetamide;
2- [6- (sulfamoyl) -2-methyl-3-pyridyl ] -2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] acetamide;
2- [4- (sulfamoyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-dicyanobenzoyl) phenoxy ] acetamide;
2- { 4-chloro-2- [ 3-cyano-5- (trifluoromethyl) benzoyl ] phenoxy } acetamide;
And pharmaceutically acceptable derivatives thereof.
Preferred compounds of the invention include the following numbered compounds: 7. 32, 33, 36, 38, 44, 45, 49, 51, 52, 61, 65, 66, 71, 75, 76, 111, 112, 115, 118, 119, 128, 129, 171, 172, 191, 192, 199, 200, 206, 207, 224, 225, 232, 233, 235, 236, 246, 247, 253, 254, 255, 256, 259, 260, 261, 262, 264, 265, 267, 268, 288, 289, 290, 409, 412, 428, 430, 431, 433, 491, 564, 587, 475, 478, 498, 593, 483, 637, 503, 601, 658 and pharmaceutically acceptable derivatives thereof.
More preferred compounds of the invention are selected from the group consisting of N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyanobenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-fluoro-5- (trifluoromethyl) benzoyl ] acetamide, N- {4- [3- (aminosulfonyl) propoxy ] -2-methylphenyl } -2- { 4-chloro-2- [ 3-fluoro-5- (trifluoromethyl) benzoyl ] phenoxy } acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro- 2- (3-cyano-5-fluorobenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] acetamide, N- [6- (aminosulfonyl) -4-methyl-3-pyridinyl ] -2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-chloro-5-cyanobenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylbenzoyl ] -2- [ 4-chloro, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-dimethylbenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyano-5-ethylbenzoyl) phenoxy ] acetamide, 2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] -N- {4- [3- (2, 5-dihydro-1H-pyrrol-1-yl) propoxy ] -2-methylphenyl } acetamide hydrochloride, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-cyano-5-methylbenzoyl) phenoxy ] acetamide, N- {4- [3- (2, 5-dihydro-1H-pyrrol-1-yl), N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3-chloro-5-methylbenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-dichlorobenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- { 4-chloro-2- [ (6-cyano-2-pyridinyl) carbonyl ] phenoxy } acetamide, N- [6- (aminosulfonyl) -2-methyl-3-pyridinyl ] -2- [ 4-chloro-2- (3-cyano- 5-methylbenzoyl) phenoxy ] acetamide, N- [4- (aminosulfonyl) -2-methylphenyl ] -2- [ 4-chloro-2- (3, 5-dicyanobenzoyl) phenoxy ] acetamide, and pharmaceutically acceptable derivatives thereof.
Preferred compounds of the invention are those wherein R is as defined above, except that one or more other substituents are1Is C substituted in the meta position, especially by halogen6-14Aryl and wherein R3Is hydrogen and R4Is composed of C1-8Alkyl, especially methyl, substituted C6-14And (4) an aryl group.
The term "alkyl", alone or in combination with any other term, refers to a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, n-hexyl, and the like.
The term "alkenyl", alone or in combination with any other term, refers to a straight or branched chain alkyl group containing at least one carbon-carbon double bond. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, hexenyl, hexadienyl, and the like.
The term "alkynyl" refers to a hydrocarbon group of straight or branched configuration containing at least one or more carbon-carbon triple bonds, which may occur at any stable point along the chain, such as ethynyl, propynyl, butynyl, pentynyl, and the like.
The term "alkoxy" refers to an alkyl ether group, wherein the term "alkyl" is as defined above. Examples of suitable alkyl ether groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "aryl", alone or in combination with any other term, refers to a carbocyclic aromatic group (e.g., phenyl or naphthyl) containing the indicated number of carbon atoms, preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to: phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl and the like.
The term "heterocycle" or "heterocyclic" as used herein refers to a 3-to 7-membered monocyclic heterocycle or an 8-to 11-membered bicyclic heterocycle, which is saturated, partially saturated or unsaturated, and which, when monocyclic, may optionally be benzo-fused. Each heterocyclic ring is composed of one or more carbon atoms and 1 to 4 heteroatoms selected from N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and includes any bicyclic group in which any heterocyclic ring as defined above is fused to a benzene ring. The heterocyclic ring may be attached to any carbon or heteroatom that results in the creation of a stable structure. Preferred heterocycles include 5-7 membered monocyclic heterocycles and 8-10 membered bicyclic heterocycles. Examples of such groups include imidazolyl, imidazolinyl, imidazolidinyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, indazolinyl (indolizolinyl), perhydropyridazinyl, pyridazinyl (pyridazyl), pyridyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxalinyl (quinoxolyl), piperidinyl, pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, morpholinyl, thiomorpholinyl, furanyl, thienyl, triazolyl, thiazolyl, carbolinyl, tetrazolyl, thiazolidinyl, benzofuranyl, thiomorpholinyl sulfone, oxazolyl, benzoxazolyl, oxopiperidinyl, oxopyrrolidinyl, oxazepine *, aza * yl, isoxazolyl, isothiazolyl, furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazolyl, dioxolyl, dioxathiostyryl, oxathinyl, thiazolyl, triazolyl, pyrazolyl, etc, Benzodioxolyl, dithiacyclopentadienyl, thienyl, tetrahydrothienyl, sulfolane, dioxanyl, dioxolanyl, tetrahydrofurandihydrofuranyl, tetrahydropyrandihydrofuranyl, dihydropyranyl, tetrahydrofuranyhydrofuranyl and tetrahydropyranyhydrofuranyl groups.
Preferred heterocycles include imidazolidinyl, indazolyl, pyrrolidinyl, thiomorpholinyl, thienyl, furyl, benzofuryl, thiazolyl, oxazolyl, pyrrolyl, indolinyl, benzothiazolyl, pyridyl, quinolinyl and benzothienyl
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "pharmaceutically effective amount" refers to an amount effective to treat a viral infection, such as an HIV infection, in a patient as monotherapy or in combination with other drugs. The term "treating" as used herein refers to alleviating the symptoms of a particular disease in a patient, or ameliorating a detectable measure associated with a particular disease, and may include inhibiting the recurrence of symptoms in an asymptomatic patient, such as a patient in which the viral infection is recessive. The term "prophylactically effective amount" refers to an amount effective to prevent viral infection, such as HIV infection, or to prevent the onset of symptoms in a patient having such infection. As used herein, the term "patient" refers to a mammal, including a human.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient with a compound of the present invention that does not destroy the pharmacological activity of the compound of the present invention and is non-toxic when administered in a dosage sufficient to release a therapeutic amount of the antiviral agent.
As used herein, a compound according to the present invention is defined to include pharmaceutically acceptable derivatives thereof. By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the invention, which is capable of providing (directly or indirectly) a compound of the invention or an inhibitory metabolite or residue thereof upon administration to a recipient. Particularly advantageous derivatives and prodrugs are those compounds which, when administered to a mammal, are those compounds which, e.g., by oral administration, are more readily absorbed into the blood, increase the bioavailability of the compounds of the invention or facilitate, relative to the parent drug, delivery of the parent compound to a biological compartment, e.g., the brain or lymphatic system. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Other acids, such as oxalic, while not per se pharmaceutically acceptable, may be used as intermediates in the preparation of the salts to obtain the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from suitable bases include alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammoniumAnd NW +4 (where W is C)1-4Alkyl) salts. Physiologically acceptable salts of hydrogen atoms or amino groups include salts or organic carboxylic acids such as acetic acid, lactic acid, tartaric acid, maleic acid, isethionic acid, lactobionic acid and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid. Pharmaceutically acceptable salts of compounds having a hydroxy group include those with a suitable cation such as Na+、NH4 +And NW4 +(wherein W is C1-4Alkyl) to the anion of said compound.
The esters of the compounds according to the invention are independently selected from the following groups: (1) carboxylic acid esters obtained by esterification of a hydroxyl group, wherein the non-carbonyl moiety of the carboxylic acid moiety of the ester is selected from the group consisting of linear or branched alkyl (such as ethyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (such as methoxymethyl), aralkyl (such as benzyl), aryloxyalkyl (such as phenoxymethyl), aryl (such as substituted by, for example, halogen, C, or N-alkyl), and the like1-4Alkyl radical, C1-4Phenyl optionally substituted with alkoxy or amino); (2) sulfonates, such as alkyl-or aralkylsulfonyl (e.g., methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonates and (5) mono-, di-or triphosphates. The phosphate ester may be represented by, for example, C 1-20Alcohols or reactive derivatives thereof, or by 2, 3-di (C)6-24) The acylglycerols are further esterified.
In such esters, unless otherwise specified, any alkyl moiety herein advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters is advantageously to include phenyl.
Any reference to any of the above compounds also includes references to pharmaceutically acceptable salts thereof.
In a further aspect of the invention there is provided a compound according to the invention for use in medical therapy, in particular in the treatment or prophylaxis of viral infections such as HIV infections. The compounds according to the invention have been shown to be active in inhibiting HIV infection, although these compounds are also active in inhibiting HBV infection.
The compounds according to the invention are particularly suitable for the treatment or prophylaxis of HIV infections and related diseases. The treatment referred to herein extends to the prevention and treatment of established infections, symptoms and associated clinical conditions such as AIDS-related complex (ARC), Kaposi's sarcoma and AIDS dementia.
According to a particular embodiment of the present invention, there is provided a method of treating a mutant virus infection of HIV that exhibits resistance to NNRTI drugs, the method comprising administering to a mammal, especially a human, a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable derivative thereof. In particular, the compounds of the invention may be used for the treatment of wild type HIV-1 as well as several drug resistant mutants, e.g., K103N, L1001 or Y181C infections.
According to another aspect, the present invention provides a method of treating or preventing the symptoms or effects of a viral infection in an infected animal, for example a mammal including a human, which method comprises treating said animal with a therapeutically effective amount of a compound according to the present invention. According to a particular embodiment of the invention, the viral infection is a retroviral infection, in particular an HIV infection. Another aspect of the invention includes a method of treating or preventing symptoms or effects of HBV infection.
The compounds according to the invention may also be used as adjunctive therapy in the treatment of HIV infection or HIV-related symptoms or effects, such as kaposi's sarcoma.
The present invention also provides a method of treating clinical conditions, including those discussed in the preamble, in an animal, e.g. a mammal, including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the present invention. The invention also includes methods of treating or preventing any of the above infections or diseases.
In another aspect, the invention provides the use of a compound according to the invention in the manufacture of a medicament for the treatment or prevention of any of the viral infections or diseases described above.
The above compounds and pharmaceutically acceptable derivatives thereof according to the present invention may be used in combination with other therapeutic agents for the treatment of the above infections or diseases. The combination therapy according to the present invention comprises the administration of at least one compound of the present invention or a pharmaceutically acceptable derivative thereof and at least one further pharmaceutically active ingredient. The active ingredient and pharmaceutically active agent may be administered simultaneously or sequentially in any order in the same or different pharmaceutical formulations. The amounts and relative timing of administration of the active ingredients and pharmaceutically active agents can be selected to achieve the desired effect of the combination therapy. Preferably the combination therapy comprises the administration of a compound according to the invention and a drug to be mentioned hereinafter.
Examples of such other therapeutic agents include drugs effective for the treatment of viral infections or related diseases, for example, (1 α, 2 β, 3 α) -9- [2, 3-bis (hydroxymethyl) cyclobutyl]Guanine [ (-) BHCG, SQ-34514]Oxacyclocycline-G (3, 4-bis- (hydroxymethyl) -2-oxolanyl) guanine), acyclic nucleosides (e.g., acyclovir, valacyclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleosides phosphate (e.g., (S) -1- (3-hydroxy-2-phosphono-methoxypropyl) cytosine (HPMPC), PMEA ribonucleotide reductase inhibitors such as 2-acetylpyridine 5- [ (2-chloroanilino) thiocarbonyl ]Thiocarbonylhydrazone (thiocarbohydrazone), 3 '-azido-3' -deoxythymidine, other 2 ', 3' -dideoxynucleosides such as 2 ', 3' -dideoxycytidine, 2 ', 3' -dideoxyadenosine, 2 ', 3' -dideoxyinosine, 2 ', 3' -didehydrothymidine, protease inhibitors such as indinavir, ritonavir, nelfinavir, amprenavir, oxathiolane (oxathiolane) nucleoside analogues such as cis (-) -1- (2-hydroxymethyl) -1, 3-oxathiolan-5-yl) -cytosine (lamivudine) or cis-1- (2-hydroxymethyl) -1, 3-oxathiolan-5-yl) -5-Fluorocytosine (FTC), 3 '-deoxy-3' -Fluorothymidine (FTC), 5-chloro-2 ', 3 ' -dideoxy-3 ' -fluorouridine, (-) -cis-4- [ 2-amino-6- (cyclopropylamino) -9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir), ribavirin,9- [ 4-hydroxy-2- (hydroxymethyl) but-1-yl]Guanine (H2G), tat inhibitors such as 7-chloro-5- (2-pyrrolyl) -3H-1, 4-benzodiazepine * -2- (H) one (Ro5-3335), 7-chloro-1, 3-dihydro-5- (1H-pyrrol-2-yl) -3H-1, 4-benzodiazepine * -2-amine (Ro24-7429), interferons such as alpha-interferon, renal secretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole, pentoxifylline, N-acetylcysteine (NAC), Procysteine, alpha-trichosanthin, phosphonoformic acid, and immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factor, erythropoietin, Soluble CD 4And their genetically engineered derivatives, or other non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine (BI-RG-587), loviramine (alpha-APA) and delavirdine (BHAP), and phosphonoformic acid and 1, 4-dihydro-2H-3, 1-benzoxazin-2-one NNRTIs such as (-) -6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1, 4-dihydro-2H-3, 1-benzoxazin-2-one (L-743726 or DMP-266), and quinoxaline NNRTIs such as (2S) -7-fluoro-3, 4-dihydro-2-ethyl-3-oxo-1 (2H) -quinoxalinecarboxylic acid isopropyl ester (HBY 1293).
The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
More preferred combination therapies comprise administration of one of the above-mentioned agents and one compound in one of the preferred or particularly preferred subgroups of formulae (I) - (IV) as described above, including formulae IA, IB, IC and ID. Most preferably, the combination therapy comprises the combined use of one of the above mentioned drugs and one of the compounds of the invention specifically mentioned herein.
The invention also includes the use of a compound according to the invention in the manufacture of a medicament for simultaneous or sequential administration with at least one other therapeutic agent, such as those defined above.
The compounds of the present invention may be synthesized by the following methods or by any method known in the art.
The compounds of the invention may be prepared according to representative schemes I-XXXIV, which are illustrated below. The compounds that can be prepared according to these schemes are not limited by the compounds included in the schemes or by any particular substituents used in these schemes for illustration purposes.
Compounds of formulae IV and V (wherein R is R) can be readily prepared using suitable coupling conditions known in the art1、R2、R3、R4And R5As defined above and R6Is hydrogen) to the preparation of R1A compound of formula (I) as defined above.
NHR3R4
I IV v
For example, a compound of formula IV may be reacted with a compound of formula V in the presence of a suitable dehydrating agent such as carbodiimide, Dicyclohexylcarbodiimide (DCC), for example or more preferably in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC). In addition, the presence of a suitable activator, such as 1-hydroxybenzotriazole (HOBt), is often required to promote efficient coupling of the carboxylic acid with the appropriate amine. These reactions are typically carried out in an aprotic solvent such as acetonitrile, tetrahydrofuran or more preferably in N, N-Dimethylformamide (DMF) at 0-150 ℃, most preferably at room temperature. For example, carboxylic acid 49 (scheme I) is reacted with amine 399 in DMF and in the presence of EDAC and HOBt at room temperature to give compound 46.
Scheme I
Alternatively, one may first make R therein1、R2And R5A compound of formula IV as defined above is converted to the corresponding acid chloride, which is then reacted with a compound of formula IV wherein R3And R4The compound of formula V as defined above is reacted to give compound (I). Need to makeThe preparation of the acid chloride may be accomplished by methods well known in the art. The carboxylic acid may be reacted with a suitable dehydrating agent such as thionyl chloride or more preferably oxalyl chloride. These reactions are generally carried out in aprotic solvents such as acetonitrile or pyridine or halogenated solvents such as chloroform or more preferably dichloromethane. The corresponding acid chloride is usually not isolated in pure form but can be reacted directly with the compound of the formula V. Most commonly, the reaction of the acid chloride is carried out in an aprotic solvent such as acetonitrile or chloroform, or more preferably in acetone. Furthermore, the presence of compounds capable of acting as bases, such as triethylamine or pyridine, or more preferably sodium bicarbonate, is required in order to obtain a sufficient yield of the coupling product. When an inorganic base such as sodium bicarbonate is used, a small amount of water may be added to the reaction mixture to promote efficient coupling reactions. For example, carboxylic acid 71 (scheme II) is reacted with oxalyl chloride in dichloromethane in the presence of a catalytic amount of DMF to give the corresponding acid chloride. The acid chloride is then reacted with an amine 466 in a mixture of acetone and water in the presence of sodium bicarbonate to provide compound 78.
Scheme II
Finally, by compounds of the formula VI (wherein R is7Is hydrogen) with a compound of the formula VII (in which R is2、R3And R4As defined above, and R8In which R is a suitable leaving group such as halogen, preferably chlorine or bromine, or mesylate or p-toluenesulfonate) can be readily prepared1-R5A compound of formula I as defined above.
The alkylation of the compound of formula VI by the compound of formula VII is typically carried out in an aprotic solvent such as acetonitrile, DMF or more preferably in acetone. Furthermore, the presence of compounds capable of acting as bases, such as triethylamine, pyridine, or more preferably sodium carbonate, is generally required to promote efficient reactions. Moreover, the reaction is generally carried out at relatively high temperatures of from 40 to 100 ℃. For example, phenol 4 (scheme III) is reacted with 2' -chloro-N-acetanilide in the presence of sodium carbonate in refluxing acetone to give compound 1.
Scheme III
By reacting a compound of formula VI (R thereof)1And R5As defined above and R7Is hydrogen) with a compound of the formula VIII (wherein R is6Is C1-6Alkyl radical, R2As defined above, R8For a suitable leaving group such as halogen, preferably chlorine or bromine, or mesylate or p-toluenesulfonate) to prepare a compound of the formula IV in which R is1、R2And R5As defined above and R 6Is C1-6An alkyl group. Typically the reaction is carried out in an aprotic solvent such as acetonitrile, DMF or more preferably acetone at a temperature in the range 40-100 ℃. In addition, for efficient reaction, the presence of a base such as triethylamine, pyridine, or more preferably potassium carbonate is generally required. For example, reaction of phenol 47 (scheme IV) with ethyl bromoacetate in refluxing acetone and in the presence of potassium carbonate affords ester 48.
The compounds of formula VIII are either commercially available or can be prepared using literature methods known in the art.
Procedure IV
From the compound of formula IV (R thereof) by reaction with an aqueous base or other suitable methods known in the art1、R2And R5As defined above and R6Is C1-6Alkyl) can be prepared to compounds of formula IV, wherein R is1、R2And R5As defined above and R6Is hydrogen. Various inorganic bases, such as sodium carbonate, sodium hydroxide or more preferably lithium hydroxide, can be used to carry out the saponification of the ester of formula IV. Typically, these reactions are carried out in water, but also in a solvent which is miscible with water and which is capable of dissolving the compound of formula IV, such as tetrahydrofuran, methanol or ethanol.
For example, ester 48 (scheme V) is reacted with lithium hydroxide in a mixture of THF, water, and ethanol to provide carboxylic acid 49.
Procedure V
The following is a scheme showing the preparation of compounds of formula VI, wherein R1And R5As defined above, R7Is hydrogen or methyl. Wherein R is1And R5As defined above and R7Compounds of formula VI which are methyl may be prepared by reacting a compound of formula VI wherein R is5As defined above and R7A compound of formula IX which is methyl and wherein R1And R10A compound of formula X as defined above, with the further proviso that these groups are chemically compatible with the reaction conditions, R7Is methyl, R9Is halogen, preferably bromine or iodine, and R10Is N, O-dimethylhydroxyamino.
The compound of formula IX is typically treated with a reagent capable of undergoing a halogen-metal exchange reaction, such as sec-butyllithium, methyllithium, tert-butyllithium, or more preferably n-butyllithium. The halogen-metal exchange can be carried out in an ethereal solvent, such as THF, dioxane or more preferably diethyl ether, at a low temperature of-100 to 0 ℃, more preferably-78 ℃. After completion of the halogen-metal exchange reaction, the resulting compound of formula IX (wherein R is9Lithium) with a compound of formula X again in an ether solvent and at low temperature. For example, in2-bromo-4-chloroanisole (scheme VI) was treated with n-butyllithium in diethyl ether at-78 ℃. After 15 minutes at-78 deg.C, the resulting lithium species is reacted with amine 68 to provide the desired ketone 69.
Scheme VI
Wherein R is5As defined above, R7Is methyl and R9The compounds of formula IX, which are bromine or iodine, are either commercially available or can be prepared using literature methods known in the art.
Compounds of formula X (wherein R is R) can be prepared from compounds of formula X (wherein R is R) by reaction with N, O-dimethylhydroxylamine in an aprotic solvent, preferably acetonitrile, chloroform or dichloromethane, in the presence of a base, preferably triethylamine10Preparation of a Compound of formula X (wherein R is chlorine) for a suitable leaving group, preferably chlorine1As defined above and R10Is N, O-dimethylhydroxyamino). By literature methods known in the art, for example, reaction with oxalyl chloride in an aprotic solvent, preferably dichloromethane or chloroform, and in the presence of catalytic amounts of DMF, can be prepared from10Preparation of a Compound of formula X wherein R is hydroxy10A compound of formula X which is chloro. For example, 1-methyl-2-pyrrolidinecarboxylic acid (scheme VII) is reacted with an excess of oxalyl chloride in dichloromethane in the presence of catalytic amounts of DMF. The acid chloride produced cannot be isolated in pure form but is reacted with N, O-dimethylhydroxylamine in chloroform and in the presence of triethylamine to give the amide 14.
Scheme VII
Or, wherein R1And R5As defined above and R7Compounds of formula VI which are methyl may be prepared by reacting a compound of formula IX with a compound of formula VI wherein R is 1And R5A compound of formula X as defined above, but concomitantly therewithProvided that in one step, these groups are chemically compatible with the reaction conditions, R7Is methyl, R9Is halogen, preferably bromine or iodine, and R10Is N, O-dimethylhydroxyamino. Compounds of formula IX may be converted into wherein R9Substances which are magnesium halides, such as magnesium bromide or magnesium iodide, so-called Grignard reagents. Then reacting such materials containing a magnesium halide with R10Reacting a compound of formula X which is N, O-dimethylhydroxyamino. These reactions are usually carried out in ethereal solvents such as THF, dioxane or diethyl ether at 0-100 deg.C, preferably at room temperature. Wherein R can be achieved by literature methods known in the art9Preparation of the compound of formula IX as a magnesium halide. In general, the formula is such that R9The compound of formula IX, which is bromine or iodine, is reacted with elemental magnesium in an aprotic solvent, an ether solvent.
Or, by reaction with R wherein1As defined above and R10Reaction of a compound of formula X, which is hydrogen, with a compound of formula IX (wherein R is5As defined above, R7Is methyl and R9Is halogen, preferably bromine or iodine) may be prepared wherein R1And R5As defined above and R7A compound of formula VI which is methyl, with the proviso that R is1Chemically compatible with the subsequent reaction conditions. Wherein R is 1As defined above and R10Compounds of formula X which are hydrogen are either commercially available or may be prepared using literature methods known in the art. In an ethereal solvent, preferably diethyl ether, at low temperature, preferably-78 ℃, in which R is first treated with a reagent capable of undergoing a halogen-metal exchange reaction, preferably n-butyllithium9A compound of formula IX which is bromine or iodine. In the formation of R9After being a lithium compound of formula IX, it is reacted with R10The compound of formula X, which is hydrogen, reacts to give an intermediate alcohol. The intermediate alcohol is then treated with a reagent capable of oxidizing the alcohol to a compound of formula VI, preferably an oxidizing agent which is magnesium (IV) oxide. The oxidation reaction is generally carried out in an aprotic solvent, preferably chloroform or dichloromethane, and at room temperature. For example, 2-bromo-4-chloroanisole is treated with n-butyllithium in diethyl ether at-78 ℃. Then the obtained lithium compoundThe intermediate alcohol 2 is obtained by the reaction of the intermediate alcohol and 2-thiazole formaldehyde. Alcohol 2 is then reacted with excess manganese dioxide at room temperature to afford ketone 3.
Scheme VIII
Or, wherein R1And R5As defined above and R7Compounds of formula VI which are methyl may be prepared by reacting a compound of formula IX with a compound of formula VI wherein R is1And R5A compound of formula X as defined above, with the further proviso that these groups are chemically compatible with the reaction conditions, R 7Is methyl, R9Is halogen, preferably bromine or iodine, and R10And (3) hydrogen. Compounds of formula IX may be converted into wherein R9Substances which are magnesium halides, such as magnesium bromide or magnesium iodide, so-called Grignard reagents. Then reacting such materials containing a magnesium halide with R10The compound of formula X, which is hydrogen, reacts to give an intermediate alcohol. These reactions are usually carried out in ethereal solvents such as THF, dioxane or diethyl ether at 0-100 deg.C, preferably at room temperature. Wherein R can be achieved by literature methods known in the art9Preparation of the compound of formula IX as a magnesium halide. In general, the formula is such that R9A compound of formula IX, which is bromine or iodine, is reacted with elemental magnesium in an aprotic, ether solvent. The intermediate alcohol is then reacted with a substance capable of oxidizing the alcohol to the desired ketone, preferably manganese (IV) oxide, in an aprotic solvent, preferably dichloromethane or chloroform, and at room temperature.
Finally, where R is1And R5As defined above and R7Compounds of formula VI which are methyl may be prepared by reacting a compound of formula VI wherein R is5A compound of formula XII as defined above and wherein R1As defined above and R11A compound of formula XIII which is halogen, preferably bromine or iodine, with the concomitant further proviso that R is1And R5Is chemically compatible with subsequent chemical steps.
R1-R11
XII XIII
The compound of formula XIII, wherein R is treated with a reagent capable of halogen-metal exchange reaction, preferably n-butyllithium, usually in an ethereal solvent, preferably diethyl ether, at low temperature, preferably-78 deg.C11Is halogen, preferably iodine or bromine.
Or, wherein R1And R5As defined above and R7Compounds of formula VI which are methyl may be prepared by reacting a compound of formula XII with a compound of formula XII wherein R is1And R5A compound of formula XIII as defined above, with the further proviso that these groups are chemically compatible with the reaction conditions, and R11Is halogen, preferably bromine or iodine. Compounds of formula XIII may be converted into those in which R11Substances which are magnesium halides, such as magnesium bromide or magnesium iodide, so-called Grignard reagents. Such materials containing magnesium halide are then reacted with compounds of formula XII to give the desired ketone. These reactions are usually carried out in ethereal solvents such as THF, dioxane or diethyl ether at 0-100 deg.C, preferably at room temperature. Wherein R can be achieved by literature methods known in the art11Preparation of a compound of formula XIII which is a magnesium halide. In general, the formula is such that R11A compound of formula XIII, being bromine or iodine, is reacted with elemental magnesium in an aprotic solvent, an ether solvent.
Wherein R is11Compounds of formula XIII which are halogens, preferably bromine or iodine, are either commercially available or can be prepared by literature methods.
Alternatively, a compound of formula VI (wherein R is a compound of formula VI) may be prepared by reaction with a reagent capable of demethylating an aryl methyl ether7Is methyl) to the preparation of a compound in which R is1And R5As defined above and R7A compound of formula VI which is hydrogen, with the proviso that R1And R5Are chemically stable under these reaction conditions. Reagents useful in demethylation of aryl methyl ethersAmong these are trimethylsilyl iodide, Lewis acids such as aluminum chloride, or more preferably boron tribromide. These reactions are generally carried out in aprotic solvents, such as chloroform or dichloromethane, and at temperatures of-78 ℃ to 100 ℃, preferably-78 ℃ to room temperature. For example, ketone 69 (scheme IX) is reacted with excess boron tribromide in dichloromethane at-78 deg.C to afford phenol 70.
Procedure IX
Or, wherein R1And R5As defined above and R7Compounds of formula VI which are hydrogen may be prepared by reacting compounds of formula IX, wherein R is5As defined above, R9Is hydrogen and R7Is methyl, and wherein R1As defined above and R10A compound of formula X which is halogen, preferably chlorine, is prepared by reaction, but with the further proviso that R is1And R5Is chemically compatible with the reaction conditions. These reactions, commonly known as Friedel-Craft acylation reactions, are carried out in aprotic solvents such as nitrobenzene, 1, 2-dichloroethane, sulfolane, or more preferably dichloromethane, at temperatures of 0 to 150 deg.C, preferably 35 to 60 deg.C. Furthermore, it is desirable to use a compound capable of acting as a Lewis acid, such as titanium (IV) chloride, tin (IV) chloride, or more preferably aluminum chloride. For example, 4-chloroanisole (scheme X) is reacted with 3, 5-difluorobenzoyl chloride in the presence of aluminum chloride in refluxing dichloromethane to afford ketone 47.
Procedure X
Wherein R is1As defined above and R10The compounds of formula X which are halogen are either commercially available or can be prepared by literature methods. Alternatively, by a compound of formula IX (wherein R5As defined above, R7And R9Is hydrogen) with a compound of the formula X (wherein R is1As defined above and R10Is halogen, preferably chlorine), may be prepared1And R5As defined above and R7A compound of formula VI which is hydrogen. These reactions, commonly referred to as Fries rearrangement, are carried out in aprotic solvents such as nitrobenzene, sulfolane or chloroform at temperatures of 0 to 150 ℃. In addition, the reaction generally requires the presence of a compound capable of acting as a Lewis acid, such as aluminum chloride. A compound of formula IX, wherein R5As described above and R9And R7Are hydrogen or are commercially available or can be prepared by literature methods familiar to those skilled in the art.
Through with C2-8Olefin reaction, from compounds of formula XIV, wherein R5As defined above, R7Is hydrogen, methyl or methylene carboxyl ester and R12Prepared from C for a group capable of undergoing a palladium-catalysed reaction, e.g. bromo, iodo or triflate2-8Alkenyl-substituted compounds of the formula VI in which R is1Is C6-14Aryl or C6-14A heterocyclic ring. These reactions are typically carried out in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium, bis (acetonitrile) palladium dichloride, or more preferably palladium acetate. The solvent used for these reactions is typically an aprotic solvent, such as acetonitrile, or more preferably DMF. The reaction is generally carried out at a temperature ranging from room temperature to 130 ℃, preferably from 50 to 90 ℃. Furthermore, the presence of a base such as potassium or sodium carbonate, or triethylamine is generally desirable. Finally, the reaction of some substrates may require the addition of compounds capable of stabilizing any intermediate palladium species. The most common of these compounds are triarylarsine or phosphine derivatives such as triphenylphosphine or tri-o-tolylphosphine.
C for these reactions2-8The olefins are either commercially available or can be prepared by literature methods familiar to those skilled in the art.
A compound of the formula XIV, wherein R7And R5As defined above, R12Are groups capable of undergoing palladium-catalyzed reactions, such as bromine, iodine or triflate, or are commercially available or can be prepared by literature methods.
By reaction with a reagent capable of selectively reducing olefinic bonds, from C2-8Alkenyl-substituted compounds of the formula VI in which R is1Is C6-14Aryl radical, preparation from C2-8Alkyl substituted compounds of formula VI, wherein R1Is C6-14Aryl or C6-14A heterocyclic ring. Among the reagents that can be used to carry out the desired reduction are palladium on carbon and Raney nickel. Furthermore, the presence of reducing agents such as ammonium formate or pressurized hydrogen is required. These reactions are usually carried out in a solvent capable of dissolving the olefin substrate, such as ethyl acetate, acetone, methanol or ethanol.
Through with C2-8Alkynes, can be prepared from compounds of the formula XIV, where R5As mentioned above, R7Is hydrogen, methyl or methylene carboxyl ester and R12Is a group capable of undergoing a palladium-catalyzed reaction, preferably iodine or bromine, prepared from C2-8Alkynyl-substituted compounds of formula VI, wherein R1Is C6-14Aryl or C6-14A heterocyclic ring. These reactions are usually carried out in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium, bis (acetonitrile) palladium dichloride or palladium acetate. The solvent used for these reactions is typically an aprotic solvent such as acetonitrile, or more preferably DMF. The reaction is generally carried out at a temperature ranging from room temperature to 130 ℃, preferably from 50 to 90 ℃. Furthermore, the presence of a base such as potassium or sodium carbonate, or triethylamine is generally desirable. Moreover, the reaction of some substrates may require the addition of compounds capable of stabilizing any intermediate palladium species. The most common of these compounds are triarylarsine or phosphine derivatives such as triphenylphosphine or tri-o-tolylphosphine. Finally, these reactions require the presence of catalytic amounts of copper (I) iodide. For example, ester 223 (scheme XI) is reacted with trimethylsilylacetylene in the presence of tetrakis (triphenylphosphine) palladium, triethylamine, and copper (I) iodide to give the intermediate trimethylsilyl-protected product. This intermediate was treated with tetrabutylammonium fluoride in THF, Compound 224 is obtained.
Scheme XI
C for these reactions2-8Alkynes are either commercially available or can be prepared by literature methods familiar to those skilled in the art.
Compounds of formula VI, wherein R is a compound of formula VI, can be prepared by reaction with a composition of reagents capable of reducing the nitro functionality to an amino group1Is C6-14Aryl or C substituted by nitro radicals6-14Aryl heterocycles, preparation of compounds of formula VI, wherein R1Is C6-14Aryl or C substituted by amino6-14Aryl-heterocycles, R5As defined above, and R7Is hydrogen, methyl or methylene carboxyl ester. In the composition of these reagents are a metal-containing compound, such as the element iron, palladium or Raney nickel, and a reducing agent, such as ammonium formate, formic acid, hydrochloric acid or pressurized hydrogen. These reactions are usually carried out in a solvent such as ethyl acetate, acetone, methanol or ethanol at 20-100 deg.C, preferably at room temperature.
A compound of formula VI wherein R1Is C6-14Aryl radicals or C substituted by nitro functional groups6-14Aryl-heterocycles, R5As defined above and R7Hydrogen or methyl, may be prepared by methods previously described herein, or by literature methods known in the art.
By reaction with a reagent capable of oxidizing a sulfide to a sulfone, a compound of formula VI, wherein R 1Is C6-14Aryl radicals or from SR13Substituted C6-14Aryl heterocycles, preparation of compounds of formula VI, wherein R1Is C6-14Aryl radicals or from-SO2R13Substituted C6-14Aryl heterocyclic ring, wherein R5As defined above, R7Is hydrogen, methyl or methylene carboxyl ester and R13Is C1-8Alkyl, which may be substituted by hydroxy, alkylaminoOptionally substituted with halo or halogen. Among the reagents capable of performing the desired, selective oxidation reaction are m-chloroperbenzoic acid (m-CPBA), hydrogen peroxide in acetic acid, and oxone. These reactions are usually carried out in a solvent such as dichloromethane, chloroform, ethanol, water or a mixture of these solvents at 0 to 100 ℃.
A compound of formula VI wherein R1Is C6-14Aryl or by-SR13Substituted C6-14Aryl heterocyclic ring, wherein R13The above definitions may be prepared from commercially available starting materials or may be prepared by literature methods familiar to those skilled in the art.
By reaction with an agent or combination of agents capable of substituting halogen with a nitrile function, it is possible to obtain compounds of formula VI, in which R is1Is C6-14Aryl or C substituted by halogen, preferably bromine or iodine6-14Aryl heterocycles, preparation of compounds of formula VI, wherein R1Is C6-14Aryl or C substituted by nitriles6-14Aryl heterocycles. Among these agents are copper (I) cyanide or palladium catalysts in combination with a suitable cyanide source such as potassium cyanide, sodium cyanide or zinc cyanide. Among the palladium reagents that can be used for this conversion are tetrakis (triphenylphosphine) palladium, palladium acetate or bis (acetonitrile) palladium dichloride. These reactions are generally carried out in an aprotic solvent such as acetonitrile, or more preferably DMF, in the presence of a phosphine ligand such as triphenylphosphine at from 20 to 150 ℃, preferably from 80 to 85 ℃.
A compound of formula VI wherein R1As defined above, R7Is hydrogen, methyl or methylene carboxyl ester and R5Is hydrogen, halogen, nitro, trifluoromethyl, C1-8Alkyl or alkoxy groups may be prepared from commercially available starting materials using the methods described herein or may be prepared by literature methods familiar to those skilled in the art.
By reaction with a reagent or combination of reagents capable of reducing a nitro group to an amino function, from which R may be5A compound of formula VI which is nitro, the preparation of a compound of formula VI wherein R is1As defined above, R7Is hydrogen or methylOr esters of methylene-or-carboxyl groups and R5Is an amino group. In the composition of these reagents are a metal-containing compound, such as the element iron, palladium or Raney nickel, and a reducing agent, such as ammonium formate, formic acid, hydrochloric acid or pressurized hydrogen. These reactions are usually carried out in a solvent such as ethyl acetate, acetone, methanol or ethanol at 20-100 deg.C, preferably at room temperature.
By reaction with a reagent capable of selectively alkylating amino groups, from which R5A compound of formula VI which is an amino group, preparation of a compound of formula VI wherein R1As defined above, R7Is hydrogen, methyl or methylene carboxyl ester and R5Is C1-8An alkylamino group. Among these agents are alkyl halides such as methyl iodide, alkyl sulfonates or alkyl aryl sulfonates. These reactions are usually carried out in polar, aprotic solvents such as N-methylpyrrolidine or DMF at temperatures ranging from room temperature to 150 ℃.
A compound of formula V wherein R3And R4Which may be the same or different, are hydrogen, hydroxy, C1-8Alkyl, heterocycle, C6-14Aryl heterocyclic ring or C6-14Aryl groups are either commercially available or can be prepared by literature methods familiar to those skilled in the art.
A compound of formula V wherein R3Is hydrogen and R4Is prepared from-SO2NR6R7Substituted C6-14Aryl, wherein R6And R7As defined above, or is commercially available, or can be prepared from compounds of formula XV by reaction with an aqueous base or aqueous acid, wherein R is14Is a nitrogen protecting group, such as trifluoromethylacetyl or more preferably acetyl, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R16is-SO2NR6R7. These reactions are generally carried out at temperatures of from 25 to 100 deg.C, preferably from 60 to 70 deg.C, for example in water, methanol, ethanol or mixtures thereof. For example, compound 465 (scheme XII) is reacted with 1N aqueous hydrochloric acid in ethanol at reflux temperature to afford 466.
Scheme XII
By reaction with a suitable amine, a compound of formula XV, wherein R14Is a nitrogen protecting group, such as trifluoromethylacetyl or more preferably acetyl, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R 16is-SO2Cl to prepare a compound of formula V, wherein R3Is hydrogen and R4Is prepared from-SO2NR6R7Substituted C6-14Aryl, wherein R6And R7As defined above. These reactions are usually carried out in a solvent such as ethanol, THF or acetone at a temperature of-10 to 50 deg.C, preferably 20-25 deg.C. For example, sulfonyl chloride 464 (scheme XIII) is reacted with ammonium hydroxide in THF at room temperature to provide sulfonamide 465.
Scheme XIII
By reaction with a reagent capable of converting a sulfonic acid or salt thereof to a sulfonyl chloride, from which R may be16is-SO3H or a salt thereof, to prepare a compound of formula XV, wherein R14Is a nitrogen protecting group, such as trifluoromethylacetyl or more preferably acetyl, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R16is-SO2And (4) Cl. Among the reagents capable of carrying out this conversion are phosphorus oxychloride (POCl)3) Or thionyl chloride. These reactions are carried out in aprotic solvents such as DMF at temperatures of-10 to 100 ℃, preferably at 0 ℃. For example, compound 463 (scheme XIV) is reacted with thionyl chloride in DMF at 0 ℃ to give sulfonyl chloride 464.
Scheme XIV
By reaction with a reagent capable of selectively protecting the amino group, from which R14A compound of formula XV which is hydrogen, the preparation of a compound of formula XV wherein R 14Is a nitrogen protecting group, such as trifluoromethylacetyl or more preferably acetyl, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R16is-SO3H or a salt thereof. Among the reagents capable of carrying out this conversion are trifluoroacetic anhydride, acetyl chloride, or more preferably acetic anhydride. These reactions are carried out in aprotic solvents such as acetonitrile, dichloromethane, chloroform, or more preferably pyridine, and at temperatures of 0-100 deg.C, preferably at room temperature. For example, 2-aminotoluene-5-sulfonic acid (scheme XV) is reacted with acetic anhydride in pyridine at room temperature to provide compound 462.
Procedure XV
A compound of formula XV wherein R14Is hydrogen, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R16is-SO3H or a salt thereof is commercially available or can be prepared by literature methods familiar to those skilled in the art.
By reaction with a reagent or combination of reagents capable of selectively reducing a nitro group to an amino group, a compound of formula XVI wherein R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R17Is prepared from-SO2-S (O) or C(O) substituted heterocycles to prepare compounds of formula V, wherein R3Is hydrogen and R 4Is prepared from-SO2C substituted by-S (O) or C (O)6-14Aryl heterocycles. Among the reagents capable of carrying out this conversion are palladium on carbon in combination with hydrogen, Raney nickel in combination with hydrogen, iron in combination with hydrochloric acid, or tin (II) chloride in combination with hydrochloric acid. These reactions are generally carried out in protic solvents such as water, methanol, ethanol or mixtures thereof, and at temperatures of from room temperature to 100 ℃ and preferably from 40 ℃ to 85 ℃. For example, compound 397 (scheme XVI) is reacted with palladium on carbon in combination with hydrogen in ethanol at room temperature to provide compound 399.
Scheme XVI
By reaction with a reagent capable of oxidising the sulphide to a sulphoxide or sulphone, from which R may be17Preparation of a Compound of formula XVI which is a heterocycle substituted by-S15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R17Is prepared from-SO2or-S (O) substituted heterocycle. Among the reagents capable of performing this conversion are m-chloroperbenzoic acid (m-CPBA), hydrogen peroxide or oxone. These reactions are usually carried out in a solvent such as water, THF, acetonitrile, dichloromethane, methanol, ethanol or a mixture thereof at 0-100 ℃. For example, compound 394 (scheme XVII) is reacted with MCPBA in chloroform at room temperature to give sulfoxide 397 and sulfone 398.
Scheme XVII
By and being able to substitute forReaction of the deprotected heterocyclic compound may be effected from a compound of formula XVI wherein R17Preparation of a compound of formula XVI for or containing a suitable leaving group, e.g. halo, preferably fluoro, chloro or bromo, wherein R is15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R17Is a heterocycle substituted by-S or-O. Among the heterocycles capable of undergoing such conversion are imidazole, 1, 2, 3-triazole, 1, 2, 4-triazole, morpholine, thiomorpholine, N-methylpiperazine, piperazine and piperidine. These reactions are generally carried out in an aprotic solvent such as dioxane, THF, dimethyl sulfoxide or pyridine in the presence of a base such as triethylamine, or more preferably sodium or potassium carbonate, and at a temperature of from 0 ℃ to 150 ℃, preferably from 50 ℃ to 100 ℃. Two such examples are shown below in scheme XIX. In a first example, 5-fluoro-2-nitrotoluene is reacted with thiomorpholine in pyridine and water and in the presence of potassium carbonate to give compound X. In a second example, 5-fluoro-2-nitrotoluene was reacted with imidazole in dimethyl sulfoxide in the presence of potassium carbonate at 70 ℃ to give compound 394.
Scheme XIX
The desired heterocycles, such as those used in the above schemes, are either commercially available or can be prepared using literature methods familiar to those skilled in the art.
By reaction with a reagent or combination of reagents capable of selectively reducing a nitro group to an amino group, a compound of formula XVI wherein R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile or trifluoromethyl, and R17is-OR8Preparing a compound of formula XV wherein R14Is hydrogen, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile or trifluoromethyl, and R16is-OR8Wherein R is8Is C1-8Alkyl (optionally represented by C)1-8Alkoxide, alkylamine, -SO2NR6R7Is substituted in which R6And R7As defined above) or heterocyclic. Among the reagents capable of performing this conversion are palladium on carbon in combination with hydrogen, Raney nickel in combination with hydrogen, iron in combination with hydrochloric acid, or tin (II) chloride in combination with hydrochloric acid. These reactions are generally carried out in protic solvents such as water, methanol, ethanol or mixtures thereof, and at temperatures of from room temperature to 100 ℃, preferably from 40 to 85 ℃. For example, compound 139 (scheme XX) is reacted with palladium on carbon in ethanol and in the presence of pressurized hydrogen to provide amine 140.
Scheme XX
By reaction with a compound of formula XVII wherein R18Is optionally formed from C1-8Alkoxide, -SO2NR6R7Substituted C1-8Alkyl (wherein R6And R7As defined above) or a heterocyclic ring, and R19Is a leaving group, preferably bromine or chlorine, may be substituted by R17A compound of formula XVI which is hydroxy, the preparation of a compound of formula XVI wherein R is15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile or trifluoromethyl, and R17is-OR8Wherein R is8Is C1-8Alkyl (optionally represented by C)1- 8Alkoxide, alkylamine, -SO2NR6R7Is substituted in which R6And R7As defined above) or heterocyclic. These reactions are usually carried out in aprotic solvents such as DMF, N-methylpyrrolidine, acetonitrile or pyridine. Furthermore, the presence of a base such as triethylamine, or more preferably sodium or potassium carbonate, is generally required. For example, 4-nitro-3-methylphenol (scheme XXI) is reacted with 1, 3-dibromopropane in DMF and in the presence of potassium carbonate to give compound 249.
R19-R18
XVII
Scheme XXI
By reaction with ammonia or a suitable amine, from which R may be8Is prepared from-SO2C substituted by Cl1-8Alkyl of a compound of formula XVI, preparation of a compound of formula XVI, wherein R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile or trifluoromethyl, and R17is-OR8Wherein R is8Is prepared from-SO2NR6R7Substituted C 1-8An alkyl group. These reactions are typically carried out in an aprotic solvent such as acetonitrile, or more preferably dichloromethane or chloroform. For example, sulfonyl chloride 260 (scheme XXII) is reacted with dimethylamine in dichloromethane at 0 ℃ to give sulfonamide 264.
Scheme XXII
A compound of formula XVI or a salt thereof, wherein R is a compound of formula XVI or a salt thereof, by reaction with a reagent capable of converting the sulphonic acid or salt thereof to a sulphonyl chloride17is-OR8And R8Is prepared from-SO3H substituted C1-8Alkyl, to prepare a compound of formula XVI wherein R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile or trifluoromethyl, and R17is-OR8Wherein R is8Is prepared from-SO2C substituted by Cl1-8An alkyl group. Among the reagents capable of carrying out this transformation are POCl3Or more preferably thionyl chloride. These reactions are usually carried out in aprotic solvents such as dichloromethane, chloroform or DMF. For example, compound 253 (scheme XXIII) is reacted with thionyl chloride in DMF at 0 ℃,to give sulfonyl chloride 254.
Scheme XXIII
By reaction with cyclic sulfonates, more commonly known as sultones, compounds of formula XVI can be prepared wherein R is17is-OR8Wherein R is8To hydrogen, a compound of formula XVI or a salt thereof, wherein R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile or trifluoromethyl, and R 17is-OR8Wherein R is8Is prepared from-SO3H substituted C1-8An alkyl group. These reactions are carried out in an aprotic solvent such as DMF, acetonitrile, acetone, or more preferably THF, in the presence of a base such as potassium carbonate, or more preferably sodium hydride. For example, 3-methyl-4-nitrophenol (scheme XXIV) is reacted with 1, 3-propane sultone in THF in the presence of sodium hydride to give the sulfonate 253.
Scheme XXIV
The desired sultones, such as 1, 3-propane sultone, are either commercially available or can be prepared using literature methods familiar to those skilled in the art.
By reaction with a suitable amine, a compound of formula XVI, wherein R17Preparation of a Compound of formula XVI for a suitable leaving group such as halo, preferably chloro or fluoro, wherein R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile or trifluoromethyl, and R17is-NR6N7. These reactions are carried out in a solvent such as DMF, acetonitrile, dioxane, water, pyridine, or mixtures thereof, and in the presence of a base such as sodium or potassium carbonate, or more preferably sodium bicarbonate. For example, 5-fluoro-2-nitrotoluene (scheme)XXV) reaction with 4- (3-aminopropyl) morpholine in pyridine and water in the presence of sodium bicarbonate affords compound 308.
Scheme XXV
Desired formula HNR6N7The amines of (a) are either commercially available or can be prepared using literature methods known in the art.
A compound of formula V wherein R3Is hydrogen and R4Are aromatic heterocycles, are either commercially available or can be prepared using literature methods familiar to those skilled in the art.
A compound of formula (V) wherein R3Is hydrogen and R4Is heterocyclic, e.g. represented by-SO2NR6R7Substituted pyridines in which R6And R7As defined above, can be prepared by the methods shown below, or by methods known to those skilled in the art. For example, as shown in scheme XXVI, 5-amino-4-methyl-2-pyridinesulfonamide can be prepared from 2-chloro-4-methyl-5-nitropyridine. Commercially available 2-chloro-4-methyl-5-nitropyridine is reacted with a reagent capable of substituting the 2-chloro group with a sulfur atom to give 4-methyl-5-nitro-2-pyridinethiol, e.g., thiourea. These reactions are typically carried out in a polar, protic solvent, e.g., acetic acid, in the presence of a base such as potassium hydroxide and sodium hydroxide, and at temperatures of 20 ℃ to 150 ℃. The resulting thiol is then reacted with a reagent capable of oxidizing the thiol to the sulfonic acid derivative, for example, hydrogen peroxide, oxone or chlorine. The oxidation reaction can advantageously be carried out in an acidic solvent, for example 1N hydrochloric acid, using chlorine as oxidizing agent, with the formation of the corresponding, desired sulfonyl chloride. The resulting sulfonyl chloride is then reacted with a reagent capable of converting it to the corresponding sulfonamide, ammonia gas or a solution of ammonia in a suitable solvent such as dichloromethane to give 4-methyl-5-nitro-2-pyridinesulfonamide. Then adopting the method that the skilled person in the art has Known methods, such as palladium on carbon in the presence of hydrogen as a reducing agent, can reduce the nitro group to give the desired 5-amino-4-methyl-2-pyridinesulfonamide. The reduction is usually carried out in a polar, protic solvent such as methanol, at 20 ℃ to 100 ℃, preferably at room temperature.
Scheme XXVI
Or, a compound of formula (V) wherein R3Is hydrogen and R4Is heterocyclic, e.g. represented by-SO2NR6N7Substituted pyridines in which R6And R7As defined above, can be prepared by the methods shown below, or by methods known to those skilled in the art. For example, as shown in scheme XXVII, 5-amino-6-methyl-2-pyridinesulfonamide can be prepared. Commercially available 2-amino-5-methylpyridine is reacted with a reagent capable of nitrating the pyridine ring, for example a mixture of nitric and sulphuric acids. These reactions are usually carried out in concentrated sulfuric acid as solvent at-10 ℃ to 25 ℃, preferably at 0 ℃, to give the desired 5-amino-2-methyl-3-nitropyridine. The amino group is then reacted with a composition of reagents capable of converting the amino group to a chlorine substituent. For example, 5-amino-2-methyl-3-nitropyridine is reacted with tert-butyl nitrite to give the corresponding diazonium salt, which is subsequently reacted with trimethylsilyl chloride in an aprotic solvent, such as dichloromethane, to give 5-chloro-2-methyl-3-nitropyridine. The chloro group is then reacted with a reagent capable of substitution on the pyridine ring to give the corresponding thiol derivative. For example, 5-chloro-2-methyl-3-nitropyridine is reacted with thiourea in a mixture of acetic acid, potassium hydroxide and sodium hydroxide to give the desired 6-methyl-5-nitro-2-pyridinethiol. The resulting thiol is then reacted with an agent capable of oxidizing the thiol to the sulfonic acid derivative, such as hydrogen peroxide, oxone, or chlorine. The oxidation reaction can advantageously be carried out in an acidic solvent, for example 1N hydrochloric acid, using chlorine as oxidizing agent, with the formation of the corresponding, desired sulfonyl chloride . The resulting sulfonyl chloride is then reacted with a reagent capable of converting it to the corresponding sulfonamide, ammonia gas or a solution of ammonia in a suitable solvent such as dichloromethane to give 6-methyl-5-nitro-2-pyridinesulfonamide. The nitro group can then be reduced with palladium on carbon in the presence of hydrogen as a reducing agent using methods known to those skilled in the art to give the desired 5-amino-6-methyl-2-pyridinesulfonamide. The reduction is usually carried out in a polar, protic solvent such as methanol, at 20 ℃ to 100 ℃, preferably at room temperature.
Scheme XXVII
Or, a compound of formula (V) wherein R3Is hydrogen and R4Is heterocyclic, e.g. represented by-SO2NR6R7Substituted pyridines in which R6And R7As defined above, can be prepared by the methods shown below, or by methods known to those skilled in the art. For example, as shown in scheme XXVIII, 6-amino-5-methyl-3-pyridinesulfonamide can be prepared. Commercially available 2-amino-3-methylpyridine is reacted with a reagent capable of sulfonylating the pyridine ring, for example oleum. These reactions are typically carried out at 20% SO3In a mixture with sulfuric acid at 75 ℃ to 200 ℃, preferably at 160 ℃ to give 6-amino-5-methyl-3-pyridinesulfonic acid. The amino group is then reacted with a composition of reagents capable of protecting the amino group from oxidation in a subsequent step. For example, 6-amino-5-methyl-3-pyridinesulfonic acid is reacted with a mixture of N, N-Dimethylformamide (DMF) and thionyl chloride, the so-called Vilsmier reagent, to give the desired 6- [ (dimethylamino) methylene group ]Amino-5-methyl-3-pyridinesulfonic acid intermediates. This compound is then reacted with a composition of reagents capable of converting the sulfonic acid to the corresponding sulfonyl chloride, followed by a reagent capable of converting the sulfonyl chloride to the corresponding sulfonamide derivative. For example, reacting the desired 6- [ (dimethylamino) methylene group]Reacting amino-5-methyl-3-pyridinesulfonic acid with phosphoryl chloride to obtain intermediate sulfonyl chloride, and graftingThen reacting with ammonium hydroxide to obtain the required 6-amino-5-methyl-3-pyridine sulfonamide.
Scheme XXVIII
A compound of formula (XV) wherein R14Is hydrogen, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R16is-SO2NR6R7Wherein R is6And R7As defined above, can be prepared by methods known in the art, or by the methods shown in scheme XXIX. For example, 4-amino-N, 3-dimethylbenzenesulfonamide may be prepared from commercially available 4-amino-3-methylbenzenesulfonic acid by reaction with a composition of reagents capable of protecting the amino groups from oxidation in a subsequent chemical step. For example, 4-amino-3-methylbenzenesulfonic acid is reacted with N, N-Dimethylformamide (DMF) and oxalyl chloride in dichloromethane to carry out the conversion of the sulfonic acid to the desired sulfonyl chloride accompanied by protection of the amino group as the corresponding amidine. The sulfonyl chloride is then reacted with an amine, such as methylamine, to give 4- [ (dimethylamino) methylene ]amino-N, 3-dimethylbenzenesulfonamide. The amidine protecting group was then removed with hydrazine hydrochloride.
Scheme XXIX
Alternatively, a compound of formula (XV) wherein R14Is hydrogen, R15Is hydrogen, halogen, C1-8Alkyl radical, C1-8Alkoxy, nitro, nitrile, trifluoromethyl, and R16is-SO2NR6R7Wherein R is6And R7As defined above, can be prepared by methods known in the art, or by the methods shown in scheme XXX. For example, by methods known in the art or in scheme XXX, 4-amino-N, N, 3-trimethylbenzenesulfonamide may be prepared. Commercially available 4-amino-3-methylbenzenesulfonic acid can be reacted with reagents capable of protecting the amino group from oxidation during further synthetic steps. For example, 4-amino-3-methylbenzenesulfonic acid is reacted with benzyl bromide in the presence of a base such as sodium carbonate or potassium carbonate to give sodium 4- (dibenzylamino) -3-methylbenzenesulfonate. These reactions are generally carried out in a polar, aprotic solvent, such as N, N-dimethylformamide, at a temperature in the range of from 25 ℃ to 125 ℃, preferably from 75 ℃ to 100 ℃. The sodium salt is then reacted with a reagent capable of converting the salt to the corresponding sulfonyl chloride. For example, the resulting sodium 4- (dibenzylamino) -3-methylbenzenesulfonate is reacted with thionyl chloride in N, N-Dimethylformamide (DMF) to give the desired 4- (dibenzylamino) -3-methylbenzenesulfonyl chloride. These reactions are generally carried out in an aprotic solvent, such as dichloromethane, and at a temperature of from 0 ℃ to 75 ℃, preferably at 0 ℃. The sulfurous chloride is then reacted with a suitable amine to provide the desired sulfonamide. For example, 4- (dibenzylamino) -3-methylbenzenesulfonyl chloride is reacted with dimethylamine to give the desired 4- (dibenzylamino) -N, N, 3-trimethylbenzenesulfonamide. This sulfonamide is then reacted with a combination of reagents capable of deprotecting the amine to give the desired aniline derivative. For example, the desired 4- (dibenzylamino) -N, N, 3-trimethylbenzenesulfonamide is reacted with hydrogen in the presence of a palladium on carbon catalyst to cleave the benzyl protecting group to provide the desired 4-amino-N, N, 3-trimethylbenzenesulfonamide.
Scheme XXX
Can be prepared from compounds of formula XIX and compounds of formula X, wherein R1As defined above and R10Preparation of a Compound of formula XVIII for halogen, preferably chlorine, wherein R2Is hydroxy or methoxy, R1And R3As defined above and X is a heteroatom, preferably oxygen or sulfur, with the proviso that R is1And R3And contrary toIs chemically compatible with the conditions, and R2、R3And R1CO is regiochemically compatible in these reactions. These reactions, commonly referred to as Friedel-Craft acylation reactions, are carried out according to the methods previously described (see, e.g., scheme X). For example, 3-methoxythiophene (scheme XXXI) is reacted with benzoyl chloride in refluxing dichloromethane in the presence of aluminum chloride to give ketone 664.
Scheme XXXI
A compound of the formula XX, wherein R2And R3As defined above, with a compound of the formula XIII, wherein R1As defined above and R11For halogen, preferably bromine or iodine, compounds of formula XVIII may be prepared, wherein R is1And R3As defined above and R2Is methoxy, and X is a heteroatom, preferably sulfur or oxygen, with the proviso that R is1And R5Is chemically compatible with the subsequent chemical steps, and is N, O-dimethylhydroxyacetamide, R2And R3The groups are regiochemically compatible in these reactions. In general, the conditions for these reactions are similar to those described for the synthesis of compounds of formula XII.
For example, 3, 5-dibromotoluene is treated with n-butyllithium in diethyl ether at-78 ℃. After 15 minutes at-78 deg.C, the resulting lithium species is reacted with 675 to afford the desired ketone 676 (see scheme XXXIII).
Scheme XXXIII
Finally, using the aforementioned method for synthesizing compounds of formula X (see scheme VII), one can synthesize compounds of formula X from the compound of formula X wherein R2And R3A compound of formula XX is prepared by a compound of formula XXI as defined above.
In turn, the compounds of formula XXI can be prepared according to methods described in the literature. See, e.g., Synthesis, 1984, 847 (Synthesis 673), which upon hydrolysis affords compound 674 (scheme XXXIV).
Scheme XXXIV
Another object of the invention is characterized by the following intermediates used in the preparation of the compounds of the invention: 7. 32, 33, 36, 38, 44, 45, 49, 51, 52, 61, 65, 66, 71, 75, 76, 111, 112, 115, 118, 119, 128, 129, 171, 172, 191, 192, 199, 200, 206, 207, 224, 225, 232, 233, 235, 236, 246, 247, 253, 254, 255, 256, 259, 260, 261, 262, 264, 265, 267, 268, 288, 289, 290, 409, 412, 428, 430, 431, 433, 477, 490, 495, 496, 507, 511, 514, 515, 518, 519, 522, 523, 526, 527, 529, 530, 532, 533, 537, 538, 540, 541, 543, 544, 546, 433, 662, 558, 559, 561, 562, 567, 568, 572, 573, 576, 577, 582, 584, 585, 588, 58584, 595, 602, 603, 648, 620, 676, 67608, 67, 608, 67, 639, 67, 63608.
The compounds according to the present invention, also referred to herein as active ingredients, may be administered for treatment by any suitable route including oral, rectal, intranasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal and intravitreal). It will be appreciated that the preferred route will vary with the condition and age of the recipient, the nature of the infection and the active ingredient selected.
In general, suitable dosages for each of the above-mentioned conditions will be in the range of 0.01-250mg per kg body weight per day of the recipient (e.g. human), preferably in the range of 0.1-100mg per kg body weight per day, most preferably in the range of 0.5-30mg per kg body weight per day, particularly preferably in the range of 1.0-20mg per kg body weight per day. All weights of active ingredient are calculated as the parent compound of formula (I), unless otherwise specified; for salts or esters thereof, the weight will increase proportionately. The desired dose may be provided as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases, the desired dose may be administered every other day. These sub-doses may be administered in unit dosage forms, e.g. containing 10-1000mg or 50-500mg, preferably 20-500mg, and most preferably 100-400mg of active ingredient per unit dosage form.
Although it is possible to administer the active ingredient alone, it is preferred that it is provided as a pharmaceutical formulation. The formulations of the invention comprise at least one active ingredient as defined above together with one or more acceptable carriers thereof and optionally other therapeutic agents. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Formulations include those suitable for oral, rectal, intranasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal and intravitreal) 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. These methods represent another feature of the present invention and include the step of bringing into association the active ingredient with the carrier (which includes one or more accessory ingredients). Generally, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
The invention also further comprises a pharmaceutical formulation as defined hereinbefore, wherein the compound of formula (I) or a pharmaceutically acceptable derivative thereof and at least one other therapeutic agent are present independently of each other as parts of a kit.
Compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Such patches suitably contain 1) the active compound optionally present as a buffered aqueous solution or 2) dissolved and/or dispersed in an adhesive or 3) dispersed in a polymer. Suitable concentrations of the active compound are about 1% to 25%, preferably about 3% to 15%. As a particular possibility, the active compound may be delivered from the patch by electrotransport or iontophoresis, as outlined in Pharmaceutical Research 3(6), 318 (1986).
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, caplets, cachets or tablets, each unit containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be provided as a bolus (bolus), electuary or paste.
Tablets may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with the following adjuvants: binders (e.g., polyvinylpyrrolidone, gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose), surfactants or dispersants. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated with, for example, hydroxypropylmethyl cellulose in varying proportions to provide a slow or controlled release of the active ingredient of the invention to provide the desired release profile. The tablets may optionally be coated with enteric coating materials to provide release in parts of the intestinal tract other than the stomach.
Formulations suitable for topical administration in the oral cavity include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth; lozenges comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base such as cocoa butter or a salicylate.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Pharmaceutical formulations suitable for rectal administration in which the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. Suppositories may conveniently be formed by mixing the active ingredient with the softened or molten carrier, followed by cooling and shaping in a mould.
Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions may contain suspending agents and thickening agents; liposomes or other microparticulate systems can be designed to target compounds to blood components, or to one or more organs. The formulations may be presented as unit-dose or multi-dose sealed containers, for example ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or daily sub-dose of the active ingredient as hereinbefore described, or a suitable fraction thereof.
It will be understood that in addition to the active ingredients particularly mentioned above, the formulations of this invention may contain other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may contain other such agents as sweetening, thickening and flavoring agents.
The following examples are intended to be merely illustrative of the present invention and are not intended to limit the scope of the invention in any way. "active ingredient" means one or more compounds according to the invention or a physiologically functional derivative of any of the above-mentioned compounds.
The general method comprises the following steps:
general procedure I: Friedel-Crafts reaction of acyl chlorides with 4-chloroanisole
4-chloro anisole (1-1.25mmol/mmol acyl chloride) and aluminum chloride (AlCl)31-1.75mmol/mmol of acid chloride) and methylene chloride were placed in a round bottom flask equipped with a stirring bar, reflux condenser and, if necessary, nitrogen gas. To the resulting mixture at room temperature, the appropriate acid chloride is added. When the addition was complete, the orange mixture was heated to reflux and stirred for 2-24 hours. The mixture was allowed to cool to room temperature and carefully poured into ice water to give a two-phase mixture which was stirred at room temperature for 30 minutes to 2 hours. It was then poured into a separatory funnel containing water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. For further purification details see the specific examples.
General procedure II: alkylation of phenols with ethyl bromoacetate
The appropriate phenol, potassium carbonate (2-10mmol/mmol phenol), ethyl bromoacetate (1-1.5mmol/mmol phenol) and acetone (1-10ml/mmol phenol) were placed in a round bottom flask equipped with a stir bar, reflux condenser and, if necessary, nitrogen gas supply. The resulting mixture was heated to reflux for 1-20 hours, after which it was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure leaving an oil. For further purification details see the specific examples.
General procedure III: saponification of ethyl ester to carboxylic acid
A round bottom flask equipped with a stirring rod, supplied with nitrogen if necessary, was purged with nitrogen. The flask was charged with tetrahydrofuran (THF, 1-5ml/mmol ester), ethanol (EtOH, 1-5ml/mmol ester), water (1-5ml/mmol ester) and lithium hydroxide monohydrate (1-5mmol/mmol ester). The resulting suspension was stirred vigorously and the ester was added in one portion. The mixture was stirred at room temperature for 1-20 hours, after which the pH was adjusted to about pH5 by slow addition of 1N aqueous hydrochloric acid. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure leaving a white solid. See the specific examples to determine if the product requires further purification.
General procedure IV: coupling of acids with aromatic amines with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC)
A round bottom flask equipped with a stirring rod, supplied with nitrogen if necessary, was purged with nitrogen. To the flask was added the appropriate carboxylic acid, N-dimethylformamide (DMF, 5-20ml/mmol acid), 1-hydroxybenzotriazole (HOBt, 1-2mmol/mmol acid), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDAC, 1-5mmol/mmol acid) and the appropriate aromatic amine (1-2mmol/mmol ester). In some cases triethylamine (Et) is used3N, 2-5mmol/mmol acid). The resulting mixture was stirred at room temperature for 2-24 hours, after which it was poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. For further details on the purification of the product, see the specific examples.
General procedure V: synthesis of acid chlorides from carboxylic acids using oxalyl chloride
The appropriate carboxylic acid, dichloromethane (CH)2Cl21-10ml/mmol acid) and N, N-dimethylformamide (1-10 drops) were placed in a round bottom flask. The mixture was cooled to 0 ℃ and oxalyl chloride (1-2mmol/mmol acid) was added dropwise, after which the mixture was allowed to warm to room temperature and stirred for 1-24 h. The solvent was removed under reduced pressure and the remaining residue was dried in vacuo. In most cases, the acid chloride is used immediately in the subsequent reaction without further purification.
General procedure VI: coupling of acid chlorides with aromatic amines using sodium bicarbonate
The appropriate aromatic amine, acetone (1-10ml/mmol amine), sodium bicarbonate (2-10mmol/mmol amine) and water (0.25-10ml) were placed in a round bottom flask. The acid chloride was added dropwise to a solution of acetone (1-10ml/mmol of acid chloride) and the reaction mixture was stirred at room temperature for 1-24 hours. When the reaction was judged complete, the mixture was poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. For further details on the purification of the product, see the specific examples.
General procedure VII: synthesis of Weinreb amides from acid chlorides with N, O-dimethylhydroxylamine hydrochloride
N, O-dimethylhydroxylamine (1-2mmol/mmol acid chloride) and chloroform (CHCl)31-10ml/mmol of acid chloride) was placed in a round bottom flask equipped with a stirring bar and supplied with nitrogen if necessary. The mixture was cooled to 0 ℃ and triethylamine (Et) was added in one portion3N, 1-5mmol/mmol acid chloride). The acid chloride was added and the reaction mixture was stirred at 0 ℃ for 0.5-5 hours, after which it was poured into a separatory funnel containing chloroform and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. See the specific examples to determine if the product requires further purification.
General procedure VIII: halogen-Metal exchange of 2-bromo-4-chloroanisole followed by the addition of Weinreb amide
2-bromo-4-chloroanisole (1mmol/mmol amide) and diethyl ether (1-10ml/mmol anisole) were placed in a round bottom flask equipped with a stir bar, supplied with nitrogen if necessary, and an addition funnel, and the mixture was cooled to-78 ℃ by a dry ice/acetone bath. N-butyllithium (1-2mmol/mmol of a 2.5M solution of anisole in hexane) was added dropwise, followed by the addition of Weinreb amide. The reaction was stirred at-78 ℃ for 0.5-1 hour, at which time the reaction was allowed to warm to room temperature. When the reaction was judged complete, the reaction was poured into a separatory funnel containing ether and water. The organic layer was collected, washed with water, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. See the specific examples to determine if the product requires further purification.
General procedure IX: deprotection of anisole derivatives with boron tribromide
Mixing the appropriate anisole derivative and dichloromethane (CH)2Cl21-15ml/mmol anisole) is added to a round bottom flask equipped with a stirring bar, if necessary with nitrogen and an addition funnel, the mixture is cooled to-78 ℃ and boron tribromide is added dropwise at-78 ℃. The resulting mixture was stirred at-78 ℃ for 30-120 minutes, after which the reaction was allowed to warm to room temperature and stirred for an additional 15-120 minutes. When the reaction was judged to be complete, the reaction was poured into ice and extracted with dichloromethane. The organic layer was collected, washed with water, dried over magnesium sulfate, filtered and the solvent was removed. See the specific examples to determine if the product requires further purification.
General procedure x. the appropriate acid chloride in acetonitrile was added dropwise via an addition funnel to a stirred solution of triethylamine (0-2.5mmol/mmol acid chloride), acetonitrile (1-20ml/mmol acid chloride) and the appropriate aniline (0.5-2.5mmol/mmol acid chloride). The reaction was refluxed for 0-12 hours. The heating bath was removed and the reaction mixture was stirred for 12-336 hours. The mixture was concentrated, dissolved and washed with water. The resulting organics were dried over magnesium sulfate, concentrated in vacuo and purified as described in each example.
General procedure XI. amine (1-2.5mmol/mmol benzene) was added dropwise via an addition funnel to a stirred suspension of a solution of p-nitrohalobenzene or toluene in pyridine (20-40mmol/mmol benzene), sodium bicarbonate (1.5-4mmol/mmol benzene) and water (0.2-5ml/mmol benzene). The resulting suspension was refluxed (150 ℃ C.) for 1 to 7 days. The mixture was filtered, acetone (10-200ml/mmol benzene) was added to the filtrate and allowed to reflux. Water was added to the cloud point and the solution was allowed to cool to room temperature. The precipitate was filtered and the resulting solid was washed with water and ether to give the substituted product.
General procedure XII. add the appropriate nitrobenzene to a suspension of palladium on carbon (0.1-0.8mmol/mmol benzene, 10% w/w), ethanol, THF and methanol, evacuate the reaction vessel and charge with nitrogen several times. After evacuation of the reaction vessel under reduced pressure, hydrogen (14-100psi) was charged. The resulting suspension was stirred at room temperature for 0-72 hours, filtered through a pad of celite, and concentrated in vacuo to give the appropriate aniline.
General procedure xiii the appropriate carboxylic acid, hexachloroacetone (HCA, 0.5mmol/mmol acid) and THF (1-10ml/mmol acid) are placed in a round bottom flask equipped with a stir bar, a cooling bath and, if necessary, nitrogen gas supply, and the mixture is cooled to-78 ℃. Triphenylphosphine (PPh) in THF (1-10ml/mmol acid)31mmol/mmol acid) was added to the mixture and stirred for 5-120 min. The appropriate aniline (1mmol/mmol acid) and pyridine (5-20mmol/mmol acid) in THF (1-10ml/mmol acid) are added dropwise and the mixture is stirred at-78 deg.C for 5-60 min. The cold bath was removed and the mixture was stirred at room temperature for 1 hour to 14 days. The reaction mixture was concentrated in vacuo and purified as described in the examples.
General procedure xiv thionyl chloride (1-100mmol/mmol acid) is added to a solution of the appropriate carboxylic acid in dichloromethane (1-100ml/mmol acid) and the resulting solution is refluxed under nitrogen for 1-12 hours. The mixture was concentrated in vacuo and placed under a nitrogen atmosphere to afford the appropriate acid chloride.
General procedure XV: palladium-mediated cyanation of benzophenone derivatives
Suitable bromobenzophenones were treated according to the method outlined in Anderson et al, J.org.chem.1998, 63, 8224-8228. Bromine-or trifluoromethylsulfonyl-benzophenone (1eq), tetrakis (triphenylphosphine) palladium (10-20%), copper iodide (2eq vs palladium), sodium cyanide (2eq) and propionitrile (0.5-1.0M in bromobenzophenone) were placed in a hot-dry flask equipped with a reflux condenser. Before use, the mixture was purged with nitrogen for 30 minutes. The mixture was heated to 120 ℃ and stirred until TLC analysis showed complete disappearance of starting material (1-16 hours). The mixture was then cooled to room temperature, diluted with ethyl acetate, filtered through silica gel and the filtrate concentrated in vacuo. The corresponding product was purified as described in each example.
General procedure XVI: synthesis of N- [4- (aminosulfonyl) -2-methylphenyl ] acetamide and N- [4- (alkyl and dialkylaminosulfonyl) -2-methylphenyl ] acetamide
Sulfonyl chloride 464(1-100mmol) is added to a solution of the appropriate amine in pyridine (1-10ml/mmol amine), and the resulting solution is stirred under nitrogen for 1-48 hours. Water was added, the resulting mixture was extracted with dichloromethane, and the organics were concentrated in vacuo. The resulting product is then purified by flash chromatography to give the appropriate acetyl protected sulfonamide.
General procedure XVII: deacetylation of N- [4- (aminosulfonyl) -2-methylphenyl ] acetamide and N- [4- (alkyl and dialkylaminosulfonyl) -2-methylphenyl ] acetamide
The appropriate sulfonamide (1-100mmol) was added to a solution of ethanol (1-50ml), water (0-5ml) and hydrochloric acid (1-28.9M, 1-50ml) in a large test tube. The mixture is then heated to 60 ℃ for 1-36 hours with stirring. The mixture was cooled to room temperature and concentrated in vacuo. The resulting product was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and purified by flash chromatography using 95: 5 dichloromethane to methanol as eluent to give the desired aniline.
Example (b):
Example 1:
step A:
a solution of 2-bromo-4-chloroanisole (8.98g, 40.54mmol) in diethyl ether (65ml) was cooled to-78 ℃ and n-butyllithium (26ml of a 1.6M solution in hexane, 41.6mmol) was added via syringe. The resulting orange solution was stirred at-78 ℃ for 30 minutes, after which time only 2-thiazolecarboxaldehyde (4.53g, 40.04mmol) was added, yielding a reddish purple solution. The mixture was stirred at-78 ℃ for 15 minutes, after which time water (50ml) was added and the mixture was allowed to warm to room temperature. The mixture was poured into a separatory funnel containing ether and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a white solid. The solid was washed with hexane and dried in vacuo to give white needles (5.21g, 51%).1H NMR(CDCl3，400MHz)δ7.70(d，J＝4Hz，1H)，7.38(d，J＝4Hz，1H)，7.28(d，J＝4Hz，1H)，7.23(m，1H)，6.83(d，J＝8Hz，1H)，6.23(d，J＝8Hz，1H)，3.99(d，J＝8Hz，1H)，3.83(s，3H)。
And B:
under nitrogen atmosphere, 2(5.21g, 20.6mmol), manganese dioxide (17.66g, 203.1mmol) and dichloromethane (CH)2Cl275ml) were mixed and stirred at room temperature for 2.5 hours. The mixture was filtered through a pad of celite, washed with several portions of dichloromethane and the solvent was removed under reduced pressure to give a brown solid (4.96g, 95%) which was used for the subsequent reaction without any further purification.1HNMR(CDCl3，300MHz)δ8.06(d，J＝3Hz，1H)，7.76(d，J＝3Hz，1H)，7.63(d，J＝3Hz，1H)，7.49(dd，J＝9，3Hz，1H)，7.00(d，J＝9Hz，1H)，3.82(s，3H)。
And C:
3(4.96g, 19.6mmol) in dichloromethane (60ml) was cooled to-78 ℃ and boron tribromide (100ml of a 1.0M solution in dichloromethane, 100mmol) was added via syringe over 30 minutes. The resulting magenta solution was stirred at-78 ℃ for 15 minutes, after which it was allowed to warm slowly to room temperature. After 30 minutes at room temperature, the mixture was slowly poured into ice water and the resulting biphasic mixture was stirred for 30 minutes. The mixture was then poured into a separatory funnel containing water and dichloromethane. The organic layer was collected, washed with water, brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The product was isolated by flash chromatography eluting with 7: 3 hexane/dichloromethane to give a yellow solid (3.59g, 76%).1H NMR(CDCl3，300MHz)δ12.25(s，1H)，9.29(d，J＝3Hz，1H)，8.19(d，J＝3Hz，1H)，7.83(d，J＝3Hz，1H)，7.53(dd，J＝9，3Hz，1H)，7.05(d，J＝9Hz，1H)。
Step D:
under nitrogen atmosphere, 4(0.12g, 0.49mmol), 2' -chloro-N-acetanilide (0.09g, 0.52mmol), sodium carbonate (Na)2CO30.54g, 5.1mmol), potassium iodide (0.47g, 3.1mmol) and acetone (8ml) were mixed and the resulting mixture was heated to reflux. After refluxing for 18 hours, the mixture was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure leaving an orange oil. The product was isolated by flash chromatography using 4: 1 hexane/ethyl acetate as eluent to give 1 as a white solid (0.09g, 49%). 1H NMR(CDCl3，300MHz)d 9.66(s，1H)，9.04(d，J＝3Hz，1H)，7.93(d，J＝2.7Hz，1H)，7.78(d，J＝3Hz，1H)，7.72(d，J＝8Hz，2H)，7.51(dd，J＝3Hz，1H)，7.35(m，2H)，7.15(m，1H)，6.97(d，J＝9Hz，1H)，4.67(s，2H)。
Example 2:
step A:
according to general method II, phenol 4(2.31g, 9.64mmol), potassium carbonate (6.95g, 50.3mmol), ethyl bromoacetate (1.1ml, 1.7g, 9.9mmol) and acetone (150ml) were used. The product was used in the next reaction without any further purification.1H NMR(CDCl3，300MHz)δ8.05(d，J＝3Hz，1H)，7.76(d，J＝3Hz，1H)，7.66(d，J＝3Hz，1H)，7.48(dd，J＝9，3Hz，1H)，6.93(d，J＝9Hz，1H)，4.61(s，2H)，4.21(q，J＝6Hz，2H)，1.26(t，J＝6Hz，3H)。
And B:
according to general procedure III, ester 6(3.1g, 9.6mmol), THF (30ml), water (10ml), ethanol (10ml) and lithium hydroxide (1.0g, 23.8mmol) were used. The product was used in the next reaction without any further purification.1H NMR(DMSO-d6，300MHz)δ8.30(d，J＝3Hz，1H)，8.15(d，J＝3Hz，1H)，7.63(d，J＝3Hz，1H)，7.57(dd，J＝9，3Hz，1H)，7.05(d，J＝9Hz，1H)，4.45(s，2H)。
And C:
according to general method IV, carboxylic acid 7(0.1g, 0.33mmol), HOBt (0.05g, 0.4mmol), EDAC (0.09g, 0.46mmol), triethylamine (0.1ml, 0.07g, 0.72mmol), DMF (6ml) and 5-aminoindazole (0.05g, 0.35 mmol) were usedl). The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 5 as a brown solid (0.03g, 25%).1H NMR(CDCl3，400MHz)δ9.55(s，1H)，8.46(s，1H)，8.21(s，1H)，8.05(m，2H)，7.77(m，3H)，7.54(m，1H)，6.99(d，J＝8Hz，2H)，4.74(s，2H)。
Example 3:
according to general procedure IV, carboxylic acid 7, HOBt (0.10g,. 75mmol), EDAC (0.15g, 0.79mmol), triethylamine (0.16ml, 0.12g, 1.15mmol), DMF (5ml) and sulfoxide 399(0.15g, 0.68mmol) were used. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give a brown solid (0.09g, 34%). 1H NMR(CDCl3，300MHz)δ9.14(s，1H)，8.00(m，2H)，7.80(d，J＝3Hz，1H)，7.56(m，2H)，7.05(d，J＝9Hz，2H)，6.87(br s，1H)，4.77(s，2H)，4.04(m，1H)，3.54(m，1H)，3.0(m，2H)，2.21(s，3H)。
Example 4:
step A:
the corresponding acid chloride was prepared according to general procedure V using 2-benzofurancarboxylic acid (2.51g, 15.48mmol), dichloromethane (50ml), DMF (4 drops) and oxalyl chloride (1.5ml, 2.18g, 17.19 mmol). The acid chloride was immediately used in admixture with 4-chloroanisole (2.16g, 15.15mmol), aluminium chloride (3.01g, 22.57mmol) and dichloromethane (50ml) according to general procedure I. Compound 10 was purified by flash chromatography using 7: 3 hexane/dichloromethane as eluent,10(2.39g, 57%) was obtained as a yellow solid.1H NMR(CDCl3，300MHz)δ12.05(s，1H)，8.48(d，J＝3Hz，1H)，7.82(d，J＝9Hz，1H)，7.79(s，1H)，7.73(d，J＝9Hz，1H)，7.56(m，2H)，7.42(t，J＝7.5Hz，1H)，7.09(d，J＝9Hz，1H)。
And B:
phenol 10(0.14g, 0.51mmol), 2' -chloroanilide (0.10g, 0.59mmol), potassium carbonate (0.50g, 3.62mmol) and acetone (10ml) were placed in a round bottom flask equipped with a stir bar, reflux condenser and, if necessary, nitrogen gas. The mixture was heated to reflux for 16 hours, after which it was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure leaving an orange oil. The product was purified by flash chromatography using 4: 1 hexane/ethyl acetate as eluent to give 9 as a white solid (0.12g, 58%). 1H NMR(CDCl3，300MHz)δ9.33(s，1H)，7.75(m，5H)，7.61(m，3H)，7.39(m，3H)，7.15(m，2H)，4.77(s，2H)。
Example 5:
step A:
the corresponding acid chloride was prepared according to general procedure V using 2-benzothiophenecarboxylic acid (2.51g, 14.08mmol), dichloromethane (35ml), DMF (4 drops) and oxalyl chloride (1.3ml, 1.89g, 14.9 mmol). The acid chloride was immediately used in admixture with 4-chloroanisole (2.08g, 14.59mmol), aluminium chloride (3.15g, 23.62mmol) and dichloromethane (35ml) according to general procedure I. Compound 12 was purified by flash chromatography using 7: 3 hexane/dichloromethane as eluent to give a yellow solid (2.25g, 55%)。1H NMR(CDCl3，300MHz)δ11.45(s，1H)，8.02(m，3H)，7.55(m，4H)，7.10(d，J＝9Hz，1H)。
And B:
phenol 12(0.22g, 1.23mmol), 2' -chloroanilide (0.22g, 1.30mmol), potassium carbonate (1.46g, 10.6mmol) and acetone (25ml) were placed in a round bottom flask equipped with a stir bar, reflux condenser and, if necessary, nitrogen gas. The mixture was heated to reflux for 16 hours, after which it was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure leaving an orange oil. The product was purified by flash chromatography using 4: 1 hexane/ethyl acetate as eluent to give a white solid (0.27g, 52%).1H NMR(CDCl3，400MHz)δ9.16(s，1H)，7.90(t，J＝10Hz，2H)，7.82(s，1H)，7.64(m，2H)，7.53(m，2H)，7.42(t，J＝8Hz，1H)，7.30(t，J＝8Hz，2H)，7.10(t，J＝8Hz，1H)，7.04(d，J＝8Hz，1H)，4.70(s，2H)。
Example 6:
Step A:
according to general method V, 1-methyl-2-pyrrolidinecarboxylic acid (4.75g, 37.96mmol), dichloromethane (100ml), DMF (0.5ml) and oxalyl chloride (3.6ml, 5.24g, 41.27mmol) were used. N, O-dimethylhydroxylamine hydrochloride (4.45g, 45.62mmol), triethylamine (26ml, 19g, 187mmol) and chloroform (100ml) were placed in another flask. The resulting solution was cooled to 0 ℃ and the acid chloride (in 20ml chloroform) was added dropwise. The resulting mixture was stirred at 0 ℃ for an additional 1 hour, after which it was allowed to warm to room temperature. The mixture is then poured into a container containing chlorineChloroform and water in a separatory funnel. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a brown oil which was used in the subsequent reaction without further purification.1H NMR(CDCl3，300MHz)δ6.95(m，1H)，6.78(m，1H)，6.15(m，1H)，3.94(s，3H)，3.73(s，3H)，3.36(s，3H)。
And B:
2-bromo-4-chloroanisole (5.97g, 26.95mmol) and THF (75ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The resulting solution was cooled to-78 deg.C and n-butyllithium (19.5ml of a 1.6M solution in hexane, 31.2mmol) was added via syringe. The resulting solution was stirred at-78 ℃ for 30 minutes and amide 14(4.2g, 24.97mmol in 15ml THF) was added via syringe. The mixture was stirred at-78 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for a further 30 minutes. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a viscous clear oil which was used in the subsequent reaction without any further purification.
And C:
15(2.19g, 8.77mmol) and dichloromethane (80ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The solution was cooled to-78 ℃ and boron tribromide (43ml of a 1.0M solution in dichloromethane, 43mmol) was added via syringe. The resulting dark red mixture was warmed to room temperature and stirred for 2 hours. The mixture was then carefully poured into ice water to give a two phase mixture which was stirred for 30 minutes. Then pouring the mixture into a liquid separation drain containing waterIn the bucket. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a yellow solid (1.56g, 75%) which was used in the subsequent reaction without any further purification.1H NMR(CDCl3，300MHz)δ11.65(s，1H)，7.90(d，J＝3Hz，1H)，7.43(dd，J＝9，3Hz，1H)，7.02(m，2H)，6.91(m，1H)，6.28(m，1H)，4.01(s，3H)。
Step D:
phenol 16(0.15g, 0.64mmol), 2' -chloroanilide (0.13g, 0.78mmol), potassium carbonate (0.47g, 3.39mmol) and acetone (10ml) were placed in a round bottom flask equipped with a stir bar, reflux condenser and, if necessary, nitrogen gas. The resulting mixture was heated to reflux for 18 hours, after which it was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography eluting with 4: 1 hexane/ethyl acetate to give 13 as a white solid (0.18g, 77%). 1H NMR(CDCl3，300MHz)δ9.69(s，1H)，7.81(d，J＝9Hz，2H)，7.54(d，J＝3Hz，1H)，7.47(dd，J＝6，3Hz，1H)，7.38(t，J＝6Hz，2H)，7.16(t，J＝6Hz，1H)，7.03(m，2H)，6.75(m，1H)，6.23(m，1H)，4.75(s，2H)，4.17(s，3H)。
Example 7:
step A:
according to general method V, 5- (2-pyridyl) thiophene-2-carboxylic acid (2.62g, 12.77mmol), oxalyl chloride (1.4ml, 2.04g, 16.05mmol), DMF (0.25ml) and dichloromethane (25ml) were used. The acid chloride was used immediately without any further purification. N, O-dimethylhydroxylamine hydrochloride (1.63g, 16.71mmol), triethylamine (9ml, 6.53g, 64.57mmol) and dichloromethane (25ml) were placed in another flask equipped with a stir bar and supplied with nitrogen if necessary. The resulting solution was cooled to 0 ℃ and the acid chloride (in 10ml dichloromethane) was added dropwise. When the addition was complete, the mixture was stirred at 0 ℃ for a further 30 minutes, then allowed to warm to room temperature and stirred for a further 1 hour. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a white solid (2.69g, 85%) which was used in the subsequent reaction without any further purification.1H NMR(CDCl3，300MHz)δ8.64(d，J＝3Hz，1H)，8.00(d，J＝3Hz，1H)，7.75(m，2H)，7.60(d，J＝6Hz，1H)，7.26(m，1H)，3.88(s，3H)，3.43(s，3H)。
And B:
2-bromo-4-chloroanisole (2.42g, 10.93mmol) and THF (35ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The solution was cooled to-78 ℃ and n-butyllithium (7.5ml of a 1.6M solution in hexane, 12mmol) was added via syringe. The resulting yellow mixture was stirred at-78 ℃ for 30 minutes, after which time amide 18(2.25g, 9.06mmol) in THF (10ml) was added slowly. The resulting mixture was stirred at-78 ℃ for 30 minutes, then allowed to warm to room temperature and stirred for an additional 1 hour. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was further purified by flash chromatography, eluting with 7: 3 hexanes/ethyl acetate, to give a yellow solid (1.42g, 48%). 1H NMR(CDCl3，300MHz)δ8.66(d，J＝6Hz，1H)，7.79(m，2H)，7.64(d，J＝6Hz，1H)，7.56(d，J＝6Hz，1H)，7.45(m，2H)，7.30(m，2H)，6.18(d，J＝6Hz，1H)，3.84(s，3H)。
And C:
ketone 19(1.42g, 4.31mmol) and methylene chloride (70ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The mixture was cooled to-78 ℃ and boron tribromide (20ml of a 1.0M solution in dichloromethane, 20mmol) was added via syringe. The resulting dark red mixture was stirred at-78 ℃ for 1 hour, allowed to warm to room temperature and stirred for an additional 1 hour. The mixture was carefully poured into ice water and the resulting biphasic mixture was stirred for 30 minutes. It was then poured into a separatory funnel containing dichloromethane and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a brown solid (1.32g, 97%).1H NMR(CDCl3，300MHz)δ11.55(s，1H)，8.70(d，J＝6Hz，1H)，8.00(d，J＝3Hz，1H)，7.82(m，3H)，7.75(d，J＝3Hz，1H)，7.51(dd，J＝9，3Hz，1H)，7.34(m，1H)，7.08(d，J＝9Hz，1H)。
Step D:
phenol 20(0.13g, 0.42mmol), 2' -chloroanilide (0.10g, 0.57mmol), potassium carbonate (0.29g, 2.09mmol) and acetone (10ml) were placed in a round bottom flask equipped with a stir bar, reflux condenser and, if necessary, nitrogen gas. The resulting mixture was heated to reflux for 18 hours, after which it was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography using 65: 35 hexane/ethyl acetate as eluent to give 17 as a white solid (0.16g, 85%). 1H NMR(CDCl3，300MHz)δ9.34(s，1H)，8.70(d，J＝6Hz，1H)，7.80(m，3H)，7.68(m，3H)，7.55(dd，J＝9，3Hz，1H)，7.35(m，4H)，7.14(t，J＝6Hz，1H)，7.07(d，J＝9Hz，1H)，4.75(s，2H)。
Example 8:
step A:
2-bromo-4-chloroanisole (7.02g, 31.69mmol) and diethyl ether (Et)2O, 75ml) was placed in a round bottom flask equipped with a stir bar and supplied with nitrogen gas as needed. The resulting solution was cooled to-78 deg.C and n-butyllithium (21ml of a 1.6M solution in hexane, 33.6mmol) was added via syringe. The resulting mixture was stirred at-78 ℃ for 15 minutes, after which 3-pyridinecarboxaldehyde (3.73g, 34.82mmol) was added slowly. The resulting solution was stirred at-78 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for a further 30 minutes. The mixture was poured into a separatory funnel containing ether and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear, viscous oil (6.97g, 88%) which was used without any further purification.1H NMR(CDCl3，300MHz)δ8.65(s，1H)，8.53(d，J＝3Hz，1H)，7.80(d，J＝9Hz，1H)，7.40(d，J＝3Hz，1H)，7.31(m，3H)，6.84(d，J＝9Hz，1H)，6.10(s，1H)，3.82(s，3H)。
And B:
alcohol 22(6.97g, 28mmol), manganese dioxide (MnO)220.27g, 233mmol) and chloroform (200ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen gas as needed. The resulting suspension was heated to reflux for 1 hour, after which it was allowed to cool to room temperature. The suspension was filtered through a pad of celite, washing with several portions of dichloromethane. Removing the solvent under reduced pressure Agent to give a brown solid (6.55g, 95%). The solid was used for the subsequent reaction without any further purification.
1H NMR(CDCl3，300MHz)δ8.94(d，J＝3Hz，1H)，8.81(dd，J＝6，3Hz，1H)，8.19(m，1H)，7.49(m，2H)，6.98(d，J＝9Hz，1H)，3.74(s，3H)。
And C:
ketone 23(6.55g, 26.45mmol) and methylene chloride (200ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The resulting solution was cooled to-78 ℃ and boron tribromide (50ml of a 1.0M solution in dichloromethane, 50mmol) was added via syringe. The resulting solution was stirred at-78 ℃ for 1 hour, after which it was allowed to warm to room temperature and stirred for a further 30 minutes. The mixture was carefully poured into ice water and the resulting two-phase system was stirred for 30 minutes. It was then poured into a separatory funnel containing dichloromethane and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 21 as a yellow solid (5.25g, 85%).1H NMR(CDCl3，300MHz)δ11.77(s，1H)，＝3Hz，1H)，8.90(dd，J＝3，1.5Hz，1H)，8.07(m，1H)，7.55(m，3H)，7.11(m，1H)。
Example 9:
step A:
n, O-dimethylhydroxylamine hydrochloride (7.79g, 79.86mmol), triethylamine (24ml, 172.2mmol) and chloroform (150ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen gas if necessary. The resulting solution was cooled to 0 ℃ and 5-methyl-3-isoxazolecarbonyl chloride (10.0g, 68.70mmol) in chloroform (15ml) was added dropwise, this The resulting solution was then stirred at 0 ℃ for 1 hour. The mixture was poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear oil (10.53g, 90%).1H NMR(CDCl3，400MHz)δ6.92(s，1H)，3.75(br s，6H)，2.44(s，3H)。
And B:
2-bromo-4-chloroanisole (5.02g, 22.66mmol) and diethyl ether (150ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The solution was cooled to-78 deg.C and n-butyllithium (15.6ml of a 1.6M solution in hexane, 24.96mmol) was added via syringe. The resulting solution was stirred at-78 ℃ for 15 minutes, then amide 25(4.03g, 23.68mmol) in diethyl ether (20ml) was added slowly, after which the solution was stirred at-78 ℃ for 30 minutes. It was then allowed to warm to room temperature and stirred for an additional 2 hours. The mixture was then poured into ice water and the two phase system was stirred for 30 minutes. It was then poured into a separatory funnel containing ether and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a white solid (5.37g, 94%).1H NMR(CDCl3，400MHz)δ7.51(d，J＝3Hz，1H)，7.42(dd，J＝6，3Hz，1H)，6.92(d，J＝6Hz，1H)，6.45(s，1H)，3.76(s，3H)，2.49(s，3H)。
And C:
ketone 26(5.36g, 21.30mmol) and dichloromethane (100ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The solution was cooled to-78 ℃ and boron tribromide (40ml of a 1.0M solution in dichloromethane) was added via syringe. The resulting dark red solution was stirred at-78 ℃ for 1 hour, after which it was allowed to warm to room temperature and stirred for an additional 2 hours. The mixture was carefully poured into ice water and the resulting two-phase system was stirred for 30 minutes. The mixture was then poured into a separatory funnel containing ether and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a brown solid (5.44g) which was used in the subsequent reaction without any further purification.
Step D:
according to general procedure II, phenol 27(5.44g crude weight, 21mmol), ethyl bromoacetate (2.3ml, 20.74mmol), potassium carbonate (12.32g, 89.14mmol) and acetone (150ml) were used. The product was used in the subsequent reaction without any further purification.
Step E:
according to general procedure III, ester 28(21mmol), THF (35ml), ethanol (15ml), water (15ml) and lithium hydroxide (2.04g, 48.62mmol) were used. Trituration with hexane afforded 29 as a white foam, which was used for subsequent reactions without any further purification.
Step F:
according to general method IV, acid 29(0.215g, 0.727mmol), HOBt (0.112g, 0.829mmol), EDAC (0.198g, 1.03mmol), triethylamine (0.25ml, 1.79mmol), DMF (5ml) and sulfoxide 399(0.198g, 0.884mmol) were used. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 24 as a brown solid (0.124g, 34%).1H NMR(CDCl3，400MHz)δ8.78(s，1H)，7.77(d，J＝4Hz，1H)，7.53-7.47(m，2H)，6.97(d，J＝8Hz，1H)，6.80(m，2H)，6.49(s，1H)，4.69(s，2H)，3.98-3.92(m，2H)，3.53(m，2H)，2.94-2.84(m，4H)，2.18(s，3H)，1.55(s，3H)。
Example 10:
step A:
according to general method I, 4-chloroanisole (4.06g, 28.47mmol), 3-fluorobenzoyl chloride (4.53g, 28.57mmol), aluminium chloride (6.23g, 46.72mmol) and dichloromethane (100ml) are used. The product was purified by flash chromatography using 7: 3 hexane/dichloromethane as eluent to give 31 as a yellow solid (2.60g, 36%). 1H NMR(CDCl3，300MHz)δ11.80(s，1H)，7.50(m，6H)，7.09(d，J＝9Hz，1H)。
And B:
according to general method II, phenol 31(2.60g, 10.37mmol), ethyl bromoacetate (1.3ml, 11.72mmol), potassium carbonate (7.15g, 51.73mmol) and acetone (80ml) were used. The product was used in the subsequent reaction without any further purification.
And C:
according to general procedure III, using ester 32(10mmol), THF (30ml), ethanol (10ml), water (10ml) and lithium hydroxide (1.02g, 24.31mmol), 33(3.01g, 98%) was obtained as a white solid.1H NMR(DMSO-dd，300MHz)δ7.71-7.38(m，6H)，6.91(d，J＝9Hz，1H)，4.26(s，2H)。
Step D:
according to general procedure IV, acid 33(0.22g, 0.71mmol), HOBt (0.115g, 0.851mmol), EDAC (0.205g, 1.07mmol), triethylamine (0.25ml, 1.79mmol), DMF (5ml) and sulfoxide 399(0.185g, 0.826mmol) were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 30 as a white solid (0.05g, 14%).1H NMR(CDCl3，400MHz)δ8.21(s，1H)，7.58-7.38(m，6H)，7.28(m，1H)，7.01(d，J＝8Hz，1H)，6.76(m，2H)，4.66(s，2H)，3.98-3.91(m，2H)，3.53(m，2H)，2.91-2.83(m，4H)，1.54(s，3H)。
Example 11:
according to general method V, carboxylic acid 33(0.224g, 0.726mmol), oxalyl chloride (0.2ml, 2.29mmol) and dichloromethane (4ml) were used. Sulfonamide 466(0.158g, 0.848mmol), triethylamine (0.25ml, 1.79mmol) and acetonitrile (CH)3CN, 8ml) was placed in another flask. The mixture was cooled to 0 ℃ and the acid chloride (in 2ml acetonitrile) was added dropwise over a few minutes. The resulting mixture was stirred at 0 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for a further 5 hours. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 34 as a white solid (0.117g, 34%). 1H NMR(DMSO-d6，300MHz)δ9.39(s，1H)，7.71-7.52(m，9H)，7.31-7.27(m，3H)，4.85(s，2H)，2.21(s，3H)。
Example 12:
step A:
according to general method I, 4-chloroanisole (4.02g, 28.19mmol), 3-fluorobenzoyl chloride (3.8ml, 4.94g, 28.22mmol), aluminium chloride (5.62g, 42.15mmol) and dichloromethane (75ml) are used. The product was purified by flash chromatography using 7: 3 hexane/dichloromethane as eluent to give 36 as a yellow solid (5.35g, 71%).1H NMR(CDCl3，400MHz)δ1.72(s，1H)，7.64(s，1H)，7.58(d，J＝8Hz，1H)，7.53-7.44(m，4H)，7.03(d，J＝12Hz，1H)。
And B:
according to general procedure II, phenol 36(5.35g, 20.03mmol), ethyl bromoacetate (2.5ml, 22.54mmol), potassium carbonate (12.91g, 93.41mmol) and acetone (125ml) were used. The product was used in the subsequent reaction without any further purification.
And C:
according to general procedure III, ester 37(20mmol), THF (60ml), ethanol (15ml), water (15ml) and lithium hydroxide (2.09g, 49.81mmol) were used. The product was used in the subsequent reaction without any further purification.
Step D:
according to general procedure IV, carboxylic acid 38(0.29g, 0.892mmol), sulfoxide 399(0.24g, 1.07mmol), EDAC (0.261g, 1.36mmol), HOBt (0.142g, 1.05mmol) and DMF (7ml) were used, but triethylamine was not used. Purifying the product by flash chromatography using 97: 3 bisMethyl chloride/methanol as eluent gave 35 as a brown solid (0.34g, 72%). 1HNMR(CDCl3，300MHz)δ8.21(s，1H)，7.86(d，J＝3Hz，1H)，7.72(d，J＝6Hz，1H)，7.60-7.43(m，4H)，7.07(d，J＝9Hz，2H)，6.85-6.82(m，3H)，4.72(s，2H)，4.06-3.98(m，2H)，3.62-3.55(m，2H)，3.00-2.90(m，4H)，2.18(s，3H)。
Example 13:
according to general method V, carboxylic acid 38(0.229g, 0.704mmol), oxalyl chloride (0.2ml, 2.29mmol) and dichloromethane (4ml) were used. 466 sulfonamide (0.156g, 0.838mmol), triethylamine (0.25ml, 1.79mmol) and CH3CN (8ml) was placed in another flask. The acid chloride (in 2ml CH) was added dropwise over a few minutes3In CN). The resulting solution was stirred at 0 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for a further 5 hours. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 39 as a white solid (0.110g, 32%).1H NMR(DMSO-d6，300MHz)δ9.39(s，1H)，7.82-7.53(m，9H)，7.30(m，3H)，4.84(s，2H)，2.20(s，3H)。
Example 14:
step A:
n, O-dimethylhydroxylamine hydrochloride (3.16g, 32.40mmol), triethylamine (9ml, 64.57mmol) and dichloromethane (85ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen gas as needed. The resulting solution was allowed to cool to 0 deg.C and 3-trifluoromethylbenzoyl chloride (4ml, 5.53g, 26.52mmol) was added dropwise over a few minutes. The resulting solution was stirred at 0 ℃ for 30 minutes, after which it was warmed to room temperature and stirred for a further 30 minutes. The mixture was poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a clear oil, which was used without any further purification.
And B:
2-bromo-4-chloroanisole (5.23g, 23.61mmol) and diethyl ether (100ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The solution was cooled to-78 deg.C and n-butyllithium (17ml of a 1.6M solution in hexane, 27.2mmol) was added dropwise. The resulting mixture was stirred at-78 ℃ for 15 minutes, after which time amide 41(5.56g, 23.84mmol) was added dropwise. The mixture was stirred at-78 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for a further 2 hours. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a yellow oil which was used in the subsequent reaction without any further purification.
And C:
42(23mmol) and dichloromethane (150ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen if necessary. The solution was cooled to-78 ℃ and boron tribromide (35ml of a 1.0M solution in dichloromethane, 35mmol) was added dropwise over a period of a few minutes. The resulting dark mixture was stirred at-78 ℃ for 30 minutes, whereuponThen allowed to warm to room temperature and stirred for an additional 1 hour. The mixture was carefully poured into ice and the resulting biphasic mixture was stirred for 30 minutes. It was then poured into a separatory funnel containing dichloromethane and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a yellow solid (5.04g, 73%). 1H NMR(CDCl3，300MHz)δ11.76(s，1H)，8.25-7.84(m，3H)，7.73(t，J＝9Hz，1H)，7.56-7.52(m，2H)，7.12(d，J＝9Hz，1H)。
Step D:
according to general procedure II, phenol 43(5.04g, 16.76mmol), ethyl bromoacetate (2.1ml, 18.94mmol), potassium carbonate (9.01g, 65.19mmol) and acetone (100ml) were used. The solvent was removed under reduced pressure to give 44 as an oil (6.28g, crude weight). The product was used in the subsequent reaction without any further purification.
Step E:
according to general procedure IV, ester 44(6.28g, crude weight, 16.24mmol), THF (50ml), water (25ml) and ethanol (25ml) were used. The solvent was removed under reduced pressure to give acid 45 as a white solid (2.81g, 48%), which was used without any further purification.
Step F:
according to general method IV, carboxylic acid 45(0.208g, 0.58mmol), sulfoxide 399(0.152g, 0.679mmol), EDAC (0.19g, 0.991mmol), HOBt (0.103g, 0.76mmol) and DMF (5ml) were used. The product was purified by flash chromatography eluting with 95: 5 dichloromethane/methanol to give 40 as an off-white solid (0.23g, 70%).1H NMR(CDCl3，300MHz)δ8.19(d，J＝9Hz，2H)，8.01(d，J＝9Hz，1H)，7.88(d，J＝9Hz，1H)，7.66(t，J＝6Hz，1H)，7.60(dd，J＝9，3Hz，1H)，7.50(d，J＝9Hz，1H)，7.44(d，J＝3Hz，1H)，7.09(d，J＝9Hz，1H)，6.83(m，3H)，4.72(s，2H)，4.05-3.96(m，2H)，3.62-3.54(m，2H)，3.0-2.89(m，4H)，2.16(s，3H)。
Example 15:
step A:
according to general method I, 4-chloroanisole (4.12g, 28.89mmol), 3, 5-difluorobenzoyl chloride (5.0g, 28.3mmol), aluminum chloride (5.65g, 42.37mmol) and dichloromethane (75ml) were used. The product was purified by flash chromatography using 7: 3 hexane/dichloromethane as eluent to give a yellow solid (2.72g, 36%). 1H NMR(CDCl3，300MHz)δ11.64(s，1H)，7.54(m，2H)，7.23(m，2H)，7.11(m，2H)。
And B:
according to general procedure II, phenol 47(2.72g, 10.13mmol), ethyl bromoacetate (1.3ml, 11.7mmol), potassium carbonate (5.28g, 38.2mmol) and acetone (100ml) were used. The solvent was removed under reduced pressure to give 48 as a clear oil (3.8g, crude weight) which was used without any further purification.
And C:
according to general procedure III, ester 48(10mmol), THF (50ml), water (25ml) and ethanol (25ml) were used. The solvent was removed under reduced pressure to give 49 as a white solid, which was used in the subsequent reaction without any further purification.
Step D:
according to general procedure IV, carboxylic acid 49(0.20g, 0.612mmol), sulfoxide 399(0.167g, 1.22mmol), EDAC (0.23g, 1.2mmol), HOBt (0.106g, 0.784mmol) and DMF (5ml) were used, but triethylamine was not used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent followed by trituration with ether to give 46 as an off-white solid (0.24g, 74%).1H NMR(CDCl3，300MHz)δ8.29(s，1H)，7.61-7.54(m，2H)，7.42(d，J＝3Hz，1H)，7.38(m，1H)，7.08(m，2H)，6.85(m，2H)，4.73(s，2H)，4.73(，2H)，4.05-3.96(m，2H)，3.62-3.55(m，2H)，2.94-2.89(m，4H)，2.21(s，3H)。
Example 16
Step A:
according to general method I, 4-chloroanisole (4.16g, 29.17mmol), 3-methylbenzoyl chloride (4.42g, 28.59mmol), aluminum chloride (6.12g, 45.9mmol) and dichloromethane (150ml) were used. The product was purified by flash chromatography using 7: 3 hexane/dichloromethane as eluent to give 50 as a yellow solid (1.54g, 22%). 1H NMR(CDCl3，400MHz)δ11.91(s，1H)，7.54(d，J＝4Hz，1H)，7.47-7.39(m，5H)，7.02(d，J＝8Hz，1H)，2.44(s，3H)。
And B:
according to general method II, phenol 50(1.54g, 6.24mmol), ethyl bromoacetate (0.8ml, 7.21mmol), potassium carbonate (3.15g, 22.79mmol) and acetone (35ml) were used. The solvent was removed under reduced pressure to give 51 as a clear oil, which was used without any further purification.
And C:
according to general procedure III, ester 51(6.3mmol), lithium hydroxide (0.700g, 16.68mmol), THF (20ml), water (10ml) and ethanol (10ml) were used. The solvent was removed under reduced pressure to give 52 as a white solid (1.82g, 96%), which was used without any further purification.
Step D:
according to general procedure IV, carboxylic acid 52(0.21g, 0.70mmol), sulfoxide 399(0.19g, 0.853mmol), EDAC (0.212g, 1.11mmol), HOBt (0.121g, 0.895mmol) and DMF (5ml) were used, but triethylamine was not used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 50 as an off-white solid (0.09g, 25%).1HNMR(CDCl3，300MHz)δ8.13(s，1H)，7.69-7.30(m，8H)，7.04(d，J＝9Hz，1H)，6.81(m，3H)，4.69(s，2H)，4.05-3.96(m，2H)，3.60-3.51(m，2H)，2.93-2.85(m，4H)，2.38(s，3H)，2.14(s，3H)。
Example 17
According to general method IV, carboxylic acid 129(0.316g, 1.00mmol), amine 143(0.241g, 1.03mmol), EDAC (0.251g, 1.31mmol), HOBt (0.167g, 1.24mmol) and DMF (5ml) were used, but triethylamine was not used. The product was purified by flash chromatography using 9: 1 chloroform/methanol as eluent to give 53 as a brown powder (0.082g, 15%).
466 aniline (0.246g, 1.32mmol), triethylamine (0.9ml, 0.65g, 6.5mmol), chloroform (5ml) and CH3CN (5ml) was placed in a round bottom flask. The resulting mixture was cooled to 0 ℃ and 2' -chloroacetyl chloride (0.2ml, 2.51mmol) was added dropwise over a few minutes. The mixture was stirred at 0 ℃ for 30 minutes, then warmed to room temperature and stirred for an additional 30 minutes. The mixture was then poured into a separatory funnel containing water and ethyl acetate. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a dark green oil. Several portions of hexane were added and the solvent was removed under reduced pressure to give 54 as a green solid, which was used without any further purification.1H NMR(DMSO-d6，300MHz)δ9.84(s，D1H)，7.69(m，3H)，7.31(s，2H)，4.38(s，3H)，2.31(s，3H)。
Example 18
Amine 54(0.16g, 0.61mmol), phenol 185(0.14g, 0.60mmol), potassium carbonate (0.66g, 4.8mmol) and acetone (10ml) were placed in a round bottom flask. The resulting mixture was heated to reflux and stirred overnight. The mixture was then allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography eluting with 95: 5 dichloromethane/methanol to give 55 as an off-white solid (0.02g, 7%). 1H NMR(DMSO-d6，400MHz)δ9.74(s，1H)，7.63-7.53(m，4H)，7.26-7.19(m，4H)，6.97(s，2H)，4.81(s，2H)，3.99(s，3H)，2.08(s，3H)。
Example 19:
amine 54(0.16g, 0.62mmol), potassium carbonate (0.51g, 3.7mmol), phenol 4(0.22g, 0.90mmol) and acetone (5ml) were placed in a round bottom flask. The same procedure was followed as in example 55. The product was purified by flash chromatography eluting with 97: 3 chloroform/methanol to give 56 as a brown solid (0.03g, 10%).1H NMR(DMSO-d6，300MHz)δ9.39(s，1H)，8.33(d，J＝3Hz，1H)，8.16(d，J＝3Hz，1H)，7.83-7.64(m，5H)，7.39-7.30(m，3H)，4.86(s，2H)，2.23(s，3H)。
Example 20
According to general procedure IV, acid 49(0.351g, 1.07mmol), amine 143(0.253g, 1.08mmol), EDAC (0.341g, 1.78mmol), HOBt (0.193g, 1.43mmol) and DMF (7ml) were used, but triethylamine was not used. The product was purified by flash chromatography eluting with 9: 1 chloroform/methanol to give a brown solid (0.09g, 15%).1H NMR(CDCl3，300MHz)δ8.19(s，1H)，7.49(dd，J＝9，3Hz，1H)，7.42(d，J＝9Hz，1H)，7.33(d，J＝3Hz，H)，7.27(d，J＝3Hz，1H)，7.19(m，1H)，7.01-6.96(m，2H)，6.65-6.63(m，2H)，4.62(s，2H)，4.00-3.96(t，J＝6Hz，2H)，3.76(m，2H)，3.23-3.15(m，2H)，2.75(m，2H)，2.39-2.12(m，6H)，2.09(s，3H)。
Example 21
Step A:
according to general procedure I, 4-fluorobenzoyl chloride (3.2ml, 27.08mmol), 4-chloroanisole (3.98g, 27.91mmol), aluminium chloride (5.78g, 43.34mmol) and dichloromethane (120ml) were used. The product was purified by flash chromatography, eluting with 7: 3 hexanes/ethyl acetate, to give 59 as a yellow solid (3.48g, 51%).
And B:
according to general procedure II, using phenol 59(3.48g, 13.88mmol), ethyl bromoacetate (1.7ml, 15.32mmol), potassium carbonate (7.74g, 56.0mmol) and acetone, 60 was obtained as a white solid, which was washed with several portions of diethyl ether, dried in vacuo and used for the subsequent reaction without any further purification.
And C:
using ester 60(4.7g, 13.9mmol), lithium hydroxide (1.45g, 34.56mmol), water (20ml), THF (40ml) and ethanol (20ml) according to general procedure III, 61 was obtained as a viscous clear oil. Diethyl ether was added to the oil, causing the formation of a white solid, which was filtered and dried to give 61 as a white solid, which was used without any further purification.
Step D:
according to general procedure IV, carboxylic acid 61(0.237g, 0.786mmol), sulfoxide 399(0.198g, 0.88mmol), EDAC (0.285g, 1.49mmol), HOBt (0.131g, 0.97mmol) and DMF (5ml) were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 58 as a brown solid (0.280g, 71%).1H NMR(DMSO-d6，300MHz)δ8.95(s，1H)，7.90(m，2H)，7.66(dd，J＝9，3Hz，1H)，7.49(d，J＝3Hz，1H)，7.36(t，J＝6Hz，2H)，7.26(d，J＝9Hz，1H)，7.14(d，J＝9Hz，1H)，6.84(m，2H)，4.73(s，2H)，3.75(m，2H)，3.58(m，2H)，2.91(m，2H)，2.71(m，2H)，2.03(s，3H)。
Example 22
Acid chloride was prepared according to general procedure V using carboxylic acid 49(0.123g, 0.377mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (2 drops) and chloroform (5 ml). Using this acid chloride, sulfonamide 466(0.07g, 0.37mmol), sodium bicarbonate (0.13g, 1.55mmol), water (1ml) and acetone (5ml) according to general procedure VI, 62 was obtained as a brown solid (0.07g, 40%).1H NMR(DMSO-d6，300MHz)δ9.46(s，1H)，7.68-7.45(m，8H)，7.28(m，3H)，4.85(s，2H)，2.21(s，3H)。
Example 23
Step A:
according to general method I, 3, 4-difluorobenzoyl chloride (5.01g, 28.37mmol), 4-chloroanisole (4.04g, 28.33mmol), aluminum chloride (5.61g, 42.07mmol) and dichloromethane (100ml) were used. The product was purified by flash chromatography using 7: 3 hexane/ethyl acetate as eluent to give 64 as a yellow solid (2.65g, 35%). 1H NMR(CDCl3，300MHz)δ11.64(s，1H)，7.64-7.30(m，5H)，7.09(d，J＝9Hz，1H)。
And B:
according to general procedure II, using phenol 64(2.65g, 9.86mmol), ethyl bromoacetate (1.20ml, 10.82mmol), potassium carbonate (5.37g, 38.85mmol) and acetone (35ml), 65(3.39g, 96%) was obtained as a white solid, which was used without any further purification.
And C:
according to general procedure III, using ester 65(3.39g, 9.56mmol), lithium hydroxide (0.80g, 19.07mmol), water (20ml), THF (40ml) and ethanol (20ml), 66 was obtained as a white solid, which was used without any further purification.
Step D:
according to general procedure IV, carboxylic acid 66(0.146g, 0.447mmol), sulfoxide 399(0.096g, 0.429mmol), EDAC (0.183g, 0.955mmol), HOBt (0.077g, 0.569mmol) and DMF (5ml) were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 63 as a brown solid (0.150g, 63%).1H NMR(CDCl3，300MHz)δ8.35(s，1H)，7.79-7.56(m，3H)，7.41(d，J＝3Hz，1H)，7.32(m，2H)，7.09(d，J＝9Hz，1H)，6.87(br s，1H)，4.73(s，2H)，4.04(m，2H)，3.58(m，2H)，3.02(m，4H)，1.62(s，3H)。
Example 24
Step A:
n, O-dimethylhydroxylamine hydrochloride (2.80g, 28.7mmol), triethylamine (9.0 ml)64.57mmol) and chloroform (50ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen gas as needed. The solution was allowed to cool to 0 ℃ and 3-trifluoromethyl-5-fluorobenzoyl chloride (5.0g, 22.07mmol) was added dropwise over a few minutes. The resulting solution was stirred at 0 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for a further 30 minutes. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 68 as a clear oil, which was used without any further purification. 1H NMR(CDCl3，300MHz)δ7.83(s，1H)，7.65(d，J＝9Hz，1H)，7.46(d，J＝9Hz，1H)，3.59(s，3H)，3.42(s，3H)。
And B:
2-bromo-4-chloroanisole (4.05g, 18.29mmol) and diethyl ether (75ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The solution was cooled to-78 deg.C and n-butyllithium (13ml of a 1.6M solution in hexane, 20.8mmol) was added dropwise. The resulting mixture was stirred at-78 ℃ for 15 minutes, after which time amide 68(5.04g, 20.07mmol) was added dropwise. The mixture was stirred at-78 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for a further 2 hours. The mixture was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 69(6.14g, 92%) as a yellow solid, which was used without any further purification.1HNMR(CDCl3，300MHz)δ7.84(s，1H)，7.68(d，J＝9Hz，1H)，7.58-7.51(m，2H)，7.44(d，J＝3Hz，1H)，7.00(d，J＝9Hz，1H)，3.74(s，3H)。
And C:
69(6.14g, 18.46mmol) and dichloromethane (100ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The solution was cooled to-78 ℃ and boron tribromide (50ml of a 1.0M solution in dichloromethane, 50mmol) was added dropwise over a few minutes. The resulting dark mixture was stirred at-78 ℃ for 30 minutes, after which it was allowed to warm to room temperature and stirred for an additional 1 hour. The mixture was carefully poured into ice and the biphasic mixture was stirred for 30 minutes. It was then poured into a separatory funnel containing dichloromethane and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 70(5.68g, 96%) as a yellow solid, which was used without any further purification. 1H NMR(CDCl3，300MHz)δ11.61(s，1H)，7.77(s，1H)，7.65-7.54(m，3H)，7.47(d，J＝3Hz，1H)，7.12(d，J＝9Hz，1H)。
Step D:
according to general procedure II, using phenol 70(5.68g, 17.83mmol), ethyl bromoacetate (2ml, 18.03mmol), potassium carbonate (9.61g, 69.53mmol) and acetone (35ml), the ester was obtained as a yellow viscous oil, which was used without any further purification. This ester (6.83g, 16.88mmol), lithium hydroxide (1.42g, 33.84mmol), water (20ml), THF (50ml) and ethanol (20ml) were used according to general procedure III. The product was washed with several portions of diethyl ether to give 71 as a white solid, which was used without any further purification.
Step E:
according to general procedure IV, carboxylic acid 71(0.168g, 0.445mmol), sulfoxide 399(0.098g, 0.438mmol), EDAC (0.211g, 1.10mmol), HOBt (0.076g, 0.562mmol) and DMF (5ml) were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 67 as a white solid (0.18g, 69%).1H NMR(CDCl3，300MHz)δ8.26(s，1H)，7.92(s，1H)，7.73(d，J＝6Hz，1H)，7.64-7.59(m，3H)，7.44(d，J＝3Hz，1H)，7.10(d，J＝9Hz，1H)，6.90(m，1H)，4.74(s，2H)，4.03(m，2H)，3.58(m，2H)，3.02(m，4H)，2.21(s，3H)。
Example 25:
according to general method IV, carboxylic acid 105(0.195g, 0.65mmol), 6-aminobenzothiazole (Lancaster, 0.105g, 0.70mmol), EDAC (0.23g, 1.20mmol), HOBt (0.105g, 0.78mmol) and DMF (5ml) were used, but triethylamine was not used. The product was purified by flash chromatography using 1: 1 hexane/ethyl acetate as eluent to give 72 as a white solid (0.24g, 87%). 1H NMR(CDCl3，400MHz)δ9.51(s，1H)，8.92(s，1H)，8.64(s，1H)，8.08(d，J＝8Hz，1H)，7.92(d，J＝8Hz，1H)，7.67-7.63(m，2H)，7.55-7.50(m，3H)，7.42(s，1H)，7.04(d，J＝8Hz，1H)，4.73(s，2H)。
Example 26
Step A:
according to general method I, 3, 5-dichlorobenzoyl chloride (5.0g, 23.87mmol), 4-chloroanisole (3.40g, 23.84mmol), aluminium chloride (5.56g, 41.70mmol) and dichloromethane (100ml) are used. The product was purified by flash chromatography, eluting with 7: 3 hexane/dichloromethane, to give 74 as a yellow solid (1.18g, 16%).1H NMR(CDCl3，300MHz)δ11.62(s，1H)，7.65(s，1H)，7.56-7.49(m，4H)，7.09(d，J＝9Hz，1H)。
And B:
according to general procedure II, using phenol 74(1.18g, 3.91mmol), ethyl bromoacetate (0.6ml, 5.41mmol), potassium carbonate (2.66g, 19.25mmol) and acetone (15ml), 75 was obtained as a yellow, viscous oil, which was used without any further purification.
And C:
using ester 75(3.9mmol), lithium hydroxide (0.396g, 9.44mmol), water (10ml), THF (40ml) and ethanol (10ml) according to general procedure III, 76 was obtained as a white solid, which was washed with hexane and dried in vacuo (1.32g, 94%).
Step D:
according to general procedure IV, carboxylic acid 76(0.128g, 0.356mmol), sulfoxide 399(0.076g, 0.339mmol), EDAC (0.114g, 0.595mmol), HOBt (0.057g, 0.422mmol) and DMF (5ml) were used. The product was purified by flash chromatography using 95: 5 chloroform/methanol as eluent to give 73 as a white solid (0.125g, 65%). 1H NMR(CDCl3，300MHz)δ8.20(s，1H)，7.70(s，1H)，7.62-7.59(m，2H)，7.42(d，J＝3Hz，1H)，7.08(d，J＝9Hz，1H)，6.86(br s，2H)，4.72(s，2H)，4.04(m，2H)，3.62-3.55(m，2H)，3.06-2.92(m，4H)，2.21(s，3H)。
Example 27
According to general method IV, carboxylic acid 105(0.125g, 0.417mmol), 3-aminophthalimide (TCI, 0.062g, 0.382mmol), EDAC (0.132)g, 0.689mmol), HOBt (0.063g, 0.467mmol) and DMF (5 ml). The product was purified by flash chromatography using 95: 5 chloroform/methanol as eluent to give 77 as a white solid (0.038g, 22%).1H NMR(CDCl3，300MHz)δ10.10(s，1H)，8.39(s，1H)，8.25(dd，J＝9，3Hz，1H)，7.97(d，J＝9Hz，2H)，7.80(d，J＝9Hz，1H)，7.73(t，J＝6Hz，1H)，7.63-7.56(m，4H)，7.48(d，J＝3Hz，1H)，7.10(d，J＝9Hz，1H)，4.82(s，2H)。
Example 28
According to general procedure V, carboxylic acid 71(11.24g, 29.84mmol), oxalyl chloride (3.9ml, 44.71mmol), DMF (5ml) and chloroform (250ml) were used to prepare the acid chloride, which was used without further purification. The acid chloride, sulfonamide 466(5.12g, 27.49mmol), sodium bicarbonate (11.12g, 132mmol), acetone (300ml) and water (10ml) were used according to general procedure VI. The product was purified by crystallization from acetonitrile/water to yield 78(9.01g, 60%) as a white solid.1H NMR(DMSO-d6，300MHz)δ9.47(s，1H)，8.05(d，J＝9Hz，1H)，7.93-7.90(m，2H)，7.73-7.50(m，5H)，7.30-7.26(m，3H)，4.84(s，2H)，2.19(s，3H)。C23H17ClF4N2O5Analytical calculation of S: c, 50.70; h, 3.14; and N, 5.14. Measured value: c, 50.75; h, 3.10; n, 5.21.
Example 29
The acid chloride was prepared according to general procedure V using carboxylic acid 76(0.157g, 0.437mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (3 drops) and dichloromethane (5ml), which was used without any further purification. According to general method VI, the acid chloride, sulfonamide 466(0.072g, 0.387mmol), sodium bicarbonate (0.210g, 2.5mmol) were used Acetone (5ml) and water (0.5 ml). The product was purified by flash chromatography eluting with 95: 5 chloroform/methanol to give 79 as a white solid (0.117g, 57%).1H NMR(DMSO-d6，300MHz)δ9.45(s，1H)，7.94(s，1H)，7.76(s，2H)，7.75-7.55(m，5H)，7.30-7.25(m，3H)，4.85(s，2H)，2.22(s，3H)。
Example 30
According to general procedure IV, carboxylic acid 131(0.109g, 0.345mmol), 6-aminobenzothiazole (Lancaster, 0.056g, 0.373mmol), EDAC (0.164g, 0.855mmol), HOBt (0.064g, 0.474mmol) and DMF (5ml) were used. The product was purified by flash chromatography eluting with 95: 5 chloroform/methanol to give 80 as a white solid (0.120g, 77%).1H NMR(DMSO-d6，300MHz)δ10.18(s，1H)，9.30(s，1H)，8.50(s，1H)，8.26(s，1H)，8.13(d，J＝9Hz，1H)，8.05(t，J＝9Hz，2H)，7.75-7.66(m，2H)，7.56(m，2H)，7.26(d，J＝9Hz，1H)，4.81(s，2H)。
Example 31
According to general method IV, carboxylic acid 49(0.106g, 0.324mmol), 6-aminobenzothiazole (Lancaster, 0.051g, 0.3393mmol), EDAC (0.158g, 0.824mmol), HOBt (0.0584g, 0.429mmol) and DMF (5ml) were used. The product was purified by flash chromatography eluting with 95: 5 chloroform/methanol to give 81 as a white solid (0.105g, 70%).1H NMR(DMSO-d6，300MHz)δ10.22(s，1H)，9.31(s，1H)，8.48(d，J＝3Hz，1H)，8.04(d，J＝9Hz，1H)，7.67(dd，J＝9,3Hz，1H)，7.59-7.48(m，5H)，7.25(d，J＝9Hz，1H)，4.82(s，2H)。
Example 32
Acid chloride was prepared according to general procedure V using carboxylic acid 105(0.129g, 0.43mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and dichloromethane (3 ml). The acid chloride, 5-amino-2-methylbenzothiazole dihydrochloride (0.087g, 0.367mmol), sodium bicarbonate (0.324g, 3.86mmol), water (0.5ml) and acetone (5ml) were used according to general procedure VI. The product was purified by flash chromatography eluting with 95: 5 chloroform/methanol to give 82 as a white solid (0.118g, 74%).
1H NMR(DMSO-d6，300MHz)δ10.02(s，1H)，8.20(d，J＝3Hz，1H)，7.95(d，J＝9Hz，1H)，7.85(d，J＝9Hz，2H)，7.66-7.47(m，6H)，7.26(d，J＝9Hz，1H)，4.78(s，2H)，2.80(s，3H)。
Example 33
Acid chloride was prepared according to general procedure V using carboxylic acid 49(0.110g, 0.337mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and dichloromethane (5 ml). This acid chloride, 5-amino-2-methylbenzothiazole dihydrochloride (0.078g, 0.329mmol), sodium hydrogen carbonate (0.293g, 3.49mmol), water (0.5ml) and acetone (5ml) were used according to general procedure VI. The product was purified by flash chromatography using 95: 5 chloroform/methanol to give 83 as a white solid (0.079g, 49%).1H NMR(DMSO-d6，300MHz)δ10.12(s，1H)，8.22(s，1H)，7.95(d，J＝9Hz，1H)，7.67(dd，J＝9，3Hz，1H)，7.58-7.48(m，5H)，7.25(d，J＝9Hz，1H)，4.81(s，2H)，2.80(s，3H)。
Example 34
Acid chloride was prepared according to general procedure V using carboxylic acid 129(0.094g, 0.298mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and dichloromethane (5 ml). The acid chloride, 5-amino-2-methylbenzothiazole dihydrochloride (0.068g, 0.287mmol), sodium bicarbonate (0.310g, 3.69mmol), water (0.5ml) and acetone (5ml) were used according to general procedure VI. The product was purified by flash chromatography eluting with 95: 5 chloroform/methanol to give 84 as a brown solid (0.042g, 31%).1H NMR(DMSO-d6，300MHz)δ10.09(s，1H)，8.22(d，J＝9Hz，2H)，8.13(d，J＝6Hz，1H)，8.06(d，J＝9Hz，1H)，7.94(d，J＝9Hz，1H)，7.75-7.66(m，2H)，7.55(d，J＝3Hz，1H)，7.49(d，J＝3Hz，1H)，7.25(d，J＝6Hz，1H)，4.78(s，2H)，2.80(s，3H)。
Example 35
Acid chloride was prepared according to general procedure V using carboxylic acid 105(0.104g, 0.347mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and dichloromethane (4 ml). The acid chloride, 4-methylsulfonylaniline (0.06g, 0.350mmol), sodium bicarbonate (0.214g, 2.55mmol), water (0.5ml) and acetone (6ml) were used according to general procedure VI. The product was purified by flash chromatography, eluting with 3: 2 ethyl acetate/hexanes to give 85 as a white solid (0.061g, 40%). 1H NMR(DMSO-d6，300MHz)δ10.34(s，1H)，7.90-7.76(m，6H)，7.66-7.47(m，5H)，7.22(d，J＝9Hz，1H)，3.18(s，3H)。
Example 36
Step A:
2-chloro-5-nitrobenzaldehyde (1.84g, 9.92mmol), sulphur (0.360g, 11.23mmol), ammonia (5ml) and methanol (30ml) were placed in a stirred Parr tank (bomb). The tank was sealed and heated to 85-90 c for 16 hours with stirring. The mixture was cooled to room temperature and poured into a separatory funnel containing dichloromethane and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed to give 87 as an orange solid (1.26g, 70%).1HNMR(DMSO-d6，400MHz)δ9.33(s，1H)，9.13(d，J＝4Hz，1H)，8.47(d，J＝12Hz，1H)，8.36(dd，J＝12，4Hz，1H)。
And B:
compound 87(1.26g, 6.97mmol), iron powder (1.89g, 33.84mmol), concentrated hydrochloric acid (7ml) and ethanol (35ml) were charged to a round bottom flask. The mixture was heated to reflux and stirred for 2 hours, after which it was allowed to cool to room temperature. The mixture was then poured into water and made basic by slow addition of solid sodium bicarbonate. It was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 88 as a brown solid (0.470g, 45%).1H NMR(DMSO-d6，400MHz)δ8.82(s，1H)，7.81(d，J＝9Hz，1H)，7.20(d，J＝3Hz，1H)，6.99(dd，J＝9，3Hz，1H)5.40(s，2H)。
And C:
acid chloride was prepared according to general procedure V using carboxylic acid 129(0.125g, 0.396mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and dichloromethane (5 ml). Using the acid chloride, amine 88(0.063g, 0.419mmol), sodium bicarbonate (0.173g, 2.06mmol), water (0.5ml) and acetone (5ml) according to general procedure VI, a yellow solid was obtained. The solid was washed with several portions of ether and dried under vacuum to give 86 as a yellow solid (0.083g, 47%).
Example 37
Step A:
5-fluoro-2-nitrotoluene (Lancaster, 2.03g, 13.09mmol), 2-thioimidazole (1.54g, 15.38mmol), potassium carbonate (6.31g, 45.66mmol) and DMF (25ml) were placed in a round bottom flask. The resulting mixture was heated to 80-90 ℃ for 3 hours, then cooled to 50 ℃ and stirred overnight. The mixture was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 90 as an orange oil, which was used without purification.1HNMR(CDCl3，300MHz)δ7.85(d，J＝9Hz，1H)，7.80-7.30(br m，2H)，7.08(s，1H)，7.03(d，J＝6Hz，1H)，2.53(s，3H)。
And B:
compound 90(0.121g, 0.51mmol), glacial acetic acid (3ml) and hydrogen peroxide (0.491g of a 30% w/w solution, 4.33mmol) were placed in a round bottom flask. The resulting mixture was heated to 85-90 ℃ for 2 hours, then allowed to cool to room temperature and poured into a flask containing saturated sodium bisulfite solution. The mixture was adjusted to pH7 by slowly adding solid sodium bicarbonate and then poured into a separatory funnel containing ethyl acetate. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 91 as a white solid (0.092g, 67%). 1H NMR(DMSO-d6，400MHz)δ8.16(d，J＝8Hz，1H)，8.04(s，1H)，7.93(d，J＝8Hz，1H)，7.35-7.32(br m，2H)，2.47(s，3H)。
And C:
compound 91(0.092g, 0.34mmol), Pd/C (0.01g, 10% w/w) and ethanol were placed in a Parr bottle. The bottle was purged with hydrogen (3X) to a final pressure of 40 psig. The mixture was stirred at room temperature for 30 minutes, after which the bottle was depressurized and the mixture was filtered through a pad of celite and the solvent was removed under reduced pressure to give 92 as a yellow solid (0.083g, yield > 100%), which was used without any further purification.1H NMR(DMSO-d6，400MHz)δ13.54(br s，1H)，8.77(s，1H)，8.74(s，1H)，7.60(dd，J＝8，4Hz，1H)，7.45(d，J＝4Hz，1H)，7.18(br s，2H)，7.09(d，J＝8Hz，1H)，2.05(s，3H)。
Step D:
acid chloride was prepared according to general procedure V using carboxylic acid 49(0.100g, 0.31mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and chloroform (3 ml). Using this acid chloride, amine 92(0.065g, 0.273mmol), sodium bicarbonate (0.134g, 1.59mmol), water (0.5ml) and acetone (4ml) according to general procedure VI, a brown solid was obtained. The solid was washed with several portions of ether and dried to give 89(0.105g, 62%) as a brown solid.1H NMR(DMSO-d6，300MHz)δ13.74(s，1H)，10.26(s，1H)，7.70-7.27(m，10H)，6.95(d，J＝9Hz，1H)，5.19(s，2H)，2.20(s，3H)。
Example 38
Step A:
5-fluoro-2-nitrotoluene (Lancaster, 1.65g, 13.09mmol), 2-thiathiazole (1.46g, 12.46mmol), potassium carbonate (5.04g, 36.47mmol) and DMF (25ml) were placed in a round bottom flask. The resulting mixture was heated to 80-90 ℃ for 3 hours, then cooled to 50 ℃ and stirred overnight. The mixture was allowed to cool to room temperature and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 94(2.51g, 93%) as an orange solid, which was used without purification. 1H NMR(CDCl3，400MHz)δ7.94(d，J＝8Hz，1H)，7.87(d，J＝4Hz，1H)，7.44(d，J＝4Hz，1H)，7.38-7.34(m，2H)，2.57(s，3H)。
And B:
compound 94(0.103g, 0.41mmol), glacial acetic acid (3ml) and hydrogen peroxide (0.210g of a 30% w/w solution, 1.85mmol) were placed in a round bottom flask. The resulting mixture was heated to 85-90 ℃ for 2 hours, then allowed to cool to room temperature and poured into a flask containing saturated sodium bisulfite solution. The mixture was adjusted to pH7 by slowly adding solid sodium bicarbonate and then poured into a separatory funnel containing ethyl acetate. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 95(0.103g, 89%) as a white solid.1H NMR(CDCl3，400MHz)δ8.10-8.00(m，4H)，7.73(d，J＝4Hz，1H)，2.64(s，3H)。
And C:
compound 95(0.074g, 0.34mmol), Pd/C (0.018g, 10% w/w) and ethanol (2ml) were placed in a Parr flask. The bottle was purged with hydrogen (3X)The final pressure was set at 45 psig. The mixture was stirred at room temperature for 30 minutes, after which the bottle was depressurized and the mixture was filtered through a pad of celite and the solvent was removed under reduced pressure to give 96 as a yellow oil, which was used without any further purification.1H NMR(CDCl3，300MHz)δ7.94(d，J＝3Hz，1H)，7.87(d，J＝9Hz，1H)，7.74(s，1H)，7.65(d，J＝3Hz，1H)，7.31(d，J＝9Hz，1H)，5.81(br s，2H)，2.13(s，3H)。
Step D:
the acid chloride was prepared according to general procedure V using carboxylic acid 49(0.104g, 0.31mmol), oxalyl chloride (0.6ml of a 2.0M solution in dichloromethane, 1.2mmol), DMF (4 drops) and chloroform (4 ml). Using the acid chloride, amine 96(0.071g, 0.2793mmol), sodium bicarbonate (0.1434g, 1.70mmol), water (0.5ml), and acetone (4ml) according to general procedure VI, a brown solid was obtained. The solid was washed with several portions of ether and dried to give 93(0.129g, 82%) as a brown solid. 1H NMR(DMSO-d6，300MHz)δ10.35(s，1H)，8.25(d，J＝3Hz，1H)，8.09(d，J＝3Hz，1H)，7.75-7.39(m，7H)，7.28(d，J＝9Hz，1H)，6.97(d，J＝9Hz，1H)，5.20(s，2H)，2.22(s，3H)。
Example 39
Acid chloride was prepared according to general procedure V using carboxylic acid 49(0.108g, 0.331mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and chloroform (3 ml). Using this acid chloride, aniline (prepared according to the method of Erlenmeyer (Helv, Chim. acta, 30, 2058-.1H NMR(DMSO-d6，300MHz)δ10.19(s，1H)，7.95-7.90(m，3H)，7.76(d，J＝3Hz，1H)，7.70-7.48(m，7H)，7.23(d，J＝9Hz，1H)，4.80(s，2H)。
Example 40
Acid chloride was prepared according to general procedure V using carboxylic acid 49(0.112g, 0.343mmol), oxalyl chloride (0.1ml, 1.15mmol), DMF (4 drops) and chloroform (3 ml). This acid chloride, aniline (prepared according to the method of Brown, E.V. (Journal of Organic chemistry, 42(19), 3208-.1H NMR(DMSO-d6，300MHz)δ10.22(s，1H)，8.20(s，1H)，7.95(d，J＝9Hz，1H)，7.72(d，J＝9Hz，1H)，7.69-7.47(m，7H)，7.37(s，1H)，7.23(d，J＝9Hz，1H)，4.81(s，2H)。
EXAMPLE 41
Step A:
5-fluoro-2-nitrotoluene (5.0g, 32.2mmol), potassium carbonate (15.34g, 111mmol), 3-mercaptoethanol (3.2ml, 37mmol) and DMF (30ml) were placed in a round bottom flask. The resulting mixture was stirred at room temperature for 16 hours, after which it was poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 100 as a thick yellow oil, which was used without any further purification.
And B:
compound 100 (ca. 32mmol) and methanol (100ml) were charged to a round bottom flask. Oxone (Aldrich, 29.43g, 47.9mmol) and water (125ml) were placed in another flask. A solution of oxone was added dropwise to the solution of compound 100 over a few minutes at room temperature. The resulting solution was stirred at room temperature for 1 hour. It was then poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a yellow oil which was dried in vacuo to give 101(7.91g, 95%) as a yellow solid.
And C:
compound 101(0.522g, 2.01mmol), Pd/C (0.04g, 10% w/w) and ethanol (5ml) were placed in a Parr bottle. The bottle was purged with hydrogen (3X) to a final hydrogen pressure of 40 psig. The resulting mixture was stirred at room temperature for 1 hour, after which it was filtered through a pad of celite and the solvent was removed under reduced pressure to give a green oil which solidified in vacuo to give 102 as a yellow solid (0.44g, 95%).
Step D:
acid chloride was prepared according to general procedure V using carboxylic acid 49(0.302g, 0.924mmol), oxalyl chloride (0.15ml, 1.72mmol), DMF (4 drops) and chloroform (10 ml). Using the acid chloride, amine 102(0.190g, 0.86mmol), sodium bicarbonate (0.323g, 4.16mmol), water (0.5ml), and acetone (10ml) according to general procedure X, 99(0.326g, 70%) was obtained as a brown solid.
Example 43:
step A:
the reaction was carried out according to general procedure II using 5-chloro-2-hydroxybenzophenone (15g, 64mmol), ethyl bromoacetate (7.7ml, 71mmol) and potassium carbonate (44g, 320mmol) to give 104 as a white solid in 96% yield.1H NMR(DMSO-d6，300MHz)δ1.8(t，3H)，4.1(q，2H)，4.8(s，2H)，7-7.8(m，8H)。
And B:
according to general method III, 104(19.6g, 62mmol), LiOH. H are reacted at room temperature2O (3.18g, 76mmol) was stirred in ethanol (250ml) and water (70ml) for 1 hour to effect the reaction. After extraction with dichloromethane, drying (magnesium sulfate) and removal of the solvent gave 105 as a white foam in 86% yield.1H NMR(DMSO-d6，300MHz)δ4.6(s，2H)，7-7.8(m，8H)，13(s，1H)。
And C:
a mixture of 105(1g, 3.4mmol) and 18ml of thionyl chloride was refluxed for 1 hour. The reaction mixture was concentrated to give the crude product dissolved in acetonitrile. This was added dropwise to a stirred mixture of 1- (4' -aminophenyl) -1, 2, 4-triazole (0.54g, 3.4mmol) and triethylamine (0.73ml, 5.25mmol) in acetonitrile (10 ml). The mixture was refluxed for 6 hours and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction mixture. After washing with water, drying (magnesium sulfate) and removal of the solvent, the crude product was purified by flash column chromatography on silica gel using 4% methanol in dichloromethane as eluent. This gave 0.039g (3%) of 103 as a white solid. 1H NMR(DMSO-d6，300MHz)δ4.7(s，2H)，7.2-7.8(m，12H)，8.2(s，1H)，9.2(s，1H)，10.0(s，1H)。
Example 44:
following the procedure used for the synthesis of 103, using 4-morpholino (morpholino) aniline, 106 was obtained in 38% yield as a grey solid.1H NMR(DMSO-d6，300MHz)δ3(s，4H)，3.7(s，4H)，4.6(s，2H)，6.82(m，2H)，7.1-7.8(m，10H)，9.4(s，1H)。
Example 45:
according to the method used for the synthesis of 103, using sulfanilamide, purification by silica gel flash column chromatography eluting with 20% acetone in dichloromethane gave 107 as a white solid in 6% yield.1H NMR(DMSO-d6，300MHz)δ4.7(s，2H)，6.82(m，2H)，7.1-7.8(m，12H)，10.1(s，1H)。
Example 46:
following the procedure used for the synthesis of 103, using 4- (4-aminophenyl) -1, 2, 3-thiadiazole as aniline, 108 was obtained as a grey solid in 20% yield.1H NMR(DMSO-d6，300MHz)δ4.7(s，2H)，7.2(d，1H)，7.4-8.1(m，112H)，9.41(s，1H)，10.0(s，1H)。
Example 47:
step A:
the reaction was carried out according to general procedure I, using 2-thiophenecarbonyl chloride (1.5ml, 14mmol), p-chloroanisole (1.7ml, 14mmol) and aluminium chloride (1.9g, 14mmol) in dichloromethane (200ml) at reflux for 24 h. Purification by flash column chromatography on silica gel eluting with methylene chloride/hexane (1: 1) gave 110 in 39% yield.1H NMR(DMSO-d6，300MHz)δ6.95(d，1H)，7.19(t，1H)，7.32(d，1H)，7.38(dd，1H)，7.51(d，1H)，8.06(d，1H)，10.3(s，1H)。
And B:
the reaction was carried out according to general procedure II using 110(0.5g, 2.17mmol) in acetone (25ml), ethyl bromoacetate (0.24ml, 2.17mmol) and potassium carbonate (1.53g, 10.85mmol) for 3 h. After workup, 111 was obtained as an oil in 97% yield. 1H NMR(DMSO-d6，300MHz)δ1.1(t，3H)，4.1(q，2H)，4.8(s，2H)，7.07(d，1H)，7.19(t，1H)，7.43(d，1H)，7.49-7.52(m，2H)，8.07(d，1H)。
And C:
112 was obtained as a solid in 22% yield according to the procedure described in general procedure III.1H NMR(DMSO-d6，300MHz)δ4.7(s，2H)，7.05(d，1H)，7.18(t，1H)，7.41(d，1H)，7.42-7.6(m，2H)，8.06(d，1H)。
Step D:
according to general method IV, 112(0.14g, 0.43mmol), HOBT (0.06g, 0.43mmol), 5-aminoindazole (0.06g, 0.43mmol), EDAC (0.08g, 0.43mmol) and triethylamine are used(0.12ml, 0.86mmol) was performed. Purification by flash column chromatography on silica gel eluting with 5% methanol in dichloromethane gave 109 in 23% yield.1H NMR(DMSO-d6，300MHz)δ4.8(s，2H)，7.1-7.3(m，2H)，7.32(d，1H)，7.46(d，1H)，7.48(s，1H)，7.56(d，1H)，7.7(d，1H)，7.98(s，1H)，8.04(s，1H)，8.1(d，1H)，9.8(s，1H)，13(s，1H)。
Example 48:
step A:
following the procedure described in general procedure I, using 2-furoyl chloride and p-chloroanisole, 114 was obtained as a yellow solid in 73% yield.1H NMR(DMSO-d6，300MHz)δ6.7(m，1H)，6.93(d，1H)，7.2(2，1H)，7.4(m，2H)，8.04(s，1H)，10.4(1H)。
And B:
a mixture of 114(1g, 4.49mmol), ethyl bromoacetate (0.5ml, 4.49mmol) and potassium carbonate (3.17g, 22.45mmol) was stirred in acetone (50ml) for 24 h. 1N sodium hydroxide was added thereto until the solid dissolved. The sodium hydroxide solution was extracted 1 time with ethyl acetate and then acidified with 1N HCl. Followed by extraction with ethyl acetate. After drying (magnesium sulfate) and removal of the solvent in vacuo, the crude product was recrystallized from hexane/ethyl acetate. Compound 115(1g, 79%) was collected as a white solid.1H NMR(DMSO-d6，300MHz)δ4.8(s，2H)，6.7(m，1H)，7.1(d，1H)，7.2(d，1H)，7.5(m，1H)，7.6(d，1H)，8.1(s，1H)，13.1(br s，1H)。
And C:
following the procedure described in general procedure IV, using 5-indazole, 113 was obtained as a solid in 61% yield. 1H NMR(DMSO-d6，300MHz)δ4.8(s，2H)，6.8(m，1H)，7.21(d，1H)，7.3-7.7(m，5H)，8.06(s，1H)，8.1(s，2H)，10(s，1H)，13(s，1H)。
Example 49:
step A:
a mixture of 3-thiophenecarboxylic acid (3.58g, 28mmol) and thionyl chloride (15ml) was refluxed for 3 hours. The reaction mixture was concentrated and further dried in vacuo. The resulting concentrate was added to a suspension of aluminum chloride (7.61g, 56mmol) and p-chloroanisole (3.41ml, 28 mmol). The suspension was heated to reflux for 24 hours. Water was slowly added to the reaction mixture and the aqueous mixture was extracted with dichloromethane followed by ethyl acetate. The organic solutions were combined and dried over magnesium sulfate. After removal of the solvent, the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane/hexane (1: 1). This gave 0.13g (2%) of 117 as an oil.1HNMR(DMSO-d6，300MHz)δ7(d，1H)，7.3-7.5(m，3H)，7.6-7.7(m，1H)，8.2(m，1H)，10.4(s，1H)。
And B:
following general procedure II, 118 was obtained as an oil in 45% yield.1H NMR(DMSO-d6，300MHz)δ1.1(t，3H)，4.08(q，2H)，4.8(s，2H)，7.07(d，1H)，7.38(d，1H)，7.44(d，1H)，7.49(dd，1H)，7.6(dd，1H)，8.11(d，1H)。
And C:
119 was obtained as an oil in 67% yield according to general procedure III.1H NMR(DMSO-d6，300MHz)δ4.7(s，2H)，7.1(d，1H)，7.38(d，1H)，7.5-7.6(m，2H)，7.6-7.7(m，1H)，8.2(m，1H)。
Step D:
according to general procedure IV, using 5-indazole, 116 was obtained as a white solid in 36% yield.1H NMR(DMSO-d6300MHz) delta 4.8(s, 2H), 7.2(d, 1H), 7.35(d, peak with fine cleavages, 1H), 7.42(d, 1H), 7.45(d, 1H), 7.5-7.6(m, 2H), 7.6-7.65(m, 1H), 8(s, 1H), 8.05(s, 1H), 8.3(m, 1H), 9.8(s, 1H), 13(s, 1H).
Example 50:
purification by flash column chromatography on silica gel using 4- (3-morpholino) propoxy-2-methylaniline according to general procedure IV eluting with 20% methanol in dichloromethane gave 120 as a white solid in 7% yield.1H NMR(DMSO-d6，300MHz)δ1.7-1.9(m，2H)，2(s，3H)，2.2-2.4(m，6H)，3.5-3.6(m，4H)，3.9(t，2H)，4.75(s，2H)，6.7(d，1H)，6.74(s，1H)，7.1-7.3(m，3H)，7.5(s，1H)，7.6(dd，1H)，7.63(d，1H)，8.08(d，1H)，9(s，1H)。
Example 51:
following general procedure IV, using 4-morpholinosulfonyl-2-methylaniline, flash column chromatography on silica gel eluting with 20% methanol in dichloromethane afforded 121 as a white solid in 26% yield.1H NMR(DMSO-d6，300MHz)δ3.1(br s，4H)，3.7(s，4H)，4.8(s，2H)，7(d，2H)，7.2-7.3(m，2H)，7.43(d，2H)，7.54(d，1H)，7.6(dd，1H)，7.7(d，1H)，8.2(d，1H)，9.8(s，1H)。
Example 52:
purification by flash column chromatography on silica gel eluting with 5% methanol in dichloromethane afforded 122 as a white solid in 24% yield according to general procedure IV using 4-morpholinosulfonyl-2-methylaniline.1H NMR(DMSO-d6，300MHz)δ2.6-2.8(m，2H)，2.9(t，2H)，3.5-3.6(m，2H)，3.7(t，2H)，4.8(s，2H)，7(d，2H)，7.2-7.3(m，2H)，7.43(d，2H)，7.54(d，1H)，7.6(dd，1H)，7.7(d，1H)，8.2(d，1H)，9.8(s，1H)。
Example 53:
purification by flash column chromatography on silica gel eluting with 3% methanol in dichloromethane afforded 123 as a white solid in 35% yield according to general procedure IV.1H NMR(DMSO-d6，300MHz)δ2.0(s，3H)，2.5-2.7(m，2H)，2.9(t，2H)，3.5-3.6(m，2H)，3.7(t，2H)，4.8(s，2H)，6.7(s，1H)，6.78(d，1H)，6.8(s，1H)，7.1-7.3(m，2H)，7.3(d，1H)，7.5(d，1H)，7.6(dd，1H)，8.05(s，1H)，9(s，1H)。
Example 54:
purification by flash column chromatography on silica gel eluting with 5% methanol in dichloromethane afforded 124 as a white solid in 32% yield according to general procedure IV.1H NMR(DMSO-d6300MHz) delta 2.1(s, 3H), 4.8(s, 2H), 7.1-7.3(m, 3H), 7.4(s, peak with fine cleavages, 1H), 7.42-7.5(m, 2H), 7.5-7.7(m, 5H), 7.8(d, 2H), 9.2(s, 1H).
Example 55:
purification by flash column chromatography on silica gel eluting with 3% methanol in dichloromethane afforded 125 as a white solid in 42% yield according to the procedure described for the synthesis of compound 103.1H NMR(DMSO-d6，300MHz)δ2.2(s，3H)，4.8(s，2H)，7.1-7.3(m，3H)，7.5(d，1H)，7.5-7.7(m，5H)，7.73(d，1H)，8.1(d，1H)，9.3(s，1H)。
Example 56:
step A:
purification by flash column chromatography on silica gel eluting with 30% hexane in dichloromethane afforded 127 in 9% yield according to general procedure I.1H NMR(DMSO-d6，300MHz)δ6.97(d，1H)，7.38(s，1H)，7.42(d，1H)，7.7(t，1H)，7.98(d，1H)，8-8.1(m，2H)，10.4(s，1H)。
And B:
according to general procedure II, 128 was obtained as oil in quantitative yield, which was used for the subsequent reaction without any additional purification.
And C:
129 was obtained as white solid in quantitative yield according to general procedure III.1H NMR(DMSO-d6，300MHz)δ4.6(s，2H)，7.1(d，1H)，7.5(s，1H)，7.5-7.6(m，1H)，7.6-7.7(m，1H)，8-8.1(m，2H)，12(br s，1H)。
Step D:
purification by flash column chromatography on silica gel eluting with 4% methanol in dichloromethane afforded 126 as a yellow solid in 11% yield according to general procedure IV.1H NMR(DMSO-d6，300MHz)δ2.0(s，3H)，2.5-2.7(m，2H)，2.9(t，2H)，3.5-3.6(m，2H)，3.7(t，2H)，4.7(s，2H)，6.7(d，1H)，6.8(s，1H)，7.1(d，1H)，7.2(d，1H)，7.5(d，1H)，7.6-7.7(m，2H)，8-8.1(m，2H)，8.2(s，1H)，9(s，1H)。
Example 57:
acid 49(0.1g, 0.3mmol) was converted to the acid chloride by reaction with oxalyl chloride (0.1ml, 0.8mmol) in dichloromethane (5ml) and 1 drop of DMF (Aldrich, Sure Seal). The reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo. According to general procedure VI, the acid chloride was added to acetone (10ml) and water (1)ml) of 6-amino-homo-triazolo (1, 5-a) pyridine (0.04g, 0.3 mmol; the title compound was prepared by the method of Potts, k.t. and Surapaneni, c.r. (j.heterocyclic chem., 1970, 7, 1019) and sodium bicarbonate (0.2g, 2.2 mmol). The product was isolated by silica gel chromatography eluting with chloroform/methanol (95: 5, v/v) in 15% yield. MS (ES (+): m +1/z 443. 1H NMR(CDCl3，300MHz)δ9.85(s，1H)，9.66(s，1H)，8.32(s，1H)，7.79(m，2H)，7.57(dd，1H)，7.4(m，3H)，7.15-7.05(m，2H)，4.79(s，2H)。
Example 58:
acid 49(0.1g, 0.3mmol) was converted to the acid chloride by reaction with oxalyl chloride (0.1ml, 0.8mmol) in dichloromethane (5ml) and 1 drop of DMF (Aldrich, Sure Seal). The reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The title compound was prepared according to general procedure VI by adding the acid chloride to 6-aminoquinoxaline (0.045g, 0.3 mmol; prepared by the method of Case, F.H. and Brennan, J.A. (JACS, 1959, 81, 6297)) and sodium bicarbonate (0.2g, 2.2mmol) in acetone (10ml) and water (1 ml). The product was isolated by silica gel chromatography eluting with chloroform/methanol (95: 5, v/v) in 15% yield. MS (ES (+): m +1/z 454.1H NMR(CDCl3，300MHz)δ9.78(s，1H)，8.82(s，1H)，8.76(s，1H)，8.64(s，1H)，8.18(dd，1H)，8.09(d，1H)，7.56(dd，1H)，7.6(m，3H)，7.15-7.05(m，2H)，4.79(s，2H)。
Example 59:
acid 49(0.1g, 0.3mmol) was converted to the acid chloride by reaction with oxalyl chloride (0.1ml, 0.8mmol) in dichloromethane (5ml) and 1 drop of DMF (Aldrich, Sure Seal). The reaction was stirred at room temperature for 1 hour. Vacuum removalA solvent. According to general procedure VI, by adding the acid chloride to 6-amino-1H-imidazo [4, 5-b ] in acetone (10ml) and water (1ml)]The title compound was prepared from pyridine (0.04g, 0.3 mmol; prepared by the method of Brooks, w. and Day, A.R. (j. heterocyclic chem., 1969, 6(5), 759)) and sodium bicarbonate (0.2g, 2.2 mmol). The product was isolated by silica gel chromatography eluting with chloroform/methanol (9: 1, v/v) in 10% yield. MS (ES (+): m +1/z 443. 1H NMR(CDCl3，300MHz)δ9.66(s，1H)，8.83(s，1H)，8.66(s，1H)，8.28(s，1H)，7.58(dd，1H)，7.4(m，3H)，7.15-7.05(m，2H)，4.79(s，2H)。
Example 60:
2-hydroxy-5-nitrobenzophenone (1.09g, 4.50mmol, which can be prepared by the method of Hayashi, I.et al (Bull. chem. Soc. Jpn., 1983, 56(8), 2432-7)), 2-bromo-N-phenylacetamide (1.01g, 4.74mmol, which can be prepared by the method of Vlon, W.et al (J.Med. chem., 1987, 30, 20-24)) and potassium carbonate (656mg, 4.74mmol) were added to DMF (20 ml). The reaction was stirred at room temperature for 16 hours. The reaction was poured into ice water and a precipitate formed. The precipitate was filtered and washed with water. The product was purified by silica gel chromatography using a Biotage flash chromatography system eluting with hexane/ethyl acetate (3: 1) to give 1g (2.66mmol, 59% yield). MS (ES (+): m +1/z 377, MS (ES (-)): m-1/z 375.1H NMR(CDCl3，300MHz)δ8.96(s，1H)，8.46(dd，1H)，8.36(d，1H)，7.90(d，2H)，7.66(m，3H)，7.55(m，2H)，7.34(t，2H)，7.19(d，1H)，7.13(t，1H)，4.79(s，2H)。
Example 61:
compound 133(50mg, 133mmol) and Raney nickel catalyst (Aldrich, 4)5mg, 90% by weight) was added to ethanol (30ml) and placed in a Parr hydrogenator under a pressure of 50psig hydrogen. Additional catalyst (100mg) was added every 1 hour. After 3 hours, the catalyst was filtered and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with chloroform/methanol (98: 2) to give 38.6mg (112mmol, 84% yield). MS (ES (+): m +1/z 347. 1H NMR(CDCl3，300MHz)δ9.06(s，1H)，7.90(d，2H)，7.60(m，3H)，7.48(m，2H)，7.30(t，2H)，7.09(t，1H)，6.90(d，1H)，6.84(dd，1H)，6.74(d，1H)，4.59(s，2H)，3.62(br s，2H)。
Example 62:
step A:
2-bromo-4-chloroanisole (24.4g, 0.11mol) was added dropwise to a stirred suspension of magnesium (2.7g, 0.11mol) in diethyl ether (150ml) containing crystalline iodine. The mixture was heated to reflux for 2 hours. A solution of 2-cyanopyridine (11.4g, 0.11mol) in diethyl ether (100ml) was added dropwise, and the resulting suspension (which formed a yellow-brown precipitate) was refluxed for 2 hours, cooled to room temperature, and poured into cold 2N HCl (300 ml). The ether layer was separated and discarded. The aqueous layer was made alkaline by the addition of 50% aqueous sodium hydroxide solution and extracted with diethyl ether (4X 300 ml). The combined ether extracts were washed with water, dried over sodium sulfate and evaporated to give a brown solid. The product was purified by silica gel chromatography eluting with ethyl acetate/hexane (1: 3) to give 10.9g, 40% yield. MS (ES)+)：m/z：248.0(M+1，85％)，270(M+23，45％)；1H NMR(CDCl3，300MHz)δ8.64(d，1H)，8.02(d，1H)，7.85(t，1H)，7.41-7.47(m，3H)，6.91(d，1H)，3.64(s，3H)。
And B:
1- (5-chloro-2-methoxyphenyl) -1- (2-pyridyl) methanone (125mg, 0.505mmol) was dissolved in dichloromethane (5ml) and cooled to-78 ℃ in a dry ice/acetone bath. A nitrogen atmosphere is provided. Boron tribromide (1M in dichloromethane, 2ml, 2mmol) was added dropwise and the flask was warmed to room temperature overnight. Water (5ml) was added dropwise, the contents of the flask were washed 1 time with water, 1 time with brine, dried over sodium sulfate and the solvent removed in vacuo. The crude sample was dissolved in DMF (5 ml). 2-bromo-N-phenylacetamide (113mg, 0.532mmol, which can be prepared by the method of Vlon, W et al (J.Med.chem., 1987, 30, 20-24)) and potassium carbonate (73.5mg, 0.532mmol) were added. After 64 hours, the contents of the flask were poured into ice water (50ml) and the precipitate was filtered. The product was purified by silica gel chromatography using a Biotage flash chromatography system eluting with hexane/ethyl acetate (3: 1) to give 15.5mg (42.3mmol, two steps 8.4%). MS (ES (+): m +1/z 367. 1HNMR(CDCl3，300MHz)δ9.38(s，1H)，8.60(d，1H)，8.20(d，1H)，7.93(td，1H)，7.60(m，3H)，7.47(m，2H)，7.33(t，2H)，7.12(t，1H)，6.94(d，1H)，4.63(s，2H)。
Example 63:
2- (2-benzoyl-4-chlorophenoxy) acetyl chloride (0.1g, 0.32mmol) was dissolved in anhydrous acetonitrile (2 ml). 2-phenylhydroxylamine (which can be prepared by the method outlined in org. syn. cumulative volume I, page 445, 0.35g) was dissolved in diethyl ether and dried over magnesium sulfate. The mixture was filtered and the ether removed in vacuo. The residue was dissolved in acetonitrile (2ml) and added to the acid chloride solution. The reaction was stirred at room temperature for 3 hours. A precipitate formed and was filtered. The reaction solvent was removed in vacuo. The product was purified by silica gel chromatography eluting with hexane/ethyl acetate (3: 1, v/v). Fractions containing product were combined and solvent was removed in vacuo to give a 50% yield. MS (APCI (+): m + Na/z 404.1H NMR(CDCl3，300MHz)δ9.85(s，1H)，7.85-7.0(m，13H)，4.95(s，2H)。
Example 64:
step A:
4- (3-bromopropoxy) -2-methyl-1-nitrobenzene (8.0, 29.2mmol, which can be prepared according to the method found in the patent; Wellcome Foundation; GB 982572; 1960; chem.Abstr.; EN; 63; 2928 b; 1965), pyrrolidine (92.5ml, 29.2mmol) and potassium carbonate (5.0g, 35mmol) are mixed together in DMF (30ml) at room temperature for 16 hours. The reaction mixture was filtered, the solvent removed under reduced pressure leaving an oil which was dissolved in dichloromethane, washed with aqueous sodium hydroxide (1N), water, dried and the solvent removed under reduced pressure. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 139 as an orange oil (7.5g, 97%). 1H NMR(CDCl3，300MHz)δ1.84(m，4H)，2.06(ddd，2H)，2.57(m，6H)，2.58(s，3H)，4.14(t，2H)，6.84(m，3H)，8.10(d，1H)。
And B:
compound 139(7.5g, 28.4mmol), Pd/C (0.75g, 10%) and ethanol (300ml) were placed in a stirred Parr bottle. The flask was pressurized to 5atm with hydrogen and stirred at room temperature for 3 hours. The mixture was then filtered through a pad of celite and the solvent removed under reduced pressure to give 140 as an orange oil (6.0g, 98%).1H NMR(CDCl3，300MHz)δ1.84(m，4H)，1.98(ddd，2H)，2.19(s，3H)，2.42(m，6H)，3.28(br s，1H)，3.98(t，2H)，6.84(m，3H)。
And C:
according to general method IV, carboxylic acid 105(1.0g, 3.9mmol), amine 140(1.22g, 3.9mmol), HOBt (5.25g, 3.9mmol), EDAC (0.9g, 4.7mmol), triethylamine (1.3ml, 3.9mmol) and DMF (50ml) were used. The product was purified by flash chromatography, eluting with 95: 5 dichloromethane/methanol, to give 138 as an orange oil (0.84g, 36%).1H NMR(CDCl3，300MHz)δ2.07(s，3H)，2.11(m，6H)，2.30(ddd，2H)，3.22(m，4H)，4.01(t，2H)，4.63(s，2H)，6.65(m，2H)7.01-7.55(m，6H)，7.79(dd，2H)，7.98(s，1H)，8.13(s，1H)。
Example 65:
step A:
4- (3-Bromopropoxy) -2-methyl-1-nitrobenzene and morpholine (5.0g, 18.2mmol) were used in the same manner as for the preparation of compound 139. Compound 142(5.1g, 100%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ2.02(ddd，2H)，2.38-2.56(m，6H)，2.64(s，3H)，3.73(m，4H)，4.11(t，2H)，6.81(m，2H)，8.09(d，1H)。
And B:
compound 142(5.1g, 18.2mmol) was used in the same manner as preparation of compound 140. Amine 143(4.3g, 95%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ1.94(ddd，2H)，2.19(s，3H)，2.49-2.54(m，6H)，3.39(br s，1H)，3.75(m，4H)，3.96(t，2H)，6.64-6.70(m，3H)。
And C:
according to general procedure IV, carboxylic acid 105, amine 143, HOBt, EDAC, triethylamine and DMF were used. The product was purified by flash chromatography eluting with 95: 5 dichloromethane/methanol to give 141 as an oil (1.3g, 67%). 1H NMR(CDCl3，300MHz)δ1.98(ddd，2H)，2.11(s，3H)，2.48-2.56(m，6H)，3.75(m，4H)，4.02(t，2H)，4.68(s，2H)，6.6-7.37(m，9H)7.86(d，2H)，8.11(s，1H)。
Example 66:
step A:
4- (3-Bromopropoxy) -2-methyl-1-nitrobenzene and 1-methylpiperazine (5.0g, 18.2mmol) were used in the same manner as for the preparation of compound 139. Compound 144(3.4g, 63%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ1.98(ddd，2H)，2.26(s，3H)，2.38-2.60(m，10H)，2.65(s，3H)，4.11(t，2H)，6.80(m，2H)，8.10(d，1H)。
And B:
compound 144(3.4g, 12.5mmol) was used in the same manner as preparation of compound 140. Amine 145(3.1g, 95%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ1.88(ddd，2H)，2.10(s，3H)，2.25(s，3H)，2.26-2.65(m，10H)，3.35(br s，1H)，3.89(t，2H)，6.50-6.70(m，3H)。
And C:
according to general procedure IV, using a carboxyl groupAcid 105, amine 145, HOBt, EDAC, triethylamine and DMF. The product was purified by flash chromatography eluting with 95: 5 dichloromethane/methanol to give 144 as an oil (0.95g, 47%).1H NMR(CDCl3，300MHz)δ1.92(m，2H)，2.05(s，3H)，2.29(s，3H)，2.40-2.70(m，10H)，3.39(s，1H)，3.95(t，2H)，4.62(s，2H)，6.70(s，2H)，6.90(d，1H)，6.72-7.60(m，5H)7.81(d，2H)，8.06(s，1H)。
Example 67:
step A:
in the same manner as for the preparation of compound 139, 4- (3-bromopropoxy) -2-methyl-1-nitrobenzene and thiomorpholine-1-oxide (5.0g, 18.2mmol, which can be prepared according to the method of Nachtergaele, Willy A., Anteusis, Marc J.O (Bull. Soc. Chim. Belg.; EN; 89; 7; 1980; 525-one 536)) were used. Compound 147(2.1g, 37%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ2.05(ddd，2H)，2.65(s，3H)，2.63(t，2H)，2.65-3.20(m，8H)，4.12(t，2H)，6.82(m，2H)，8.10(s，1H)。
And B:
compound 147(2.1g, 6.7mmol) was used in the same manner as in the preparation of compound 140. Amine 148(2.1g, 98%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ1.84(ddd，2H)，2.15(s，3H)，2.58(t，2H)，2.65-3.25(m，10H)，3.84(t，2H)，6.28(m，3H)。
And C:
According to general procedure IV, carboxylic acid 105, amine 148, HOBt, EDAC, triethylamine and DMF were used. The product was purified by flash chromatography eluting with 95: 5 dichloromethane/methanol to give 146 as an oil (0.7g, 32%).1H NMR(CDCl3，300MHz)δ1.95(ddd，2H)，2.71(s，3H)，2.63(t，2H)，2.65-3.20(m，8H)，4.00(t，2H)，4.67(s，2H)，6.72(s，2H)，7.03(d，2H)，7.38-7.85(m，6H)，7.85(m，2H)，8.15(s，1H)。
Example 68:
step A:
4- (3-Bromopropoxy) -2-methyl-1-nitrobenzene and imidazole (5.0g, 18.2mmol) were used in the same manner as for the preparation of compound 139. Compound 150(3.1g, 61%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ2.35(ddd，2H)，2.66(s，3H)，3.64(d，2H)，4.00(d，2H)，6.8(s，2H)，6.95(d，2H)，7.11(d，2H)，7.53(s，1H)，8.10(d，1H)。
And B:
compound 150(3.1g) was used in the same manner as in the preparation of compound 140. Amine 148(0.71g, 26%) was obtained as an oil.1H NMR(CDCl3，300MHz)δ1.27(ddd，2H)，2.18(s，3H)，3.88(t，2H)，4.06(br s，1H)，4.25(t，2H)，6.60(m，3H)，6.98(d，2H)，7.13(d，2H)，7.13(d，2H)，7.82(s，1H)。
And C:
according to general procedure IV, carboxylic acid 105, amine 151, HOBt, EDAC, triethylamine and DMF were used. The product was purified by flash chromatography eluting with 95: 5 dichloromethane/methanol to give 149 as an oil (1.1g, 51%).1H NMR(CDCl3，300MHz)δ1.27(ddd，2H)，2.18(s，3H)，3.80(t，2H)，4.18(t，2H)，4.63(s，2H)，6.60-6.72(m，8H)，7.82(d，2H)，8.18(s，1H)。
Example 69:
step A:
and B:
and C:
according to general procedure II, using a mixture of 5-chloro-2-hydroxybenzophenone (25g, 107.4mmol), methyl 2-bromopropionate, potassium carbonate (23.0g, 161mmol) and acetone (250ml), 155(32.0g, 94%) was obtained as a yellow oil.1H NMR(CDCl3，300MHz)δ1.22(d，3H)，3.64(s，3H)，4.62(q，1H)，6.78(d，1H)，7.22-7.61(m，5H)。
Step D:
according to general procedure III, ester 155(11g, 34.5mmol), water (5ml) and ethanol (150ml) were used, but sodium hydroxide (5ml of 5N solution, 25mmol) was used instead of lithium hydroxide. Acid 156(4.5g, 43%) was obtained as a brown oil. 1H NMR(CDCl3，300MHz)δ1.65(d，3H)，4.96(q，1H)，7.10-7.98(m，8H)。
Step E:
using carboxylic acid 156, amine 154(0.68g, 3.3mmol), EDAC, HOBt and DMF according to general procedure IV, compound 152 was obtained as an orange oil (1.1g, 61%).1H NMR(CDCl3，300MHz)δ1.6(d，3H)，1.95(ddd，2H)，2.05(s，3H)，2.26(s，6H)，2.45(t，2H)，3.88(t，2H)，4.92(q，1H)，6.64(m，9H)，7.84(d，2H)，8.22(s，1H)。
Example 70:
step A:
a mixture of 5-chloro-2-hydroxybenzophenone (6.3g, 27mmol), bromofluoroacetate, potassium carbonate (4.5g, 32mmol) and DMF (50ml) was combined and the reaction mixture was stirred at 80 ℃ for 24 h. The mixture was then filtered and poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 158 as an oil (7.0g, 77%).1H NMR(CDCl3，300MHz)δ1.22(t，3H)，4.17(q，2H)，5.66(d，1H)，5.87(d，1H)，7.19-8.82(m，8H)。
And B:
according to general procedure III, ester 158, water and ethanol (150ml) were used, but lithium hydroxide was replaced by sodium hydroxide (5ml of 5N in water). The solvent was removed under reduced pressure to give 159 as white crystals (5.4g, 84%).1H NMR(CDCl3，300MHz)δ5.85(d，1H)，6.05(d，1H)，7.89(m，8H)。
And C:
using carboxylic acid 159, amine 140, EDAC, HOBt and DMF according to general procedure IV, 157(0.28g, 17%) was obtained as a yellow foam.1H NMR(CDCl3，300MHz)δ1.92(m，4H)，2.08(ddd，2H)，2.22(s，3H)，2.62-2.85(m，6H)，4.03(t，2H)，5.96(d，1H)，6.16(d，1H)，6.73(br，s，2H)，7.30-7.85(m，7H)，7.85(m，7H)，8.2(s，1H)。
Example 71:
step A:
2-mercapto-5-nitrobenzimidazole (2.0g, 10.2mmol), potassium carbonate (2.8g, 20.4mmol), 3- (N, N-dimethylamino) -1-chloropropane hydrochloride (1.6g, 10.2mmol) and DMF (50ml) were placed in a round bottom flask. The resulting mixture was stirred at room temperature for 24 hours, after which DMF was removed under reduced pressure to give a brown oil. The product was purified by flash chromatography using 9: 1 dichloromethane/ethanol as eluent to give 161(1.5g, 54%). 1H NMR(CDCl3，300MHz)δ2.12(ddd，2H)，2.24(s，6H)，3.68(t，2H)，3.28(t，2H)，5.28(s，1H)，7.24(dd，1H)，8.18(dd，1H)，8.28(s，1H)。
And B:
compound 161(1.50g, 5.36mmol), Pd/C (0.15g, 10% w/w) and ethanol (300ml) were placed in a stirred Parr bottle. The flask was pressurized to 5atm with hydrogen, and the mixture was stirred at room temperature for 3 hours. The mixture was then filtered through a pad of celite and the solvent removed under reduced pressure to give 162(0.80g, 58%) as a clear oil.1H NMR(CDCl3，300MHz)δ1.91(ddd，2H)，2.27(s，6H)，3.18(t，2H)，3.47(br s，2H)，3.68(brs，2H)，6.54(dd，1H)，6.71(s，1H)，7.26(dd，1H)，8.27(s，1H)。
And C:
according to general procedure IV, carboxylic acid 105, amine 162, EDAC, HOBt and DMF were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 160 as white crystals (0.24g, 14%).1H NMR(CDCl3，300MHz)δ2.05(ddd，2H)，2.48(s，6H)，2.96(t，2H)，3.20(br s，2H)，4.62(s，2H)，5.22(s，1H)，6.86-8.20(m，11H)，9.00(s，1H)。
Example 72:
according to general procedure IV, carboxylic acid 105, 5-aminobenzimidazole, HOBt, EDAC and DMF were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 163 as white crystals (0.28g, 35%).1H NMR(CDCl3，300MHz)δ4.66(s，2H)，6.97-8.16(m，11H)，9.11(s，1H)，10.1(br s，1H)。
Example 73:
according to general procedure IV, carboxylic acid 105, 5-aminoindole, HOBt, EDAC and DMF were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 164 as white crystals (0.25g, 32%).1H NMR(CDCl3，300MHz)δ4.71(s，2H)，6.58(s，1H)，7.06-8.72(m，14H)。
Example 74:
according to general procedure IV, carboxylic acid 105, 5-aminobenzimidazole ketone, HOBt, EDAC and DMF were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 165 as white crystals (0.44g, 27%). 1H NMR(CDCl3，300MHz)δ4.71(s，2H)，6.83-7.86(m，11H)，9.62(s，1H)，10.55(s，1H)，10.59(s，1H)。
Example 75:
according to general procedure IV, carboxylic acid 105, 5-aminobenzotriazole, HOBt, EDAC and DMF were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 166 as white crystals (0.75g, 91%).1H NMR(CDCl3，300MHz)δ4.79(s，2H)，7.06-8.61(m，11H)，9.81(s，1H)，12.60(br s，1H)。
Example 76:
according to general procedure IV, carboxylic acid 105, N1- [2- (diethylamino) ethyl ] is used]-4-aminobenzamide, HOBt, EDAC and DMF. The product is purified by flash chromatography and is treated with 95: 5 methylene chlorideMethanol as eluent gave 167(0.12g, 12%) as white crystals.1HNMR(CDCl3，300MHz)δ1.21(t，6H)，2.83(q，4H)，2.90(dd，2H)，3.66(dd，2H)，4.73(s，2H)，7.04-7.95(m，13H)，9.43(s，1H)。
Example 77:
according to general procedure IV, carboxylic acid 105, 4-aminobenzamide, HOBt, EDAC and DMF were used. The product was purified by flash chromatography using 95: 5 dichloromethane/methanol as eluent to give 168 as white crystals (0.13g, 13%).1H NMR(CDCl3，300MHz)δ4.75(s，2H)，5.34(s，2H)，7.06-7.97(m，12H)，9.53(s，1H)。
Example 78:
according to general method IV, carboxylic acid 112(0.15g, 0.51mmol), amine 399(0.11g, 0.51mmol), HOBt (0.7g, 0.51mmol), EDAC (0.98g, 0.51mmol), triethylamine (0.14ml, 0.10g, 1.0mmol) and anhydrous DMF (7ml) were used. The resulting yellow oil was treated with diethyl ether to give 169(0.052g, 20%) as a yellow solid.1H NMR(400MHz，DMSO-d6)δ8.99(s，1H)，8.08(d，J＝4.8Hz，1H)，7.63(d，J＝3.2Hz，1H)，7.58(d，J＝9.2Hz，1H)，7.50(s，1H)，7.20(m，3H)，6.84(s，1H)，6.78(d，J＝8Hz，1H)，4.75(s，2H)，3.70(m，2H)，3.54(m，2H)，2.87(m，2H)，2.64(m，2H)，2.02(s，3H)。
Example 79:
step A:
using phenol 21(1.5g, 6.4mmol), potassium carbonate (4.4g, 32.2mmol), ethyl bromoacetate (0.79ml, 1.18g, 7.1mmol) and acetone (150ml) according to general procedure II, 171(4.0g, > 100%) was obtained as an oil. The product was used in the next step without any further purification. 1H NMR(400MHz，CDCl3)δ8.97(d，J＝1.6Hz，1H)，8.75(d，J＝4Hz，1H)，8.18(d，J＝7.6Hz，1H)，7.43(m，3H)，6.78(d，J＝8.8Hz，1H)，4.50(s，2H)，4.17(m，2H)，1.20(m，3H)。
And B:
according to general procedure III, ester 171(4.0g, 12.5mmol), THF (25ml), water (12ml), ethanol (12ml) and LiOH (1.32g, 31.5mmol) were used. The resulting yellow gel was treated with diethyl ether to give 172 as a pale yellow solid (1.09g, 29%). The product was used in the next reaction without any further purification.1H NMR(400MHz，DMSO-d6)δ8.85(d，J＝2Hz，1H)，8.75(d，J＝4.8Hz，1H)，8.10(d，J＝8Hz，1H)，7.56(m，2H)，7.47(d，J＝2.8Hz，1H)，7.10(d，J＝8.8Hz，1H)，4.82(s，2H)。
And C:
according to general method IV, carboxylic acid 172(0.10g, 0.34mmol), amine 399(0.076g, 0.34mmol), HOBt (0.046g, 0.34mmol), EDAC (0.19g, 0.34mmol), triethylamine (0.1ml, 0.68mmol) and anhydrous DMF (5ml) were used. The resulting oil was treated with diethyl ether to give 170 as a light yellow solid (0.036g, 21%):1H NMR(400MHz，DMSO-d6)δ8.99(s，1H)，8.88(s，1H)，8.75(s，1H)，8.10(d，J＝7.6Hz，1H)，7.63(d，J＝8.8Hz，1H)，7.49(m，2H)，7.20(d，J＝8.8Hz，1H)，7.05(d，J＝8.8Hz，1H)，6.81(s，1H)，6.75(d，J＝8.8Hz，1H)，4.67(s，2H)，3.69(m，2H)，3.51(m，2H)，2.86(m，2H)，2.63(m，2H)，1.96(s，3H)。
example 80:
according to general procedure IV, carboxylic acid 172(0.10g, 0.34mmol), 5-aminoindazole (0.045g, 0.34mmol), HOBt (0.046g, 0.34mmol), EDAC (0.19g, 0.34mmol), triethylamine (0.1ml, 0.68mmol) and anhydrous DMF (5ml) were used. The resulting oil was treated with diethyl ether to give 173(0.067g, 49%) as a brown solid:1H NMR(400MHz，DMSO-d6)δ12.97(s，1H)，9.82(s，1H)，8.91(d，J＝2Hz，1H)，8.71(m，1H)，8.14(d，J＝8Hz，1H)，7.99(s，2H)，7.61(dd，J＝2.4，8.8Hz，1H)，7.50(m，2H)，7.44(d，J＝8.8Hz，1H)，7.29(d，J＝9Hz，1H)，7.19(d，J＝9Hz，1H)，4.70(s，2H)。MS(ES)：407(M+)。
example 81:
according to general method IV, carboxylic acid 119(0.15g, 0.51mmol), amine 399(0.11g, 0.51mmol), HOBt (0.07g, 0.51mmol), EDAC (0.1g, 0.51mmol), triethylamine (0.14ml, 0.10g, 1.0mmol) and anhydrous DMF (5ml) were used. The product was purified by flash chromatography using 2% methanol in dichloromethane as eluent to give a yellow oil. The oil was treated with diethyl ether to give 174(0.065g, 26%) as a light yellow solid: 1H NMR(400MHz，DMSO-d6)δ9.61(s，1H)，8.26(s，1H)，7.62(m，1H)，7.58(m，2H)，7.45(m，3H)，7.16(d，J＝9Hz，1H)，6.93(m，2H)，4.70(s，2H)，3.66(m，2H)，3.50(m，2H)，2.87(m，2H)，2.66(m，2H)。MS(ES)：489(M+)。
Example 82:
according to general method IV, carboxylic acid 119(0.15g, 0.51mmol), amine 399(0.11g, 0.51mmol), HOBt (0.07g, 0.51mmol), EDAC (0.1g, 0.51mmol), triethylamine (0.14ml, 0.10g, 1.0mmol) and anhydrous DMF (5ml) were used. The product was purified by flash chromatography using 2% methanol in dichloromethane as eluent to give a yellow oil. The oil was treated with diethyl ether to give 175(0.046g, 18%) as a light yellow solid:1H NMR(400MHz，DMSO-d6)δ8.94(s，1H)，8.24(s，1H)，7.58(m，2H)，7.49(s，1H)，7.42(s，1H)，7.18(m，2H)，6.78(m，2H)，4.73(s，2H)，3.69(m，2H)，3.54(m，2H)，2.87(m，2H)，2.65(m，2H)，2.01(s，3H)。MS(ES)：503(M+)。
example 83:
step A:
1-Benzylimidazole (2.0g, 12.6mmol) and anhydrous THF (50ml) were placed in a round bottom flask equipped with a stir bar, addition funnel and nitrogen supply as required and cooled to-78 ℃ via a dry ice/acetone bath. N-butyllithium (8.8ml, 1.6M in hexane, 13.7mmol) was added dropwise and the reaction stirred at-78 ℃ for 15-20 min. Anhydrous N, N-dimethylformamide (1.3ml, 0.0013mmol) was added dropwise and the reaction was stirred at-78 ℃ for an additional 45 minutes. When the reaction was judged to be complete, the reaction was quenched by dropwise addition of water and extracted with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 177 as a white solid (2.1g, 88%):1H NMR(400MHz，DMSO-d6)δ9.68(s，1H)，7.73(s，1H)，7.30(m，4H)，7.16(d，J＝7Hz，2H)，5.57(s，2H)。
and B:
2-bromo-4-chloroanisole (1.5ml, 2.4g, 11.4mmol) and diethyl ether (17ml) were placed in a round-bottomed flask equipped with a stir bar, addition funnel and, if necessary, with nitrogen supply and cooled to-78 ℃ via a dry ice/acetone bath. N-butyllithium (7.8ml, 1.6M in hexane, 12.5mmol) was added dropwise through an addition funnel, the reaction was stirred at-78 ℃ for 30 minutes, after which the reaction was quenched by dropwise addition of water and extracted with ethyl acetate. The organics were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 178(1.5g, 42%) as a white solid: 1H NMR(300MHz，CDCl3)δ7.27(m，4H)，7.16(m，1H)，7.00(m，3H)，6.83(d，J＝2.4Hz，1H)，6.71(dd，J＝3，9Hz，1H)，6.11(d，J＝2.4Hz，1H)，5.07(m，2H)，4.49(bs，1H)，3.73(s，3H)。
And C:
alcohol 178(1.5g, 4.6mmol), dichloromethane (55ml) and manganese dioxide (4.0g, 46mmol) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The reaction was stirred at room temperature for 30 minutes, after which it was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 179(1.5g, > 99%) as a transparent gel.1H NMR(400MHz，CDCl3)δ7.43(d，J＝4Hz，1H)，7.37(m，4H)，7.32(m，3H)，7.11(s，1H)，6.91(d，J＝12Hz，1H)，5.71(s，2H)，3.75(s，3H)。
Step D:
according to general method IX, anisole 179(1.5g, 4.6mmol), dichloromethane (30ml) and boron tribromide (12ml of a 1.0M solution in dichloromethane, 11.5mmol) were used. The resulting brown oil was filtered through a pad of silica gel using dichloromethane as eluent and the solvent was removed under reduced pressure to give 180 as a yellow solid (0.9g, 64%).1H NMR(400MHz，CDCl3)δ8.48(s，1H)，7.34(m，9H)，6.96(d，J＝9Hz，1H)，5.65(s，2H)。
Step E:
phenol 180(0.1g, 0.32mmol), acetone (7ml), potassium carbonate (0.22g, 1.6mmol) and 2' -chloro-N-acetanilide (0.058g, 0.34mmol) were placed in a round bottom flask equipped with a stir bar, reflux condenser and, if necessary, nitrogen gas. The reaction was allowed to stir at reflux for 18-24 hours, after which it was poured into a separatory funnel containing water and ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash chromatography eluting with a gradient of 3: 1 hexane/ethyl acetate to 1: 3 hexane/ethyl acetate as solvent to give 176 as a white solid (0.077g, 54%). 1H NMR(300MHz，CDCl3)δ10.17(s，1H)，7.70(m，3H)，7.39(m，11H)，6.94(d，J＝9Hz，1H)，5.79(s，2H)，4.71(s，2H)。MS(ES)：445(M+)，446(M+H)+。
Example 84:
step A:
according to general method V, 5-chloro-o-methoxybenzoic acid (7.5g, 40.2mmol), dichloromethane (75ml), oxalyl chloride (3.7ml, 5.3g, 42.2mmol) and N, N-dimethylformamide (4-5 drops) were used. 182 was obtained as a yellow oil (8.0g, 97%). The product was used in the next step without further purification or characterization.
And B:
according to general procedure VII, acid chloride 182(8.0g, 39mmol), N, O-dimethylhydroxylamine hydrochloride (7.6g, 78.0mmol), chloroform (100ml) and triethylamine (27ml, 19.7g, 195mmol) were used. The resulting colorless oil was treated with diethyl ether to give 183 as a white solid (6.0g, 67%). The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ7.40(d，J＝8.4Hz，1H)，7.27(d，J＝2.4Hz，1H)，3.75(s，3H)，3.42(bs，3H)，3.19(bs，3H)。MS(ES)：229(M+)。
And C:
in a round bottom flask equipped with a stir bar, addition funnel and nitrogen supply as required, 1-methylimidazole (2.0g, 24.4mmol) was dissolved in diethyl ether (50ml) and cooled to-78 ℃ via a dry ice/acetone bath. N-butyllithium (15ml, 1.6M in hexane, 24.4mmol) was added dropwise and the reaction was stirred at-78 ℃ for 30 min. Amide 183(5.1g, 22.2mmol) was added as a solid, maintaining the reaction temperature at-78 ℃. When the reaction was judged to be complete, the reaction was quenched by dropwise addition of water and extracted with ethyl acetate. The organics were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by flash chromatography, eluting with 1: 1 hexane/ethyl acetate, to give 184(3.3g, 55%). 1H NMR(300MHz，DMSO-d6)δ7.60(s，1H)，7.53(dd，J＝3，9Hz，1H)，7.42(d，J＝3Hz，1H)，7.17(m，1H)，7.13(s，1H)，4.03(s，3H)，3.73(s，3H)。
Step D:
according to general procedure IX, using anisole 184(3.3g, 13.2mmol), dichloromethane (60ml) and boron tribromide (53ml of a 1.0M solution in dichloromethane, 53mmol), 185(2.0g, 69%) was obtained as a yellow solid. The product was used in the next step without further purification.1H NMR(300MHz，DMSO-d6)δ7.90(s，1H)，7.83(d，J＝2Hz，1H)，7.62(s，1H)，7.56(dd，J＝3，9Hz，1H)，7.04(d，J＝9Hz，1H)，4.03(s，3H)。
Step E:
phenol 185(0.15g, 0.67mmol), acetone (5ml), potassium carbonate (0.46g, 3.3mmol) and amide 142(0.12g, 0.70mmol) were charged to a round bottom flask equipped with a stir bar, reflux condenser and nitrogen gas as needed. The reaction was allowed to stir at reflux for 18-24 hours, after which time the reaction was poured into a separatory funnel containing water and ethyl acetate. The organic layer was collected, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash chromatography eluting with a gradient of 3: 1 hexane/ethyl acetate to 1: 3 hexane/ethyl acetate as solvent to give 181 as a white solid (0.065g, 25%).1H NMR(400MHz，DMSO-d6)δ10.06(s，1H)，7.55(m，5H)，7.29(t，J＝8Hz，2H)，7.10(m，3H)，4.74(s，2H)，4.02(s，3H)。
Example 85:
step A:
2-bromo-4-chloroanisole (9.8ml, 15.7g, 71.3mmol) and anhydrous THF (120ml) were placed in a round bottom flask equipped with a stir bar, addition funnel and, if necessary, nitrogen, and the reaction was cooled to-78 ℃ via a dry ice/acetone bath. N-butyllithium (45ml, 1.6M in hexane, 72mmol) was added dropwise and the reaction stirred at-78 ℃ for 30 min. 4-bromo-2-thiophenecarboxaldehyde (15g, 79mmol) was added and the reaction temperature was maintained at-78 ℃. When the reaction was judged to be complete, the reaction was quenched by dropwise addition of water and extracted with ethyl acetate. The organics were collected, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 187(16.3g, 62%). The product was used in the next step without further purification or characterization.
And B:
alcohol 187(16.3g, 49mmol), dichloromethane (200ml) and manganese dioxide (21.1g, 240mmol) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The reaction was stirred at room temperature for 18-24 hours, after which the mixture was filtered through a pad of celite and the solvent was removed under reduced pressure to give 188 as an orange oil (2.3g, 14%). The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ8.19(s，1H)，7.55(m，1H)，7.45(m，2H)，7.19(d，J＝9Hz，1H)，3.72(s，3H)。
And C:
according to the general procedure, using anisole 188(2.3g, 7.0mmol), dichloromethane (100ml) and boron tribromide (21ml of a 1.0M solution in dichloromethane, 21mmol) gave 189(2.1g, 94%) as a yellow solid. The product was used in the next step without further purification.1H NMR(300MHz，DMSO-d6)δ10.45(s，1H)，8.24(s，1H)，7.57(d，J＝1.2Hz，1H)，7.46(m，2H)，7.02(d，J＝9Hz，1H)。
Step D:
phenol 189(2.1g, 6.6mmol), N-methylpyrrolidinone (100ml) and CuCN (1.2g, 13.2mmol) are added to a round bottom flask equipped with a stir bar and supplied with nitrogen as needed, and the reaction is heated to reflux for 2-5 hours. When the reaction was judged complete, the reaction was poured into a separatory funnel containing ethyl acetate and water. The organics were collected, treated with activated carbon, dried over sodium sulfate, filtered through a pad of celite and the solvent removed under reduced pressure. The resulting brown oil was purified by flash chromatography using 5% methanol in dichloromethane as eluent to give 190 as a yellow solid (0.5g, 29%). 1H NMR(400MHz，CDCl3)δ11.17(s，1H)，8.26(s，1H)，7.85(s，1H)，7.79(s，1H)，7.51(d，J＝9Hz，1H)，7.05(d，J＝9Hz，1H)。
Step E:
using phenol 190(0.5g, 1.9mmol), potassium carbonate (0.66g, 4.7mmol), ethyl bromoacetate (0.2ml, 0.32g, 1.9mmol) and acetone (20ml) according to general procedure II, 191(0.7g, > 100%) was obtained as a clear oil. The product was used in the next step without further purification.1H NMR(300MHz，DMSO-d6)δ9.00(s，1H)，8.09(s，1H)，7.62(dd，J＝3，9Hz，1H)，7.54(d，J＝3Hz，1H)，7.17(d，J＝9Hz，1H)，4.81(s，2H)，4.07(m，2H)，1.21(m，3H)。
Step F:
using ester 191(0.7g, 2mmol), THF (10ml), water (5ml), ethanol (5ml) and LiOH (0.2g, 5mmol) according to general procedure III, 192(0.5g, 80%) was obtained as an orange gum. The product was used in the next step without further purification or characterization.
Step G:
according to general method IV, carboxylic acid 192(0.16g, 0.49mmol), amine 399(0.13g, 0.34mmol), HOBt (0.079g, 0.34mmol), EDAC (0.14g, 0.34mmol) and anhydrous DMF (7ml) were used. The resulting product was treated with diethyl ether to afford 186(0.052g, 21%) as a light yellow solid:1H NMR(400MHz，DMSO-d6)δ9.11(s，1H)，8.94(s，1H)，8.12(s，1H)，7.62(d，J＝9Hz，1H)，7.53(d，J＝2.4Hz，1H)，7.20(d，J＝9Hz，1H)，7.14(d，J＝9Hz，1H)，6.84(s，1H)，6.77(d，J＝8Hz，1H)，4.77(s，2H)，3.70(m，2H)，3.52(m，2H)，2.87(m，2H)，2.63(m，2H)，2.03(s，3H)。MS(ES)：528(M+)。
example 86:
acid 192(0.36g, 1.1mmol), dichloromethane (20ml) and oxalyl chloride (0.1ml, 0.14g, 1.1mmol) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The mixture was cooled to 0 ℃ and N, N-dimethylformamide (1-2 drops) was added. The reaction was allowed to warm to room temperature over 30-60 minutes, after which the mixture was concentrated under reduced pressure to give the acid chloride. The acid chloride, acetonitrile (20ml), triethylamine (0.4ml, 0.29g, 2.9mmol) and sulfonamide (0.26g, 1.4mmol) were mixed and stirred at room temperature for 18-24 hours. When the reaction was judged complete, the reaction was poured into a separatory funnel containing water and ethyl acetate. The organics were collected, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The resulting gum was treated with diethyl ether to give a pale yellow solid 193(0.11g, 20%).1H NMR(400MHz，DMSO-d6)δ9.45(s，1H)，8.95(s，1H)，8.11(s，1H)，7.61(m，6H)，7.23(s，2H)，4.87(s，2H)，2.23(s，3H)。
Example 87:
step A:
2-bromo-4-chloroanisole (9.8ml, 15.7g, 71.3mmol) and diethyl ether (250ml) were added to a round bottom flask equipped with a stir bar, addition funnel and, if necessary, nitrogen. The reaction was cooled to-78 ℃ via a dry ice/acetone bath, n-butyllithium (45ml, 1.6M solution in hexanes, 72mmol) was added dropwise, the reaction stirred at-78 ℃ for 30 minutes, after which 5-bromo-2-thiophenecarboxaldehyde (15g, 79mmol) was added. When the reaction was judged to be complete, the reaction was quenched by dropwise addition of water and extracted with ethyl acetate. The organics were collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 195(20g, 77%). The product was used in the next step without further purification or characterization.
And B:
alcohol 195(20g, 60mmol), dichloromethane (300ml) and manganese dioxide (15.6g, 180mmol) were charged to a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The reaction was stirred at room temperature for 90 minutes, after which it was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 196(15.3g, 77%) as a light yellow oil. The product was used in the next step without further purification. 1H NMR(400MHz，DMSO-d6)δ7.55(m，1H)，7.42(s，1H)，7.33(t，J＝3，9Hz，1H)，7.26(t，J＝3Hz，1H)，7.17(m，1H)，3.72(s，3H)。
And C:
using anisole 196(8.2g, 25mmol), dichloromethane (175ml) and boron tribromide (74ml of a 1.0M solution in dichloromethane, 74mmol) according to general procedure IX, 197(6.8g, 87%) was obtained. The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ10.35(s，1H)，7.39(dd，J＝2.4，6Hz，1H)，7.35(m，4H)，6.94(dd，J＝3，9Hz，1H)。
Step D:
phenol 197(8.5g, 27mmol), N-methylpyrrolidone (350ml) and ketone cyanide (I) (4.8g, 54mmol) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen if necessary, and the reaction mixture was heated to reflux for 2-5 hours. When the reaction was judged complete, the reaction was cooled and poured into a beaker containing ethyl acetate and water. The organics were collected, treated with activated carbon, dried over sodium sulfate, filtered through a pad of celite and the solvent removed under reduced pressure to give a brown oil which was purified by flash chromatography using 5% methanol/dichloromethane as eluent to give 198(6.8g, 21%) as a yellow solid.1H NMR(300MHz，DMSO-d6)δ10.57(s，1H)，8.04(t，J＝2Hz，1H)，7.68(m，1H)，7.48(m，2H)，7.03(d，J＝8.4Hz，1H)。MS(ES)：262(M-H)+。
Step E:
using phenol 198(1.5g, 5.7mmol), potassium carbonate (3.9g, 29mmol), ethyl bromoacetate (0.7ml, 1.1g, 6.3mmol) and acetone (125ml) according to general procedure II, 199 was obtained as a clear oil (2.0g, > 100%). The product was used in the next step without further purification or characterization.
Step F:
using ester 199(2.0g, 5.7mmol), THF (20ml), water (10ml), ethanol (10ml) and LiOH (1.0g, 22.8mmol) according to general procedure III, 200 was obtained as an orange gum (0.42g, 23%). The product was used in the next step without further purification or characterization.
Step G:
according to general method IV, carboxylic acid 200(0.42g, 1.3mmol), amine 399(0.36g, 1.6mmol), HOBt (0.22g, 1.6mmol), EDAC (0.38g, 2.0mmol) and anhydrous DMF (7ml) were used. The resulting brown oil was purified by flash chromatography using 2% methanol in dichloromethane as eluent. The resulting product was treated with diethyl ether to give 194(0.071g, 10%) as a white solid:1H NMR(300MHz，DMSO-d6)δ9.08(s，1H)，7.83(d，J＝4.5Hz，1H)，7.69(m，2H)，7.61(s，1H)，7.27(d，J＝9Hz，1H)，7.18(d，J＝9Hz，1H)，6.90(s，1H)，6.83(d，J＝8.4Hz，1H)，4.80(s，2H)，3.76(m，2H)，3.58(m，2H)，2.93(m，2H)，2.71(m，2H)，2.07(s，3H)。
example 88:
step A:
following general procedure V, using 5-bromonicotinic acid (5.0g, 0.025mol), oxalyl chloride (2.4ml, 3.5g, 0.027mol), dichloromethane (125ml) and N, N-dimethylformamide (2 drops), 202 was obtained as a white solid (6.0g, > 100%). The product was used in the next step without further purification.1H NMR(300MHz，DMSO-d6)δ9.04(d，J＝1.5Hz，1H)，8.97(d，J＝2.1Hz，1H)，8.44(t，J＝1.8Hz，1H)。
And B:
according to general procedure VII, using acid chloride 202(4.0g, 0.018mol), N, O-dimethylhydroxylamine hydrochloride (3.5g, 0.036mol), triethylamine (7.5ml, 5.5g, 0.054mol) and chloroform (150ml), 203 was obtained as a yellow oil (3.2g, 74%). The product was used in the next step without further purification. 1H NMR(400MHz，DMSO-d6)δ8.79(d，J＝2Hz，1H)，8.72(d，J＝1.6Hz，1H)，8.20(t，J＝2Hz，1H)，3.53(s，3H)，3.25(s，3H)。
And C:
according to general method VIII, amide 203(1.8g, 7.3mmol), n-butyllithium (5.0ml, 1.6M solution in hexane, 8.0mmol), 2-bromo-4-chloroanisole (1.0ml, 1.6g, 7.3mmol) and diethyl ether (20ml) are used. The product was purified by flash chromatography using 7: 3 hexane/ethyl acetate as eluent to give 204 as a pale yellow solid (1.5g, 63%).1H NMR(400MHz，DMSO-d6)δ8.93(d，J＝2.4Hz，1H)，8.71(d，J＝2Hz，1H)，8.21(t，J＝2Hz，1H)，7.63(dd，J＝2.8，9.2Hz，1H)，7.48(d，J＝2.8Hz，1H)，7.22(d，J＝9.2Hz，1H)，3.65(s，3H)。
Step D:
according to general procedure IX, using anisole 204(2.0g, 6.1mmol), boron tribromide (18.4ml of a 1.0M solution in dichloromethane, 18.4mmol) and dichloromethane (50ml), 205(3.4g, > 100%) was obtained as a yellow foam. The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ10.57(s，1H)，8.91(d，J＝2.4Hz，1H)，8.75(d，J＝1.6Hz，1H)，8.21(t，J＝2Hz，1H)，7.48(dd，J＝2.8，8.8Hz，1H)，7.41(d，J＝2.8Hz，1H)，6.97(d，J＝8.8Hz，1H)。MS(ES)：314(M+H)+，312(M-H)-。
Step E:
using phenol 205(0.55g, 1.77mmol), ethyl bromoacetate (0.21ml, 0.32g, 1.9mmol), potassium carbonate (0.73g, 5.3mmol) and acetone (25ml) according to general procedure II, 206 was obtained as a red oil (0.58g, 83%). The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ8.97(d，J＝2.4Hz，1H)，8.84(d，J＝1.8Hz，1H)，8.30(t，J＝1.8Hz，1H)，7.66(dd，J＝2.7，9Hz，1H)，7.57(d，J＝2.7Hz，1H)，7.19(d，J＝9Hz，1H)，4.82(s，2H)，4.18(m，2H)，1.2(m，3H)。
Step F:
according to general procedure III, ester 206(0.58g, 1.45mmol), LiOH (0.15g, 3.64mmol) and a solution of THF, ethanol and water (20ml) were used. The resulting orange residue was treated with diethyl ether to give 207(0.2g, 42%) as a yellow solid. The product was used in the next step without further purification or characterization.
Step G:
using acid 207(91mg, 0.25mmol), oxalyl chloride (0.023ml, 33mg, 0.26mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 466(42mg, 0.23mmol), sodium bicarbonate (105mg, 1.25mmol), acetone (10ml) and water (0.5ml) were used according to general procedure VI. The resulting yellow residue was washed with several portions of diethyl ether to give 201 as a yellow solid (20mg, 15%).1H NMR(400MHz，DMSO-d6)δ9.41(s，1H)，8.89(d，J＝2.4Hz，1H)，8.83(d，J＝1.6Hz，1H)，8.29(t，J＝2Hz，1H)，7.65(dd，J＝2.8，8.8Hz，1H)，7.62(s，1H)，7.58(m，2H)，7.53(d，J＝2.8Hz，1H)，7.22(m，3H)，4.79(s，2H)，2.15(s，3H)。MS(ES)：538(M-H)-。
Example 89:
step A:
to a round bottom flask equipped with a stir bar were added 5-methylbenzimidazole (4.0g, 0.030mol) and concentrated sulfuric acid (65 ml). The reaction was cooled to 0 ℃ and potassium nitrate (2.75g, 0.027mol) was added in portions. After stirring for 1 hour, the reaction was poured into ice, solid sodium carbonate was added and the pH was adjusted to > 8. The aqueous layer was extracted with ethyl acetate, the organics were dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give a yellow solid. The solid was recrystallized from 1: 1 methanol: water ensuring that any insoluble material was filtered off (filtration while hot) to give 209(1.8g, 34%) as a pale yellow solid.1H NMR(300MHz，DMSO-d6)δ12.96(bs，1H)，8.48(s，1H)，8.34(s，1H)，7.65(s，1H)，2.64(s，3H)。MS(ES)：222(M-H)-。
And B:
to a plastic coated reaction vessel equipped with a stir bar was added nitro derivative 209(2.2g, 0.012mol), absolute ethanol (75ml), and palladium on charcoal (0.23g of 10% Pd/C, 10% by weight). The vessel was placed in a hydrogenation unit at 50psig for 16 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to give a residue. The residue was washed several times with diethyl ether to give 210 as a pink solid (1.0g, 57%). The product exists as a mixture of tautomers at room temperature. 1H NMR(300MHz，DMSO-d6，100℃)δ11.60(bs，1H)，7.79(s，1H)，7.20(s，1H)，6.82(s，，1H)，4.39(bs，2H)，2.20(s，3H)。MS(ES)：148(M+H)+。
And C:
according to general procedure IV, acid 207(0.1g, 0.27mmol), HOBt (40mg, 0.27mmol), EDAC (52mg, 0.27mmol), aniline 210(40mg, 0.27mmol) and N, N-dimethylformamide (5ml) were used. The product was purified by flash chromatography using 2% methanol: 1% triethylamine: chloroform as eluent to give 208 as a pale yellow solid (7.6mg, 5%).1H NMR(400MHz，DMSO-d6)δ9.18(s，1H)，8.85(m，2H)，8.30(s，1H)，8.12(s，1H)，7.66(d，J＝7Hz，1H)，7.53(m，2H)，7.37(m，1H)，7.23(d，J＝9Hz，1H)，4.75(s，2H)，2.12(s，3H)。MS(ES)：501(M+H)+。
Example 90:
step A:
following general procedure V, using 3- (trifluoromethylthio) benzoic acid (2.0g, 9.0mmol), oxalyl chloride (0.8ml, 1.14g, 9.0mmol), dichloromethane (50ml) and N, N-dimethylformamide (4 drops), 212 was obtained (2.0g, 94%). The product was used in the next step without further purification or characterization.
And B:
using acid chloride 212(2.0g, 8.3mmol), N, O-dimethylhydroxylamine hydrochloride (2.0g, 20.5mmol), triethylamine (2.4ml, 1.7g, 16.8mmol) and chloroform (40ml) according to general procedure VII, 213 was obtained as a clear oil (1.6g, 70%). The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ7.87(s，1H)，7.79(m，2H)，7.60(t，1H)，3.50(s，3H)，3.24(s，3H)。
And C:
according to general method VIII, amide 213(0.8g, 3.0mmol), n-butyllithium (1.3ml, 2.5M solution in hexane, 3.3mmol), 2-bromo-4-chloroanisole (0.41ml, 0.66g, 3.0mmol) and diethyl ether (10ml) are used. The product was purified by flash chromatography using 7: 3 hexane/ethyl acetate as eluent to give 214(0.56g, 55%). 1H NMR(400MHz，DMSO-d6)δ7.97(d，J＝8Hz，1H)，7.87(m，2H)，7.68(d，J＝8Hz，1H)，7.60(dd，J＝2.4，8.8Hz，1H)，7.45(d，J＝2.8Hz，1H)，7.21(d，J＝8.8Hz，1H)，3.62(s，3H)。
Step D:
using anisole 214(0.56g, 1.6mmol), boron tribromide (2.0ml of a 1.0M solution in dichloromethane, 2.0mmol) and dichloromethane (10ml) according to general procedure IX, 215(0.45g, 86%) was obtained. The product was used in the next step without further purification.1H NMR(400 MHz，DMSO-d6)δ10.42(s，1H)，7.95(m，2H)，7.87(d，J＝8Hz，1H)，7.66(t，J＝8Hz，1H)，7.44(dd，J＝2.8，8.8Hz，1H)，7.35(d，J＝2.8Hz，1H)，6.96(d，J＝8.8Hz，1H)。MS(ES)：331(M-H)-。
Step E:
using phenol 215(0.45g, 1.4mmol), ethyl bromoacetate (0.17ml, 0.25g, 1.5mmol), potassium carbonate (0.48g, 2.5mmol) and acetone (20ml) according to general procedure II, 216(0.6g, > 100%) was obtained as a yellow oil. The product was used in the next step without further purification or characterization.
Step F:
according to general procedure III, ester 216(0.6g, 1.4mmol), LiOH (0.15g, 3.64mmol) and a solution of THF, ethanol and water (15ml) were used. The resulting yellow oil was treated with hexanes to give 217 as a white solid (0.2g, 36%).1H NMR(400MHz，DMSO-d6)δ8.13(d，J＝7.6Hz，1H)，8.06(s，1H)，7.92(d，J＝7.2Hz，1H)，7.60(t，J＝7.6Hz，1H)，7.46(dd，J＝2.8，9.2Hz，1H)，7.33(d，J＝2.4Hz，1H)，6.85(d，J＝9.2Hz，1H)，3.96(s，2H)。MS(ES)：389(M-H)-。
Step G:
according to general procedure IV, acid 217(50mg, 0.13mmol), HOBt (18mg, 0.13mmol), EDAC (25mg, 0.13mmol), aniline 399(29mg, 0.13mmol) and N, N-dimethylformamide (5ml) were used. The product was purified by flash chromatography, treated with several portions of hexane using 5% methanol: chloroform as eluent to give 211 as a beige solid (40mg, 51%). 1H NMR(400MHz，DMSO-d6)δ8.92(s，1H)，8.00(s，1H)，7.96(d，J＝1.6Hz，1H)，7.94(d，J＝1.2Hz，1H)，7.64(m，2H)，7.49(d，J＝2.4Hz，1H)，7.20(d，J＝8.8Hz，1H)，7.06(d，J＝8.8Hz，1H)，6.81(d，J＝2.8Hz，1H)，6.75(dd，J＝2.4，8.8Hz，1H)，4.65(s，2H)，3.69(m，2H)，3.51(m，2H)，2.86(m，2H)，2.64(m，2H)，1.96(s，3H)。MS(ES)：597(M+)，596(M-H)-。
Example 91:
using acid 217(70mg, 0.18mmol), oxalyl chloride (0.017ml, 25mg, 0.20mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 466(39mg, 0.21mmol), sodium bicarbonate (84mg, 1.0mmol), acetone (7ml) and water (0.5ml) were used according to general procedure VI. The resulting yellow solid was washed with a minimum amount of diethyl ether to give 218(50mg, 45%) as a yellow solid.1H NMR(300MHz，DMSO-d6)δ9.44(s，1H)，8.38(m，3H)，8.01(m，1H)，7.70(m，5H)，7.31(m，3H)，4.80(s，2H)，2.16(s，3H)。MS(ES)：559(M+)。
Example 92:
step A:
ester 216(0.56g, 1.34mmol) and dichloromethane (25ml) were placed in a round bottom flask equipped with a stir bar, nitrogen supplied if necessary and addition funnel, and the resulting reaction mixture was allowed to cool to 0 ℃. A solution of m-chloroperbenzoic acid in dichloromethane (10ml) was added dropwise through the addition funnel and the resulting mixture was stirred at 0 ℃ for 0.5 h, after which it was allowed to warm to room temperature and stirred for a further 16 h. When the reaction was judged to be complete, the reaction was quenched with 10% sodium metabisulfite solution and extracted with dichloromethane. The organics were collected, washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 220(0.56g, 93%) as a light yellow oil. The product was used in the next reaction without further purification. 1H NMR(400MHz，DMSO-d6)δ8.38(d，J＝8Hz，1H)，8.29(d，J＝8Hz，1H)，8.22(s，1H)，7.96(t，J＝7.6Hz，1H)，7.62(dd，J＝2.8，9.2Hz，1H)，7.55(d，J＝2.8Hz，1H)，7.17(d，J＝8.8Hz，1H)，4.70(s，2H)，4.05(m，2H)，1.21(m，3H)。
And B:
according to general procedure III, using ester 220(0.56g, 1.2mmol), LiOH (0.13g, 3.1mmol) and a solution of THF, ethanol and water (15ml), 221(0.1g, 19%) was obtained. The product was used in the next step without further purification or characterization.
And C:
using acid 221(100mg, 0.24mmol), oxalyl chloride (0.023ml, 33mg, 0.26mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 466(41mg, 0.22mmol), carbon were used according to general procedure VISodium hydrogen carbonate (100mg, 1.2mmol), acetone (10ml) and water (0.5 ml). The product was purified by flash chromatography eluting with 5% methanol in chloroform to give 219 as a white solid (72mg, 51%).1H NMR(400MHz，DMSO-d6)δ9.34(s，1H)，8.01(s，1H)，7.96(m，2H)，7.61(m，6H)，7.49(s，1H)，7.23(m，2H)，4.76(s，2H)，2.12(s，3H)。
Example 93:
step A:
according to general procedure II, using phenol 432(10g, 0.032mol), ethyl bromoacetate (3.5ml, 5.3g, 0.032mol), potassium carbonate (11g, 0.080mol) and acetone (120ml), 223(11.5g, 91%) was obtained as a yellow oil. The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ7.82(m，2H)，7.68(d，J＝7.6Hz，1H)，7.53(dd，J＝2.4，8.8Hz，1H)，7.44(m，2H)，7.09(d，J＝9.2Hz，1H)，4.74(s，2H)，4.04(q，J＝7.2Hz，2H)，1.13(m，3H)。
And B:
ester 223(1.5g, 3.8mmol), trimethylsilylacetylene (0.6ml, 0.4g, 4.1mmol), tetrakis (triphenylphosphine) palladium (0) (0.31g, 0.27mmol), copper (I) iodide (0.15g, 0.80mmol), triethylamine (1.7ml, 1.2g, 0.80mmol) and N, N-dimethylformamide (15ml) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as needed, and the reaction was stirred at 80 ℃ for 18 hours. When the reaction was judged to be complete, the reaction mixture was poured into B Ethyl acetate and water. The organics were collected, washed with water and brine, dried over sodium sulfate, filtered through a pad of celite and the solvent removed under reduced pressure. To the resulting residue were added tetrahydrofuran (20ml) and tetrabutylammonium fluoride (3 ml). The mixture was allowed to stir at room temperature for 10 minutes, after which it was poured into a separatory funnel containing ethyl acetate and water. The organics were collected, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The resulting product was purified by flash chromatography, eluting with 7: 3 hexanes: ethyl acetate, to give 224(0.69g, 53%).1H NMR(400MHz，DMS0-d6)δ7.73(m，2H)，7.54(m，2H)，7.44(s，1H)，7.34(m，1H)，7.09(d，J＝9.2Hz，1H)，4.74(s，2H)，4.04(m，2H)，1.11(m，3H)。MS(ES)：343(M+)。
And C:
according to general procedure III, using ester 224(0.69g, 2.0mmol), LiOH (0.2g, 5.0mmol) and a solution of THF, ethanol and water (12ml), 225(0.37g, 59%) was obtained.1HNMR(400MHz，DMSO-d6)δ13.30(bs，1H)，7.86(s，1H)，7.73(m，2H)，7.54(m，2H)，4.62(s，2H)，4.25(s，1H)。
Step D:
according to general procedure IV, acid 225(75mg, 0.24mmol), HOBt (32mg, 0.24mmol), EDAC (46mg, 0.24mmol), aniline 399(53mg, 0.24mmol) and N, N-dimethylformamide (5ml) were used. The product was purified by flash chromatography, treated with several portions of hexane using 5% methanol: chloroform as eluent to give 222 as a pale yellow solid (17mg, 14%).1H NMR(400MHz，DMSO-d6)δ8.86(s，1H)，7.75(m，2H)，7.70(d，J＝7.6Hz，1H)，7.60(dd，J＝2.8，9.2Hz，1H)，7.49(t，J＝8Hz，1H)，7.45(d，J＝2.8Hz，1H)，7.21(d，J＝9.2Hz，1H)，7.09(d，J＝8.8Hz，1H)，6.81(s，1H)，6.75(m，1H)，4.66(s，2H)，4.28(s，1H)，3.69(m，2H)，3.52(m，2H)，2.86(m，2H)，2.63(m，2H)，1.96(s，3H)。MS(ES)：521(M+)。
Example 94:
using acid 225(80mg, 0.25mmol), oxalyl chloride (0.024ml, 35mg, 0.28mmol), N-dimethylformamide (1 drop), and dichloromethane (3ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 466(48mg, 0.26mmol), sodium bicarbonate (105mg, 1.3mmol), acetone (7ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography, eluting with 5% methanol: chloroform, to give 226 as a white solid (20mg, 16%). 1H NMR(400MHz，DMSO-d6)δ9.30(s，1H)，7.77(d，J＝7.6Hz，1H)，7.70(d，J＝7.6Hz，1H)，7.58(m，4H)，7.45(m，2H)，7.22(m，3H)，4.77(s，2H)，4.27(s，1H)，2.13(s，3H)。MS(ES)：482(M+)，481(M-H)-。
Example 95
Step A:
5-fluoro-2-nitrotoluene (2.4ml, 3.0g, 0.019mol), sodium thiomethoxide (1.5g, 0.021mol), N-dimethylformamide (50ml) were added to a round-bottomed flask equipped with a stirring rod and supplied with nitrogen gas if necessary. The reaction was stirred at 85 ℃ for 2-4 hours, after which it was poured into a separatory funnel containing ethyl acetate and water. The organic layer was collected, washed with water, dried over sodium sulfate, treated with activated carbon, filtered through celite, and the solvent removed under reduced pressure to give 228 as an orange oil (2.95g, 85%). The product is free ofFurther purification was required for the next step.1H NMR(400MHz，DMSO-d6)δ7.92(s，1H)，7.29(d，J＝1.6Hz，1H)，7.24(dd，J＝2，8.4Hz，1H)，2.52(s，3H)，2.50(s，3H)。
And B:
228(2.95g, 0.016mol) and dichloromethane (50ml) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as required. The reaction was allowed to cool to 0 ℃, a solution of m-chloroperbenzoic acid (5.8g, 0.33mol) in dichloromethane (10ml) was added dropwise through the addition funnel, and the resulting mixture was stirred at 0 ℃ for 0.5 h, after which it was allowed to warm to room temperature and stirred for an additional 3-4 h. When the reaction was judged to be complete, the reaction was quenched with 10% sodium metabisulfite solution and extracted with dichloromethane. The organics were collected, washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 229(3.0g, 88%) as a yellow solid. The product was used in the next reaction without further purification. 1H NMR(400MHz，CDCl3)δ8.06(d，J＝8.4Hz，1H)，7.92(m，2H)，3.08(s，3H)，2.65(s，3H)。
And C:
to a plastic coated reaction vessel equipped with a stir bar was added nitro derivative 229(1.5g, 6.9mmol), toluene (50ml) and palladium on charcoal (0.15g of 10% Pd/C, 10% by weight). The vessel was placed in a 50p.s.i. hydrogenation apparatus for 7 hours. When the reaction was judged to be complete, the reaction was filtered through a pad of celite, and the solvent was removed under reduced pressure to give a crystalline material. The residue was washed several times with ether to give 230(1.3g, > 99%).1H NMR(400MHz，DMSO-d6)δ7.36(m，2H)，6.65(d，J＝8.4Hz，1H)，5.81(s，，2H)，2.98(s，3H)，2.06(s，3H)。
Step D:
using acid 225(107mg, 0.34mmol), oxalyl chloride (0.032ml, 47mg, 0.37mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 230(63mg, 0.34mmol), sodium bicarbonate (143mg, 1.7mmol), acetone (7ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography eluting with 5% methanol in chloroform to give 227 as a white solid (8mg, 5%).1H NMR(400MHz，DMSO-d6)δ9.34(s，1H)，7.73(m，6H)，7.60(dd，J＝2.8，8.8Hz，1H)，7.50(t，J＝8Hz，1H)，7.46(d，J＝2.4Hz，1H)，7.21(d，J＝8.8Hz，1H)，4.79(s，2H)，4.29(s，1H)，3.27(s，3H)，2.18(s，3H)。MS(ES)：481(M-H)-。
Example 96
Step A:
ester 223(0.2g, 0.5mmol), cyclopentylacetylene (52mg, 0.55mmol), tetrakis (triphenylphosphine) palladium (0) (40mg, 0.035mmol), copper (I) iodide (20mg, 0.11mmol), triethylamine (0.22ml, 0.16g, 1.6mmol) and N, N-dimethylformamide (5ml) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as needed, and the reaction was stirred at 80 ℃ for 18 hours. When the reaction was judged complete, the reaction mixture was poured into ethyl acetate and water. The organics were collected, washed with water, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography, eluting with 8: 2 hexanes to ethyl acetate, to give 232 as an orange oil (130mg, 63%). 1H NMR(300MHz，DMSO-d6)δ7.68(m，3H)，7.59(dd，J＝2.7，9Hz，1H)，7.48(m，2H)，7.13(d，J＝9Hz，1H)，4.79(s，2H)，4.10(m，2H)，2.88(m，1H)，2.00(m，2H)，1.63(m，6H)，1.17(m，3H)。
And B:
according to general procedure III, using ester 232(0.13g, 0.32mmol), LiOH (33mg, 0.79mmol) and a solution of THF, ethanol and water (8ml), 233(0.15g, > 99%) was obtained. The product was used in the next step without further purification or characterization.
And C:
using acid 233(140mg, 0.37mmol), oxalyl chloride (0.033ml, 48mg, 0.38mmol), N-dimethylformamide (1 drop) and dichloromethane (5ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 466(73mg, 0.39mmol), sodium bicarbonate (155mg, 1.85mmol), acetone (7ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography, eluting with 5% methanol: chloroform, to give 231(88mg, 43%) as a white solid.1HNMR(400MHz，DMSO-d6)δ9.28(s，1H)，7.61(m，8H)，7.44(m，2H)，7.21(m，2H)，4.77(s，2H)，2.81(m，1H)，2.14(s，3H)，1.93(m，2H)，1.58(m，6H)。
Example 97
Step A:
ester 223(0.2g, 0.5mmol), phenylacetylene (52mg, 0.55mmol), tetrakis (triphenylphosphine) palladium (40mg, 0.035mmol), copper (I) iodide (20mg, 0.11mmol), triethyleneacetateAmine (0.22ml, 0.16g, 1.6mmol) and N, N-dimethylformamide (5ml) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as needed, and the reaction was stirred at 80 ℃ for 18 hours. When the reaction was judged complete, the reaction mixture was poured into ethyl acetate and water. The organics were collected, washed with water, dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography, eluting with 8: 2 hexanes to ethyl acetate, to give 235 as an orange oil (150mg, 72%). 1H NMR(300MHz，DMSO-d6)δ7.87(d，J＝4.8Hz，1H)，7.82(m，2H)，7.60(m，4H)，7.50(d，J＝3Hz，1H)，7.46(m，3H)，7.15(d，J＝9Hz，1H)，4.82(s，2H)，4.10(m，2H)，1.21(m，3H)。
And B:
according to general procedure III, using ester 235(0.15g, 0.36mmol), LiOH (38mg, 0.90mmol) and a solution of THF, ethanol and water (8ml), 236(64mg, 46%) was obtained. The product was used in the next step without further purification or characterization.
And C:
using acid 236(64mg, 0.16mmol), oxalyl chloride (0.015ml, 23mg, 0.17mmol), N-dimethylformamide (1 drop) and dichloromethane (5ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 466(31mg, 0.17mmol), sodium bicarbonate (67mg, 0.8mmol), acetone (5ml) and water (0.5ml) were used according to general procedure VI. The product was filtered through a pad of silica gel to give 234 as a white solid (10mg, 11%).1H NMR(400MHz，DMSO-d6)δ9.34(s，1H)，7.90(s，1H)，7.79(m，2H)，7.62(m，3H)，7.54(m，4H)，7.47(d，J＝3Hz，1H)，7.38(m，3H)，7.22(m，3H)，4.80(m，2H)，2.15(s，3H)。
Example 98
Step A:
using acid 49(120mg, 0.37mmol), oxalyl chloride (0.035ml, 50mg, 0.40mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 230(69mg, 0.37mmol), sodium bicarbonate (155mg, 1.85mmol), acetone (7ml) and water (0.5ml) were used according to general procedure VI. The resulting yellow oil was treated with pentane to give 237 as a light yellow solid (39mg, 21%).1H NMR(300MHz，DMSO-d6)δ9.51(s，1H)，7.66(m，5H)，7.53(d，J＝2.7Hz，1H)，7.49(m，2H)，7.25(d，J＝9Hz，1H)，4.87(s，2H)，3.20(s，3H)，2.26(s，3H)。MS(ES)：494(M+)。
Example 99
Using acid 129(120mg, 0.38mmol), oxalyl chloride (0.037ml, 53mg, 0.42mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 230(70mg, 0.38mmol), sodium bicarbonate (160mg, 1.9mmol), acetone (7ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography, eluting with 5% methanol: chloroform, to give 238 as a yellow solid (18mg, 10%). 1H NMR(400MHz，DMSO-d6)δ9.42(s，1H)，8.16(s，1H)，8.06(m，2H)，7.67(m，25H)，7.49(d，J＝2.8Hz，1H)，7.21(d，J＝9.2Hz，1H)，4.80(s，2H)，3.14(s，3H)，2.18(s，3H)。MS(ES)：481(M-H)-。
Example 100
According to the general procedure IV, the procedure,acid 71(300mg, 0.8mmol), HOBt (108mg, 0.8mmol), EDAC (153mg, 0.8mmol), aniline 210(118mg, 0.8mmol) and N, N-dimethylformamide (7ml) were used. The product was purified by flash chromatography using 3% methanol: 1% triethylamine: dichloromethane as eluent to give 239(60mg, 15%) as a white solid. The product exists as a mixture of tautomers at room temperature.1H NMR(400MHz，DMSO-d6)δ12.27(m，1H)，9.15(m，1H)，8.00(s，1H)，7.99(d，J＝8Hz，1H)，7.87(m，2H)，7.66(d，J＝9Hz，1H)，7.45(m，3H)，4.74(s，2H)，2.12(m，3H)。MS(ES)：506(M+)，507(M+H)+。
Example 101
Using acid 49(120mg, 0.37mmol), oxalyl chloride (0.035ml, 50mg, 0.40mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 210(54mg, 0.37mmol), sodium bicarbonate (155mg, 1.9mmol), acetone (10ml) and water (0.5ml) were used according to general procedure VI. Purify the product by flash chromatography, eluting with 5% methanol: chloroform to give 240 as a pale yellow solid (22mg, 13%). The product exists as a mixture of tautomers at room temperature.1H NMR(400MHz，DMSO-d6)δ12.26(m，1H)，9.14(m，1H)，8.09(s，1H)，7.64(d，J＝9Hz，1H)，7.50(m，4H)，7.23(m，2H)，4.75(m，2H)，2.12(m，3H)。MS(ES)：456(M+)，457(M+H)+，455(M-H)-。
Example 102
According to general method V, acid 76(120mg, 0.33mmol), oxalyl chloride (0.032ml, 46mg, 0.37mmol), N-dimethylformamide (1 drop) and dimethylformamide are usedMethyl chloride (10ml) gave the acid chloride. The acid chloride, aniline 210(51mg, 0.35mmol), sodium bicarbonate (139mg, 1.7mmol), acetone (10ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography, eluting with 2% methanol: dichloromethane, to give 241 as a white solid (11mg, 7%). The product exists as a mixture of tautomers at room temperature. 1H NMR(400MHz，DMSO-d6)δ12.26(s，1H)，9.15(m，1H)，8.09(s，1H)，7.87(m，1H)，7.70(m，2H)，7.64(m，1H)，7.55(m，2H)，7.21(m，1H)，4.75(m，2H)，2.12(m，3H)。MS(ES)：490(M+H)+，488(M-H)-。
Example 103
Step A:
according to general procedure VII, using 3, 5-bis (trifluoromethyl) benzoyl chloride (5.0g, 0.018mol), N, O-dimethylhydroxylamine hydrochloride (3.5g, 0.036mol), triethylamine (7.5ml, 5.5g, 0.054mol) and dichloromethane (50ml), 243(5.0g, 92%) was obtained as a clear oil. The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ8.24(s，1H)，8.22(s，2H)，3.52(s，3H)，3.28(s，3H)。
And B:
according to general procedure VIII, amide 243(5.0g, 0.017mol), n-butyllithium (11.4ml, 1.6M solution in hexane, 0.018mol), 2-bromo-4-chloroanisole (2.3ml, 3.8g, 0.017mol) and diethyl ether (60ml) were used. The product is purified by fast chromatographyAlkylation using 85: 15 hexane: ethyl acetate as eluent gave 244(3.76g, 58%).1H NMR(400MHz，DMSO-d6)δ8.43(s，1H)，8.18(s，2H)，7.65(t，J＝2.8Hz，1H)，7.52(d，J＝2.8Hz，1H)，7.24(d，J＝8.8Hz，1H)，3.61(s，3H)。
And C:
using anisole 244(3.76g, 9.8mmol), boron tribromide (29ml of a 1.0M solution in dichloromethane, 29mmol) and dichloromethane (80ml) according to general procedure IX, 245(3.2g, 89%) was obtained as a pale green solid. The product was used in the next step without further purification.1H NMR(400MHz，DMSO-d6)δ10.6(s，1H)，8.40(s，1H)，8.21(s，2H)，7.48(m，2H)，6.98(d，J＝8.8Hz，1H)。
Step D:
according to general procedure II, using phenol 245(3.2g, 8.7mmol), ethyl bromoacetate (1.1ml, 1.6g, 9.5mmol), potassium carbonate (3.0g, 21.7mmol) and acetone (50ml), 246 was obtained as a light yellow solid (3.8g, 97%). The product was used in the next step without further purification. 1H NMR(300MHz，DMSO-d6)δ8.47(s，1H)，8.31(s，2H)，7.68(dd，J＝3，9Hz，1H)，7.61(d，J＝2.4Hz，1H)，7.21(d，J＝9Hz，1H)，4.79(s，2H)，4.06(q，J＝7Hz，2H)，1.13(t，J＝7Hz，3H)。
Step E:
according to general procedure III, ester 246 (3) is used8g, 8.4mmol), LiOH (0.88g, 20.9mmol) and a solution of THF, ethanol and water (25 ml). The resulting white foam was treated with diethyl ether to give 247 as a white solid (3.1g, 86%).1H NMR(300MHz，DMSO-d6)δ8.44(s，1H)，8.34(s，2H)，7.67(dd，J＝3，9Hz，1H)，7.58(d，J＝3Hz，1H)，7.16(d，J＝9Hz，1H)，4.63(s，2H)。
Step F:
according to general procedure IV, acid 247(150mg, 0.35mmol), HOBt (47mg, 0.35mmol), EDAC (67mg, 0.35mmol), aniline 210(52mg, 0.35mmol) and N, N-dimethylformamide (5ml) were used. The product was purified by flash chromatography using 3% methanol: chloroform as eluent to give 242 as a white solid (9mg, 5%). The product exists as a mixture of tautomers at room temperature.1H NMR(300MHz，DMSO-d6)δ12.32(s，1H)，9.20(s，1H)，8.44(s，1H)，8.35(m，2H)，8.14(m，1H)，7.76(m，1H)，7.62(m，1H)，7.51(s，1H)，7.30(d，J＝9Hz，1H)，4.77(s，2H)，2.13(s，3H)。MS(ES)：556(M+)，557(M-H)-。
Example 104
Step A:
3-methyl-4-nitrophenol (2.0g, 0.013mol), dibromopropane (10.6ml, 21.0g, 0.10mol), potassium carbonate (2.7g, 0.02mol) and N, N-dimethylformamide (50ml) were placed in a round bottom flask equipped with a stirring rod and supplied with nitrogen as needed, and the mixture was stirred at room temperature for 18 hours. When the reaction was judged complete, the reaction mixture was poured into a separatory funnel containing dichloromethane and water. Collecting the organic matter, washing with 0.5N sodium hydroxide solution, passing through sulfuric acidThe magnesium was dried, filtered and the solvent removed under reduced pressure. The resulting red oil was distilled to yield 249(2.46g, 69%): 1H NMR(400MHz，DMSO-d6)δ7.49(d，J＝2.4Hz，1H)，7.37(d，J＝8.4Hz，1H)，7.21(dd，J＝2.4，8.4Hz，1H)，4.11(t，J＝6Hz，2H)，3.63(t，J＝6Hz，2H)，2.38(s，3H)，2.22(m，2H)。
And B:
249(1.5g, 5.47mmol), pyrrolidine (0.91ml, 0.78g, 10.9mmol), potassium carbonate (1.1g, 8.2mmol) and N, N-dimethylformamide (30ml) were placed in a bottom flask equipped with a stirring rod and supplied with nitrogen as needed, and the mixture was stirred at room temperature for 4 hours. When the reaction was judged complete, the reaction mixture was poured into a separatory funnel containing ethyl acetate and water. The organics were collected, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 250 as a brown oil (1.24g, 89%). The product was used in the next step without further purification or characterization.
And C:
compound 250(1.3g, 4.9mmol), absolute ethanol (20ml) and palladium on charcoal (0.13g of 10% Pd/C, 10% w/w) were added to a plastic coated reaction vessel equipped with a stir bar. The vessel was placed in a 60p.s.i. hydrogenation apparatus for 3 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to give a dark oil. The residue was treated with small amounts of ethyl acetate and hexane, the resulting precipitate was filtered, and the mother liquor was concentrated under reduced pressure to give 251(1.0g, 87%) as an orange solid.1H NMR(400MHz，DMSO-d6)δ6.72(d，J＝8.4Hz，1H)，6.14(d，J＝2.4Hz，1H)，5.98(dd，J＝2.4，8.4Hz，1H)，4.73(s，2H)，3.82(t，J＝6.4Hz，2H)，2.46(m，2H)，2.37(m，4H)，1.92(s，3H)，1.77(m，2H)，1.63(m，4H)。
Step D:
Using acid 49(120mg, 0.37mmol), oxalyl chloride (0.035ml, 50mg, 0.40mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 251(87mg, 0.37mmol), sodium bicarbonate (155mg, 1.85mmol), acetone (8ml) and water (0.5ml) were used according to general procedure VI. The resulting yellow oil was treated with pentane to give 248(92mg, 46%) as a pale yellow solid.1H NMR(400MHz，DMSO-d6)δ9.08(s，1H)，7.62(dd，J＝2.8，8.8Hz，1H)，7.55(t，J＝9.2Hz，1H)，7.47(d，J＝2.4Hz，1H)，7.42(m，2H)，7.19(d，J＝8.8Hz，1H)，7.01(m，2H)，6.63(d，J＝8.4Hz，1H)，4.74(s，2H)，3.89(t，J＝6.4Hz，2H)，2.45(m，2H)，2.39(bs，4H)，1.98(s，3H)，1.81(t，J＝6.8Hz，2H)，1.63(s，4H)。MS(ES)：543(M+)。
Example 105
Step A:
sodium hydride (7.8g, 60% by weight in mineral oil, 0.20mol) and anhydrous tetrahydrofuran (THF, 300ml) were placed in a round bottom flask equipped with an overhead stirrer, addition funnel and, if necessary, a nitrogen gas supply. The mixture was cooled to 0 ℃ and a solution of 2-methyl-3-nitrophenol (30g, 0.20mol) in THF (100ml) was added dropwise. The reaction was then allowed to warm to room temperature, heated to 40 ℃ for 15 minutes, and then cooled to room temperature. At this time, a solution of 1, 3-propane sultone (25.6g, 0.21mol) in THF (100ml) was added dropwise and the reaction heated to reflux4-6 hours. When the reaction was judged to be complete, the reaction mixture was filtered, and the resulting solid was washed with anhydrous ethanol and ether and dried in a vacuum oven. The solid precipitated from the mother liquor was filtered, washed with absolute ethanol and ether, and dried in a vacuum oven to give 253 as a pale yellow solid (27g, 46%): 1H NMR(300MHz，DMSO-d6)δ8.06(d，J＝9Hz，1H)，7.05(d，J＝2.7Hz，1H)，6.98(dd，J＝2.7，9.3Hz，1H)，4.22(t，J＝6.6Hz，2H)，2.58(m，2H)，2.52(s，3H)，2.04(m，2H)。
And B:
sulfonate 253(11g, 0.037mol) and N, N-dimethylformamide (250ml) were added to a round bottom flask equipped with a stir bar, addition funnel and nitrogen supply as needed and the reaction was cooled to 0 ℃. Thionyl chloride (8.0ml, 13.0g, 0.11mol) was added dropwise and the mixture was stirred at 0 ℃ for 0.5 h, after which it was allowed to warm to room temperature and stirred for a further 3 h. When the reaction was judged complete, the reaction mixture was poured into a beaker containing ice, and the resulting white precipitate was filtered and placed in a vacuum oven to give 254(8.7g, 80%) as a white solid.1H NMR(300MHz，DMSO-d6)δ8.06(d，J＝9Hz，1H)，7.05(d，J＝2.7Hz，1H)，6.98(dd，J＝2.7，9.3Hz，1H)，4.22(t，J＝6.3Hz，2H)，2.61(m，2H)，2.57(s，3H)，2.04(m，2H)。
And C:
ammonium hydroxide (10ml) and THF (20ml) were added to a round bottom flask equipped with a stir bar, addition funnel and nitrogen gas supply as required, the reaction was cooled to 0 deg.C, sulfonyl chloride 254(2g, 6.8mmol) was added dropwise, the reaction was stirred at 0 deg.C for 15 minutes, after which the reaction was pouredPut into a beaker containing ice and extracted with ethyl acetate. The organics were collected, washed with water, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 255 as a white solid (1.4g, 77%).1H NMR(300MHz，DMSO-d6)δ8.07(d，J＝9Hz，1H)，7.06(d，J＝2.7Hz，1H)，7.00(dd，J＝2.7，9Hz，1H)，6.91(s，2H)，4.24(t，J＝6Hz，2H)，3.16(t，J＝7.5Hz，2H)，2.56(s，3H)，2.18(m，2H)。
Step D:
nitro derivative 255(0.29g, 1.1mmol), absolute ethanol (25ml) and palladium on charcoal (29mg of 10% Pd/C, 10% by weight) were added to a plastic coated reaction vessel equipped with a stir bar. The vessel was placed in a 60p.s.i. hydrogenation apparatus for 2-4 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to give 256(0.25g, 98%) as a light brown solid. 1H NMR(400MHz，DMSO-d6)δ6.80(s，2H)，6.54(s，1H)，6.49(s，2H)，4.34(s，2H)，3.89(t，J＝6Hz，2H)，2.58(m，2H)，3.05(m，2H)，1.99(m，5H)。
Step E:
using acid 49(120mg, 0.37mmol), oxalyl chloride (0.035ml, 50mg, 0.40mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) according to general procedure V gave the acid chloride. Using the acid chloride, aniline 256(81mg, 0.33mmol), sodium bicarbonate (155mg, 1.85mmol), acetone (8ml), and water (0.5ml) according to general procedure VI, 252(103mg, 50%) was obtained as a white solid.1H NMR(400MHz，DMSO-d6)δ9.09(s，1H)，7.62(dd，J＝2.8，9.2Hz，1H)，7.55(m，1H)，7.47(d，J＝2.8Hz，1H)，7.41(m，2H)，7.19(d，J＝9.2Hz，1H)，7.11(d，J＝8.4Hz，1H)，6.83(s，2H)，6.76(d，J＝2.8Hz，1H)，6.69(dd，J＝2.8，8.4Hz)，4.70(s，2H)，4.01(t，J＝6.4Hz，2H)，3.08(t，J＝8Hz，2H)，2.07(m，2H)，2.00(s，3H)。MS(ES)：553(M+)。
Example 106
Using acid 71(13g, 0.035mol), oxalyl chloride (7.0ml, 9.8g, 0.077mol), N-dimethylformamide (1 drop) and dichloromethane (100ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 256(7.81g, 0.032mol), sodium bicarbonate (15mg, 0.18mol), acetone (125ml) and water (10ml) were used according to general procedure VI. The product crystallized from methanol to give 257(10.5g, 50%) as a white solid.1H NMR(300MHz，DMSO-d6)δ9.16(s，1H)，8.05(d，J＝8.4Hz，1H)，7.90(m，2H)，7.71(dd，J＝2.7，9Hz，1H)，7.57(d，J＝2.7Hz，1H)，7.25(d，J＝9Hz，1H)，7.13(d，J＝9Hz，1H)，6.88(s，2H)，6.80(d，J＝2.7Hz，1H)，6.73(dd，J＝2.7，9Hz，1H)，4.74(s，2H)，4.07(t，J＝6Hz，2H)，3.13(m，2H)，2.13(m，2H)，2.03(s，3H)。MS(ES)：602(M-H)-，603(M+)。C26H23N2O6ClF4Analytical calculation of S: c, 51.79; h, 3.84; and N, 4.65. Measured value: c, 51.91; h, 3.88; and N, 4.66.
Example 107
Step A:
2-methyl-3-nitrophenol (10g, 0.065mol), acetone (100ml), potassium carbonate (27g, 0.20mol) and 1, 3-propane sultone (6.0ml, 8.3g, 0.068mol) were added to a flask equipped with a stir bar and, if necessary I.e. a round bottom flask supplied with nitrogen. The mixture was heated to reflux for 1 hour, after which it was allowed to cool to room temperature and stirred for a further 72 hours. When the reaction was judged complete, the reaction mixture was concentrated under reduced pressure. The resulting yellow residue was dissolved in a minimum amount of water, acidified to pH2 with concentrated hydrochloric acid and extracted with a mixture of absolute ethanol/ethyl acetate. The organics were collected, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 259(10.2g, 57%) as a pale yellow solid.1H NMR(400MHz，DMSO-d6)δ8.00(d，J＝9.2Hz，1H)，6.99(d，J＝2.4Hz，1H)，6.92(dd，J＝2.4，8.8Hz，1H)，4.16(t，J＝6.4Hz，2H)，2.47(m，5H)，1.98(m，2H)。
And B:
sulfonic acid 259(3g, 0.011mol) and phosphorus oxychloride (POCl)3100ml) was charged into a round-bottomed flask equipped with a stirring rod, a reflux condenser and, if necessary, a nitrogen gas supply. The reaction was heated to reflux for 18 hours, after which it was stirred at room temperature for a further 24 hours. The mixture was filtered and POCl was removed under reduced pressure3Yield 260 as a brown oil (3.8g, > 100%). The product was used in the next step without further purification or characterization.
And C:
tert-butylamine (0.33ml, 0.23g, 3.1mmol), triethylamine (0.72ml, 0.52g, 5.2mmol) and chloroform (20ml) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as required. Sulfonyl chloride 260(0.76g, 2.6mmol) in chloroform (3ml) was added dropwise and the reaction stirred at room temperature for 2 hours. When the reaction was judged complete, the reaction mixture was poured into a separatory funnel containing chloroform and water, the organics were collected, washed with brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting brown residue was filtered through a pad of silica gel eluting with hexane to give 261(0.37g, 43%) as a white solid. The product was used in the next step without further purification or characterization.
Step D:
compound 261(0.37g, 1.1mmol), ethanol (20ml) and palladium on charcoal (37mg of 10% Pd/C, 10w/w) were added to a plastic coated reaction vessel equipped with a stir bar. The vessel was placed in a 60p.s.i. hydrogenation apparatus for 2-4 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to give 262(0.32g, 95%) as a brown oil.1H NMR(400MHz，DMSO-d6)δ6.92(s，1H)，6.85(s，1H)，6.53(m，1H)，6.49(m，1H)，4.51(bs，2H)，3.90(t，J＝6Hz，2H)，3.09(m，2H)，2.08(m，2H)，1.99(s，3H)，1.22(m，9H)。
Step E:
using acid 49(120mg, 0.37mmol), oxalyl chloride (0.035ml, 50mg, 0.40mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 262(111mg, 0.37mmol), sodium bicarbonate (155mg, 1.85mmol), acetone (10ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography, eluting with 5% methanol: dichloromethane, to give 258 as a white solid (28mg, 12%).1H NMR(400MHz，DMSO-d6)δ9.08(s，1H)，7.63(dd，J＝4，8Hz，1H)，7.54(m，1H)，7.47(d，J＝4Hz，1H)，7.41(m，2H)，7.20(d，J＝8Hz，1H)，7.12(d，J＝8Hz，1H)，6.87(s，1H)，6.75(m，1H)，6.68(dd，J＝4，8Hz，1H)，4.70(s，2H)，4.02(t，J＝8Hz，2H)，3.09(t，J＝8Hz，2H)，2.05(t，J＝8Hz，2H)，2.00(s，3H)，1.22(s，9H)。MS(ES)：608(M-H)-。
Example 108
Step A:
sulfonyl chloride 260(3.8g, 0.013mol) and dichloromethane (100ml) were added to a round bottom flask equipped with a stir bar and gas distribution tube and the reaction was cooled to 0 ℃. Dimethylamine gas was bubbled through the reaction mixture for 1 hour, after which the reaction mixture was poured into dichloromethane and water. The organics were collected, washed with water, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 264 as a pale yellow solid (2.1g, 54%). The product was used in the next step without further purification or characterization.
And B:
nitro derivative 264(2.1g, 7.0mmol), absolute ethanol (40ml) and palladium on charcoal (0.21g of 10% Pd/C, 10% by weight) were added to a plastic coated reaction vessel equipped with a stir bar. The vessel was placed in a 50p.s.i. hydrogenation apparatus for 2-4 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to give 265(1.7g, 90%) as a pale yellow solid. The product was used in the next step without further purification or characterization.
And C:
using acid 71(120mg, 0.32mmol), oxalyl chloride (0.032ml, 44mg, 0.35mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 265(78mg, 0.29mmol), carbon were used according to general procedure VISodium hydrogen carbonate (134mg, 1.6mmol), acetone (6ml) and water (0.5 ml). The resulting residue was treated several times with pentane to give 263 as a beige solid (90mg, 45%).1H NMR(400MHz，DMSO-d6)δ9.09(s，1H)，7.98(d，J＝8.4Hz，1H)，7.84(m，2H)，7.65(dd，J＝2.4，8.8Hz，1H)，7.51(d，J＝2.8Hz，1H)，7.20(d，J＝8.8Hz，1H)，7.08(d，J＝8.8Hz，1H)，6.76(d，J＝2.4Hz，1H)，6.68(dd，J＝2.8，8.8Hz，1H)，4.69(s，2H)，4.00(t，J＝6Hz，2H)，3.13(m，2H)，2.75(s，6H)，2.05(m，2H)，1.98(s，3H)。MS(ES)：631(M+)。
Example 109
Step A:
sulfonyl chloride 260(3.2g, 0.011mol) and dichloromethane (75ml) were added to a round bottom flask equipped with a stir bar and gas distribution tube and the reaction was cooled to 0 ℃. Methylamine gas was bubbled through the reaction mixture for 1 hour, after which the reaction mixture was poured into dichloromethane and water. The organics were collected, washed with water, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was recrystallized from methanol to yield 267(2.0g, 63%) as a light yellow solid. 1H NMR(300MHz，DMSO-d6)δ8.08(d，J＝9Hz，1H)，7.03(m，3H)，4.23(t，J＝8.4Hz，2H)，3.19(m，2H)，2.57(m，6H)，2.12(m，2H)。MS(ES)：617(M+)。
And B:
the nitro derivative 267(2.0g,6.9mmol), toluene (25ml) and palladium on charcoal (0.20g of 10% Pd/C, 10% by weight) were added to a plastic coated reaction vessel equipped with a stir bar. The vessel was placed in a 50p.s.i. hydrogenation apparatus for 4 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the solvent was removed under reduced pressure. The resulting residue was treated with several portions of hexane to give 268(1.1g, 62%) as a pink solid.1H NMR(400MHz，DMSO-d6)δ6.92(q，J＝5Hz，1H)，6.55(s，1H)，6.48(m，2H)，4.36(bs，2H)，3.88(t，J＝6.4Hz，2H)，3.08(m，2H)，2.53(d，J＝5Hz，3H)，1.95(m，5H)。
And C:
using acid 71(120mg, 0.32mmol), oxalyl chloride (0.032ml, 44mg, 0.35mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 268(75mg, 0.29mmol), sodium bicarbonate (134mg, 1.6mmol), acetone (6ml) and water (0.5ml) were used according to general procedure VI. The resulting residue was treated several times with hexane to give 266 as a beige solid (80mg, 41%).1H NMR(400MHz，DMSO-d6)δ9.09(s，1H)，7.98(d，J＝8.4Hz，1H)，7.84(m，2H)，7.65(dd，J＝2.4，8.8Hz，1H)，7.52(d，J＝2.8Hz，1H)，7.20(d，J＝9.2Hz，1H)，7.08(d，J＝8.4Hz，1H)，6.94(q，J＝5Hz，1H)，6.74(d，J＝2.8Hz，1H)，6.68(dd，J＝2.8，8.8Hz，1H)，4.68(s，3H)，4.00(m，2H)，3.10(t，J＝8Hz，2H)，2.54(d，J＝5Hz)，2.01(m，5H)。MS(ES)：617(M+)。
Example 110
Step A:
2-A is prepared fromIn a round-bottomed flask equipped with a stirring rod and supplied with nitrogen as required, there were placed mesityl-3-nitrophenol (5.0g, 0.033mol), dibromopropane (26ml, 52.7g, 0.26mol), potassium carbonate (6.8g, 0.05mol) and N, N-dimethylformamide (100ml), and the mixture was stirred at room temperature for 2.5 hours. When the reaction was judged complete, the reaction mixture was poured into a separatory funnel containing ethyl acetate and water. The organics were collected, washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting oil was distilled to give 270(8.0g, 89%) as a brown oil. 1H NMR(400MHz，DMSO-d6)δ8.01(d，J＝9.2Hz，1H)，7.02(d，J＝2.8Hz，1H)，6.96(dd，J＝2.4，8.8Hz，1H)，4.16(t，J＝6Hz，2H)，3.63(t，J＝6Hz，2H)，2.51(s，3H)，2.24(m，2H)。
And B:
270(0.8g, 2.9mmol), imidazole (0.24g, 3.49mmol), potassium carbonate (0.8g, 5.83mmol) and N, N-dimethylformamide (20ml) were placed in a round bottom flask equipped with a stirring bar and supplied with nitrogen if necessary, and the mixture was stirred at 55 ℃ for 18 hours. When the reaction was judged complete, the reaction mixture was poured into a separatory funnel containing ethyl acetate and water. The organics were collected, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography eluting with 1: 1 hexane: ethyl acetate to give 271(0.3g, 40%).1H NMR(400MHz，DMSO-d6)δ8.06(d，J＝9Hz，1H)，7.65(s，1H)，7.22(s，1H)，7.04(d，J＝2.4Hz，1H)，6.98(dd，J＝2.7，9Hz，1H)，6.92(s，1H)，4.16(t，J＝7Hz，2H)，4.04(t，J＝6Hz，2H)，2.57(s，3H)，2.22(m，2H)。
And C:
nitro derivative 271(0.3g, 1.15mmol), ethanol (20ml) and palladium on charcoal (30mg of 10% Pd/C, 10% w/w) were added to a plastic coated reaction vessel equipped with a stir bar. The vessel was placed in a hydrogenation apparatus at 55p.s.i. for 2 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the solvent was removed under reduced pressure to give 272 as a purple-red oil (0.23g, 88%).1H NMR(400MHz，DMSO-d6)δ7.57(s，1H)，7.14(s，1H)，6.85(s，1H)，6.54(s，1H)，6.48(s，2H)，4.44(bs，2H)，4.06(t，J＝6.8Hz，2H)，3.70(t，J＝6Hz，2H)，2.03(m，2H)，1.99(s，3H)。
Step D:
using acid 71(120mg, 0.32mmol), oxalyl chloride (0.032ml, 44mg, 0.35mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 272(67mg, 0.29mmol), sodium bicarbonate (134mg, 1.6mmol), acetone (6ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography using 5% methanol: chloroform as eluent to afford 269(84mg, 45%) as a pink solid. 1H NMR(300MHz，DMSO-d6)δ9.15(s，1H)，8.05(d，J＝9Hz，1H)，7.90(m，2H)，7.71(dd，J＝3，9Hz，1H)，7.65(s，1H)，7.57(d，J＝3Hz，1H)，7.24(m，2H)，7.13(d，J＝6Hz，1H)，6.92(s，1H)，6.79(d，J＝3Hz，1H)，6.73(dd，J＝3，9Hz，1H)，4.74(s，2H)，4.14(t，J＝6Hz，2H)，3.88(t，J＝6Hz，2H)，2.16(m，2H)，2.03(s，3H)。MS(ES)：589(M+)，590(M+H)+。
Example 111
Step A:
4-bromo-2-methylaniline (0.8g, 4.3mmol), palladium (II) acetate (97mg, 0.43mmol), tri-o-tolylphosphine (0.52g, 1.72mmol), N-dimethylformamide (15ml), N-butenylpyrrolidine (2.7g, 21.5mmol) and triethylamine (4.2ml, 3.0g, 30.1mmol) were added to a reaction vessel equipped with a stirring rod and a sealed tube type to which nitrogen gas can be supplied if necessary. The tube was sealed and stirred at 80 ℃ for 18 hours. When the reaction was judged complete, the reaction was filtered through a pad of celite and the filtrate was poured into ethyl acetate and water. The organics were collected, washed with water and brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by flash chromatography using 93: 7 chloroform: methanol as eluent to give 273 as a yellow oil (0.2g, 20%). The product was present as a 2.7: 1 mixture of E: Z isomers.1H NMR(400MHz，DMSO-d6)δ6.87(m，2H)，6.51(m，1H)，6.18(m，1H)，5.87(m，1H)，4.81(m，2H)，2.44(m，8H)，2.31(m，2H)，2.00(m，2H)，1.85(s，3H)。MS(ES)：231(M+H)+。
And B:
using acid 71(132mg, 0.35mmol), oxalyl chloride (0.034ml, 48mg, 0.38mmol), N-dimethylformamide (1 drop) and dichloromethane (10ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 273(72mg, 0.31mmol), sodium bicarbonate (152mg, 1.7mmol), acetone (6ml) and water (0.5ml) were used according to general procedure VI. The product was recrystallized from absolute ethanol to yield 272(20mg, 10%) as a white solid. The product was present as a 2.7: 1 mixture of E: Z isomers. 1H NMR(400MHz，DMSO-d6)δ9.15(m，1H)，7.98(m，1H)，7.85(m，2H)，7.65(m，1H)，7.51(m，1H)，7.20(m，4H)，6.32(m，1H)，6.21(m，1H)，4.72(s，2H)，2.46(m，8H)，2.31(m，2H)，2.04(m，2H)，1.65(s，3H)。MS(ES)：590(M+H)+。
Example 112
The title compound was prepared according to general method VI from acid 49(0.51mmol) and 5-amino-2-methoxypyridine (0.04ml, 0.44 mmol). Purification by flash chromatography using 25% ethyl acetate/hexane as eluent followed by trituration with ether afforded 274(0.146g, 77%). mp185-187 ℃; MS (ES +): m/z 433(M + H);1H NMR(400MHz，CDCl3)δ9.30(s，1H)，8.49(d，1H)，8.09(dd，1H)，7.56(dd，1H)，7.41-7.38(m，3H)，7.13-7.09(m，1H)，7.05(d，1H)，6.76(d，1H)，4.72(s，2H)，3.94(s，3H)。
example 113
The title compound was prepared according to general method VI from acid 49(0.51mmol) and 5-amino-2-methoxypyridine (0.05ml, 0.44 mmol). Purification by flash chromatography using 25% ethyl acetate/hexane as eluent followed by trituration with ether gave 275(0.134g, 70%). mp198-200 ℃; MS (ES +): m/z 437(M + H);1H NMR(400MHz，CDCl3)δ9.79(s，1H)，8.80(d，1H)，8.30(dd，1H)，7.58(dd，1H)，7.41(dd，1H)，7.39-7.38(m，2H)，7.32(d，1H)，7.15-7.11(m，1H)，7.07(d，1H)，4.76(s，2H)。
example 114
The title compound was prepared according to general method VI from acid 49(0.51mmol) and indoline (0.05ml, 0.44 mmol). Purification by flash chromatography using 25% ethyl acetate/hexane as eluent followed by crystallization from dichloromethane/hexane gave 276(0.069g, 37%). mp158-160 ℃; MS (ES +): m/z 428(M + H);1H NMR(400MHz，CDCl3)δ8.14(d，1H)，7.44-7.39(m，4H)，7.22-7.18(m，2H)，7.07-6.97(m，3H)，4.70(s，2H)，3.98(t，2H)，3.18(t，2H)ppm。
example 115
According to general method VI, starting from acid 49(0.51mmol) and 5-amino-1, 3-dihydro-benzo [ c ]]Thiophene-2, 2-dioxide (0.081g, 0.44mmol) the title compound is prepared. Purification by flash chromatography using 40-60% ethyl acetate/hexanes as the eluent followed by crystallization from ethyl acetate gave 277(0.080g, 37%). mp 197-199 deg.C; MS (ES-): m/z 490 (M-H); 1HNMR(400 MHz，CDCl3)δ9.43(s，1H)，7.92(s，1H)，7.65(dd，1H)，7.57(dd，1H)，7.41-7.38(m，3H)，7.30(d，1H)，7.15-7.10(m，1H)，7.05(d，1H)，4.72(s，2H)，4.39(s，2H)，4.35(s，2H)。
Example 116
The title compound was prepared according to general method VI from acid 49(0.49mmol) and 1, 2, 3, 4-tetrahydroquinoline (0.05ml, 0.41 mmol). Separation by flash chromatography using 15% ethyl acetate/hexane as eluent followed by trituration with hexane afforded 278(0.081g, 45%) in about 80% purity: MS (ES +) M/z 442(M + H), 464(M + Na);1H NMR(400MHz，CDCl3)δ7.38(dd，1H)，7.33-7.31(m，3H)，7.11-7.09(m，3H)，7.00-6.95(m，1H)，6.88(br s，1H)，4.73(s，2H)，3.73(br s，2H)，2.64(br s，2H)，1.93-1.86(m，2H)。
example 117
According to the general principleThe title compound was prepared by method VI from acid 49(0.49mmol) and 1, 2, 3, 4-tetrahydroisoquinoline (0.035ml, 0.41 mmol). Separation by flash chromatography using 15% ethyl acetate/hexane as eluent followed by trituration with hexane afforded 279(0.072g, 40%) in approximately 80% purity: MS (ES +) M/z 442(M + H), 464(M + Na);1H NMR(400MHz，CDCl3)δ7.43-7.39(m，1H)，7.34-7.27(m，3H)，7.19-7.15(m，2H)，7.13-7.08(m，2H)，7.02-6.93(m，2H)，4.70(s，2H)，4.65(s，1H)，4.46(s，1H)，3.73(t，1H)，3.57(t，1H)，2.81-2.75(m，2H)。
example 118
The title compound was prepared according to general method VI from acid 49(0.50mmol) and o-toluidine (0.05ml, 0.43 mmol). Separation by flash chromatography using 10% ethyl acetate/hexanes as eluent gave 280(0.121g, 58%): MS (ES +) M/z 416(M + H), 438(M + Na); MS (ES-) M/z 414(M-H),1H NMR(400MHz，CDCl3)δ8.30(br s，1H)，7.71(d，1H)，7.53(dd，1H)，7.36(d，1H)，7.34-7.31(m，2H)，7.22-7.17(m，2H)，7.09(app t，1H)，7.05-7.01(m，2H)，4.77(s，2H)，2.18(s，3H)ppm。
example 119
Step A:
a mixture of trifluoro-p-cresol (18.9g, 117mmol), potassium carbonate (16.4g, 119mmol) and methyl iodide (9.8ml, 158mmol) in 200ml of acetone was warmed to reflux for 8.5 h and then stirred at room temperature for a further 16 h. Then the The reaction mixture was concentrated in vacuo and the residue was partitioned between 150ml water and 150ml ethyl acetate. The aqueous layer was extracted with another 150ml of ethyl acetate, then the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 282(18.97g, 92%):1H NMR(400MHz，CDCl3)δ7.55(d，2H)，6.96(d，2H)，3.85(s，3H)。
and B:
bromine (4.1ml, 79mmol) was added dropwise over 35 minutes to a solution of 282(13.2g, 75.2mmol) and sodium acetate (6.48g, 79mmol) in 150ml of glacial acetic acid. The reaction mixture was stirred at room temperature for an additional 23 hours, then 10% sodium bisulfite (aq) was added until the orange reaction mixture became colorless. The mixture was then extracted with two portions of 150ml each of dichloromethane and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 26.48g of crude material. Purification by flash chromatography using 2% ethyl acetate/hexanes as eluent gave 283(2.232g, 12%):1H NMR(400MHz，CDCl3)δ7.79(d，1H)，7.53(dd，1H)，6.94(d，1H)，3.93(s，3H)ppm。
and C:
oxalyl chloride (48ml, 96.5mmol) was added dropwise over 1 hour to a solution of 3-cyanobenzoic acid (5.767g, 38.6mmol) in 200ml dichloromethane and 0.10ml DMF and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo to give 284(8.516g), which was used immediately without further purification or characterization.
Step D:
a solution of N, O-dimethylhydroxylamine (4.90g, 50.2mmol) in 20ml triethylamine and 100ml chloroform was cooled to 0 ℃ and 284(8.52g, 38.6mmol) was added dropwise over 10 min. The resulting mixture was stirred at 0 ℃ for 10 minutes and then warmed to room temperature over 1.25 hours. The reaction mixture is diluted with 150ml of ethyl acetate and washed with two 100ml portions of water and a small amount of brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo to afford 285(6.381g, 90%):1H NMR(400MHz，CDCl3)δ8.02(s，1H)，7.95(d，1H)，7.75(d，1H)，7.55(dd，1H)，3.54(s，3H)，3.39(s，3H)。
step E:
n-butyllithium (7.7ml of 1.6M in hexane) was added dropwise to a solution of 283(2.735g, 10.7mmol) in 40ml of diethyl ether at-78 ℃ over 15 minutes. The reaction mixture is stirred at-78 ℃ for a further 15 minutes and then a solution of 285(2.24g, 11.8mmol) in 15ml of diethyl ether is added dropwise over the course of 20 minutes. The resulting mixture was stirred at-78 ℃ for 1 hour, then warmed to room temperature and stirred for an additional 4.67 hours. The reaction mixture was quenched by slowly adding 20ml of water, stirred under air for 45 minutes, and partitioned between 100ml of diethyl ether and 100ml of water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 4.036g of an orange liquid. Purification by flash chromatography using 5-10% ethyl acetate/hexanes as eluent gave 286(1.850g, 57%) as a white solid: 1H NMR(400MHz，CDCl3)δ8.01-7.99(m，2H)，7.83(d，1H)，7.78(d，1H)，7.67(s，1H)，7.59(dd，1H)，7.08(d，1H)，3.76(s，3H)。
Step F:
according to the general purposeMethod IX, the title compound (1.781g, 100%) was prepared from anisole derivative 286(1.805g, 5.91 mmol). This intermediate was used without further purification.1H NMR(400MHz，CDCl3)δ11.99(s，1H)，7.97(s，1H)，7.92(d，1H)，7.87(d，1H)，7.77(dd，1H)，7.73(s，1H)，7.69(t，1H)，7.21(d，1H)。
Step G:
the title compound (2.196g, 100%) was prepared according to general method II from phenol derivative 287(1.78g, 5.91 mmol). This intermediate was used without further purification.1H NMR(400MHz，CDCl3)δ8.13(s，1H)，8.09(d，1H)，7.82(d，1H)，7.74(d，1H)，7.73(s，1H)，7.58(t，1H)，6.90(d，1H)，4.58(s，2H)，4.20(q，2H)，1.24(t，3H)。
Step H:
the title compound (1.758g, 85%) was prepared according to general method III from ester derivative 288(2.2g, 5.91 mmol). This intermediate was used without further purification.1H NMR(400MHz，CDCl3)δ8.18(s，1H)，8.11(d，1H)，7.90(d，1H)，7.78(dd，1H)，7.69(d，1H)，7.64(t，1H)，7.12(d，1H)，4.86(s，2H)。
Step I:
the title compound (0.432g) was prepared according to general method V from acid derivative 289(0.345g, 0.99 mmol). The intermediate was used immediately without further purification or identification.
Step J:
compound 281 was prepared according to general procedure VI from acid chloride 290(0.49mmol) and aniline derivative 466(0.076g, 0.41 mmol). Purification by flash chromatography using 1% methanol in dichloromethane as eluent gave 281(0.113g, 53%). MS (ES +) M/z 516(M + H);1H NMR(400MHz，DMSO-d6)δ9.48(s，1H)，8.20(s，1H)，8.10-8.06(m，2H)，7.94(dd，1H)，7.80(d，1H)，7.70(spp t，1H)，7.65-7.62(m，2H)，7.57(dd，1H)，7.36(d，1H)，7.24(s，2H)，4.90(s，2H)，2.17(s，3H)。
example 120
Compound 291 was prepared according to general procedure VI from acid chloride 290(0.49mmol) and aniline derivative 210(0.060g, 0.41 mmol). Purification by flash chromatography eluting with 1-3% methanol/dichloromethane followed by crystallization from dichloromethane/hexane afforded 291(0.046g, 20%). MS (ES +) M/z 479(M + H); MS (ES-) M/z 477 (M-H); 1H NMR(400MHz，CD3OD)δ8.18-8.16(m，2H)，8.07(d，1H)，7.94-7.89(m，2H)，7.79(d，1H)，7.65(app t，1H)，7.62(s，1H)，7.44-7.41(m，2H)，4.85(s，2H)，2.20(s，3H)。
Example 121
Step A:
a mixture of 4-methyl-3-nitropyridine (1.102g, 7.24mmol) and 10% palladium on carbon (0.096g) in 20ml of methanol was stirred at room temperature under 49psi of hydrogen atmosphere for 2 hours. Then go toThe reaction mixture was filtered through Celite and concentrated in vacuo to afford 293(0.849g, quant.).1H NMR(400MHz，CDCl3)δ8.00(s，1H)，7.92(d，1H)，6.93(d，1H)，3.59(br s，2H)，2.14(s，3H)。
And B:
compound 292 was prepared according to general procedure IV from acid 71(0.188g, 0.5mmol) and aminopyridyl derivative 293(0.065g, 0.6 mmol). Purification by flash chromatography using 0.5-2% methanol in dichloromethane as eluent gave 292(0.071g, 30%) as a white solid. MS (ES +) M/z 467(M + H); MS (ES-) M/z 465 (M-H);1H NMR(400MHz，CDCl3)δ8.84(s，1H)，8.65(s，1H)，8.35(d，1H)，7.88(s，1H)，7.70(d，1H)，7.62-7.58(m，2H)，7.40(d，1H)，7.16(d，1H)，7.10(d，1H)，4.76(s，2H)，2.26(s，3H)ppm。
example 122
Step A:
a mixture of 3-methyl-4-nitroaniline (1.052g, 6.91mmol) and triethylamine (1.16ml, 8.29mmol) in 20ml of dichloromethane was cooled to 0 deg.C and acryloyl chloride (0.62ml, 7.61mmol) was added dropwise over 5 minutes. The resulting mixture was stirred at 0 ℃ for an additional 1.5 h, then diluted with 35ml dichloromethane, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 295(1.941g), which was used without further purification.1H NMR(400MHz，CDCl3)δ8.52(br s，1H)，8.01(d，1H)，7.75(d，1H)，7.65(dd，1H)，6.49-6.40(m，2H)，5.78(dd，1H)，2.60(s，3H)。
And B:
a mixture of compound 295(6.91mmol) and morpholine (0.63ml, 7.26mmol) in 25ml ethanol was heated to reflux for 2.3 h. The reaction mixture was then concentrated in vacuo, suspended in ethyl acetate and filtered. The filtrate was concentrated in vacuo, dissolved in ethyl acetate and crystallized. The crystalline impurities were removed by filtration and the filtrate was concentrated in vacuo to give 296(1.767g, 87%). 1H NMR(400MHz，CDCl3)δ11.24(br s，1H)，8.03(d，1H)，7.54(d，1H)，7.43(dd，1H)，3.84-3.82(m，4H)，2.76-2.73(m，2H)，2.64(br s，4H)，2.62(s，3H)，2.58-2.55(m，2H)ppm。
And C:
a mixture of compound 296(0.202g, 0.69mmol) and 10% palladium on carbon (0.018g) in 10ml of methanol was stirred under a 53psi hydrogen atmosphere at room temperature for 2.17 hours. The reaction mixture was then filtered through Celite and concentrated in vacuo to give 297(0.192g, quantitative).1HNMR(400MHz，CDCl3)δ10.44(br s，1H)，7.38(s，1H)，7.27(dd，1H)，6.76(s，1H)，3.97-3.92(m，4H)，2.91-2.83(m，2H)，2.77-2.72(m，4H)，2.66-2.62(m，2H)，2.25(s，3H)。
Step D:
compound 294 was prepared according to general procedure VI from acid chloride 49(0.5mmol) and aniline derivative 297(0.180g, 0.68 mmol). Purification by flash chromatography using 1-2% methanol in dichloromethane as eluent gave 294(0.203g, 71%). MS (ES-) M/z 570 (M-H);1HNMR(400MHz，CDCl3)δ10.64(s，1H)，8.27(s，1H)，7.57(d，1H)，7.52-7.48(m，2H)，7.35(d，1H)，7.31-7.30(m，2H)，7.22-7.20(d，1H)，7.04-7.00(m，2H)，4.64(s，2H)，3.77(br s，4H)，2.71-2.68(m，2H)，2.57(br s，4H)，2.50-2.47(m，2H)，2.14(s，3H)。
example 123
Step A:
a mixture of 5-fluoro-2-nitrotoluene (0.24ml, 2.0mmol), 1- (3-aminopropyl) -imidazole (0.41ml, 3.4mmol) and sodium bicarbonate (0.302g, 3.6mmol) in 5ml pyridine and 0.5ml water was heated to reflux for 3 hours. The reaction mixture was then partitioned between 50ml water and 50ml ethyl acetate. The organic layer was concentrated to give a yellow solid which was purified by crystallization from ethyl acetate/hexane to give 299(0.255g, 49%):1H NMR(400MHz，CDCl3)δ7.92(d，1H)，7.60(s，1H)，7.16(s，1H)，7.08(t，1H)，6.87(s，1H)，6.47(dd，1H)，6.40(d，1H)，4.04-3.98(m，2H)，3.06-3.01(m，2H)，2.47(s，3H)，1.98-1.91(m，2H)。
and B:
a mixture of compound 299(0.233g, 0.90mmol) and 10% palladium on carbon (0.020g) in 20ml of methanol was stirred at room temperature under a hydrogen atmosphere of 53psi for 1 hour. The reaction mixture was then filtered through Celite and concentrated in vacuo to give 300(0.166g, 80%). 1H NMR(400MHz，CDCl3)δ7.48(s，1H)，7.07(s，1H)，6.92(s，1H)，6.58(d，1H)，6.40(d，1H)，6.36(dd，1H)，4.08(t，2H)，3.49-3.48(m，1H)，3.26(br s，2H)，3.08-3.05(m，2H)，2.13(s，3H)，2.08-2.02(m，2H)。
And C:
compound 298 was prepared according to general procedure IV from acid 49(0.196g, 0.6mmol) and aniline derivative 300(0.155g, 0.67 mmol). Purification by flash chromatography using 2% methanol in dichloromethane as eluent gave 298(0.219g, 68%). MS (ES +) M/z 539(M + H); MS (ES-) M/z 537 (M-H);1H NMR(400 MHz，CDCl3)δ8.08(s，1H)，7.55(dd，1H)，7.49(s，1H)，7.39(d，1H)，7.35-7.31(m，2H)，7.30(d，1H)，7.08(s，1H)，7.06-7.01(m，2H)，6.93(s，1H)，6.43-6.40(m，2H)，4.67(s，2H)，4.09-4.06(m，2H)，3.54(br s，1H)，3.11(t，2H)，2.11-2.06(m，5H)。
example 124
Step A:
a mixture of 5-fluoro-2-nitrotoluene (0.37ml, 3.0mmol), N-diethyl-1, 3-propanediamine (0.80ml, 5.1mmol) and sodium bicarbonate (0.454g, 5.4mmol) in 7.5ml pyridine and 0.75ml water was heated to reflux for 3 hours. The reaction mixture was stirred at room temperature for a further 3 hours and then partitioned between 50ml of water and 50ml of ethyl acetate. The aqueous layer was extracted with another 20ml of ethyl acetate and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.833g of crude material. Purification by flash chromatography using 1-5% methanol/dichloromethane as eluent gave 302(0.742g, 93%):1H NMR(400MHz，CDCl3)δ8.06(d，1H)，6.66(br s，1H)，6.34(dd，1H)，6.27(d，1H)，3.29-3.25(m，2H)，2.61(s，3H)，2.60-2.51(m，6H)，1.81-1.75(m，2H)，1.06(t，6H)。
and B:
a mixture of compound 302(0.730g, 2.75mmol) and 10% palladium on carbon (0.070g) in 20ml of methanol was stirred at room temperature under a hydrogen atmosphere of 55psi for 1.17 h. The reaction mixture was then filtered through Celite and concentrated in vacuo to yield 303(0.581g, 90%). 1H NMR(400MHz，CDCl3)δ6.57(d，1H)，6.42-6.37(m，2H)，3.11-3.08(m，2H)，2.54-2.49(m，6H)，2.14(s，3H)，1.78-1.71(m，2H)，1.03(t，6H)。
And C:
compound 301 was prepared according to general procedure IV from acid 49(0.196g, 0.6mmol) and aniline derivative 303(0.158g, 0.67 mmol). Purification by flash chromatography using 3% methanol/0.1% triethylamine/dichloromethane as eluent followed by crystallization from ethyl acetate/hexane afforded 301(0.113g, 35%). MS (ES +) M/z 544(M + H); MS (ES-) M/z 542 (M-H);1H NMR(400MHz，CDCl3)δ7.96(br s，1H)，7.54(dd，1H)，7.39(d，1H)，7.34-7.31(m，2H)，7.25(d，1H)，7.05-6.99(m，2H)，6.43-6.41(m，2H)，4.65(s，2H)，3.15(t，2H)，2.57-2.52(m，6H)，2.07(s，3H)，1.80-1.73(m，2H)，1.05(t，6H)。
example 125
Step A:
a mixture of 5-fluoro-2-nitrotoluene (0.37ml, 3.0mmol), 1- (3-aminopropyl) pyrrolidine (0.64ml, 5.1mmol) and sodium bicarbonate (0.454g, 5.4mmol) in 7.5ml pyridine and 0.75ml water was heated to reflux for 3 hours. The reaction mixture was stirred at room temperature for a further 3 hours and then partitioned between 50ml of water and 50ml of ethyl acetate. With a further 20ml of ethyl acetateThe aqueous layer was extracted with an ester and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.758g of crude material. Purification by flash chromatography using 0.5-10% methanol in dichloromethane as eluent gave 305(0.595g, 75%):1H NMR(400MHz，CDCl3)δ8.06(d，1H)，6.35(dd，1H)，6.29(d，1H)，6.09(br s，1H)，3.30-3.26(m，2H)，2.65-2.62(m，2H)，2.61(s，3H)，2.58-2.52(m，4H)，1.86-1.78(m，6H)。
and B:
a mixture of compound 305(0.590g, 2.24mmol) and 10% palladium on carbon (0.060g) in 20ml of methanol was stirred under a hydrogen atmosphere at 60psi for 1.33 hours at room temperature. The reaction mixture was then filtered through Celite and concentrated in vacuo to yield 306(0.520g, 99%). 1H NMR(400MHz，CDCl3)δ6.57(d，1H)，6.42(d，1H)，6.39(dd，1H)，3.23(br s，2H)，3.12(t，2H)，2.56(t，2H)，2.53-2.48(m，4H)，2.13(s，3H)，1.84-1.75(m，6H)ppm。
And C:
compound 304 was prepared according to general procedure VI from acid 49(0.196g, 0.6mmol) and aniline derivative 306(0.156g, 0.67 mmol). Purification by flash chromatography using 3% methanol/0.1% triethylamine/dichloromethane as eluent followed by crystallization from ethyl acetate/hexane gave 304(0.064g, 20%). MS (ES +) M/z 542(M + H);1H NMR(400MHz，CDCl3)δ7.98(s，1H)，7.54(dd，1H)，7.39(d，1H)，7.36-7.31(m，2H)，7.26(s，1H)，7.05-7.00(m，2H)，6.44-6.42(m，2H)，4.65(s，2H)，3.18(t，2H)，2.65-2.59(m，6H)，2.07(s，3H)，1.87-1.79(m，6H)。
example 126
Step A:
a mixture of 5-fluoro-2-nitrotoluene (0.24ml, 2.0mmol), 4- (3-aminopropyl) morpholine (0.50ml, 3.4mmol) and sodium bicarbonate (0.302g, 3.6mmol) in 5ml pyridine and 0.5ml water was heated to reflux for 1 hour. The reaction mixture was then partitioned between 50ml water and 50ml ethyl acetate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.493g of crude material. Purification by flash chromatography using 1% methanol/dichloromethane as eluent gave 308(0.279g, 50%):1H NMR(400MHz，CDCl3)δ8.06(d，1H)，6.38(dd，1H)，6.31(s，1H)，5.92(br s，1H)，3.77-375(m，4H)，3.31-3.27(m，2H)，2.6(s，3H)，2.54-2.50(m，6H)，1.85-1.79(m，2H)。
and B:
a mixture of compound 308(0.266g, 0.95mmol) and 10% palladium on carbon (0.020g) in 5ml of methanol was stirred at room temperature under a hydrogen atmosphere of 60psi for 2 hours. The reaction mixture was then filtered through Celite and concentrated in vacuo to give 309(0.229g, 97%).1H NMR(400MHz，CDCl3)δ6.58(d，1H)，6.43(d，1H)，6.39(dd，1H)，3.74-3.72(m，4H)，3.14-3.11(m，2H)，2.48-2.45(m，6H)，2.14(s，3H)，1.81-1.75(m，2H)。
And C:
compound 307 was prepared according to general procedure IV from acid 49(0.092g, 0.28mmol) and aniline derivative 309(0.070g, 0.28 mmol). Purification by flash chromatography using 3% methanol/0.1% triethylamine/dichloromethane as eluent gave 307(0.101g, 65%). MS (ES +) M/z558(M + H); 1H NMR(400MHz，CDCl3)δ8.00(s，1H)，7.54(dd，1H)，7.40-6.72(m，6H)，6.62(d，1H)，6.45-6.42(m，2H)，4.66(s，2H)，3.75-3.61(m，4H)，3.17(t，2H)，2.49-2.25(m，6H)，2.08(s，3H)，1.82-1.51(m，2H)。
Example 127
Step A:
a mixture of sulfonyl chloride 464(1.10g, 4.4mmol), ethylamine (3.3ml of a 2.0MTHF solution, 6.6mmol) and pyridine (0.39ml, 4.8mmol) in 50ml of dichloromethane was stirred at room temperature for 11 days. The reaction mixture was then diluted with 50ml of water and filtered to give 0.605g of crude material. Crystallization from methanol yielded 311(0.425g, 38%):1H NMR(400MHz，CDCl3)δ9.40(s，1H)，7.73(d，1H)，7.58(d，1H)，7.53(dd，1H)，7.39(t，1H)，2.75-2.68(m，2H)，2.26(s，3H)，2.07(s，3H)，0.93(t，3H)。
and B:
a mixture of compound 311(0.308g, 1.2mmol), 1.5M HCl (2.5ml) and ethanol (12ml) was heated to 80 ℃ for 18 h and then stirred at room temperature for a further 1 h. The reaction mixture was poured into 50ml of saturated sodium bicarbonate (aq) and extracted with two portions of 30ml each of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 312(0.337g), which was used without further purification.1H NMR(400MHz，CDCl3)δ7.54(m，2H)，6.68(d，1H)，4.29(t，1H)，4.07(br s，2H)，3.00-2.93(m，2H)，2.18(s，3H)，1.10(t，3H)。
And C:
compound 310 was prepared according to general procedure IV from acid 71(0.188g, 0.5mmol) and aniline derivative 312(0.169g, 0.6 mmol). Purification by flash chromatography using 15-25% ethyl acetate/hexanes as eluent gave 310(0.016g, 6%). MS (ES +) M/z 573(M + H); MS (ES-) M/z 571 (M-H);1H NMR(400MHz，CDCl3)δ8.67(s，1H)，8.08(d，1H)，7.88(s，1H)，7.69(m，3H)，7.59(dd，2H)，7.38(d，1H)，7.09(d，1H)，4.74(s，2H)，3.03-2.95(m，2H)，2.31(s，3H)，1.11(t，3H)。
example 128
Step A:
a mixture of sulfonyl chloride 464(1.10g, 4.4mmol), cyclopropylamine (0.46ml, 6.6mmol) and pyridine (0.39ml, 4.8mmol) in 50ml dichloromethane was stirred at room temperature for 6 days. The reaction mixture was then filtered to give 0.800g of crude material. Crystallization from methanol yielded 314(0.329g, 28%): 1H NMR(400MHz，CDCl3)δ9.41(s，1H)，7.78(s，1H)，7.77-7.60(m，2H)，7.56(dd，1H)，2.27(s，3H)，2.08(s，3H)，2.06-2.03(m，1H)，0.45-0.42(m，2H)，0.36-0.34(m，2H)。
And B:
a mixture of compound 314(0.324g, 1.2mmol), 1.5M HCl (2.5ml) and ethanol (12ml) was heated to 80 ℃ for 18 h and then stirred at room temperature for a further 1 h. Mixing the reactionThe mixture was poured into 25ml of saturated sodium bicarbonate (aq) and extracted with two portions of 25ml each of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 315(0.256g, 94%), which was used without further purification.1H NMR(400MHz，CDCl3)δ7.57-7.55(m，2H)，6.69(d，1H)，4.81(br s，2H)，2.22-2.19(m，4H)，0.59-0.55(m，4H)。
And C:
compound 313 was prepared according to general procedure IV from acid 71(0.188g, 0.5mmol) and aniline derivative 315(0.124g, 0.55 mmol). Purification by flash chromatography using 15-25% ethyl acetate/hexanes as eluent gave 313(0.026g, 9%). MS (ES +) M/z 585(M + H); MS (ES-) M/z 583 (M-H);1H NMR(400MHz，CDCl3)δ8.68(s，1H)，8.12(d，1H)，7.88(s，1H)，7.75-7.71(m，3H)，7.59(dd，2H)，7.47-7.43(m，1H)，7.38(d，1H)，7.08(d，1H)，4.75(s，2H)，2.32(s，3H)，2.25-2.19(m，1H)，0.63-0.57(m，4H)。
example 129
Step A:
a mixture of sulfonyl chloride 464(1.10g, 4.4mmol), pyrrolidine (0.55ml, 6.6mmol) and pyridine (0.39ml, 4.8mmol) in 50ml dichloromethane was stirred at room temperature for 6 days. The reaction mixture was then filtered, the filter cake was washed with dichloromethane and methanol, and dried on a vacuum pump to give 317(0.696g, 56%):1H NMR(400MHz，CDCl3)δ9.39(s，1H)，7.82(d，1H)，7.60(d，1H)，7.55(dd，1H)，3.10-3.07(m，4H)，2.28(s，3H)，2.09(s，3H)，1.64-1.58(m，4H)。
and B:
a mixture of compound 317(0.690g, 2.44mmol), 1.5M HCl (5.0ml) and ethanol (25ml) was heated to 80 ℃ for 18 h and then stirred at room temperature for 7 h. The reaction mixture was filtered to give 318(0.369g, 63%): 1H NMR(400MHz，CDCl3)δ7.29-7.26(m，2H)，6.64(d，1H)，5.73(br s，2H)，3.01-2.98(m，4H)，2.05(s，3H)，1.60-1.56(m，4H)。
And C:
compound 316 was prepared according to general procedure IV from acid 71(0.188g, 0.5mmol) and aniline derivative 318(0.132g, 0.55 mmol). Purification by flash chromatography using 15-25% ethyl acetate/hexanes as eluent gave 316(0.013g, 4%). MS (ES +) M/z 599(M + H); MS (ES-) M/z 597 (M-H);1H NMR(400MHz，DMSO-d6)δ9.36(s，1H)，7.97-7.01(m，9H)，4.78(s，2H)，3.08-3.04(m，4H)，2.15(s，3H)，1.59-1.56(m，4H)。
using carboxylic acid 105(5g, 17mmol), dichloromethane (90ml) and thionyl chloride (13.2ml, 18mmol) as described in general procedure XV gave 320(5.31g) as an orange oil. The crude product was used without further purification.
Following general procedure II, using 4' -chloro-5-fluoro-2-hydroxybenzophenone (Lancaster, 5g, 20mmol), potassium carbonate (13.8g, 100mmol), ethyl bromoacetate (2.5ml, 23mmol) and acetone (200ml), 321(6.72g, crude material) was obtained as an orange/off-white solid.1H NMR(DMSO-d6，300MHz)δ1.2(t，3H)，4.1(m，2H)，4.75(s，2H)，7.15(dd，1H)，7.3(dd，1H)，7.35-7.4(m，1H)，7.6(d，2H)，7.8(d，2H)。
Using ester 321(6.72g, 20mmol), ethanol (80ml), water (20ml) and lithium hydroxide monohydrate (1g, 24mmol) according to general procedure III, carboxylic acid 322 was obtained as an off-white solid (6.56g, crude material).1H NMR(DMSO-d6，300MHz)δ4.7(s，2H)，7.1(d，1H)，7.3(d，1H)，7.4(m，1H)，7.6(d，2H)，7.8(d，2H)，13(bs，1H)；MS(ES-)m/z 307(M-H)-。
Acid 322(3g, 10mmol) and thionyl chloride (51ml of a 2N solution in dichloromethane, 102mmol) were placed in a round bottom flask. After 1.5 hours of reflux, the mixture was concentrated in vacuo to give 323 as a dark purple oil, which was used without identification or purification.
Example 130
According to general procedure X, 3-methoxy-5- (trifluoromethyl) aniline (Aldrich, 0.309g, 1.62mmol), triethylamine (0.23ml, 1.65mmol), acetonitrile (5ml) and acid chloride 320(0.5g, 1.62mmol) in acetonitrile (7ml) were used. The product was purified by flash chromatography eluting with a gradient of 9: 1 to 4: 1 hexane: ethyl acetate to give 324 as an off-white solid (0.17g, 23%).1HNMR(DMSO-d6，300MHz)δ3.8(s，3H)，4.7(s，2H)，7(s，1H)，7.2(d，1H)，7.4(s，1H)，7.5(m，4H)，7.6(m，2H)，7.8(d，2H)，10(s，1H)；MS(ES-)m/z 462(M-H)-。
Example 131
As in general procedure X, 4- (N-methylpiperazino) aniline (Biomet research ltd., 0.237g, 1.24mmol), triethylamine (0.26ml, 1.87mmol), acetonitrile (5ml) and acid chloride 320(0.38g, 1.24mmol) in acetonitrile (2ml) were used. The product was purified by flash chromatography eluting with a gradient of 49: 1 to 24: 1 dichloromethane to methanol to give 325(0.16g, 27%) as a yellow solid.1H NMR(DMSO-d6，300MHz)δ2.2(s，3H)，2.4(t，4H)，3.1(t，4H)，4.7(s，2H)，6.9(d，2H)，7.2(d，2H)，7.3(d，2H)，7.5(s，1H)，7.55(t，2H)，7.6-7.7(m，2H)，7.8(d，2H)，9.5(s，1H)；MS(ES-)m/z 462(M-H)-。
Example 132
According to general procedure X, 4-aminophenylacetonitrile (Aldrich, 0.214g, 1.62mmol), triethylamine (0.23ml, 1.65mmol), acetonitrile (5ml) and acid chloride 320(0.5g, 1.62mmol) in acetonitrile (7ml) were used. The product was purified by flash chromatography eluting with a 7: 3 gradient of hexane to ethyl acetate containing 0.01% triethylamine to afford 326 as an orange solid (0.26g, 40%).1H NMR(DMSO-d6，300MHz)δ4(s，2H)，4.7(s，2H)，7.2(d，1H)，7.3(d，2H)，7.45(s，1H)，7.5-7.6(m，4H)，7.65(m，2H)，7.8(d，2H)，9.9(s，1H)；MS(ES-)m/z 403(M-H)-。
Example 133
According to general procedure X, procaine (ICN, 0.382g, 1.62mmol), triethylamine (0.23ml, 1.65mmol), acetonitrile (5ml) and acid chloride 320(0.38g, 1.24mmol) in acetonitrile (5ml) were used. The product was purified by flash chromatography eluting with 24: 1 dichloromethane: methanol to give 327 as an off-white solid (0.037g, 4.5%).1H NMR(DMSO-d6，300MHz)δ1(t，6H)，2.8(bs，2H)，4.3(bs，2H)，4.8(bs，2H)，7.2(d，1H)，7.5-7.7(m，8H)，7.8(d，2H)，7.9(d，2H)，10.2(s，1H)；MS(AP+)m/z 509(M+H)+。
Example 134
According to general method X, 4-aminobenzyl alcohol (Fluka, 0.2g, 1.62mmol), triethylamine (0.23ml, 1.65mmol), acetonitrile (5ml) and acid chloride 320(0.5g, 1.62mmol) in acetonitrile (5ml) were used. The product was purified by flash chromatography eluting with 4: 1 hexane: ethyl acetate to give 328 as a dark yellow solid (0.06g, 10%).1H NMR(DMSO-d6，300MHz)δ4.45(d，2H)，4.7(s，2H)，5.1(t，1H)，7.2(t，3H)，7.45(t，3H)，7.55(t，2H)，7.6(t，2H)，7.8(d，2H)，9.7(s，1H)；MS(ES-)m/z 394(M-H)-。
Example 135
According to general procedure X, 2-morpholinoaniline (Lancaster, 0.288g, 1.62mmol), triethylamine (0.23ml, 1.65mmol), acetonitrile (5ml) and acid chloride 320(0.5g, 1.62mmol) in acetonitrile (5ml) were used. The product was purified by flash chromatography eluting with a gradient of 9: 1 to 4: 1 hexane: ethyl acetate to give 329 as an off-white solid (0.082g, 11%).1HNMR(DMSO-d6，400MHz)δ2.65(s，4H)，3.5(s，4H)，4.7(s，2H)，7.1(t，2H)，7.15(s，1H)，7.3(d，1H)，7.4(t，2H)，7.5(m，2H)，7.6(d，1H)，7.7(d，2H)，7.9(s，1H)，8.7(s，1H)；MS(ES+)m/z 451(M+H)+。
Example 136
According to general procedure X, sulfonamide (Aldrich, 0.263g, 1.53mmol), triethylamine (0.23ml, 1.65mmol), acetonitrile (5ml) and acid chloride 323(0.5g, 1.53mmol) in acetonitrile (5ml) were used. The reaction mixture was concentrated under reduced pressure, triturated with dichloromethane, ethyl acetate, hexane and methanol and filtered. The resulting solid was washed with diethyl ether and ethyl acetate to give an off-white solid, which was triturated with water and filtered to give 330 as an off-white solid (0.078g, 11%). 1H NMR(DMSO-d6，400MHz)δ4.7(s，2H)，7.15(dd，1H)，7.2(s，2H)，7.25(d，1H)，7.35(t，1H)，7.5(d，2H)，7.65(d，2H)，9.87(bs，2H)，10.25(s，1H)；MS(ES-)m/z 461(M-H)-。
Example 137
According to general procedure X, sulfamethoxazole (Aldrich, 0.424g, 1.67mmol), triethylamine (0.25ml, 1.79mmol), acetonitrile (5ml) and acid chloride 320(0.52g, 1.68mmol) in acetonitrile (5ml) were used. The product was purified by flash chromatography using 3: 2 hexane: ethyl acetate as eluent to give 331 as an off-white solid (0.021g, 2.4%).1H MR(DMSO-d6，400MHz)δ2.3(s，3H)，4.7(s，2H)，6.1(s，1H)，7.15(d，1H)，7.4(s，1H)，7.45(d，2H)，7.55(m，2H)，7.7(d，2H)，7.8(d，4H)，10.3(s，1H)，11.3(s，1H)；MS(ES-)m/z 524(M-H)-。
Example 138
Step A:
as in general procedure XI, using 4-nitro-bromobenzene (Aldrich, 10.31g, 51mmol), sodium bicarbonate (7.5g, 89mmol) and water (3ml) in pyridine (85ml) gave 333(6.5g, 57%) as a yellow crystalline solid.1H NMR(DMSO-d6，400MHz)δ2.6(t，4H)，3.8(t，4H)，7(d，2H)，8(d，2H)；MS(ES+)m/z 225(M+H)+。
And B:
as in general procedure XII, using compound 333(1.04g, 4.63mmol), palladium on carbon (0.2g, 10% w/w), ethanol (20ml) and THF (20ml), 334(0.95g, crude material) was obtained as a brown solid.
And C:
compound 334(0.95g, 4.9mmol), triethylamine (1ml, 7.2mmol), acetonitrile and acid chloride 320(1.51g, 4.9mmol) in acetonitrile (20ml total reaction volume) were used according to general procedure X (but without heating). The reaction mixture was filtered, washed with acetonitrile followed by ether to give 332 as an off-white solid (1.154g, 51%).1H NMR(DMSO-d6，400MHz)δ2.6(m，4H)，3.4(m，4H)，4.6(s，2H)，6.9(d，2H)，7.15(d，1H)，7.3(d，2H)，7.4(s，1H)，7.5(t，2H)，7.55-65(m，2H)，7.8(d，2H)，9.45(s，1H)；MS(ES-)m/z 465(M-H)-。
Example 139
Step A:
4-Nitrobenzenesulfonyl chloride (Aldrich, 44.3g, 200mmol) was added portionwise to a solution of methylamine in ethanol (250ml, 208mmol) and stirred at 0 ℃ under nitrogen. After removing the ice bath, the reaction was stirred for 45 minutes. Water (250ml) was added and the resulting product was filtered to give 336(37.6g, 87%) as a crystalline solid. The crude material was used without purification.
And B:
palladium on carbon (2g, 10% w/w) was added to compound 336(17.3g, 80mmol), methanol (80ml), THF (80ml) and hydrochloric acid (concentrated, 7ml, 84mmol) as general procedure XII to give 337(14.3g, 80%) as a white solid. The crude material was used without purification.
And C:
according to general procedure X, compound 337(0.32g, 1.44mmol), triethylamine (0.5ml, 3.6mmol), acetonitrile (5ml) and acid chloride 320(0.444g, 1.44mmol) in acetonitrile (5ml) were used. After 6 days, another equivalent of acid chloride 320(0.444g, 1.44mmol) was added and the solution was stirred. The reaction mixture was filtered, and the resulting solid was washed with acetonitrile and water and suspended in ethyl acetate. The suspension was filtered and the filtrate was concentrated in vacuo to afford 335 as an off-white solid (0.152g, 23%).1H NMR(DMSO-d6，400MHz)δ2.3(d，3H)，4.7(s，2H)，7.15(d，1H)，7.3(m，1H)，7.45(s，1H)，7.5(t，2H)，7.54-7.62(m，2H)，7.7(s，4H)，7.8(d，2H)，10.2(s，1H)；MS(ES-)m/z 457(M-H)-。
Example 140
Step A:
methanesulfonyl chloride (5g, 43.9mmol) was added dropwise to a solution of 4-nitroaniline (Aldrich, 5.95g, 43.1mmol) in anhydrous pyridine (100ml) and stirred at 15 ℃ under nitrogen. The resulting solution was stored at 0 ℃ for 2 days, and the solvent was removed in vacuo. The product was triturated with ice water, filtered and washed with ice water to give 339(8.87g, 95%) as an orange/yellow solid. The crude product was used without purification.
And B:
palladium on carbon (0.14g, 10% w/w) was added to a solution of compound 339(1.0g, 4.63mmol), ethanol (15ml) and THF (20ml) and the resulting suspension was used under a hydrogen atmosphere at 50psi as in general procedure XII to give 340(0.85g) as an orange oil. The crude material was used without purification.
And C:
according to general procedure X, compound 340(0.85g, 4.6mmol), triethylamine (0.87ml, 6.2mmol), acetonitrile (8ml) and acid chloride 320(1.29g, 4.2mmol) in acetonitrile (8ml) were used. After 2 days, water was added and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography, eluting with 35% ethyl acetate in hexanes, to afford 338 as an off-white/light yellow solid (0.480g, 23%).1H NMR(DMSO-d6，300MHz)δ2.95(s，3H)，4.7(s，2H)，7.15(d，2H)，7.2(d，1H)，7.45(d，3H)，7.7(m，7H)，7.85(d，2H)，9.6(s，1H)，9.8(s，1H)；MS(ES-)m/z 457(M-H)-。
Example 141
According to general method X, 4- (N-pyrrolidine) aniline (Apin, 0.262g, 1.61mmol), triethylamine (0.23ml, 1.65mmol), acetonitrile (5ml) and acid chloride 320(0.5g, 1.62mmol) in acetonitrile (5ml) were used. The product was purified by flash chromatography eluting with a gradient of 9: 1 to 4: 1 hexane: ethyl acetate to give 341 as an off-white solid (0.112g, 16%).1HNMR(DMSO-d6，300MHz)δ2(t，4H)，3.2(t，4H)，4.66(s，2H)，6.5(d，2H)，7.2(s，1H)，7.3(t，2H)，7.45(s，1H)，7.5(t，2H)，7.6(m，2H)，7.8(d，2H)，9.3(s，1H)；MS(ES-)m/z 433(M-H)-。
Example 142
As in general procedure X, 1- (4-aminophenyl) ethanol (Apin, 0.25g, 1.82mmol), triethylamine (0.25ml, 1.79mmol), acetonitrile (7ml) and acid chloride 320(0.51g, 1.65mmol) in acetonitrile (6ml) were used. The product was purified by flash chromatography, eluting with 45% ethyl acetate in hexane to give 342 as a colorless solid (0.428g, 63%).1H NMR(DMSO-d6，400MHz)δ1.25(d，3H)，4.6(m，1H)，4.7(s，2H)，5.1(s，1H)，7.2(d，1H)，7.25(d，2H)，7.4(d，3H)，7.5(t，2H)，7.6(m，2H)，7.8(d，2H)，9.7(s，1H)；MS(ES-)m/z 408(M-H)-。
The racemic mixture was separated using the following conditions to give 2 enantiomers:
QJ chiral column, 22% IPA, 2ml/min., 26 ℃, 3000psi on SFC. Elution of enantiomer 1 at 9.214min gave 342-A as an off-white solid (0.092g, 14%). Elution of enantiomer 2 at 11.118min gave 342-B as an off-white solid (0.059g, 9%). The enantiomeric purity was found to be > 99% and absolute stereochemistry was not determined.
Example 143
3-Chloroperbenzoic acid (ca. 60%, 0.54g, 1.9mmol) was added portionwise to a solution of compound 332(0.4g, 0.86mmol) in dichloromethane (30ml) and stirred at room temperature. After 4 days, the suspension was filtered and the solid was washed with dichloromethane. The filtrate was washed with saturated sodium metabisulfite, 10% sodium hydroxide and water. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography, eluting with 99: 1 dichloromethane: methanol, and further purified by TLC preparative plate eluting with 99: 1 dichloromethane: methanol to give 343 as an off-white foam (0.062g, 14%). 1H NMR(CDCl3，300MHz)δ3.1(t，4H)，3.8(t，4H)，4.7(s，2H)，6.9(d，2H)，7.05(d，1H)，7.4(s，1H)，7.5-7.6(m，5H)，7.65(t，1H)，7.9(d，2H)，9.05(s，1H)；MS(AP-)m/z 497(M-H)-。
Example 144
Step A:
3-Chloroperbenzoic acid (ca. 60%, 20.3g, 70.6mmol) in dichloromethane was added dropwise to a cooled solution of compound 333(11.5g, 51.1mmol) in dichloromethane (250ml total reaction volume) and stirred at-78 ℃. After 2 hours, the reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was washed with saturated sodium metabisulfite, 2N sodium hydroxide and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give a mixture of 345 and 346 as a yellow solid (8.47g, crude material). The crude material can be used without purification.
And B:
as in general procedure XII, a mixture of 345 and 346 (8.47g, 35.3mmol), palladium on carbon (1.4g, 10% w/w), ethanol (100ml) and THF (50ml) was used under a 60psi hydrogen atmosphere. The product was purified by flash chromatography eluting with a gradient of 4: 1 to 9: 2 hexane: ethyl acetate to give 347(3.94g, 53.2%) as a yellow solid.1H NMR(DMSO-d6，400MHz)δ2.7(dd，2H)，2.9(m，2H)，3.16(dd，2H)，3.7(t，2H)，4.6(bs，2H)，6.46(dd，2H)，6.71(dd，2H)；MS(ES+)m/z 211(M+H)+。
And C:
according to general method XIII, carboxylic acid 105(4.15g, 14.3mmol), HCA (1.08ml, 7.1mmol), THF (60ml), triphenylphosphine (1.82g, 6.95mmol) in THF (15ml), sulfoxide 347(3g, 14.3mmol) in THF (125ml) and pyridine (15ml, 185mmol) were used. The product was purified by flash chromatography eluting with a gradient of 99: 1 to 9: 1 dichloromethane to methanol, further purified by trituration of the resulting solid with methanol and ethanol, filtration and washing of the solid with water and methanol to give 344 as a brown solid (2.7g, 39%). 1H NMR(DMSO-d6，300MHz)δ2.7(d，2H)，2.9(t，2H)，3.5(d，2H)，3.7(t，2H)，4.7(s，2H)，7(d，2H)，7.2(d，1H)，7.4(d，2H)，7.47(s，1H)，7.55(d，2H)，7.65(t，2H)，7.8(d，2H)，9.6(s，1H)；MS(AP-)m/z 481(M-H)-。
Example 145
Following general procedure X, glycerol-p-aminobenzoate (ICN, 0.342g, 1.62mmol), triethylamine (0.25ml, 1.79mmol), acetonitrile (7ml) and acid chloride 320(0.5g, 1.62mmol) in acetonitrile (8ml) were used. The product was purified by flash chromatography, eluting with 9: 1 hexane: ethyl acetate, then further purified by flash chromatography, eluting with 99: 1 dichloromethane: methanol, to give 348 as an off-white solid (0.02g, 3%).1H NMR(DMSO-d6，300MHz)δ1.3(t，3H)，4.3(q，2H)，4.8(s，2H)，7.5(d，1H)，7.6(d，2H)，7.7(d，4H)，7.8(d，2H)，7.9(d，2H)，10.2(s，1H)；MS(ES-)m/z 436(M-H)-。
Example 146
Step A:
as in general procedure XI, using 4-chloro-2-nitrotoluene (SALOR, 2g, 11.7mmol), sodium bicarbonate (2g, 23.8mmol), water (5ml) and morpholine (Aldrich, 2.03g, 23.3mmol) in pyridine (25ml) gave 350 as a yellow solid (0.804g, 31%).1HNMR(DMSO-d6300MHz) delta 2.5(s, 3H), 3.4(t, 4H), 3.7(t, 4H), 6.9(d, 2H), 8(d, 1H). The crude material can be used without purification.
And B:
as in general procedure XII, compound 350(0.72g, 4.63mmol), palladium on carbon (0.1g, 10% w/w), ethanol (20ml) and THF (20ml) were used under a 50psi hydrogen atmosphere to give 351(0.623g, crude material) as a brown solid.
And C:
as in general procedure X, compound 351(0.623g, 3.2mmol), triethylamine (1.3ml, 9.3mmol) in acetonitrile (8ml) and acid chloride 320(1.02g, 3.3mmol) in acetonitrile (7ml) were used. The product was purified by flash chromatography eluting with 99.5: 0.5 dichloromethane: methanol to give 349(0.072g, 5%) as an orange foam. 1H NMR(DMSO-d6，400MHz)δ1.9(s，3H)，3(t，4H)，3.7(t，4H)，4.65(s，2H)，6.7(d，1H)，6.73(s，1H)，7.1(d，1H)，7.2(d，1H)，7.4(s，1H)，7.5(t，2H)，7.6(t，2H)，7.75(d，2H)，8.8(s，1H)；MS(ES-)m/z 463(M-H)-。
Example 147
Step A:
as in general procedure XI, using 5-bromo-2-nitrobenzotrifluoride (Lancaster, 2g, 7.4mmol), sodium bicarbonate (1.25g, 14.8mmol), water (5 drops) and morpholine (Aldrich, 1.29g, 14.8mmol) in pyridine (20ml) gave 353(1.62g, 79%) as a yellow solid.1HNMR(DMSO-d6400MHz) delta 3.5(t, 4H), 3.8(t, 4H), 7.25(d, 1H), 7.3(s, 1H), 8.1(d, 1H). The crude material can be used without purification.
And B:
as in general procedure XII, using compound 353(1.62g, 5.9mmol), palladium on carbon (0.2g, 10% w/w), ethanol (12ml) and THF (12ml) under a 75psi hydrogen atmosphere, gave 354(1.41g, crude material) as a brown solid.
And C:
as in general procedure X, compound 354(1.41g, 5.73mmol), triethylamine (0.8ml, 5.74mmol), acetonitrile (15ml) and acid chloride 320(1.8g, 5.82mmol) in acetonitrile (15ml) were used. The product was purified by flash chromatography, eluting with 35% ethyl acetate in hexane, and further purified by flash chromatography, eluting with 1: 1 ethyl acetate: hexane, to give 352(0.426g, 14%) as an off-white solid.1H NMR(DMSO-d6，400MHz)δ3.2(t，4H)，3.75(t，4H)，4.7(s，2H)，7.15(s，1H)，7.2(m，3H)，7.45-7.55(m，3H)，7.6(t，2H)，7.8(d，2H)，9(s，1H)；MS(ES-) m/z 517(M-H)-。
Example 148
Step A:
as in general procedure XI, using 5-bromo-2-nitrobenzotrifluoride (Lancaster, 2g, 7.4mmol), sodium bicarbonate (1.25g, 14.9mmol), water (5 drops) and thiomorpholine (Aldrich, 1.52g, 14.7mmol) in pyridine (20ml) gives 356(1.63g, crude material) as a yellow solid. 1H NMR(DMSO-d6，400MHz)δ2.65(t，4H)，3.88(t，4H)，7.2(d，1H)，7.22(s，1H)，8(d，1H)。
And B:
as in general procedure XII, using compound 356(1.63g, 5.6mmol), palladium on carbon (0.3g, 10% w/w), ethanol (12ml) and THF (12ml) under a 75psi hydrogen atmosphere, yielded 357 as a brown oil (1.29g, 88%). The crude material can be used without purification.
And C:
as in general procedure X, compound 357(1.29g, 4.92mmol), triethylamine (0.7ml, 5.02mmol), acetonitrile (15ml) and acid chloride 320(1.52g, 4.92mmol) in acetonitrile (15ml) were used. The product was purified by flash chromatography, eluting with 35% ethyl acetate in hexanes, to give 355 as an orange oil (0.264g, 10%).1H NMR(DMSO-d6，400MHz)δ2.62(m，4H)，3.57(m，4H)，4.68(s，2H)，7.07(d，1H)，7.16(q，3H)，7.41(d，1H)，7.45(m，3H)，7.58(m，2H)，7.75(d，2H)，9(s，1H)；MS(ES-)m/z533(M-H)-。
Example 149
Step A:
morpholine (Aldrich, 0.74ml, 8.5mmol) was added dropwise to a solution of 4-nitro-benzyl bromide (Aldrich, 2g, 9.26mmol) in acetone (20ml) and potassium carbonate (2.4g, 17.4 mmol). The resulting suspension was stirred at room temperature under nitrogen for 6 days. The mixture was filtered and the filtrate was concentrated in vacuo to afford 359(1.89g, crude material) as a pale yellow solid.
And B:
as in general procedure XII, using compound 359(1.89g, 4.63mmol), palladium on carbon (0.325g, 10% w/w), ethanol (25ml) and THF (25ml) under a 50psi hydrogen atmosphere, gave 360(1.6g, crude material) as a brown solid.
And C:
as in general procedure X, compound 360(1.6g, 8.3mmol), triethylamine (0.95ml, 6.8mmol), acetonitrile (7ml) and acid chloride 320(1.53g, 4.95mmol) in acetonitrile (7ml) were used. The product was purified by flash chromatography eluting with a gradient of 9: 1 to 4: 1 hexane: ethyl acetate to give 358(0.264g, 12%) as an off-white solid.1H NMR(DMSO-d6，300MHz)δ2.35(d，4H)，3.41(s，3H)，3.57(t，4H)，4.73(s，2H)，7.23(m，3H)，7.47-7.67(m，7H)，7.83(d，2H)，9.78(s，1H)；MS(ES-)m/z 463(M-H)-。
Example 150 and example 151
Step A:
4-chloro-2-nitrotoluene (SALOR, 1.46g, 8.5mmol) in pyridine (5ml) was added dropwise to a solution of pyridine (22ml), sodium bicarbonate (0.73g, 8.7mmol), piperazine (Aldrich, 1.5g, 17.4mmol) and water (3ml), and the resulting mixture was refluxed under nitrogen for 2 days. Additional piperazine (1.5g, 17.4mmol) and sodium bicarbonate (0.73g, 8.7mmol) were added and the mixture was refluxed overnight. Acetone (200ml) was added to the mixture, which was subjected to hot filtration. Water was added to the filtrate and the mixture was allowed to cool to room temperature. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The concentrate was dissolved in hot methanol and diethyl ether and cooled to room temperature. Filtering the resulting mixture and vacuumThe filtrate was concentrated to give 363(4.22g) as a yellow solid; MS (ES)+)m/z 222(M+H)+. The crude product can be used without purification.
And B:
as in general procedure XII, using compound 363(1.88g, 8.5mmol), palladium on carbon (0.563g, 10% w/w), ethanol (35ml) and THF (35ml) gives 364(1.7g) as a yellow oil. The crude product can be used without purification.
And C:
as in general procedure X, compound 364(1.7g, 8.9mmol), triethylamine (1.4ml, 10mmol), acetonitrile (12ml) and acid chloride 320(2.36g, 7.6mmol) in acetonitrile (12ml) were used. Water was added to the reaction mixture and the resulting suspension was filtered. The filtrate was partitioned between 2N sodium hydroxide and ethyl acetate. The aqueous layer was acidified to pH 1 with 1N sodium hydrogen sulfate and extracted with ethyl acetate. The product was purified by flash chromatography eluting with a gradient of 3: 2 hexane: ethyl acetate, ethyl acetate and methanol to give 362 as a yellow solid (0.250 g). MS (ES)+)m/z 494(M+H)+And 361(0.005g, 0.1%) as an orange solid.1H NMR(DMSO-d6，400MHz)δ1.96(s，3H)，2.79(m，4H)，2.97(m，4H)，4.66(s，2H)，6.66(m，2H)，7.05(d，1H)，7.2(d，1H)，7.42(d，1H)，7.46(t，2H)，7.6(t，2H)，7.75(d，2H)，8.79(s，1H)；MS(ES+)m/z 464(M+H)+。
Example 152
Step A:
5-fluoro-2-nitrotoluene (Aldrich, 2g, 12.9mmol) in pyridine (5ml) was added dropwise to a solution of pyridine (15ml), sodium bicarbonate (1.62g, 19.3mmol), 1-tert-butoxycarbonylpiperazine (Aldrich, 3.6g, 19.3mmol) and water (1.2ml) and the resulting mixture was refluxed overnight. Acetone was added to the reaction, and the resulting mixture was subjected to hot filtration. Water was added and the mixture was allowed to cool to room temperature. The resulting solid was filtered, washed with water and diethyl ether to give 366(4.02g) as an orange solid. 1H NMR(DMSO-d6400MHz) delta 1.39(s, 9H), 2.47(s, 3H), 3.41(s, 8H), 6.84(m, 2H), 7.97(d, 1H). The crude product can be used without purification.
And B:
as in general procedure XII, compound 366(4.02g, 12.5mmol), palladium on carbon (1.2g, 10% w/w), ethanol (90ml) and THF (10ml) were used under an 80psi hydrogen atmosphere. The product was filtered through a pad of celite, eluting with 9: 1 dichloromethane: methanol, and concentrated in vacuo to give 367 as a pink solid (2.926g, crude material).
And C:
acid chloride 320 in dichloromethane was added dropwise to a solution of compound 367(0.362g, 1.24mmol) in pyridine (20ml) and stirred for 2 days. The reaction was concentrated in vacuo, ethanol and ice were added, the resulting solid was filtered and washed with diethyl ether to give 368(0.118g, 20.2%) as a yellow solid.1H NMR(DMSO-d6，400MHz)δ1.38(d，9H)，1.95(s，3H)，3(d，4H)，3.4(s，4H)，4.67(s，2H)，6.7(m，2H)，7.1(d，1H)，7.42(d，1H)，7.48(m，2H)，7.6(m，2H)，7.75(d，2H)，8.8(s，1H)。
Step D:
TFA (15ml, 195mmol) was added to a solution of compound 368(0.118g, 0.21mmol) in acetonitrile and stirred overnight. After addition of carbon tetrachloride to azeotropically remove TFA, the reaction mixture was concentrated in vacuo. This step is repeated several times. The mixture was concentrated in vacuo to give 365(0.085g, 88%) as a yellow solid.1H NMR(DMSO-d6，400MHz)δ1.96(s，3H)，3.08(d，4H)，3.17(d，4H)，4.67(s，2H)，6.72(m，2H)，7.1(d，1H)，7.2(d，1H)，7.42(s，1H)，7.46(m，2H)，7.6(m，2H)，7.75(d，2H)，8(bs 1H)，8.86(s，1H)；MS(ES+)m/z 464(M+H)+。
Example 153
Step A:
as in general procedure XII, using 3-methyl-4-nitrobenzyl alcohol (Aldrich, 1g, 5.98mmol), palladium on carbon (0.265g, 10% w/w), ethanol (12ml) and THF (12ml) under a 58psi hydrogen atmosphere, 370 was obtained as a yellow oil (0.65g, 79%). The crude product can be used without purification.
And B:
as in general procedure X, compound 370(0.65g, 4.74mmol), triethylamine (0.95ml, 6.82mmol), acetonitrile (10ml) and acid chloride 320(0.5g, 1.62mmol) in acetonitrile (10ml) were used. The product was purified by flash chromatography, eluting with 1: 1 hexane: ethyl acetate, to give 369(0.041g, 2.1%) as a yellow solid.1H NMR(DMSO-d6，400MHz)δ2(s，3H)，4.4(s，2H)，4.7(s，2H)，5.1(bs 1H)，7.1(m，2H)，7.25(m，2H)，7.45(m，3H)，7.6(m，2H)，7.76(d，2H)，8.9(s，1H)；MS(ES-)m/z 408(M-H)-。
Example 154
As general procedure X, 4-nitroaniline (Sigma, 0.244g, 1.77mmol), triethylamine (0.25ml, 1.79mmol), acetonitrile (5ml) and acid chloride 320(0.54g, 1.75mmol) in acetonitrile (5ml) were used. The product was purified by flash chromatography eluting with 4: 1 hexanes to ethyl acetate to give 371 as an off-white solid (0.012g, 2%).1H NMR(CDCl3，300MHz)δ4.8(s，2H)，7.05(d，1H)，7.4(d，1H)，7.5(m，3H)，7.65(t，1H)，7.9(d，2H)，8(d，2H)，8.25(d，2H)，10(s，1H)；MS(ES-)m/z 409(M-H)-。
Example 155
Step A:
as in general procedure XII, using 5-nitroindazole (Aldrich, 1.2g, 7.36mmol), palladium on carbon (0.23g, 10% w/w), ethanol (25ml) and THF (5ml) under a 78psi hydrogen atmosphere, 373(0.98g, crude material) was obtained as a pink solid.1H NMR(DMSO-d6，400MHz)δ 4.7(s，2H)，6.7(dd，2H)，7.2(d，1H)，7.7(s，1H)，12.5(s，1H)。
And B:
as in general procedure X, compound 373(1g, 7mmol), triethylamine (1.2ml, 8.6mmol), acetonitrile (20ml) and acid chloride 320(1.9g, 6.2mmol) in acetonitrile (10ml) were used. Adding ice water, filtering the obtained suspensionThe liquid, washed with water, and the solid recrystallized from ethanol and water. The resulting precipitate was filtered and washed with diethyl ether to give 372 as a pink solid (0.679g, 17.3%). 1H NMR(DMSO-d6，400MHz)δ4.7(s，2H)，7.2(d 1H)，7.3(d，1H)，7.4-7.5(m，4H)，7.55-7.6(m，2H)，7.6(dd，2H)，8(s，2H)，9.7(s，1H)，13(s，1H)；MS(ES-)m/z 406(M-H)-。
Example 156
As in general procedure X, 4-aminophenylethylmethanol (Apin, 0.254g, 1.7mmol), triethylamine (0.28ml, 2mmol), acetonitrile (6ml) and acid chloride 320(0.53g, 1.7mmol) in acetonitrile (6ml) were used. The mixture was filtered, washed with 1M sodium hydrogen sulfate and the filtrate was extracted with ethyl acetate. The organics were separated, dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography, eluting with 93: 7 dichloromethane: methanol, flash chromatography with 95: 5 dichloromethane: methanol, TLC preparative plate chromatography with 92: 8 dichloromethane: methanol, TLC preparative plate chromatography with 9: 1 dichloromethane: methanol to give 374(0.029g, 4%) as an off-white solid.1H NMR(DMSO-d6，300MHz)δ0.8(t，3H)，1.6(m，2H)，4.4(m，1H)，4.7(s，2H)，5.08(d，1H)，7.2(t，3H)，7.47(d，3H)，7.55(m，2H)，7.65(m，2H)，7.85(d，2H)，9.7(s，1H)；MS(ES-)m/z422(M-H)-。
Example 157
Compound 378(0.143g, 0.64mmol) was added to a solution of compound 377(0.15g, 0.64mmol), potassium carbonate (0.09g, 0.65mmol) and DMF (5ml) and stirred overnight. The mixture was poured into ice water, filtered and washed with diethyl ether to giveIs a solid of (2). The product was purified by TLC preparative plate chromatography eluting with 23: 1 dichloromethane: methanol to give 375 as an orange solid (0.021g, 9%).1H NMR(DMSO-d6，300MHz)δ4.7(s，2H)，7.06(t，1H)，7.25(d，1H)，7.3(t，2H)，7.55(d，2H)，7.58(s，1H)，7.67(m，3H)，8.77(d，2H)，9.86(s，1H)；MS(ES-)m/z 366(M-H)-。
As with general method IX, using compound 376(4.2g, 17mmol), THF (100ml) and boron tribromide (17g, 68mmol) in dichloromethane (100ml) and dichloromethane (68ml), after recrystallization from methanol, 377(1.1g, 28%) was obtained as a yellow solid. 1H NMR(DMSO-d6，300MHz)δ7(d，1H)，7.6(d，2H)，8.2(d，2H)，9.7(bs，2H)，10.95(s，1H)；MS(ES-)m/z 232(M-H)-。
Example 158
According to general procedure X, 3, 5-dichlorosulfonamide (Lancaster, 0.5g, 2.1mmol), triethylamine (0.25ml, 1.8mmol), acetonitrile (10ml) and acid chloride 320(0.52g, 1.7mmol) in acetonitrile (6ml) were used. The reaction was heated to 40 ℃ and stirred for 3 days. Additional acid chloride 320(0.52g, 1.7mmol) was added and the reaction stirred for 7 days. The mixture was concentrated in vacuo, suspended in dichloromethane, filtered and the filtrate concentrated in vacuo. Subjecting the product to flash chromatographyPurification, eluting with 99: 1 dichloromethane: methanol, by flash chromatography, eluting with a gradient of 1: 1 to 9: 1 ethyl acetate: hexane, by TLC preparative plate chromatography using 23: 1 dichloromethane: methanol, 7: 3 ethyl acetate: hexane and 98: 2 dichloromethane: methanol as eluents gave 379(0.038g, 4.3%) as an orange oil.1H NMR(DMSO-d6，300MHz)δ4.56(s，2H)，6.57(bs，2H)，6.94(d，1H)，7.36(s，1H)，7.4(m，3H)，7.55(m，3H)，7.7(d，2H)，12.15(bs，1H)；MS(ES-)m/z 512(M-H)-。
Example 159
According to general procedure X, 3-methoxy-4-aminosulfamine (Pfaltz Bauer, 0.5g, 2.5mmol), acetonitrile (16ml), triethylamine (0.41ml, 2.9mmol) and acid chloride 320 in acetonitrile (0.76g, 2.5mmol) were used. The reaction mixture was filtered and the resulting solid was washed with acetonitrile and diethyl ether to give 380 as an off-white solid (0.169g, 14.4%). 1H NMR(DMSO-d6，400MHz)δ3.8(s，3H)，4.8(s，2H)，7.15(d，1H)，7.22(d，3H)，7.48(m，4H)，7.58(d，2H)，7.78(d，2H)，8.5(s，1H)，8.9(s，1H)；MS(ES+)m/z 575(M+H)+。
Example 160
Acid chloride 320(0.68g, 2.2mmol) in dichloromethane (5ml) was added to a solution of 2-chloro-4-fluoroaniline (Aldrich, 0.5g, 3.4mmol), pyridine (12ml) and the mixture was stirred overnight. The reaction mixture was poured into ice, ethanol (30ml) was added, the precipitate filtered and washed with 1: 1 ethanol: water and ether to give 381 as a white solid (0.367g, 40%).1HNMR(DMSO-d6，300MHz)δ4.8(s，2H)，7.25(m，2H)，7.5(m，9H)，7.65(t，2H)，7.75(m，1H)，7.8(d，2H)，9.2(s，1H)；MS(ES+)m/z 419(M+H)+。
Example 161
According to general procedure X, resorcinol hydrochloride (Aldrich, 0.5g, 3.4mmol), acetonitrile (20mmol total reaction volume), triethylamine (0.75ml, 5.4mmol) and acid chloride 320(0.8g, 2.6mmol) in acetonitrile were used. The reaction mixture was poured into ice water, and ethanol was added to the solution. The mixture was recrystallized from ethanol and water, the resulting solid was filtered and washed with ether to give 382 as a pink solid (0.207g, 20%).1H NMR(DMSO-d6，400MHz)δ4.6(s，2H)，6.1(d，1H)，6.28(s，1H)，7.19(d，1H)，7.4(m，4H)，7.56(t，2H)，7.75(d，2H)，8.5(s，1H)，9.1(s，1H)，9.6(s，1H)；MS(ES+)m/z 398(M+H)+。
Example 162
Step A:
as in general procedure XII, 3-nitrobenzenesulfonamide (5g, 24.7mmol), palladium on carbon (1g, 10% w/w), methanol (75ml) and THF (25ml) were used under a 67psi hydrogen atmosphere to give 384(4.2g) as a solid.1H NMR(DMSO-d6，400MHz)δ5.48(bs，2H)，6.67(dd，1H)，6.88(d，1H)，6.97(t，1H)，7.12(t，3H)；MS(AP+)m/z 173(M+H)+。
And B:
according to general method XIII, carboxylic acid 105(0.29g, 1mmol), HCA (0.132ml, 0.5mmol), THF, triphenylphosphine in THF (0.26g, 1mmol), m-aminophenylsulfonamide 384(0.17g, 1mmol) in THF (4.5ml total reaction volume) and pyridine (0.5ml, 6.2mmol) were used. The reaction was concentrated in vacuo and the resulting solid was recrystallized from ethanol and water, filtered and washed with diethyl ether to give 383(0.207g, 47%) as an off-white solid. 1H NMR(DMSO-d6，400MHz)δ4.7(s，2H)，7.15(d，1H)，7.36(s，2H)，7.4-7.5(m，5H)，7.58(m，3H)，7.77(d，2H)，8.1(s，1H)，10.1(s，1H)；MS(ES+)m/z445(M+H)+。
Example 163
Carboxylic acid 105(0.29g, 1mmol), HCA (0.08ml, 0.53mmol), dichloromethane (5ml total reaction volume), and triphenylphosphine (0.26g, 1mmol) were combined in a round bottom flask at-78 deg.C under nitrogen. 4-amino-3-chlorophenol (Aldrich, 0.145g, 1mmol) was freed by partitioning it between dichloromethane and saturated sodium bicarbonate. The organics were separated, dried over magnesium sulfate and concentrated in vacuo to give a pink solid which was dissolved in dichloromethane and triethylamine (0.26ml, 1.9mmol) was added dropwise to the reaction mixture at-78 ℃. The reaction was allowed to warm to room temperature and concentrated in vacuo. The product was purified by flash chromatography eluting with 4: 1 hexanes to ethyl acetate to give 385 as an orange oil (0.120g, 29%).1H NMR(DMSO-d6，400MHz)δ4.7(s，2H)，6.67(d，1H)，6.79(s，1H)，7.2(d，1H)，7.35(d，1H)，7.4(s，1H)，7.5(m，2H)，7.6(m，2H)，7.75(d，2H)，8.9(s，1H)，9.8(s，1H)；MS(ES+)m/z 417(M+H)+。
Example 164
According to general method XIII, carboxylic acid 105(0.67g, 2.3mmol), HCA (0.17ml, 1.1mmol), THF, triphenylphosphine in THF (0.61g, 2.3mmol), 2-nitro-4-sulfonamide in THF (20ml total reaction volume) (0.5g, 2.3mmol) and pyridine (2.25ml, 28mmol) were used. The reaction mixture was concentrated in vacuo and the product was purified by flash chromatography eluting with a 9: 1 gradient of hexane to ethyl acetate and ethyl acetate to afford 386 as an off-white solid. MS (ES) -)m/z 488(M-H)-。
Example 165
According to general procedure XIII, carboxylic acid 105(0.58g, 2mmol), HCA (0.152ml, 1mmol), THF, triphenylphosphine in THF (0.52g, 2mmol), 6-aminoindazole in THF (20ml total reaction volume) (Aldrich, 0.26g, 2mmol) and pyridine (1.94ml) were used. The reaction mixture was concentrated in vacuo, and the resulting solid was dissolved in ethanol. Water was added to the mixture and the resulting solid was filtered and washed with diethyl ether to give 387(0.309g, 38%) as a pink solid.1H NMR(DMSO-d6，400MHz)δ4.7(s，2H)，6.95(d，1H)，7.15(d，1H)，7.4(s，1H)，7.5(m，2H)，7.55-7.65(m，3H)，7.79(d，2H)，7.9(s，1H)，8(s，1H)，9.89(s，1H)，12.85(bs，1H)；MS(ES+)m/z 406(M+H)+。
Example 166
N, N-dimethyl-3-chloropropylamine in acetone (5ml) and water (4 drops) was added dropwise to a suspension of compound 385(1.04g, 2.5mmol), acetone (10ml) and potassium carbonate (2.82g, 20.4mmol) and then refluxed under nitrogen for 3 days. The suspension was allowed to cool to room temperature and water and brine were added. With dichloromethaneThe mixture is extracted. To the organic layer was added 1N HCl in ether (3ml), and the resulting solution was concentrated in vacuo. The concentrate was purified by flash chromatography using a gradient of 9: 1 to 4: 1 dichloromethane to methanol as eluent to give an oil. The oil was dissolved in dichloromethane, 1N HCl in ether (3ml) was added, and the mixture was stored at room temperature for 7 days. The precipitate was filtered and washed with ether to give 388(0.125g, 10%) as an orange-yellow solid. 1H NMR(DMSO-d6，300MHz)δ1.8(m，2H)，2.28(s，6H)，2.5(m，2)，4(t，2H)，4.8(s，2H)，6.9(d，1H)，7.08(d，1H)，7.25(d，1H)，7.45-7.58(m，4H)，7.65(m，2H)，7.8(d，2H)，9.05(s，1H)；MS(ES+)m/z 502(M+H)+。
Example 167
Step A:
3-chloro-5-nitroindazole (Lancaster, 5g, 25mmol), sodium dithionate (17.6g, 101mmol), ethanol (150ml) and water (50ml) were mixed in a round bottom flask equipped with a stir bar, reflux condenser and nitrogen gas as needed, and then refluxed overnight. The reaction mixture was concentrated in vacuo, and the resulting solid was dissolved in ethyl acetate and washed with brine and water. The organic layer was separated, dried over magnesium sulfate and concentrated in vacuo to give 390(1.3g, 31%) as a yellow solid.1H NMR(DMSO-d6，400MHz)δ5(s，2H)，6.55(s，1H)，6.8(d，1H)，7.2(s，1H)，12.7(s，1H)；MS(ES+)m/z 168(M+H)+. The crude product was used without further purification.
And B:
according to general method XIII, carboxylic acid 105(2.25g, 7.74mmol) is used,HCA (0.59ml, 3.88mmol), THF, triphenylphosphine in THF (2.03g, 7.74mmol), compound 390(1.3g, 7.7mmol) in THF (45ml total reaction volume) and pyridine (7.5ml, 93 mmol). The reaction mixture was concentrated in vacuo, and the resulting solid was suspended in ethanol, methanol, acetone and water. The resulting solid was filtered off and recrystallized from ethyl acetate: hexane. The precipitate was filtered and washed with diethyl ether and 7: 3 ethyl acetate: hexanes to give 389(0.87g, 26%) as a brown solid.1H NMR(DMSO-d6，400MHz)δ4.7(s，2H)，7.2(d，1H)，7.35(d，1H)，7.415(s，1H)，7.43-7.52(m，4H)，7.55-7.6(m，4H)，7.78(m，2H)，7.9(s，1H)，9.88(s，1H)，13.2(s，1H)。
Example 168
Step A:
Ammonium hydroxide (40ml) was added to 3-chloro-4-sulphamoyl fluoride (Maybridge, 0.5g, 2.4mmol) and the mixture was heated to 62 ℃ for 1 h under nitrogen. The reaction was cooled to room temperature, and the resulting mixture was extracted with ethyl acetate. The organics were dried over magnesium sulfate and concentrated in vacuo to give 392 as a white solid (0.394g, 80%).1H NMR(DMSO-d6，400MHz)δ6.07(s，2H)，6.8(d，1H)，7(s，2H)，7.39(dd，1H)，7.55(d，1H)；MS(ES-)m/z 205(M-H)-。
And B:
according to general procedure XIII, carboxylic acid 105(0.54g, 1.9mmol), HCA (0.14ml, 0.92mmol), THF, triphenylphosphine in THF (0.49g, 1.9mmol), compound 392 in THF (40ml total reaction volume) (0.384g, 1.9mmol) and pyridine (1.8ml) were used. Concentrating the reaction mixture to obtain a solid which is dissolved in ethanol. Water was added, the precipitate filtered and washed with 1: 1 ethanol: water and ether to give 391(0.206g, 23.1%) as a white solid.1H NMR(DMSO-d6，400MHz)δ4.8(s，2H)，7.2(d，1H)，7.43(s，2H)，7.47(m，2H)，7.6(m，2H)，7.75(dd，3H)，7.8(d，1H)，8.05(d，1H)，9.3(s，1H)。
Example 169
Step A:
5-fluoro-2-nitrotoluene (Aldrich, 50.6g, 364mmol), DMSO (60ml), and thiomorpholine (37ml, 368mmol) were combined and heated to 75 ℃ for 2 hours and 100 ℃ for 4 hours under a nitrogen atmosphere. The reaction was allowed to cool to room temperature. Diethyl ether was added to the mixture and the slurry was stirred vigorously. Water was added to the slurry, and the resulting solid was filtered, washed with water and diethyl ether, and then dissolved in dichloromethane. The organics were washed with water, dried over magnesium sulfate and concentrated in vacuo to afford 394 as a yellow solid (70g, 81%): 1H NMR(DMSO-d6400MHz) delta 2.5(s, 3H), 2.6(t, 4H), 3.8(d, 1H), 6.85(s, 1H), 7.95(d, 1H). The crude product was used without further purification.
And B:
following general procedure XII, using compound 394(0.29g, 1.22mmol), palladium on carbon (0.1g, 10% w/w), ethanol (7ml) and THF (7ml) under a 68psi hydrogen atmosphere, 395(0.252g, crude material) was obtained as a brown solid.
And C:
as in general procedure X, compound 395(0.252g, 1.2mmol), acetonitrile (12ml), triethylamine (0.3ml, 2.1mmol) and acid chloride 320(0.38g, 1.2mmol) were used. The product was purified by flash chromatography using 7: 3 hexane: ethyl acetate as eluent to give 393(0.084g, 14%) as an orange solid.1H NMR(DMSO-d6，400MHz)δ1.95(d，3H)，2.6(d，2H)，2.85(t，2H)，3.5(d，2H)，3.7(t，2H)，4.67(s，2H)，6.75(dd，1H)，6.8(d，1H)，7.1(d，1H)，7.2(d，1H)，7.42(d，1H)，7.48(t，2H)，7.59(t，2H)，7.75(d，2H)，8.8(s，1H)。
Example 170
Step A:
3-Chloroperbenzoic acid (Aldrich, 0.046g, 2.7mmol) in dichloromethane was added dropwise to a stirred solution of compound 394(12.5g, 52.4mmol) in dichloromethane (300ml total reaction volume) at-20 deg.C, the mixture was stirred for 1.5 hours, after which the cold bath was removed and the reaction stirred overnight at room temperature under nitrogen. The mixture was washed with saturated sodium metabisulfite, 2N sodium hydroxide and water. The organics were separated, dried over magnesium sulfate and concentrated in vacuo to give a mixture of 397 and 398 as a yellow solid (12.2g, crude mixture).
And B:
as in general procedure XII, a mixture of 397 and 398 (12.3g), palladium on carbon (3.7g, 10% w/w), ethanol (100ml), THF (30ml) and methanol (75ml) was used under a 60psi hydrogen atmosphere. Product siliconPurification by flash chromatography on gum using 7: 3 hexane: ethyl acetate, 100% ethyl acetate, and 4: 1 ethyl acetate: methanol as eluent gave 399(4.27g, 39%) as an orange solid.1H NMR(DMSO-d6，400MHz)δ1.99(s，3H)，2.68(d，2H)，2.87(t，2H)，3.15(dd，2H)，3.44(t，2H)，4.38(bs，2H)，6.49(d，1H)，6.59(d，1H)，6.64(s，1H)；MS(ES+)m/z 225(M+H)+And 400 as a brown solid (3.57g, 31%).1H NMR(DMSO-d6，400MHz)δ1.99(s，3H)，3.08(m，4H)，3.42(m，4H)，4.42(bs，2H)，6.49(d，1H)，6.59(d，1H)，6.66(d，1H)；MS(ES+)m/z 241(M+H)+
And C:
according to general method XIII, carboxylic acid 105(2.02g, 6.95mmol), HCA (0.528ml, 3.48mmol), THF (20ml), triphenylphosphine in THF (15ml) (1.82g, 6.95mmol), sulfoxide in THF (125ml total reaction volume) 399(1.56g, 6.95mmol) and pyridine (6.75ml, 83.5mmol) were used. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The concentrate was purified by flash chromatography using a gradient of 99: 1 to 4: 1 dichloromethane to methanol as eluent to give 396 as a yellow foam (1.62g, 47%).1H NMR(DMSO-d6，400MHz)δ1.95(d，3H)，2.62(dd，2H)，2.86(t，2H)，3.5(dd，2H)，3.69(t，2H)，4.67(s，2H)，6.75(dd，1H)，6.8(d，1H)，7.1(d，1H)，7.2(d，1H)，7.42(d，1H)，7.48(t，2H)，7.59(t，2H)，7.75(d，2H)，8.8(s，1H)。
Example 171
Step A:
as in general procedure XI, use is made of a compound which is 5-chloro-2-nitrobenzonitrile (Aldrich, 5g, 27.4mmol), sodium bicarbonate (4.62g, 55mmol), pyridine (40ml), water (1ml) and thiomorpholine (5.53ml, 55mmol) to give 402 as a clear solid (5.19g, 76%). 1H NMR(DMSO-d6400MHz) delta 2.62(m, 4H), 3.9(m, 4H), 7.2(d, 1H), 7.5(d, 1H), 8.1(d, 1H). The crude product was used without purification.
And B:
3-Chloroperbenzoic acid (Aldrich, 4.85g, 17mmol) in dichloromethane was added to a cooled solution of compound 402(3g, 12mmol) in dichloromethane (100ml total reaction volume) at-20 deg.C, the mixture was stirred for 15 minutes, after which the cold bath was removed and the mixture was stirred at room temperature under nitrogen for 4 hours. The reaction mixture was washed with saturated sodium metabisulfite, 2N sodium hydroxide and brine. The organics were separated, dried over magnesium sulfate and concentrated in vacuo to give 403 as a yellow solid (0.59g, crude material).1H NMR(DMSO-d6，400MHz)δ2.63(m，4H)，3.9(m，4H)，7.2(dd，1H)，7.5(d，1H)，8.1(d，1H)。
As in general procedure XII, using palladium on carbon (0.23g, 10% w/w), compound 403(0.5g, 1.9mmol), ethanol (30ml total reaction volume), THF (20ml) and methanol (20ml) gave 404(0.41g, 93%) as a green oil.1H NMR(DMSO-d6，300MHz)δ2.68(d，2H)，2.9(t，2H)，3.3(d，2H)，3.55(t，2H)，5.6(bs，2H)，6.79(d，1H)，7.02(d，1H)，7.17(dd，1H)。
And C:
according to general method XIII, compound 404(0.41g, 1.8mmol), HCA (0.132ml, 0.87mmol), triphenylphosphine (0.46g, 1.75mmol), pyridine are usedPyridine (1.7ml, 21mmol), THF (25ml) and carboxylic acid 105(0.51g, 1.8 mmol). The concentrate was purified by flash chromatography using 95: 5 dichloromethane to methanol as eluent, by TLC preparative plate chromatography using a 7: 3 gradient of hexane to ethyl acetate to 4: 1 gradient of ethyl acetate to methanol, and 9: 1 dichloromethane to 1% triethylamine in methanol as eluent. The concentrate was dissolved in dichloromethane and washed with 2N HCl. The organics were separated, dried over magnesium sulfate and concentrated in vacuo to give 401 as a brown foam (0.145g, 16%). 1H NMR(DMSO-d6，300MHz)δ2.65(d，2H)，2.9(t，2H)，3.8(m，4H)，4.76(s，2H)，7.2-7.4(m，3H)，7.4-7.6(m，4H)，7.65(m，2H)，7.8(d，2H)，9.7(s，1H)。
Example 172
Step A:
4-Piperidinone monohydrate monohydrochloride (Lancaster, 2.73g, 17.8mmol) and saturated potassium carbonate (10ml) were mixed in a round bottom flask and stirred for 10 minutes. Pyridine (45ml) and 2-nitro-5-fluorotoluene (Aldrich, 1.41ml, 9.35mmol) were added and the reaction refluxed overnight. The two-phase solution was separated and the organics concentrated in vacuo. The concentrate was dissolved in ethyl acetate and washed with water and brine. The organics were dried over magnesium sulfate and concentrated in vacuo to give 406(0.59g, 27%) as a red oil.1H NMR(DMSO-d6，300MHz)δ2.6(t，4H)，3.8(t，4H)，7(d，2H)，8(d，2H)；MS(ES+)m/z 235(M+H)+。
And B:
as in general procedure XII, compound 406(0.57g, 2.4mmol), palladium on carbon (0.17g, 10% w/w), ethanol (25ml) and THF (25ml) were used under a 70psi hydrogen atmosphere to give 407(0.5g, crude material) as a yellow oil.
And C:
according to general method XIII, compound 407(0.5g, 2.1mmol), HCA (0.16ml, 1.05mmol), triphenylphosphine (0.56g, 2.1mmol), pyridine (2ml, 25mmol), THF (50ml) and carboxylic acid 105(0.62g, 2.1mmol) were used. The mixture was concentrated in vacuo and purified by flash chromatography using a gradient eluent of 1: 1 hexane: ethyl acetate and 100% ethyl acetate to give 405 as a yellow solid (0.32g, 31%). 1H NMR(DMSO-d6，300MHz)δ2(s，3H)，2.4(m，4H)，3.58(m，4H)，4.7(s，2H)，6.85(d，1H)，6.9(s，1H)，7.15(d，1H)，7.25(d，1H)，7.48(s，1H)，7.55(t，2H)，7.65(t，2H)，7.8(d，2H)，8.85(s，1H)；MS(ES+)m/z 478(M+H)+。
As in general procedure XV, using carboxylic acid 115(1g, 3.6mmol), dichloromethane (30ml) and thionyl chloride (7.6ml, 104mmol) gives 408(1.24g, crude material) as a purple-red oil.
According to general procedure IV, using ester 412(15.92g, 52mmol), ethanol (EtOH, 150ml), water (50ml) and lithium hydroxide monohydrate (2.71g, 65mmol), 409 was obtained as a brown solid (7.47g, 51.6%). The crude material was used without purification.
Thionyl chloride (60ml, 800mmol) was added portionwise to a solution of 3-furoic acid (11.21g, 100mmol) in dichloromethane (100ml) and the mixture refluxed for 2 hours. The solution was concentrated in vacuo to afford acid chloride 410(13g, crude material) as an oil.
As in general procedure III, acid chloride 410(13g, 100mmol), aluminum chloride (AlCl) was used313.6g, 100mmol), dichloromethane (200ml) and 4-chloroanisole (12.25ml, 100 mmol). The product was purified by flash chromatography using 7: 3 hexane: dichloromethane and 1: 1 hexane: dichloromethane as eluents. The concentrate was triturated between ether and hexane, filtered and the resulting solid washed with hexane to give 411(12.3g, 55%) as a yellow crystalline solid.1HNMR(DMSO-d6，400MHz)δ6.8(s，1H)，6.95(d，1H)，7.4(m，2H)，7.8(s，1H)，8.25(s，1H)，10.45(s，1H)。
Using phenol 411(12.3g, 55.3mmol), potassium carbonate (38.21g, 277mmol), ethyl bromoacetate (6.4ml, 57.7mmol) and acetone (250ml) according to general procedure II, 412 was obtained as a yellow/orange foam (15.9g, 93%). MS (ES) -)m/z 279(M-H)-. The crude product was used without purification.
As in general procedure XII, compound 415(0.4g, 2.3mmol), palladium on carbon (0.12g, 10% w/w) and ethanol (50ml) were used under a 60psi hydrogen atmosphere to give 413 as a brown solid (0.35g, crude material).1H NMR(DMSO-d6，400MHz)δ2.05(s，3H)，4.96(br，2H)，6.56(s，1H)，7.22(s，1H)，7.63(s，1H)，12.16(s，1H)。MS(ES-)m/z 148(M-H)-。
Potassium nitrate (10.13ml, 100mmol) in concentrated sulphuric acid (50ml) was added dropwise to a stirred solution of concentrated sulphuric acid (50ml) and 2, 4-dimethylaniline (Aldrich, 4.94g, 40.8mmol) at 0 ℃. The reaction was stirred for 3 hours. The mixture was poured into ice water (1800ml) and extracted with ethyl acetate. The organics were separated and concentrated in vacuo to give 414(2.98g, 44%) as an orange solid.1H NMR(DMSO-d6，400MHz)δ2.02(s，3H)，2.3(s，3H)，7(s，1H)，7.26(s，1H)。
Sodium nitrite (0.67g, 9.7mmol) in water (4ml) was added dropwise to a stirred solution of compound 414(1.6g, 9.6mmol) and glacial acetic acid (250ml) at 0 ℃. The reaction was stirred at 0 ℃ for 15 minutes and at room temperature for 3 hours. The reaction was stored for 9 days. The mixture was concentrated in vacuo. The concentrate was triturated with water and the resulting slurry was stirred for 1 hour. The slurry was filtered and washed with water. The solid was dissolved in dichloromethane and washed with water. The organics were separated and further purified by flash chromatography eluting with 9: 1 hexane: ethyl acetate and 1: 1 hexane: ethyl acetate to give 415 as a red solid (0.4g, 19%). 1H NMR(DMSO-d6，400MHz)δ2.5(s，3H)，7.82(s，1H)，8.17(d，2H)，13.53(bs，1H)。
As in general procedure XII, compound 420(1.07g, 6mmol), palladium on carbon (0.3 mmol) was used with 80psi of hydrogen3g, 10% w/w), ethanol (30ml) and THF (20ml) gave 416(0.53g, 60%) as a brown solid.1H NMR(DMSO-d6，300MHz)δ2.25(s，3H)，4.5(s，2H)，6.8(d，1H)，7.1(d，1H)，7.85(s，1H)，12.55(bs，1H)；MS(ES-)m/z 148(M-H)-。
Acetic anhydride (25ml, 265mmol) was added to a stirred solution of 2, 3-dimethylaniline (Aldrich, 31.2g, 257mmol) and toluene (50ml) under a nitrogen atmosphere. The resulting solid was filtered, washed with hexane and diethyl ether to give 417 as a white solid (40.59g, crude material).1H NMR(DMSO-d6，300MHz)δ2.06(d，6H)，2.26(s，3H)，7.05(m，2H)，7.15(d，1H)，9.35(bs，1H)。
Potassium nitrate (6.2g, 61mmol) in concentrated sulphuric acid (75ml) was added dropwise to a cooled stirred solution of concentrated sulphuric acid (50ml) and compound 417(10g, 61mmol) at-17 ℃ over 1 hour. The cold bath was removed and the reaction was stirred at 0 ℃ for 1 hour. The mixture was poured into ice water (2000ml) and stirred vigorously, and the solution was extracted with dichloromethane. The organics were separated, dried over magnesium sulfate and concentrated in vacuo to give a solid. The solid was purified by flash chromatography using a gradient of 7: 3 hexanes: ethyl acetate and ethyl acetate as eluent to give 418 as a yellow solid (4.24g, 33%). MS (ES)-)m/z 201(M-H)-. Compound 418 was used as a mixture without purification.
Compound 418(4.24g, 20.4mmol) is added portionwise to potassium hydroxide (1.2g, 21mmol), water (50ml) and ethanol (200ml) to a stirred solution, the mixture was refluxed for 1 hour. Water (50ml) was added dropwise to the reaction mixture, and the resulting solution was cooled to room temperature. The precipitate was filtered and washed with water and diethyl ether. The filtrate was extracted with ether, the organics combined, dried over magnesium sulfate and concentrated in vacuo to give 419(2.02g, 60%) as a yellow solid.1H NMR(DMSO-d6，400MHz)δ2(s，3H)，2.34(s，3H)，6.12(bs，2H)，6.5(d，1H)，7.6(d，1H)。
Sodium nitrite (0.42g, 6mmol) in water was added dropwise to a stirred solution of compound 419(1g, 6mmol) and glacial acetic acid (50ml) at 0 ℃ and stirred for 1 h. The reaction was stored at room temperature for 2 days. The mixture was concentrated in vacuo and the concentrate was triturated with water. The resulting solid was filtered and washed with water. 420(2.07g, crude material) was obtained as a brown solid.1H NMR(DMSO-d6，400MHz)δ2.8(s，3H)，7.5(d，1H)，7.95(d，1H)，8.45(s，1H)，13.6(bs，1H)；MS(ES-)m/z 176(M-H)-。
As in general procedure XII, using compound 423(2.69g, 15.2mmol), palladium on carbon (0.8g, 10% w/w), ethanol (100ml) and THF (20ml) with 60psi of hydrogen, gave 421(1.43g, 63.8%) as a brown solid. The crude material was used without purification.
Potassium nitrate (10.13ml, 100mmol) in concentrated sulphuric acid (50ml) was added dropwise to a stirred solution of concentrated sulphuric acid (50ml) and 2, 6-dimethylaniline (Aldrich, 12.32g, 100mmol) and stirred for 1 hour at-10 ℃. The mixture was poured into ice water and used And (5) extracting with ethyl acetate. The organics were separated, dried over magnesium sulfate and concentrated in vacuo to give 422(5.63g, 34%) as an orange solid.1H NMR(DMSO-d6400MHz) delta 2.05(d, 6H), 5.4(bs, 2H), 6.9(d, 1H), 6.96(d, 2H). The crude material was used without purification.
Sodium nitrite (2.34g, 34mmol) in water (10ml) was added dropwise to a stirred solution of compound 422(5.63g, 34mmol) and glacial acetic acid (500ml) at 0 ℃ and stirred for 15 min. The cooling bath was removed and the reaction was stored at room temperature for 6 days. The mixture was concentrated in vacuo and the concentrate was triturated with water. The resulting solid was filtered and recrystallized from methanol to give 423 as a red solid (2.69g, 45%).1H NMR(DMSO-d6，400MHz)δ2.73(s，3H)，3.15(s，3H)，7.64(d，1H)，7.9(d，1H)，8.24(s，1H)，13.85(bs，1H)；MS(ES-)m/z 176(M-H)-. The crude material was used without purification.
Using ester 426(16.72g, 42mmol), ethanol (EtOH, 200ml), water (50ml) and lithium hydroxide monohydrate (2.21g, 52mmol) according to general procedure III, 424 was obtained as an off-white solid (10.71g, 69%). The crude material was used without purification.
According to general procedure I, 4-bromobenzoyl chloride (8.73g, 40mmol), aluminum chloride (AlCl) were used35.3g, 40mmol), dichloromethane (125ml) and 4-chloroanisole (4.87ml, 40mmol) to give 425 as a yellow solid (14.27g, crude material).
According to general procedure II, using compound 425(14.27g, 65mmol), potassium carbonate (45g, 325mmol), ethyl bromoacetate (7.57ml, 68mmol) and acetone (250ml), 426(16.72g, 65%) was obtained as a brown solid.1H NMR(DMSO-d6400MHz) delta 4.6(s, 2H), 7.07(d, 1H), 7.4(d, 1H), 7.54(dd, 1H), 7.64(m, 4H), 13.04(bs, 1H). The crude product was used without purification.
As with general procedure XV, using carboxylic acid 129(1.5g, 4.8mmol), dichloromethane (30ml) and thionyl chloride (10ml, 137mmol) gives 427 as an off-white, viscous solid (1.58g, crude material).
Using ester 430(17.24g, 43mmol), ethanol (200ml), water (50ml) and lithium hydroxide monohydrate (2.27g, 54mmol) as general method III gave 123 as an off-white solid (6.53g, 41%).
As in general procedure I, 2-bromobenzoyl chloride (10g, 46mmol), aluminum chloride (AlCl) were used36.2g, 46mmol), dichloromethane (250ml) and 4-chloroanisole (5.6ml, 46mmol) gave 429(13.76g, crude material) as a brown solid.
As in generalMethod II, using compound 429(13.76g, 44mmol), potassium carbonate (30.52g, 221mmol), ethyl bromoacetate (5.14ml, 46mmol) and acetone (250ml), gave 430(17.24g, crude material) as a yellow solid. 1H NMR(DMSO-d6，400MHz)δ4.5(s，2H)，7.15(d，1H)，7.4(s，4H)，7.48(d，1H)，7.58(d，1H)，7.65(d，1H)，12.95(bs，1H)。
Using ester 433(17.24g, 43mmol), ethanol (EtOH, 200ml), water (50ml) and lithium hydroxide monohydrate (2.27g, 54mmol) as general procedure III, 431(6.53g, 41%) was obtained as a white solid.1H NMR(DMSO-d6，400MHz)δ4.65(s，2H)，7.08(d，1H)，7.42(m，2H)，7.54(dd，1H)，7.71(d，1H)，7.83(dd，2H)，13.00(bs，1H)。MS(ES+)m/z 371(M+H)+. The crude material was used without purification.
As in general procedure I, 3-bromobenzoyl chloride (24.11g, 110mmol), aluminum chloride (AlCl) were used315g, 113mmol), dichloromethane (250ml) and 4-chloroanisole (13.46ml, 110mmol) after trituration of the concentrate with hexane and filtration 432(25.57g, 75%) was obtained as a green solid. The crude material was used without purification.
As in general procedure II, using compound 432(9.08g, 29mmol), potassium carbonate (20.14g, 146mmol), ethyl bromoacetate (3.39ml, 31mmol) and acetone (200ml) gave 433(12.68g, crude material) as a red/brown oil.1H NMR(DMSO-d6，400MHz)δ1.12(t，3H)，4.06(q，2H)，4.75(s，2H)，7.11(d，1H)，7.44(t，2H)，7.54(d，1H)，7.69(d，1H)，7.83(d，2H)；MS(ES+)m/z 398(M+H)+。
As for general procedure XV, using carboxylic acid 431(3g, 8.1mmol), dichloromethane (25ml) and thionyl chloride (11.84ml, 162mmol) gives 434 as a light brown oil (2.96g, 94%). The crude material was used without purification.
Example 173
According to general procedure XIII, compound 115(0.28g, 1mmol), HCA (0.08ml, 0.5mmol), THF (50ml total reaction volume), triphenylphosphine in THF (0.26g, 1mmol) and 6-aminoindazole in THF (0.13g, 1mmol) were used. The product was purified by flash chromatography, eluting with a gradient of 1: 1 hexanes to ethyl acetate and 100% ethyl acetate, to give 435 as an orange oil (0.042g, 11%). 1H NMR(DMSO-d6，400MHz)δ4.8(s，2H)，6.7(d，1H)，7.05(d，1H)，7.2(d，2H)，7.35(d，1H)，7.5(d，1H)，7.55(dd，1H)，7.65(d，1H)，7.94(s，1H)，8.07(s，2H)，10.06(s，1H)，12.89(s，1H)。
Example 174
As general procedure IV, compound 115(0.19g, 0.68mmol), HOBt (0.09g, 0.68mmol), DMF (1ml), 416(0.1g, 0.68mmol) in DMF, EDAC (0.13g, 0.69mmol) in DMF (5ml total reaction volume) and triethylamine (0.19ml, 1.36mmol) were used. The product was purified by flash chromatography eluting with 1: 1 and 7: 3 ethyl acetate: hexane to give436 as an off-white solid (0.126g, 11%).1H NMR(DMSO-d6，400MHz)δ2.25(s，3H)，4.8(s，2H)，6.7(s，1H)，7.18-7.35(m，4H)，7.5(s，1H)，7.6(d，1H)，8.05(dd，2H)，9.35(s，1H)，13(s，1H)。
Example 175
As in general procedure X, compound 416(0.1g, 0.68mmol), triethylamine (0.14ml, 0.71mmol), acetonitrile (5ml total reaction volume) and acid chloride 1 in acetonitrile (0.53g, 1.7mmol) were used. The product was purified by flash chromatography, eluting with 1: 1 hexane: ethyl acetate, to give 437 as an off-white solid (0.095g, 33%).1H NMR(DMSO-d6，300MHz)δ2.28(s，3H)，4.78(s，2H)，7.15(d，1H)，7.3(t，2H)，7.55(dd，3H)，7.65(t，2H)，7.82(d，2H)，8.13(s，1H)，9.18(s，1H)，13.04(bs，1H)；MS(ES+)m/z420(M+H)+。
Example 176
As general method IV, compound 112(0.20g, 0.67mmol), HOBt (0.09g, 0.68mmol), DMF (2ml), compound 416(0.1g, 0.68mmol) in DMF (3ml), EDAC (0.13g, 0.69mmol) and triethylamine (0.19ml, 1.36mmol) were used. The product was purified by flash chromatography, eluting with 7: 3 ethyl acetate: hexanes and 100% ethyl acetate, to give 438 as an off-white solid (0.192g, 67%).1H NMR(DMSO-d6，300MHz)δ2.3(s，3H)，4.85(s，2H)，7.2-7.35(m，4H)，7.55(s，1H)，7.65(d，1H)，7.7(s，1H)，8.15(s，2H)，9.38(s，1H)，13.05(s，1H)；MS(ES-)m/z 424(M-H)-。
Example 177
As general procedure IV, compound 112(0.20g, 0.67mmol), HOBt (0.09g, 0.68mmol), DMF (2ml), 5-aminoindazole (Aldrich, 0.09g, 0.68mmol) in DMF (3ml), EDAC (0.13g, 0.69mmol) and triethylamine (0.19ml, 1.36mmol) were used. The product was purified by flash chromatography using 1: 1 ethyl acetate to hexanes as the eluent and further purified by dissolution in ethyl acetate, washing with water, drying the organics over magnesium sulfate and concentration in vacuo to give 439 as an off-white solid (0.071g, 26%).1H NMR(DMSO-d6，400MHz)δ4.8(s，2H)，7.2(d，2H)，7.35(d，1H)，7.5(d，2H)，7.55(d，1H)，7.65(s，1H)，8(t，3H)，9.85(s，1H)，13(s，1H)。
Example 178
As in general procedure X, compound 413(0.1g, 0.68mmol), triethylamine (0.19ml, 2.6mmol), acetonitrile (30ml) and acid chloride 320(0.21g, 0.68mmol) in acetonitrile (10ml) were used. The product was purified by flash chromatography using 7: 3 hexane: ethyl acetate followed by 1: 1 hexane: ethyl acetate as eluent in TLC preparative plates eluting with 1: 1 hexane: ethyl acetate to give 440 as an off-white solid (0.019g, 6.7%).1H NMR(DMSO-d6，300MHz)δ2.28(s，3H)，4.78(s，2H)，7.15(d，1H)，7.3(t，2H)，7.49(m，3H)，7.64(t，2H)，7.8(d，2H)，8.1(s，1H)，9.18(s，1H)，13(bs，1H)；MS(ES+)m/z 420(M+H)+。
Example 179
LikeGeneral procedure X, using compound 399(1.2g, 5.4mmol) in acetonitrile (45ml total reaction volume), acid chloride 427(1.22g, 3.65mmol) and triethylamine (0.71ml, 5.1mmol) in acetonitrile. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 441 as an off-white solid (0.59g, 31%). 1H NMR(DMSO-d6，400MHz)δ1.97(s，3H)，2.6(d，2H)，2.85(t，2H)，3.5(d，2H)，3.7(t，2H)，4.67(s，2H)，6.75(d，1H)，6.82(s，1H)，7.06(d，1H)，7.2(d，1H)，7.48(s，1H)，7.65(t，2H)，8.05(bs，2H)，8.15(s，1H)，8.96(s，1H)。
Example 180
As general procedure IV, compound 428(0.443g, 1.2mmol), HOBt (0.16g, 1.2mmol), DMF, compound 399(0.40g, 1.8mmol) in DMF (15ml total reaction volume), EDAC (0.23g, 1.2mmol) and triethylamine (0.34ml, 2.4mmol) were used. The product was purified by flash chromatography using 98: 2 dichloromethane to methanol as eluent to give 442 as an off-white foam (0.154g, 22%).1H NMR(DMSO-d6，400MHz)δ2.07(s，3H)，2.6(d，2H)，2.85(t，2H)，3.5(d，2H)，3.7(t，2H)，4.62(s，2H)，6.78(d，1H)，6.84(s，1H)，7.15(d，1H)，7.25(d，1H)，7.38(t，1H)，7.42(d，2H)，7.5(t，1H)，7.65(m，2H)，8.8(s，1H)。
Example 181
As general procedure IV, compound 424(0.443g, 1.2mmol), HOBt (0.16g, 1.2mmol), DMF, compound 399(0.40g, 1.8mmol) in DMF (15ml total reaction volume), EDAC (0.23g, 1.2mmol) and triethylamine (0.34ml, 2.4mmol) were used. The product was purified by flash chromatography using 98: 2 dichloromethane to methanolAs eluent, 443 was obtained as a pale yellow foam (0.105g, 15%).1H NMR(DMSO-d6，400MHz)δ2.06(s，3H)，2.75(d，2H)，2.95(t，2H)，3.6(d，2H)，3.8(t，2H)，4.77(s，2H)，6.88(d，1H)，6.92(s，1H)，7.15(d，1H)，7.3(d，1H)，7.55(d，1H)，7.72(d，2H)，7.78(s，4H)，8.97(s，1H)；MS(ES-)m/z 574(M-H)-。
Example 182
Cyanone (0.029g, 0.33mmol) was added to a DMSO (5ml) solution of compound 443(0.093g, 0.16mmol) and the reaction was heated to 160 ℃ and stirred overnight. The mixture was cooled and water was added thereto. The resulting solid was filtered and washed with ethyl acetate. The filtrate was separated, dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography using a 9: 1 gradient of hexane: ethyl acetate to ethyl acetate as eluent to give 444 as an orange foam (0.012g, 14%). 1H NMR(DMSO-d6，400MHz)δ1.95(s，3H)，2.65(d，2H)，2.85(t，2H)，3.5(d，2H)，3.7(t，2H)，4.64(s，2H)，6.75(dd，1H)，6.82(s，1H)，7.02(d，1H)，7.2(d，1H)，7.5(s，1H)，7.63(d，2H)，7.9(m，4H)，8.88(s，1H)；MS(ES-)m/z 521(M-H)-。
Example 183
Cyanone (0.037g, 0.42mmol) was added to a solution of compound 442(0.120g, 0.21mmol) in DMSO (5ml) and the reaction was heated to 160 ℃ and stirred overnight. The mixture was cooled and water was added thereto. The resulting solid was filtered and washed with ethyl acetate. The filtrate was separated, dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash chromatography using 9: 1 hexane: acetic acidA gradient of ethyl ester to ethyl acetate was used as eluent to give 445(0.012g, 11%) as an orange foam.1H NMR(DMSO-d6，400MHz)δ1.99(s，3H)，2.62(d，2H)，2.86(t，2H)，3.5(d，2H)，3.69(t，2H)，4.62(s，2H)，6.75(d，1H)，6.82(s，1H)，7.05(d，1H)，7.2(d，1H)，7.55(d，1H)，7.7(m，4H)，7.98(d，1H)，8.97(s，1H)；MS(ES-)m/z 521(M-H)-。
Example 184
As general procedure IV, carboxylic acid 105(0.296g, 1.2mmol), HOBt (0.136g, 1.02mmol), DMF, compound 421(0.296g, 1.02mmol) in DMF (10ml total reaction volume), EDAC (0.193g, 1.02mmol) and triethylamine (0.284ml, 2.04mmol) were used. The product was purified by flash chromatography using 1: 1 ethyl acetate: hexane as eluent. The concentrate was dissolved in dichloromethane and washed with 10% potassium carbonate. The organics were separated, dried over magnesium sulfate and concentrated in vacuo. The resulting solid was triturated with ethyl acetate and filtered to give 446(0.0081g, 2%) as an off-white solid.1H NMR(DMSO-d6，400MHz)δ2.2(s，3H)，4.74(s，2H)，6.95(d，1H)，7.22(d，1H)，7.45(m，4H)，7.6(m，2H)，7.75(d，2H)，7.98(s，1H)，9.25(s，1H)，13.05(bs，1H)；MS(ES+)m/z 420(M+H)+。
Example 185
As in general procedure X, compound 399(0.314g, 1.4mmol) in acetonitrile (10ml total reaction volume), acid chloride 408(0.3g, 1mmol) and triethylamine (0.24ml, 1.7mmol) in acetonitrile were used. The product was dissolved in dichloromethane, washed with saturated potassium carbonate and water, and then purified by flash chromatography using 95: 5 dichloromethane to methanol As eluent, 447(0.305g, 63%) was obtained as an off-white foam.1H NMR(DMSO-d6，400MHz)δ2.03(s，3H)，2.63(d，2H)，2.85(t，2H)，3.5(d，2H)，3.7(t，2H)，4.74(s，2H)，6.71(d，1H)，6.78(d，1H)，6.84(s，1H)，7.18(m，2H)，7.3(d，1H)，7.5(d，1H)，7.59(dd，1H)，8.06(s，1H)，9.02(s，1H)；MS(ES+)m/z 487(M+H)+。
Example 187
As for general procedure X, compound 466(0.15g, 0.8mmol) in acetonitrile (10ml total reaction volume), acid chloride 427(0.2g, 0.6mmol) in acetonitrile and triethylamine (0.112ml, 0.8mmol) were used. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent, by TLC preparative plate chromatography eluting twice with 98: 2 dichloromethane: methanol to give 448 as an off-white solid (0.104g, 36%).1H NMR(DMSO-d6，400MHz)δ2.14(s，3H)，4.78(s，2H)，7.22(m，3H)，7.49(d，1H)，7.61(m，3H)，7.68(t，1H)，8.06(d，2H)，8.17(s，1H)，9.39(s，1H)；MS(ES-)m/z 482(M-H)-。
Example 187
As in general procedure X, compound 466(0.141g, 0.757mmol), triethylamine (0.106ml, 0.761mmol), acetonitrile (20ml total reaction volume) and acid chloride 434(0.203g, 0.523mmol) were used. The product was purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to afford 449(0.038g, 14%) as an off-white solid.1H NMR(DMSO-d6，400MHz)δ2.14(s，3H)，4.77(s，2H)，7.22(m，3H)，7.45(dd，2H)，7.6(m，4H)，7.72(d，1H)，7.82(d，1H)，7.88(s，1H)，9.3(s，1H)；MS(ES-)m/z536(M-H)-。
Example 188
As in general procedure X, compound 399(1.43g, 6.37mmol), triethylamine (0.888ml, 6.37mmol), acetonitrile (50ml total reaction volume) and acid chloride 434(1.68g, 4.64mmol) were used. The product was purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 450 as a beige solid (1.3g, 52%). 1H NMR(DMSO-d6，400MHz)δ1.98(s，3H)，2.62(d，2H)，2.85(t，2H)，3.5(d，2H)，3.69(t，2H)，4.67(s，2H)，6.75(dd，1H)，6.82(d，1H)，7.08(d，1H)，7.2(d，1H)，7.42(d，1H)，7.46(d，1H)，7.62(dd，1H)，7.7(d，1H)，7.81(d，1H)，7.88(s，1H)，8.9(s，1H)；MS(ES-)m/z 574(M-H)-。
Example 189
Trifluoroacetic acid (TFA, 5ml, 65mmol) was added to a solution of compound 452(0.095g, 0.17mmol) in acetonitrile (10ml) and stirred at room temperature under nitrogen overnight. Carbon tetrachloride was added to the reaction mixture and the resulting solution was concentrated in vacuo to remove TFA azeotropically. This step was repeated several times. The product was purified by flash chromatography using 1: 1 hexane: ethyl acetate as eluent to give 451 as a red/orange solid (0.012g, 16%).1H NMR(DMSO-d6，400MHz)δ2.04(s，3H)，3.15(s，4H)，3.21(d，4H)，4.75(s，2H)，6.7(d，1H)，6.75(d，1H)，6.8(s，1H)，7.2(dd，2H)，7.3(d，1H)，7.5(d，1H)，7.58(d，1H)，8.06(s，2H)，8.19(bs，1H)，9.05(s，1H)；MS(ES+)m/z454(M+H)+。
Example 190
As in general procedure X, compound 367(0.409g, 1.4mmol) in acetonitrile (5ml total reaction volume), acid chloride 408(0.3g, 1mmol) in acetonitrile and triethylamine (0.24ml, 1.7mmol) were used. The product was purified by flash chromatography using 99: 1 dichloromethane: methanol as eluent to give 452 as a brown, viscous oil (0.202g, 36%).1H NMR(DMSO-d6，400MHz)δ1.38(s，9H)，2.02(s，3H)，3.01(d，4H)，3.4(d，4H)，4.74(s，2H)，6.72(d，2H)，6.77(s，1H)，7.19(t，2H)，7.3(d，1H)，7.5(d，3H)，7.57(dd，1H)，8.05(s，1H)，9.01(s，1H)；MS(ES-)m/z 553(M-H)-。
Example 191
As in general procedure X, compound 413(0.072g, 0.49mmol) in acetonitrile (10ml total reaction volume), acid chloride 427(0.163g, 0.49mmol) in acetonitrile and triethylamine (0.1ml, 0.72mmol) were used. The product was purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to afford 453 as an off-white solid (0.013g, 6%). 1H NMR(DMSO-d6，400MHz)δ2.16(s，3H)，4.77(s，2H)，7.25(d，1H)，7.5(s，2H)，7.65(m，3H)，7.89(s，1H)，8.08(d，2H)，8.16(s，1H)，9.03(s，1H)，12.84(s，1H)；MS(ES-)m/z 443(M-H)-。
Example 192
As in general method V, carboxylic acid 76(0.2g, 0.55mmol), dichloromethane (CH) are used2Cl23ml), DMF (4 drops), oxalyl chloride (0.13ml, 1.49 mmol). The resulting acid chloride was added to a solution of amine 413(0.081g, 0.55mmol), acetone (5ml), sodium bicarbonate (0.42g, 5mmol) and water (0.5ml) as used in general procedure VI. The solution was heated to 40 ℃ for 1 hour, after which water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give 454(0.045g, 17%) as a grey solid.1H NMR(DMSO-d6，300MHz)δ2.2(s，3H)，4.85(s，2H)，7.3(d，1H)，7.56(s，2H)，7.7(d，1H)，7.77(s，3H)，7.9(s，2H)，9.2(s，1H)，12.9(s，1H)；MS(ES-)m/z 486(M-H)-。
Example 193
As general method V, carboxylic acid 71(0.2g, 0.53mmol), dichloromethane (3ml), DMF (4 drops), oxalyl chloride (0.123ml, 1.41mmol) were used. The resulting acid chloride was then added to a solution of amine 103(0.078g, 0.53mmol), acetone (5ml), sodium bicarbonate (0.4g, 4.76mmol) and water (0.5ml) as used in general procedure VI. The reaction mixture was heated to 40 ℃ for 1 hour, after which water (25ml) was added to the mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give 455(0.048g, 18%) as a grey solid.1HNMR(DMSO-d6，400MHz)δ2.13(s，3H)，4.78(s，2H)，7.2(d，1H)，7.5(d，2H)，7.65(d，2H)，7.88(s，3H)，7.98(d，1H)，9.15(bs，1H)，12.8(bs，1H)；MS(ES-)m/z 504(M-H)-。
Example 194
As for general method V, carboxylic acid 49(0.2g, 0.6mmol), dichloromethane (3ml), DMF (4 drops), oxalyl chloride (0.16ml, 1.8 mmol). The resulting acid chloride was then added to a solution of amine 413(0.09g, 0.61mmol), acetone (10ml), sodium bicarbonate (0.453g, 5.4mmol) and water (0.5ml) as used in general procedure VI. The reaction mixture was heated to 40 ℃ for 1 hour, after which water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give a grey solid. The product was purified by filtration through a pad of silica gel eluting with 9: 1 hexane: ethyl acetate. Hexane was added to the filtrate until a solid was formed. The solid was filtered to give 456(0.034g, 12%) as a white solid.1H NMR(DMSO-d6，300MHz)δ2.2(s，3H)，4.85(s，2H)，7.3(d，1H)，7.5(d，2H)，7.56(d，2H)，7.62(d，1H)，7.7(d，1H)，7.77(s，1H)，7.95(s，1H)，9.19(s，1H)，12.9(s，1H)；MS(ES-)m/z 454(M-H)-。
Example 195
Step A:
sodium sulfide nonahydrate (3.19g, 13.3mmol) was added to a solution of 5-fluoro-2, 4-dinitrotoluene (Maybrid, 2.47g, 12.3mmol) in DMF (20ml) and the resulting mixture was stirred under nitrogen overnight. Water was added to the reaction and the solution was acidified to pH 2. The suspension was filtered and the solid was washed with 1N HCl to give 458(4.73g, crude material) as a yellow/orange solid.1H NMR(DMSO-d6，400MHz)δ2.46(s，3H)，7.89(s，1H)，8.7(s，1H)。
And B:
as in general procedure XII, using compound 458(2.64g, 12.3mmol), palladium on carbon (2g, 10% w/w), ethanol (200ml) and THF (100ml), gave 459(0.35g, 18%) as a yellow solid. The crude material was used without purification.
And C:
formic acid (96%, 20ml) was added to compound 459 in a round bottom flask equipped with a stir bar, reflux condenser and nitrogen gas as needed. The mixture was refluxed overnight. The mixture was poured into 2N sodium hydroxide (200ml) and the pH was adjusted to 10. The mixture was extracted with ether, dried over magnesium sulfate and concentrated in vacuo to give an oil. The product was purified by flash chromatography using a gradient of 1: 1 hexane: ethyl acetate and ethyl acetate as eluent to give 460 as a white solid (0.03g, 8%).1H NMR(DMSO-d6，300MHz)δ2.2(s，3H)，5.09(bs，2H)，7.28(s，1H)，7.66(s，1H)，9.1(s，1H)；MS(ES+)m/z 165(M+H)+。
Step D:
as general procedure V, carboxylic acid 71(0.091g, 0.24mmol), dichloromethane (3ml), DMF (4 drops), oxalyl chloride (0.057ml, 0.65mmol) were used. The resulting acid chloride was then added to a solution of amine 460(0.03g, 0.18mmol), acetone (5ml), sodium bicarbonate (0.18g, 2.1mmol) and water (0.5ml) as used in general procedure VI. The mixture was filtered and the solid was washed with water, diethyl ether and ethyl acetate to give 457 as an off-white solid (0.064g, 67%).1H NMR(DMSO-d6，400MHz)δ2.18(s，3H)，4.79(s，2H)，7.25(d，1H)，7.54(d，1H)，7.65(dd，1H)，7.88(d，2H)，7.95(s，1H)，7.98(d，1H)，8.06(s，1H)，9.27(s，1H)，9.38(bs，1H)；MS(ES-)m/z 521(M-H)-。
Example 196
Carboxylic acid 71(0.091g, 0.24mmol), dichloromethane (3ml), DMF (4 drops), oxalyl chloride (0.057ml, 0.65mmol) was used as in general procedure V and added to a solution of 6-amino-1, 1-dioxobenzo (b) thiophene (Maybrid, 0.044g, 0.24mmol), acetone (10ml), sodium bicarbonate (0.184g, 2.2mmol) and water (1ml) as used in general procedure VI. The product was purified by filtration through a pad of silica gel eluting with dichloromethane. The organics were washed with saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The product was further purified by flash chromatography using 9: 1 dichloromethane: methanol as eluent to give 461 as a yellow solid (0.013g, 10%). 1H NMR(DMSO-d6，400MHz)δ4.75(s，2H)，7.2(d，1H)，7.25(d，1H)，7.5(d，1H)，7.54-7.58(m，2H)，7.59-7.64(m，2H)，7.85(d，2H)，7.9(d，1H)，8(s，1H)，10.4(s，1H)；MS(ES-)m/z 538(M-H)-。
2-aminotoluene-5-sulfonic acid (50.0g, 267mmol) and pyridine (300ml) were placed in a round bottom flask. Acetic anhydride (38ml, 403mmol) was added dropwise from the addition funnel and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give a brown solid. Several portions of ethanol were added to the solid, which was subsequently removed under reduced pressure to give a brown solid, which was filtered and washed with additional portions of ethanol, dried in vacuo (67.03g, 81%).1H NMR(DMSO-d6，)δ2.08(s，3H)，2.22(s，3H)，7.39(s，2H)，7.45(s，1H)，8.02(t，J＝6Hz，2H)，8.53(t，J＝6Hz，1H)，8.92(d，J＝6Hz，2H)，9.31(s，1H)。
Compound 462(67.03g, 217mmol) was added to a round bottom flask containing 1N sodium hydroxide (225ml) and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure to give a brown solid. Several portions of ethanol were added and subsequently removed under reduced pressure. The remaining solid was filtered, washed with the last portion of ethanol, and the solid was dried under vacuum (42.34g, 77%).1HNMR(DMSO-d6，300MHz)δ2.08(s，3H)，2.22(s，3H)，7.39(s，2H)，7.45(s，1H)，9.31(s，1H)。
The sulfonate 463(42.34g, 169mmol) and DMF (300ml) were added to a flask equipped with a stir bar and supplied with nitrogen if necessary, and cooled to 0 ℃. Thionyl chloride (30ml, 411mmol) was added dropwise from the addition funnel at a rate to maintain the temperature of the reaction mixture at no more than 10 ℃. When the addition was complete, the mixture was allowed to warm to room temperature and stirred for an additional 2.5 hours, after which it was poured into a beaker containing crushed ice. The resulting solid was collected by filtration, washed with several portions of water and dried in vacuo (25.63g, 61%). 1H NMR(DMSO-d6，400 MHz)δ2.02(s，3H)，2.15(s，3H)，7.33(s，2H)，7.38(s，1H)，9.27(s，1H)。
Sodium acetate (19.82g, 241.6mmol) and ethanol (200ml) were placed in a round bottom flask equipped with a stir bar and supplied with nitrogen if necessary, and the mixture was cooled to 0 ℃. Ammonia gas was bubbled through the sodium acetate solution for 5 minutes, then sulfonyl chloride 464(25.63g, 103mmol) was added as a solid in one portion. The resulting mixture was stirred at 0 ℃ for 30 minutes, then allowed to warm to room temperature and stirred for a further 18 hours. The mixture was then diluted with water and poured into a separatory funnel containing water and ethyl acetate. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 465(8.4g, 36%) as a yellow solid, which was used without purification.
A round bottom flask was equipped with a stirring rod, a reflux condenser and, if necessary, a nitrogen gas-supplying device, and sulfonamide 465(8.4g, 36.80mmol), ethanol (200ml) and 2N hydrochloric acid (128ml) were placed in the flask. The resulting mixture was heated to reflux overnight, after which it was cooled to room temperature and neutralized with saturated aqueous sodium bicarbonate. It was then poured into a separatory funnel containing water and ethyl acetate. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give a brown solid (6.35g, 93%) which was used without further purification. 1H NMR(DMSO-d6，400MHz)δ2.06(s，3H)，5.54(s，2H)，6.58(d，J＝12Hz，1H)，6.82(s，2H)，7.30(d，J＝12Hz，1H)，7.33(s，1H)。
Example 197:
step A:
the title compound was prepared according to general method VII from 3, 5-dimethoxybenzoyl chloride (2.00g, 10.0 mmol). The reaction yielded 468(2.143g, 95%) as a colorless oil:1HNMR(CDCl3，400MHz)δ6.75(d，2H)，6.49(t，1H)，3.76(s，6H)，3.55(s，3H)，3.29(s，3H)。
and B:
a solution of 2-bromo-4-chlorophenol (0.830g, 4.0mmol) in 20ml THF was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (5.5ml of a 1.6M solution in hexane, 8.8mmol) was added dropwise over 5 minutes, and the resulting mixture was stirred at-78 ℃ for 1 hour. A solution of 468(0.901g, 4.0mmol) in 5ml of THF is added dropwise over 4 minutes, and the resulting mixture is stirred at-78 ℃ for 1.25 hours and then at room temperature for 14 hours. The reaction mixture is poured into 50ml of water and extracted with two portions of 50ml each of ethyl acetate. The combined organic layers were then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.193g of a brown oil. Purification by flash chromatography using 10% ethyl acetate/hexane as eluent followed by crystallization from hot ether afforded 469(0.234g, 20%) as yellow crystals.1H NMR(CDCl3，300MHz)δ11.83(s，1H)，7.62(d，1H)，7.45(dd，1H)，7.03(d，1H)，6.76(d，2H)，6.68(t，1H)，3.84(s，6H)。
And C:
a solution of 466(5.0g, 26.85mol) and pyridine (2.4ml, 29.53mmol) in 150ml chloroform was cooled to 0 ℃ in an ice bath. Bromoacetyl bromide (2.6ml, 29.53mmol) was added dropwise over 20 min and the resulting mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture is then poured into 150ml of water and extracted with two portions of 100ml each of dichloromethane. The organic and aqueous layers were filtered to give a beige solid. The solid was suspended in 40ml of 1N HCl and stirred for a few minutes. The solid was then filtered and washed with dichloromethane, methanol and hexane. Yield 470(5.705g, 69%). 1H NMR(CDCl3，400MHz)δ9.84(s，1H)，7.66-7.56(m，3H)，7.23(br s，2H)，4.09(s，2H)，2.24(s，3H)。
Step D:
mixing 469(0.144g, 0.49mmol),A mixture of 470(0.162g, 0.53mmol) and potassium carbonate (0.339g, 2.45mmol) in 5ml of acetone was warmed to reflux for 6 hours and then stirred at room temperature overnight. The reaction mixture was dried overnight, an additional 5ml of acetone was added, and the resulting mixture was heated to reflux for 8 hours and then stirred at room temperature for 22 hours. The reaction mixture is poured into 30ml of water and extracted with two portions of 30ml each of ethyl acetate. The combined organic layers were filtered to remove solids, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.195g of a yellow solid. Purification by suspension in hot ether, followed by filtration. 467(0.094g, 37%) was obtained. MS (AP +) M/z 518.9(M + H);1H NMR(DMSO-d6，400MHz)δ9.15(s，1H)，7.63-7.60(m，3H)，7.56(dd，1H)，7.39(d，1H)，7.22(s，2H)，7.18(d，1H)，6.82(d，2H)，6.71(t，1H)，4.76(s，2H)，3.69(s，6H)，2.12(s，3H)。
example 198:
step A:
a solution of 1, 3, 5-tribromobenzene (9.44g, 30mmol) in 120ml diethyl ether was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (13.2ml of a 2.5M solution in hexane, 33mmol) was added dropwise over 10 minutes, the resulting mixture was stirred at-78 ℃ for a further 10 minutes, and hexachloroethane (7.15g, 30.2mmol) was added in portions over 3 minutes. The reaction mixture was then stirred at-78 ℃ for 15 minutes, followed by stirring at room temperature for 3.2 hours. The mixture was partitioned between 100ml water and 100ml ethyl acetate. The aqueous layer was separated, extracted with another 100ml of ethyl acetate, then the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 472 as a light brown solid (7.72g, 95%). 1H NMR(CDCl3，300MHz)δ7.57(t，1H)，7.47(d，2H)。
And B:
a solution of 472(7.62g, 28.2mmol) in 100ml of diethyl ether was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (12.6ml of a 2.5M solution in hexane, 31.5mmol) was added dropwise over 30 minutes. The resulting mixture was stirred at-78 deg.C for an additional 13 minutes, then 183(6.57g, 28.6mmol) was added in small portions over 23 minutes. The bath was then warmed to room temperature and the reaction mixture was stirred for 22 hours. The mixture is poured into 100ml of water and extracted with two portions of 100ml each of ethyl acetate. The combined organic layers were then dried over magnesium sulfate, filtered and concentrated in vacuo to give 9.46g of a beige solid. Recrystallization from hot methanol gave 473(6.45g, 64%): MS (AP)-)m/z 358(M-H)；1H NMR(CDCl3，300MHz)δ7.76(t，1H)，7.70(t，1H)，7.65(t，1H)，7.47(dd，1H)，7.36(d，1H)，6.95(d，1H)，3.72(s，3H)。
And C:
the title compound was prepared according to general method IX from 473(0.338g, 0.94 mmol). The reaction yielded 474(0.325g, 100%):1H NMR(CDCl3，400MHz)δ11.54(s，1H)，7.72(t，1H)，7.62(d，1H)，7.52(d，1H)，7.46(dd，1H)，7.41(d，1H)，7.02(d，1H)。
step D:
a mixture of 474(0.173g, 0.50mmol), 470(0.154g, 0.50mmol) and potassium carbonate (0.346g, 2.5mmol) in 10ml of acetone was warmed to reflux for 15 hours and then stirred at room temperature for a further 4 hours. The reaction mixture is then poured into 35ml of water and extracted with two portions of 35ml each of ethyl acetate. The aqueous layer was then filtered and another 20ml of ethyl acetate was added And (4) ester extraction. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.230g of a yellow oil. Purification by flash chromatography eluting with 0.5-1% methanol in dichloromethane afforded 471(0.048g, 17%). MS (AP)+)m/z 573(M+H)；1H NMR(DMSO-d6，400MHz)δ9.36(s，1H)，7.97(t，1H)，7.79(s，1H)，7.71(s，1H)，7.68-7.47(m，4H)，7.45(d，1H)，7.21(s，2H)，7.20-7.18(d，1H)，4.77(s，2H)，2.13(s，3H)。
Example 199:
step A:
a solution of 473(0.299g, 0.83mmol), sodium cyanide (0.086g, 1.76mmol), copper (I) iodide (0.028g, 0.15mmol) and tetrakis (triphenylphosphine) -palladium (0.113g, 0.10mmol) in 8ml acetonitrile was heated to reflux for 40 min. The reaction mixture was diluted with 50ml of ethyl acetate and filtered through celite. The resulting solution was washed with 25ml of water, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.375g of an orange gum. Purification by flash chromatography using 5% ethyl acetate/hexanes as eluent gave 476(0.171g, 56%):1H NMR(CDCl3，400MHz)δ7.93(t，1H)，7.82(t，1H)，7.76(t，1H)，7.47(dd，1H)，7.37(d，1H)，6.93(d，1H)，3.67(s，3H)。
and B:
the title compound was prepared according to general method IX from 476(0.165g, 0.54 mmol). The reaction yielded 477(0.174g, 100%):1H NMR(CDCl3，400MHz)δ11.43(s，1H)，7.84-7.82(m，2H)，7.78(t，1H)，7.49(dd，1H)，7.34(d，1H)，7.05(d，1H)。
and C:
a mixture of 477(0.157g, 0.54mmol), 470(0.165g, 0.54mmol) and potassium carbonate (0.373g, 2.7mmol) in 10ml acetone was warmed to reflux for 17.5 h. The reaction mixture is then poured into 35ml of water and extracted with two portions of 35ml each of ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.276g of a yellow oil. Purification by flash chromatography eluting with 0.5-1% methanol in dichloromethane afforded 475(0.033g, 12%). MS (AP-) M/z 517 (M-H); 1H NMR(DMSO-d6，400MHz)δ9.42(s，1H)，8.26(s，1H)，8.11(s，1H)，8.03(t，1H)，7.63(dd，1H)，7.60-7.53(m，3H)，7.49(d，1H)，7.22(s，2H)，7.19(d，1H)，4.77(s，2H)，2.14(s，3H)。
Example 200:
step A:
the title compound was prepared according to general method V from 3, 5-dimethylbenzoic acid (1.50g, 10.0 mmol). Working up the reaction gave 479(2.214g), which was used immediately without purification.
And B:
the title compound was prepared according to general procedure VII from 479(2.214 g). Working up the reaction gave 480 (2) as a yellow oil.073g，100％)：1H NMR(CDCl3，300MHz)δ7.26(s，2H)，7.07(s，1H)，3.57(s，3H)，3.33(s，3H)，2.33(s，6H)。
And C:
a solution of 2-bromo-4-chlorophenol (0.844g, 4.07mmol) in THF (20ml) was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (5.6ml of a 1.6M solution in hexane, 8.95mmol) was added dropwise over 6 minutes, and the resulting mixture was stirred at-78 ℃ for 1 hour. A solution of 480(0.786g, 4.07mmol) in 5ml THF was added dropwise over 6 minutes and the resulting mixture was stirred at-78 deg.C for 1.25 hours and at room temperature for 14 hours. The reaction mixture was then poured into 50ml of water and extracted with two portions of 50-ml each of ethyl acetate. The combined organic layers were then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.014g of a brown solid. Purification by flash chromatography using 5% ethyl acetate/hexane as eluent followed by crystallization from hot ether afforded 481 as yellow crystals (0.296g, 28%): 1H NMR(CDCl3，300MHz)δ11.94(s，1H)，7.57(d，1H)，7.44(dd，1H)，7.25(s，3H)，7.03(d，1H)，2.40(s，6H)。
Step D:
a mixture of 470(1.27g, 3.53mmol) and sodium iodide (1.61g, 10.7mmol) in 10ml of acetone was stirred at room temperature for 20.5 hours. The reaction mixture was then diluted with 60ml of water and 60ml of dichloromethane and stirred for a further 20 minutes. The mixture was then filtered to give 482(1.197g, 96%) as a beige solid:1H NMR(DMSO-d6，300MHz)δ9.81(s，1H)，7.65-7.61(m，3H)，7.26(s，2H)，3.90(s，2H)，2.28(s，3H)。
step E:
a mixture of 481(0.130g, 0.5mmol), 482(0.195g, 0.55mmol) and potassium carbonate (0.156g, 1.13mmol) in 5ml of acetone is warmed to reflux for 8 hours and then stirred at room temperature for a further 12 hours. The reaction mixture was then partitioned between 30ml water and 30ml ethyl acetate. The aqueous layer was separated and extracted with two portions of 30-ml each of dichloromethane. The layers were filtered to give 0.172g of an off-white solid. The solid was suspended in 200ml of hot acetone and filtered again to give 0.116g of a yellow solid. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.117g of a second yellow solid. The two yellow solids were combined and purified by flash chromatography eluting with 0.5-1% methanol in dichloromethane to give 478 as a white solid (0.108g, 44%). MS (AP)+)m/z 487(M+H)；1H NMR(DMSO-d6，400MHz)δ9.08(s，1H)，7.63-7.54(m，4H)，7.36(s，3H)，7.22-7.18(m，4H)，4.75(s，2H)，2.22(s，6H)，2.10(s，3H)。
Example 201:
step A:
a solution of 3, 5-dibromotoluene (1.25g, 5.0mmol) in 25ml of diethyl ether was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (2.2ml of a 2.5M solution in hexane, 5.5mmol) was added dropwise over 3 minutes. The resulting mixture was stirred at-78 ℃ for an additional 11 minutes, then hexachloroethane (1.18g, 5.0mmol) was added in small portions over 4 minutes. The reaction mixture was then stirred at-78 ℃ for 14 minutes, followed by stirring at room temperature for 17 hours. The reaction mixture was poured into 50ml of water and extracted with two portions of 50-ml each of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 484(0.885g, 86%) as a light brown solid. 1H NMR(CDCl3，300MHz)δ7.32(s，1H)，7.22(s，1H)，7.10(s，1H)，2.31(s，3H)。
And B:
a solution of 484(0.875g, 4.26mmol) in 24ml of diethyl ether was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (2.1ml of a 2.5M solution in hexane, 5.25mmol) was added dropwise over 5 minutes. The resulting mixture was stirred at-78 ℃ for an additional 15 minutes, then 183(0.978g, 4.26mmol) was added in small portions over 6 minutes. The bath was then warmed to room temperature and the reaction mixture was stirred for 26 hours. The reaction mixture was poured into 25ml of water and extracted with 50ml of dichloromethane. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.224g of a brown solid. Recrystallization from hot ether gave 485(0.536g, 43%):1H NMR(CDCl3，400MHz)δ7.48(s，1H)，7.45(s，1H)，7.40(dd，1H)，7.33(d，1H)，7.28(d，1H)，6.90(d，1H)，3.68(s，3H)，2.34(s，3H)。
and C:
the title compound was prepared according to general method IX from 485(0.295g, 1.0 mmol). The reaction yielded 486(0.285g, 100%):1H NMR(CDCl3，400MHz)δ11.71(s，1H)，7.46(d，1H)，7.43(dd，1H)，7.39(s，1H)，7.38(s，1H)，7.29(s，1H)，7.00(d，1H)，240(s，3H)。
step D:
a mixture of 486(0.141g, 0.5mmol), 482(0.195g, 0.55mmol) and potassium carbonate (0.138g, 1.0mmol) in 10ml of acetone was warmed to reflux for 8 hours and then stirred at room temperature for a further 8 hours. The reaction mixture was poured into 30ml of water and 30ml of acetic acid was addedExtraction with ethyl ester and 30ml of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.238g of crude material. Purification by flash chromatography eluting with 0.5-2% methanol in dichloromethane afforded 483(0.111g, 44%) as a white solid: 1H NMR(DMSO-d6，400MHz)δ9.23(br s，1H)，7.62-7.54(m，4H)，7.51(s，2H)，7.49(s，1H)，7.42(d，1H)，7.21(br s，2H)，7.19(d，1H)，4.76(s，2H)，2.27(s，3H)，2.12(s，3H)。
Example 202:
step A:
2-chloro-4-methyl-5-nitropyridine (Aldrich Chemical Co., 4.12g, 23.9mmol), thiourea (1.82g, 23.9mmol) and ethanol (40ml) were added to a heated dry 3-neck round bottom flask equipped with a nitrogen inlet and reflux condenser. After the ingredients were dissolved, the mixture was warmed to reflux and the solution was stirred under reflux for 3 hours. A yellow precipitate was observed after 2 hours. A solution of potassium hydroxide (2.01g, 35.9mmol) in water (8ml) was added and the mixture was heated for an additional 1 hour. The reaction mixture was cooled to room temperature and diluted with 1M sodium hydroxide (150 ml). The mixture was extracted with dichloromethane (75ml) and the pH of the aqueous layer was adjusted from 12 to 7 with glacial acetic acid. The resulting solid was filtered and dried in vacuo to give 488(2.36g, 58%).1H NMR(DMSO-d6，300MHz)δ8.47(s，1H)，7.25(s，1H)，2.39(s，3H)。
And B:
488(850mg, 5 m)mol) were suspended in 1N hydrochloric acid (13ml) and cooled to 0 ℃. Chlorine was bubbled through the suspension for 30 minutes at a rate to maintain the reactants near 0 ℃. After stopping the introduction of chlorine, the reaction mixture was stirred at 0 ℃ for a further 15 minutes. Chloroform (30ml) was added to the mixture and stirred at 0 ℃ until the solid dissolved. The layers were separated, the aqueous layer was extracted with chloroform (10ml), and the organic layers were combined, placed in a 100ml round bottom flask and cooled in an ice/water bath. Liquid ammonia (about 5ml) was added to the solution through a cold finger trap cooled to-78 ℃ (carbon dioxide/acetone). A precipitate formed and the mixture was allowed to warm to 0 ℃ for 5 minutes, followed by 1 hour at room temperature. The mixture was then heated to 45 ℃ and concentrated in vacuo to give a yellow solid which was washed with ether and dried to give 489 as a brown solid (856mg, 79%). 1H NMR(DMSO-d6，300MHz)δ9.25(s，1H)，8.13(s，1H)，2.69(s，3H)；MS(AP-)：m/z 217(M-)。
And C:
treatment of 489(2.36g, 10.88mmol) according to general procedure XII gave 490(2.05g, > 99%) which was used without further purification.
Step D:
acid 71(200mg, 0.53mmol) was treated according to general procedure V. The resulting product was then reacted with 490(0.53mmol) according to general procedure VI. The resulting product was purified by silica gel chromatography (5% methanol/dichloromethane) followed by recrystallization from acetonitrile/water to yield 487(27mg, 9%).1H NMR(DMSO-d6，400MHz)δ9.7(s，1H)，8.61(s，1H)，7.97(d，J＝8.4，1H)，7.85(m，2H)，7.76(s，1H)，7.63(dd，J＝9，2.8，1H)，7.51(d，J＝2.7，1H)，7.34(s，1H)，7.21(d，J＝9.2，1H)，4.80(s，2H)，2.17(s，3H)；MS(ES+)：m/z 546(M+)。
Example 203:
step A:
3, 5-dibromofluorobenzene (1.12g, 4.4mmol) and dehydrated ether (8ml) were placed in a 2-necked flask equipped with a nitrogen inlet. The solution was cooled to-78 deg.C (carbon dioxide/acetone) and n-butyllithium (2.5M in hexane, 1.92ml, 4.8mmol) was added dropwise. The resulting solution was stirred at-78 ℃ for 10 minutes, after which time a solution of N-methyl-N-methoxy-2-methoxy-5-chlorobenzamide (1g, 4.37mmol) in diethyl ether (40ml) was added dropwise. The cooling bath was removed and the reaction allowed to warm to room temperature and stirred for an additional 1 hour, followed by addition of 1M phosphoric acid (50 ml). The mixture was stirred for 30 minutes and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. The product was then triturated with methanol to give 492 as a white solid (0.63mg, 42%). 1H NMR(CDCl3，300MHz)δ7.72(s，1H)，7.53-7.39(m，4H)，6.99(d，J＝8.9，1H)，3.76(s，3H)。
And B:
492(1.3g, 3.8mmol) was treated according to general procedure XV to give 493(1.09g, > 99%).1H NMR(CDCl3，300MHz)δ7.83(s，1H)，7.78(d，J＝8.7，1H)，7.60-7.53(m，2H)，7.44(d，J＝2.6，1H)，7.00(d，J＝8.8，1H)，3.75(s，3H)；MS(EI+)：m/z 289(M+)。
And C:
treatment 493 according to the procedure used for the synthesis of compound 4 gave 494(1.09g, > 99%).1H NMR(CDCl3，300MHz)δ11.51(s，1H)，7.79(s，1H)，7.67(d，J＝7.8，2H)，7.57(dd，J＝9.0，2.4，1H)，7.44(d，J＝2.4，1H)，7.13(d，J＝9.0，1H)；MS(ES-)：m/z 274(M-H)-。
Step D:
494 are treated according to general procedure II. The product was purified by silica gel chromatography (20% ethyl acetate/hexane) to afford 495 as a clear oil (1.27g, 89%).1H NMR(CDCl3，400MHz)δ7.90(s，1H)，7.80-7.78(m，1H)，7.50-7.42(m，3H)，6.76(d，J＝8.6，1H)，4.49(s，2H)，4.18(q，J＝14.2，7.1，2H)，1.21(t，J＝3.5，3H)。
Step E:
treatment 495 according to general procedure III gave 496 as a white solid (1.0g, 85%) which was used without further purification.1H NMR(DMSO-d6，400MHz)δ8.09(d，J＝7.9，1H)，8.00(s，1H)，7.90(d，J＝8.8，1H)，7.55(dd，J＝8.9，2.5，1H)，7.43(d，J＝2.6，1H)，7.03(d，J＝9.0，2H)；MS(ES-)：m/z 332(M-H)-。
Step F:
using 496 according to general procedure V and further reacting it with compound 466 according to general procedure VI gave 491(290mg, 58%) as a white solid.1H NMR(DMSO-d6，400MHz)δ9.43(s，1H)，8.1(d，J＝8.2，1H)，8.02(s，1H)，7.88(d，J＝9.0，1H)，7.64-7.48(m，5H)，7.22-7.17(m，3H)，4.77(s，2H)，2.14(s，3H)；MS(ES-)：m/z 500(M-H)-。C23H17N3O5Analytical calculation of ClFS: c, 55.04; h, 3.41; n, 8.37. Measured value: c, 55.07; h, 3.56; and N, 8.35.
Example 204:
496 was treated according to general procedure V and then further reacted with compound 490 according to general procedure VI. The product was purified by silica gel chromatography (5% methanol/dichloromethane) followed by washing with ethyl acetate/hexane to give 497(48mg, 19%).1H NMR(DMSO-d6，400MHz)δ9.73(s，1H)，8.64(s，1H)，8.10(d，J＝8.1，1H)，8.02(s，1H)，7.88(d，J＝8.8，1H)，7.76(s，1H)，7.62(dd，J＝8.9，2.7，1H)，7.49(d，J＝2.5，1H)，7.35(s，2H)，4.81(s，2H)，2.20(s，3H)；MS(ES-)：m/z 501(M-H)-。C22H16N4O5Analytical calculation of ClFS: c, 52.54; h, 3.21; n, 11.14. Measured value: c, 52.30; h, 3.34; and N, 10.96.
Example 205:
step A:
2-bromo-4-ethylphenol was treated according to the method outlined by Selnick et al in Tetrahedron Lett.1993, 34, 2043-Buchner 2046 (according to the method of Sargent et al in J.chem.Soc.Perkin Trans.l, 1984, 1621)Preparation) and N-methyl-N-methoxy-2-methoxy-5-chlorobenzamide to give 499(185mg, 11%).1H NMR(CDCl3，400MHz)δ7.37(dd，J＝8.7，2.5，1H)，7.32-7.22(m，1H)，7.16(s，1H)，7.03(s，1H)，6.98-6.84(m，2H)，5.16(bs，1H)，3.69(s，3H)，2.59(q，J＝15.2，7.5，2H)，1.18(t，J＝7.6，3H)。
And B:
499(185mg, 0.64mmol) was dissolved in DMF (2ml), treated with sodium hydride (31mg 60% suspension in oil, 0.8mmol) and the resulting mixture was stirred for 30 min until foaming ceased. N-phenyl trifluoromethanesulfonimide (triflimide) (286mg, 0.8mmol) was added in one portion. The mixture was stirred for 3 hours and then partitioned between ether and water (50 ml each). The organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo to give 500(256mg, 95%) which was used without purification. MS (ES)+)：m/z 423(M+H+)。
And C:
treatment 500(256mg, 0.61mmol) according to general procedure XV gave the crude product which was purified by silica gel chromatography (20% ethyl acetate/hexane) to give 501(158mg, 87%).1H NMR(CDCl3，400MHz)δ7.85(s，1H)，7.74(s，1H)，7.63(s，1H)，7.44(dd，J＝8.9，2.6，1H)，7.33(d，J＝2.7，1H)，6.91(d，J＝8.8，1H)，3.66(s，3H)，2.71(q，J＝15.2，7.5，2H)，1.24(t，J＝7.6，3H)。
Step D:
treatment of 501(158mg, 0.53mmol) according to the method used to synthesize compound 4 gave 502(152mg, > 99%) as a yellow solid, which was used without further purification. MS (ES) -)：m/z 284(M-H)-。
Step E:
treatment of 502(152mg, 0.53mmol) and 470 according to the method used for synthesis 467 gave the crude product, which was triturated with 10% methanol/ether to give 498(100mg, 37%).1H NMR(DMSO-d6，300MHz)δ9.42(s，1H)，8.03-7.99(m，2H)，7.69-7.61(m，4H)，7.54(d，J＝2.6，1H)，4.84(s，2H)，2.72(q，J＝15.1，7.6，2H)，2.20(s，3H)，1.19(t，J＝7.5，3H)；MS(ES-)：m/z 284(M-H)-。
Example 206:
step A:
concentrated sulfuric acid (200ml) was cooled to 5 ℃ and 6-methyl-2-pyridylamine (50g, 0.46mol, Aldrich Chemical Co.) was added over 20 minutes while maintaining the reaction temperature below 50 ℃. Fuming nitric acid (30ml) was then added slowly over 30-40 minutes, and the resulting mixture was allowed to warm to room temperature and stand for about 1 hour. The reaction was then heated to 55 ℃ for 1 hour and then carefully poured into a mixture of 5N sodium hydroxide (1L) and ice. The final pH was adjusted to 10 with 5N sodium hydroxide, then 1N sodium hydroxide and the product precipitated as a mixture of 6-methyl-4 and 5-nitro-2-pyridylamine in 75% yield. Pure sample 504 is provided by sublimation. GCMS (EI)+)153m/z。1H NMR(DMSO-d6)δ8.2(d，1H，Ar)，7.9(bs，2H，NH2)，6.6(d，1H，Ar)，2.4(s，3H，CH3). The structure of the compound is verified by heteronuclear multiple bond coherence experiments (HMBC). The proton on the 6-methyl group shows triple bond coupling with the 5-carbon atom carrying the nitro group.
And B:
a mixture of 504 and 6-methyl-4-nitro-2-pyridylamine (0.5g, 3.3mmol) was stirred with carbon tetrachloride (15 ml). A solution of trimethylsilyl chloride in dichloromethane (1M, 10ml, 10mmol) was added and the reaction heated in an oil bath at 70 ℃ for 30 min. Trimethylsilyl chloride (0.5ml, 4mmol) was added and the reaction was heated for an additional 30 minutes. Tert-butyl nitrite (4ml, 30mmol, 10eq) was added and the reaction heated to reflux overnight. The reaction was filtered and the solvent removed in vacuo. The column was separated 505 by chromatography on a 4X 15cm silica gel column, eluting with hexane/ethyl acetate (6: 1, 1L). GCMS (CI) +)173m+1/z。1H NMR(CDCl3)δ8.2(d，1H，Ar)，7.3(d，1H，Ar)，2.8(s，3H，CH3). The structure of the compound is verified by heteronuclear multiple bond coherence experiments (HMBC). The proton on the 6-methyl group shows triple bond coupling with the 5-carbon atom carrying the nitro group.
And C:
505(0.4g, 2.4mmol) was dissolved in ethanol (30ml), thiourea (0.2g, 2.6mmol, 1.1eq.) was added and the reaction was refluxed for 7 hours. Potassium hydroxide (0.2g, 3.6mol, 1.5eq.) dissolved in water (1ml) was added to the reaction and heating was continued for 1 hour. The solution was diluted with 1N sodium hydroxide (25 ml). The aqueous phase was extracted with dichloromethane (25ml, 3 ×). The pH was adjusted to 4 with concentrated HCl and precipitated 506. A yield of 30% was obtained. LCMS (APCI)+)171m+1/z。1HNMR(DMSO-d6)δ7.9(d，1H，Ar)，7.1(d，1H，Ar)，2.7(s，3H，CH3)。
Step D:
506(0.115g, 0.67mmol) was stirred in 1N hydrochloric acid (5ml) and cooled to 5 ℃. Chlorine gas was bubbled through the mixture for 30 minutes, then the reaction was stirred for an additional 15 minutes. The product was extracted with dichloromethane (5ml, 2 ×). The organic fractions were combined and cooled to 0 ℃. Liquid ammonia, after condensation of ammonia gas by means of a-78 ℃ cold finger, was added dropwise to the solution for 15 minutes. The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (15ml) and washed with sodium bicarbonate solution (15 ml). The solution was dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 507 in 40% yield, which was suitable for further use. GCMS (CI) +)218m+1/z。1H NMR(DMSO-d6)δ8.6(d，1H，Ar)，7.9(d，1H，Ar)，7.7(bs，2H，NH2)，2.8(s，3H，CH3)。
Step E:
the reduction of 507(0.06g, 0.27mmol) of the 5-nitro group was accomplished by catalytic reduction in ethanol (10ml) with 10% Pd/C (0.011 g). The reaction was allowed to proceed overnight. The catalyst was removed by filtration and the amino compound was coupled to the acid chloride 589 produced by general procedure V by the method outlined in general procedure VI to afford 503. LCMS (ES)+)499m+l/z。1H NMR(DMSO-d6)δ9.6(br s，1H，NH)，8.0(d，1H，Ar)，7.94(s，1H，Ar)，7.89(s，1H，Ar)，7.87(s，1H，Ar)，7.7(d，1H，Ar)，7.6(dd，1H，Ar)，7.45(d，1H，Ar)，7.32(bs，2H，NH2)，7.2(d，1H，Ar)，4.8(s，2H，CH2)，2.35(s，3H，CH3)，2.33(s，3H，CH3)。
Example 207:
step A:
3-methyl-2-pyridylamine (1ml, 1mmol, Aldrich Chemical Co.) was mixed with 20% oleum (2ml) at room temperature. The reaction was heated to 160 ℃ for 20 hours. The reaction was allowed to cool to room temperature and about 10ml of ice was added. The product was precipitated and collected by filtration. 509 was obtained in 50% yield. LCMS (ES)+)189m+1/z。1H NMR(DMSO-d6)δ13(br s，1H，SO3H)，7.88(s，3H，1-Ar，2H，NH2)，7.87(s，1H，Ar)，2.14(s，3H，CH3)。
And B:
509(0.9g, 4.8mmol) was mixed with DMF (30 ml). Thionyl chloride (0.5ml, 6.8mmol, 1.4eq) was added and the reaction stirred at room temperature. A solution is temporarily formed. A new precipitate formed. The reaction was stirred for 30-40 minutes and filtered. The product was washed with hexane, which was suitable for further use. Obtained in 77% yield 510. LCMS (ES)+)244 m+l/z。1H NMR(DMSO-d6) Δ 8.4(s, 1H, formyl-H), 7.9(s, 2H, Ar), 3.4(s, 3H, CH)3)，3.3(s，3H，CH3)，2.35(s，3H，CH3)。
And C:
reaction of 510(1.0g, 4.1mmol) with PCl5(0.85g, 4.1mmol) and heated in an oil bath at 130 ℃ for 1.5 hours. Removing product POCl under high vacuum 3. At room temperatureConcentrated ammonium hydroxide (25ml) was carefully added. The reaction was heated to reflux for 3-4 hours and then allowed to stand at room temperature for 60 hours. The product was collected by filtration. Obtained in 45% yield 511. LCMS (ES)+)1 88m+l/z。1H NMR(DMSO-d6)δ8.12(s，1H，Ar)，7.5(s，1H，Ar)，7.0(s，2H，NH2)，6.45(s，1H，Ar)，2.0(s，3H，CH3)。
Step D:
511(0.07g, 0.37mmol) was mixed with THF (5ml) and (TMS)2BSA (0.090ml, 2eq.) was mixed. The reaction was refluxed for 45 minutes. The solution was allowed to cool to room temperature and acid chloride 589(1eq.) prepared according to general procedure V was added. The reaction was stirred at room temperature for 2 hours and the solvent was removed in vacuo. The product was partially purified by chromatography on a 4X 6cm column of silica eluting with chloroform/methanol (96: 4) followed by chromatography on a 4X 6cm column of silica eluting with chloroform/methanol (95: 5). Final purification was done by HPLC on a Waters Symmetry C18 column (1.9X 15cm), eluting with methanol/water (3: 2) at a flow rate of 8ml/min. Obtained in 10% yield to 508. LCMS (APCI)+)499m+l/z。1H NMR(DMSO-d6)δ10.2(br s，1H，NH)，8.56(s，1H，Ar)，7.98(s，1H，Ar)，7.91(s，1H，Ar)，7.87(s，2H，Ar)，7.60(dd，1H，Ar)，7.47(s，2H，NH2)，7.44(s，1H，NH2)，7.12(d，1H，Ar)，4.8(s，2H，CH2)，2.32(s，3H，CH3)，2.10(s，3H，CH3)。
Example 208:
acid chloride was prepared according to general procedure V using carboxylic acid 71(0.258g, 0.68mmol), oxalyl chloride (0.8ml, 2.0M solution in dichloromethane, 0.92mmol), DMF (8 drops) and dichloromethane (5 ml). The acid chloride was then dissolved in acetone and added dropwise to 6-aminoindoline dihydrochloride (Aldrich, 0.140g, 0.68mmol), acetone (10ml), carbon as in general procedure VI Sodium hydrogen carbonate (0.501g, 6mmol) and water (1 ml). Ice (5ml) was added to the reaction mixture, and the resulting suspension was filtered, washed with water and diethyl ether, and then air-dried. The solid was then purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 512(0.06g, 18%).1H NMR(DMSO-d6，300MHz)δ2.92(t，2H)，3.94(t，2H)，4.93(m，3H)，6.21(dd，1H)，6.84(d，1H)，7.19(d，1H)，7.32(m，1H)，7.51(d，1H)，7.58(dd，1H)，8(m，3H)；LC-MS(ES+)m/z 493(M+H)+，LC-MS(ES-)m/z 491(M-H)-。
Example 209:
step A:
a mixture of 464(1.10g, 4.4mmol), 1- (2-aminoethyl) pyrrolidine (0.84ml, 6.6mmol) and pyridine (0.39ml, 4.8mmol) in dichloromethane (50ml) was stirred at room temperature for 6 days. The reaction mixture was then diluted with 50ml of dichloromethane and extracted with two 50-ml portions of water. The organic layer was dried over magnesium sulfate and filtered to give 1.021g of a brown oil. Purification by flash chromatography (eluting with 3-5% methanol in dichloromethane) afforded 514(0.776g, 54%) as a yellow oil: MS (ES)+)m/z 326(m+H)；1H NMR(CDCl3，400MHz)δ8.19-8.17(m，1H)，7.70-7.68(m，2H)，7.19(br s，1H)，2.98(t，2H)，2.52(t，2H)2.37-2.34(m，4H)，2.32(s，3H)，2.25(s，3H)，1.73-17.0(m，4H)。
And B:
a mixture of 514(0.765g, 2.35mmol) and 1.5M HCl (5ml) in 20ml ethanol was heated to 80 ℃ for 18 h. The reaction mixture was then poured into 50ml of saturated sodium bicarbonate (aq) and extracted with two portions of 30-ml each of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 515(0.564g, 81%): MS (ES) +)m/z284(m+H)；1H NMR(CDCl3，400MHz)δ7.54-7.50(m，2H)，6.68(d，1H)，4.07(br s，2H)，2.98-2.95(m，2H)，2.54-2.52(m，2H)2.39-2.32(m，4H)，2.18(s，3H)，1.75-1.68(m，4H)。
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, amine 515(0.07g, 0.29mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.1g, 0.29mmol) were used. Water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give 513(0.015g, 8.7%) as an off-white solid.1H NMR(DMSO-d6，300MHz)δ1.65(m，4H)，2.2(s，3H)，2.85(t，2H)，3.35(m，6H)，4.83(s，2H)，7.22(d，1H)，7.43-7.72(m，8H)，9.48(s，1H)；MS(ES+)m/z 592(M+H)+。
Example 210:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 315(0.066g, 0.29mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.1g, 0.29mmol) were used. Water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was dissolved in dichloromethane and then chromatographed by TLC preparative plate eluting with 9: 1 dichloromethane: methanol to give 516 as an off-white solid (0.074g, 48%).1HNMR(DMSO-d6，400MHz)δ0.4(m，2H)，0.42(m，2H)，2(m，1H)，2.2(s，3H)，4.8(s，2H)，7.18(d，1H)，7.38(m，2H)，7.41(d，1H)，7.46-7.61(m，4H)，7.69(d，1H)，7.76(d，1H)，9.38(s，1H)；MS(ES+)m/z 535(M+H)+，MS(ES-)m/z 533(M-H)-。
Example 211:
step A:
a mixture of 464(1.10g, 4.4mmol), cyclopropylmethylamine (Aldrich, 0.57ml, 6.6mmol) and pyridine (0.39ml, 4.8mmol) in 50ml dichloromethane was stirred at room temperature for 7 days. The reaction mixture was then filtered and washed with 50ml dichloromethane and 50ml water. The organic layer was washed with another 50ml of water, brine, dried over magnesium sulfate, filtered and concentrated. The crude material was crystallized from methanol to give 518(0.348g, 28%): 1H NMR(DMSO-d6，400MHz)δ9.39(s，1H)，7.72(d，1H)，7.58-7.52(m，3H)，2.59(t，2H)，2.25(s，3H)2.07(s，3H)，0.80-0.72(m，1H)，0.34-0.29(m，2H)，0.06-0.03(m，2H)。
And B:
a mixture of 518(0.310g, 1.1mmol) and 1.5M HCl (2.5ml) in 12ml ethanol was heated to 80 ℃ for 18 h. The reaction mixture was then poured into 50ml of saturated sodium bicarbonate (aq) and extracted with two portions of 30-ml each of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 519(0.284g), which was used without further purification: MS (ES)+)m/z 241(M+H)；1H MR(CDCl3，400MHz)δ7.54-7.51(m，2H)，6.68(d，1H)，4.41(t，1H)，4.06(br s，2H)，2.78(t，2H)，2.18(s，3H)，0.92-0.83(m，1H)，0.48-0.43(m，2H)，0.11-0.07(m，2H)。
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 519(0.07g, 0.29mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.1g, 0.29mmol) were used. Water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give 517(0.129g, 81%) as an off-white solid.1H NMR(DMSO-d6，300MHz)δ0.1(m，2H)，0.36(m，2H)，0.82(m，1H)，2.2(s，3H)，2.64(t，2H)，4.86(s，2H)，7.25(d，1H)，7.46-7.74(m，9H)，9.44(s，1H)；MS(ES+)m/z 549(M+H)+，MS(ES-)m/z 547(M-H)-。
Example 212:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 318(0.07g, 0.29mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.1g, 0.29mmol) were used. Water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give 520 as an off-white solid (0.126g, 79%). 1H NMR(DMSO-d6，300MHz)δ1.66(m，4H)，2.26(s，3H)，3.35(m，4H)，4.87(s，2H)，7.25(d，1H)，7.47-7.7(m，7H)，7.82(d，1H)，9.43(s，1H)；MS(ES+)m/z 549(M+H)+，MS(ES-)m/z 547(M-H)-。
Example 213:
step A:
a mixture of 464(1.10g, 4.4mmol), diethylamine (0.68ml, 6.6mmol) and pyridine (0.39ml, 4.8mmol) in 50ml dichloromethane was stirred at room temperature for 5 days. The reaction mixture was then diluted with 100ml of dichloromethane and washed with two 50-ml portions of water. The organic layer was washed with brine, dried over magnesium sulfate and filtered to give 1.2g of an orange oil. Crystallization from ethyl acetate/hexane gave 522 as orange crystals (0.446g, 36%): MS (ES)+)m/z285(M+H)；1H NMR(CDCl3，400MHz)δ8.08(d，1H)，7.61-7.58(m，2H)，3.21(q，4H)，2.29(s，3H)2.24(s，3H)，1.13(t，6H)。
And B:
a mixture of 522(0.341g, 1.2mmol) and 1.5M HCl (2.5ml) in 12ml ethanol was heated to 80 ℃ for 18 h. The reaction mixture was then poured into 50ml of saturated sodium bicarbonate (aq) and extracted with two portions of 30-ml each of dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 523(0.285g, 98%) as a yellow solid: MS (ES)+)m/z 243(m+H)；1H NMR(CDCl3，400MHz)δ7.48-7.45(m，2H)，6.66(d，1H)，4.02(br s，2H)，3.19(q，4H)，2.18(s，3H)，1.12(t，6H)。
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 523(0.07g, 0.29mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.1g, 0.29mmol) were used. Water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give 521 as an off-white solid (0.117g, 73%). 1H NMR(DMSO-d6，300MHz)δ1.06(t，6H)，2.24(s，3H)，3.16(m，4H)，4.86(s，2H)，7.25(d，1H)，7.47-7.70(m，7H)，7.77(d，1H)，9.43(s，1H)；MS(ES+)m/z 551(M+H)+，MS(ES-)m/z 549(M-H)-。
Example 214:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 312(0.062g, 0.29mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.1g, 0.29mmol) were used. Water (25ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was washed with diethyl ether to give 524(0.109g, 70%) as an off-white solid.1H NMR(DMSO-d6，400MHz)δ0.99(t，3H)，2.23(s，3H)，2.77(m，2H)，4.86(s，2H)，7.25(d，1H)，7.46-7.75(m，9H)，9.45(s，1H)；MS(ES+)m/z 523(M+H)+，MS(ES-)m/z 521(M-H)-。
Example 215:
step A:
sulfonyl chloride 464(0.27g, 1.09mmol) was added in portions to a large tube containing a stir bar, pyridine (5ml), and 2- (2-aminoethyl) pyridine (Aldrich, 0.28g, 2.3 mmol). The mixture was stirred for 2 days. Water was added and the mixture was extracted with dichloromethane, concentrated and purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 526(0.70g, 51%):1HNMR(DMSO-d6，400MHz)δ2.05(s，3H)，2.22(s，3H)，2.77(t，2H)，3.03(t，2H)，7.13(dd，2H)，7.48-7.71(m，5H)，8.38(dd，1H)，9.37(s，1H)。
and B:
using sulfonamide 526(0.7g, 2.09mmol), 1.5N HCl (10ml), and ethanol (10ml) according to general procedure XVII, 527(0.11g, 18%) was obtained. The crude product was used without further purification.
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 527(0.05g, 0.17mmol), acid chloride (0.19mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol) and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 525(0.03g, 33%): 1H NMR(DMSO-d6，400MHz)δ2.18(s，3H)，2.81(t，2H)，3.08(m，2H)，4.83(s，2H)，7.16-7.23(m，3H)，7.43-7.7(m，10H)，8.42(m，1H)，9.41(s，1H)；MS(ES+)m/z 600(M+H)+，MS(ES-)m/z 598(M-H)-。
Example 216:
step A:
sulfonyl chloride 464(0.27g, 1.09mmol) was added in portions to a large tube containing a stir bar, pyridine (5ml), and aminopropylmorpholine (Aldrich, 0.33g, 2.3 mmol). The mixture was stirred for 2 days, followed by addition of water and extraction with dichloromethane. The organic layer was concentrated and the product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 529(0.7g, 49%):1HNMR(DMSO-d6，400MHz)δ1.44(m，2H)，2.05(s，3H)，2.12(m，4H)，2.23(s，2H)，2.7(m，2H)，3.45(m，4H)，7.41(t，1H)，7.5(dd，1H)，7.55(d，1H)，7.71(d，1H)，9.38(s，1H)。
and B:
using sulfonamide 529(0.7g, 1.96mmol), 1.5N HCl (10ml) and ethanol (10ml) according to general procedure XVII gave 530(0.15g, 24%). The crude product was used without further purification.
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 530(0.05g, 0.16mmol), acid chloride (0.19mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol), and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 528(0.01g, 6%):1H NMR(DMSO-d6，400MHz)δ0.8(m，1H)，1.18(s，1H)，1.43(m，2H)，2.15(m，7H)，2.7(m，2H)，3.44(m，4H)，4.78(s，2H)，7.18(d，1H)，7.39-7.67(m，9H)，9.38(s，1H)；LC-MS(ES+)m/z 623(M+H)+，MS(ES-)m/z 621(M-H)-。
example 217:
step A:
add sulfonyl chloride 464(0.27g, 1.09mmol) portionwise with stirringRods, pyridine (5ml) and 1- (2-morpholinoethyl) piperazine (EMKA, 0.46g, 2.3mmol) in large tubes. The mixture was stirred for 2 days, followed by addition of water and extraction with dichloromethane. The organic layer was concentrated and the product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 532(0.3g, 19%): 1H NMR(DMSO-d6，400MHz)δ2.07(s，3H)，2.27(m，9H)，2.38(m，2H)，2.45(m，4H)，2.85(m，2H)，3.3(m，2H)，3.5(m，4H)，7.46(m，2H)，7.82(d，1H)，9.4(s，1H)。
And B:
using sulfonamide 532(0.3g, 0.73mmol), 1.5N HCl (10ml), and ethanol (10ml) according to general procedure XVII, 533(0.08g, 30%) was obtained. The crude product was used without further purification.
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 533(0.05g, 0.14mmol), acid chloride (0.19mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol), and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 531(0.01g, 7%):1H NMR(CDCl3，400MHz)δ2.29(s，3H)，2.38-2.54(m，12H)，2.97(bs，4H)，3.63(m，4H)，4.69(s，2H)，7-7.1(m，2H)，7.29-7.35(m，3H)，7.51-7.57(m，3H)，8.1(d，1H)，8.66(s，1H)。
example 218:
step A:
as in general method XVI, sulfonyl chloride 464(3mmol), pyridine (5ml), and 2- (2-methylaminoethyl) pyridine (Aldrich, 0.41g, 3.01mmol) were used. The mixture was stirred for 2 days. Water was added and the mixture was extracted with dichloromethane and the organic layer was concentrated in vacuo. The resulting product was dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo and the product purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 535(0.28g, 30%).
And B:
Acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 535(0.05g, 0.16mmol), acid chloride (0.15mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol), and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 534(0.04g, 40%):1H NMR(DMSO-d6，400MHz)δ2.21(s，3H)，2.67(s，3H)，2.93(m，2H)，4.08(m，2H)，4.83(s，2H)，7.18-7.27(m，3H)，7.43-7.77(m，9H)，8.46(m，1H)，9.41(s，1H)；LC-MS(ES+)m/z 614(M+H)+，LC-MS(ES-)m/z 612(M-H)-。
example 219:
step A:
as in general method XVI, sulfonyl chloride 464(3mmol), pyridine (5ml) and 3-picolylamine (Aldrich, 0.25g, 2.3mmol) were used. The mixture was stirred for 2 days, then addedAnd (3) water. The reaction mixture was extracted with dichloromethane, the organic layer was separated and concentrated in vacuo. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 537(0.9g, 67%).1H NMR(DMSO-d6，400MHz)δ2.06(s，3H)，2.22(s，3H)，3.96(d，2H)，7.24(dd，1H)，7.54(m，3H)，7.71(d，1H)，8.06(t，1H)，8.36(d，2H)，9.37(s，1H)。
And B:
using sulfonamide 537(0.9g, 2.81mmol), 1.5N HCl (10ml) and ethanol (10ml) according to general procedure XVII, gave 538(0.25g, 32%). The crude product was used without further purification.
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 538(0.05g, 0.18mmol), acid chloride (0.15mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol) and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to afford 536(0.03g, 27%): 1H NMR(DMSO-d6，300MHz)δ2.18(s，3H)，4(d，2H)，4.83(s，2H)，7.22(d，1H)，7.28(dd，1H)，7.45(m，2H)，7.51(d，1H)，7.57-7.72(m，6H)，8.13(t，1H)，8.41(m，2H)，9.42(s，1H)；LC-MS(ES+)m/z 586(M+H)+，LC-MS(ES-)m/z 584(M-H)-。
Example 220:
step A:
as in general method XVI, sulfonyl chloride 464(1.1mmol), pyridine (5ml) and 4-picolylamine (Aldrich, 0.25g, 2.3mmol) were used. The mixture was stirred for 2 days, followed by addition of water. The mixture was extracted with dichloromethane, the organic layer was separated and concentrated in vacuo. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 540(0.5g, 37%).1H NMR(DMSO-d6，400MHz)δ2.06(s，3H)，2.21(s，3H)，3.95(d，2H)，7.21(d，2H)，7.52(m，2H)，7.71(m，1H)，8.14(t，1H)，8.41(dd，2H)，9.38(s，1H)。
And B:
using sulfonamide 540(0.5g, 1.56mmol), 1.5N HCl (10ml), and ethanol (10ml) according to general procedure XVII, 541(0.12g, 28%) was obtained. The crude product was used without further purification.
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 541(0.05g, 0.18mmol), acid chloride (0.15mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol), and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The product was purified by flash chromatography and TLC preparative plate chromatography using 95: 5 dichloromethane: methanol as eluent to give 539(0.02g, 19%):1H NMR(DMSO-d6，400MHz)δ2.18(s，3H)，4.01(m，2H)，4.83(s，2H)，7.21-7.26(m，3H)，7.43-7.72(m，8H)，8.2(t，1H)，8.45(m，2H)，9.42(s，1H)；LC-MS(ES+)m/z 586(M+H)+，LC-MS(ES-)m/z 584(M-H)-。
example 221:
step A:
as in general method XVI, sulfonyl chloride 464(1.1mmol), pyridine (5ml) and ethanolamine (Aldrich, 0.14g, 2.3mmol) were used. The mixture was stirred for 2 days, followed by addition of water. The mixture was extracted with dichloromethane, the organic layer was separated and concentrated in vacuo. The product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 543(0.46g, 37%). 1H NMR(DMSO-d6，400MHz)δ2.05(s，3H)，2.23(s，3H)，2.7(m，2H)，3.29(m，2H)，4.62(t，1H)，7.41(t，1H)，7.51(dd，1H)，7.56(d，1H)，7.7(d，1H)，9.38(s，1H)。
And B:
using sulfonamide 549(0.46g, 1.68mmol), 1.5N HCl (10ml), and ethanol (10ml) according to general procedure XVII, 544(0.12g, 31%) was obtained. The crude product was used without further purification.
And C:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 544(0.05g, 0.22mmol), acid chloride (0.15mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol) and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The product was purified by flash chromatography and TLC preparative plate chromatography using 95: 5 dichloromethane: methanol as eluent to give 542(0.02g, 17%):1H NMR(DMSO-d6，400MHz)δ2.2(s，3H)，2.75(q，2H)，3.34(m，2H)，4.66(t，1H)，4.83(s，2H)，7.22(d，1H)，7.42-7.72(m，9H)，9.42(s，1H)；LC-MS(ES+)m/z 539(M+H)+，LC-MS(ES-)m/z 537(M-H)-。
example 222:
step A:
as in general procedure XVI, sulfonyl chloride 464(3mmol), pyridine (5ml) and 5-aminobenzotriazole (Lancaster, 0.41g, 3.06mmol) were used. The mixture was stirred for 2 days. Water was added, the mixture was extracted with dichloromethane, the organics separated and concentrated in vacuo. The resulting product was then dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight with stirring. The resulting solution was concentrated in vacuo and purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 546(0.45g, 48%). The crude product was used without further purification.
And B:
acid 49 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 546(0.05g, 0.16mmol), acid chloride (0.15mmol), acetone (5ml), sodium bicarbonate (0.3g, 3.57mmol), and water (4 drops) were used. Ice (5ml) was added to the reaction mixture and the resulting suspension was filtered. The solid was purified by flash chromatography and TLC preparative plate chromatography using 95: 5 dichloromethane: methanol as eluent to give 545(0.01g, 10%):1H NMR(DMSO-d6，400MHz)δ2.13(s，3H)，4.78(s，2H)，7.16(m，2H)，7.39-7.85(m，11H)，9.34(s，1H)，10.5(bs，1H)；LC-MS(ES+)m/z 586(M+H)+，LC-MS(ES-)m/z 584(M-H)-。
example 223:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 523(0.1g, 0.41mmol), acid chloride (0.16g, 0.4mmol), acetone (4ml) and sodium bicarbonate (0.22g, 2.6mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 547(0.085g, 34%):1H NMR(DMSO-d6，300MHz)δ1.02(t，6H)，2.18(s，3H)，3.12(m，4H)，4.81(s，2H)，7.22(d，1H)，7.54-7.71(m，5H)，7.87(d，2H)，7.98(d，1H)，9.38(s，1H)；LC-MS(ES+)m/z 601(M+H)+，LC-MS(ES-)m/z 599(M-H)-。
example 224:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 315(0.1g, 0.44mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.4mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane, purified by flash chromatography and TLC preparative plate chromatography using 98: 2 dichloromethane: methanol as eluent to give 548(0.074g, 29%): 1H NMR(DMSO-d6，300MHz)δ0.3-0.5(m，4H)，2.04(m，1H)，2.18(s，3H)，4.81(s，2H)，7.24(d，1H)，7.54-7.88(m，8H)，8(d，1H)，9.41(s，1H)；LC-MS(ES+)m/z 585(M+H)+，LC-MS(ES-)m/z 583(M-H)-。
Example 225:
by the general method VAcid 71 is converted to the acid chloride. As in general procedure VI, aniline 518(0.1g, 0.42mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.4mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane, and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 549(0.095g, 38%):1H NMR(DMSO-d6，300MHz)δ0.05(m，2H)，0.33(m，2H)，0.77(m，1H)，2.16(s，3H)，2.6(d，2H)，4.8(s，2H)，7.22(d，1H)，7.54-7.67(m，6H)，7.86(d，2H)，8(d，1H)，9.4(s，1H)；LC-MS(ES+)m/z599(M+H)+，LC-MS(ES-)m/z 597(M-H)-。
example 225:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 312(0.1g, 0.42mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.4mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 550(0.125g, 47%):1H NMR(DMSO-d6，300MHz)δ0.94(t，3H)，2.17(s，3H)，2.72(m，2H)，4.81(s，2H)，7.22(d，1H)，7.43(t，1H)，7.53-7.68(m，5H)，7.87(d，2H)，8(d，1H)，9.4(s，1H)；LC-MS(ES+)m/z 573(M+H)+，LC-MS(ES-)m/z 571(M-H)-。
example 226:
step A:
as in general method XVI, sulfonyl chloride 464(3mmol), pyridine (5ml) and 3-methoxybenzylamine (Aldrich, 0.41g, 3.01mmol) were used. The mixture was stirred for 2 days. The resulting mixture was concentrated in vacuo. Water was added and the mixture was filtered to give 552(0.24g, 69%).1H NMR(DMSO-d6，400MHz)δ2.06(s，3H)，2.21(s，3H)，3.63(s，3H)，3.89(d，2H)，6.73(m，3H)，7.13(t，1H)，7.53(m，2H)，7.7(d，1H)，7.96(t，1H)，9.36(s，1H)；LC-MS(ES+)m/z 349(M+H)+，LC-MS(ES-)m/z 347(M-H)-。
And B:
sulfonamide 552 was dissolved in ethanol (10ml) and 1.5N HCl (10 ml). The resulting mixture was heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo to afford 553. The product was used without further purification.
And C:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 553(0.1g, 0.33mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 551(0.212g, 98%):1H NMR(DMSO-d6，300MHz)δ2.14(s，3H)，3.66(s，3H)，3.92(d，2H)，4.81(s，2H)，6.77(t，3H)，7.13-7.24(m，2H)，7.55(m，3H)，7.66(dd，2H)，7.87(m，2H)，8.02(t，2H)，9.4(s，1H)；LC-MS(ES+)m/z 665(M+H)+，LC-MS(ES-)m/z 663(M-H)-。
example 227:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 544(0.1g, 0.43mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 554(0.073g, 29%):1H NMR(DMSO-d6，300MHz)δ2.17(s，3H)，2.74(m，2H)，3.35(m，2H)，4.65(t，1H)，4.81(s，2H)，7.22(d，1H)，7.45-7.68(m，6H)，7.87(d，2H)，8(d，1H)，9.41(s，1H)；LC-MS(ES+)m/z 589(M+H)+，LC-MS(ES-)m/z 587(M-H)-。
example 228:
step A:
as general method XXVI, sulfonyl chloride 464(3mmol), pyridine (5ml), and 3- (cyclopropylamino) propionitrile (Trans World Chemical, 0.33g, 3mmol) were used. The mixture was stirred for 2 days, followed by addition of water and extraction with dichloromethane. The organic layer was separated and concentrated in vacuo. The resulting product was then dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo and the product purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 556(0.22g, 26%).
And B:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 556(0.1g, 0.36mmol), acetone (4ml), sodium bicarbonate (0.22g,2.6mmol) and acid chloride (0.16g, 0.40 mmol). After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 556(0.113g, 49%):1H NMR(DMSO-d6，300MHz)δ0.63-0.82(m，4H)，2(m，1H)，2.21(s，3H)，2.78(t，2H)，3.36(m，2H)，4.82(s，2H)，7.22(d，1H)，7.54(d，1H)，7.63(m，3H)，7.79(d，1H)，7.87(d，2H)，8(d，1H)，9.42(s，1H)；LC-MS(ES+)m/z 638(M+H)+，LC-MS(ES-)m/z 638(M-H)-。
example 229:
step A:
as in general procedure XVI, sulfonyl chloride 464(3mmol), pyridine (5ml) and thiophene-2-ethylamine (Aldrich, 0.41g, 3.01mmol) were used. The mixture was stirred at room temperature for 2 days, then concentrated in vacuo. Water was added to the resulting residue and the mixture was filtered to give the protected sulfonamide 558(0.12g, 35%).1H NMR(DMSO-d6，400MHz)δ2.05(s，3H)，2.23(s，3H)，2.81-2.93(m，4H)，6.79(d，1H)，6.87(dd，1H)，7.26(dd，1H)，7.51(dd，1H)，7.55(s，1H)，7.61(t，1H)，7.71(d，1H)，9.37(s，1H)；LC-MS(ES+)m/z 339(M+H)+，LC-MS(ES-)m/z 337(M-H)-。
And B:
sulfonamide 558 was dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo to afford 559. The product was used without further purification.
And C:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 559(0.1g, 0.34mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 557(0.206g, 93%): 1H NMR(DMSO-d6，300MHz)δ2.16(s，3H)，2.87-2.95(m，4H)，4.8(s，2H)，6.83(d，1H)，6.91(t，1H)，7.22(d，1H)，7.3(d，1H)，7.54-7.68(m，6H)，7.87(d，2H)，8(d，1H)，9.4(s，1H)；LC-MS(ES+)m/z 654(M+H)+，LC-MS(ES-)m/z 653(M-H)-。
Example 230:
step A:
as in general method XXVI, sulfonyl chloride 464(3mmol), pyridine (5ml), and DL-1-phenylpropylamine (Norse, 0.41g, 3.01mmol) are used. The mixture was stirred at room temperature for 2 days, then concentrated in vacuo. Water was added to the resulting residue and the mixture was filtered to give the protected sulfonamide 561(0.19g, 55%).1H NMR(DMSO-d6，400MHz)δ0.61(t，3H)，1.5(m，2H)，2.03(s，3H)，2.08(s，3H)，4.03(m，1H)，7.03-7.12(m，5H)，7.26(d，1H)，7.35(dd，1H)，7.56(d，1H)，8(d，1H)，9.24(s，1H)；LC-MS(ES+)m/z 347(M+H)+，LC-MS(ES-)m/z 345(M-H)-。
And B:
sulfonamide 561 was dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo to afford 562. The product obtained was used without further purification.
And C:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 562(0.1g, 0.33mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane, and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 560(0.185g, 85%):1H NMR(DMSO-d6，300MHz)δ0.63(t，3H)，1.55(m，2H)，2(s，3H)，4.06(m，1H)，4.85(s，2H)，7.04-7.15(m，5H)，7.22(d，1H)，7.3(s，1H)，7.39(dd，1H)，7.53(m，2H)，7.66(dd，1H)，7.87(d，2H)，7.99-8.07(m，2H)，9.29(s，1H)；LC-MS(ES+)m/z 663(M+H)+，LC-MS(ES-)m/z 661(M-H)-。
example 231:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 535(0.1g, 0.33mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane, and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 563(0.193g, 89%): 1H NMR(DMSO-d6，400MHz)δ2.21(s，3H)，2.67(s，3H)，2.92(t，2H)，4.09(m，2H)，4.83(s，2H)，7.18-7.27(m，3H)，7.42-7.78(m，9H)，8.46(m，1H)，9.41(s，1H)；LC-MS(ES+)m/z 664(M+H)+，LC-MS(ES-)m/z 662(M-H)-。
Example 232:
step A:
the acid chloride was prepared according to general procedure V using 5-chloro-2-methoxybenzoic acid (Aldrich, 17.1g, 91mmol), oxalyl chloride (50ml of a 2.0M solution in dichloromethane, 100mmol), DMF (1.2ml) and dichloromethane (100 ml). After 2 hours, the mixture was concentrated and dissolved in chloroform (50ml) and added dropwise to a solution of N, O-dimethylhydroxylamine (Aldrich, 13.34g, 140mmol), chloroform (200ml) and triethylamine (19.06ml, 140mmol) at 0 ℃ as in general method VII. After 1 hour, water was added to the reaction mixture and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 565(18.69g, 96%):1H NMR(DMSO-d6，300MHz)δ3.2(bs，3H)，3.45(bs，3H)，3.77(s，3H)，7.1(d，1H)，7.3(d，1H)，7.42(m，1H)。
and B:
3, 5-Dibromotoluene (Avocado, 20.85g, 83.4mmol) and methyl tert-butyl ether (500ml) were added to a round bottom flask (oven dried) equipped with a stir bar, supplied with nitrogen if necessary and an addition funnel, and the mixture was cooled to-50 ℃ by a dry ice bath of acetonitrile. N-butyllithium (57.4 ml)1.6M solution in hexane, 91.8mmol) was added dropwise to the reaction and the mixture was stirred at-50 ℃ for 30 minutes. Weinreb amide 565(19.16g, 83.4mmol) was added portionwise via a powder addition funnel. The mixture was stirred at-50 ℃ and then allowed to warm to room temperature overnight. When the reaction was judged to be complete, the reaction was poured into saturated ammonium chloride (500ml) and stirred vigorously for 30 minutes. The mixture was then added to a separatory funnel. The organics were collected, washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow solid (28.64 g). This was pulverized, then triturated with methanol and filtered to give 566 as a yellow solid (19.2g, 68%). 1H NMR(DMSO-d6，400MHz)δ2.29(s，3H)，3.63(s，3H)，7.18(d，1H)，7.36(d，1H)，7.42(s，1H)，7.55(m，2H)，7.66(s，1H)。
And C:
566(4.02g, 12mmol), sodium cyanide (1.16g, 24mmol), copper iodide (0.26g, 1.4mmol) and propionitrile (50ml, degassed with nitrogen for 30 minutes) were added to a round bottom flask (oven dried) equipped with a stir bar, nitrogen supplied if necessary and a reflux condenser. To this mixture was added tetrakis (triphenylphosphine) palladium (Strem, 1.37g, 1.2mmol), triturated with methanol and filtered before addition. The mixture was heated to reflux and stirred for 30 minutes. The mixture was cooled to room temperature, and ethyl acetate (100ml) was added. The resulting suspension was filtered through celite and the solid was washed with ethyl acetate. The filtrate was washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting product was further purified by flash chromatography, eluting with 4: 1 hexane: ethyl acetate, to give 567 as an off-white solid (3.33g, 99%).1H NMR(DMSO-d6，300MHz)δ2.44(s，3H)，3.69(s，3H)，7.26(d，1H)，7.46(d，1H)，7.66(dd，1H)，7.86(d，2H)，7.99(s，1H)。
Step D:
anisole derivative 567(3.27g, 14.2mmol), dichloromethane (45ml) and boron tribromide (1.41ml solution in 15ml dichloromethane) were combined as described in general procedure IX. The reaction was stirred at-78 ℃ for 1 hour, then warmed to room temperature and stirred for an additional 4 hours. The reaction was then poured into ice water (500ml), stirred for an additional 45 minutes, and poured into a separatory funnel. The organic layer was collected, washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow solid (5.62 g). The resulting solid was recrystallized from methanol and filtered to give 568(2.65g, 85%) as pale yellow crystals. 1H NMR(DMSO-d6，400MHz)δ2.4(s，3H)，6.98(d，1H)，7.37(d，1H)，7.47(dd，1H)，7.82(d，1H)，7.87(s，1H)，7.93(d，1H)，10.43(s，1H)。
Step E:
compound 568(2.65g, 9.8mmol), potassium carbonate (6.74g, 49mmol), compound 470(3.14g, 10mmol) and acetone (50ml) were mixed in a round bottom flask and heated to reflux for 4 h. The reaction was concentrated in vacuo, then water (200ml) and dichloromethane were added and the suspension filtered. The filtrate was poured into a separatory funnel and separated. The organic layer was collected, washed with saturated sodium bicarbonate solution, water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was further purified by flash chromatography using 1: 1 hexane: ethyl acetate as eluent to give an off-white solid. The solid was recrystallized from acetonitrile and water to give 564(1.61g, 66%).1H NMR(DMSO-d6，400MHz)δ2.17(s，3H)，2.37(s，3H)，4.81(s，2H)，7.24(m，3H)，7.5(d，1H)，7.58-7.66(m，4H)，7.92(d，2H)，7.98(s，1H)，9.39(s，1H)。
Example 233:
step A:
anisole derivative 566(1.02g, 3mmol), dichloromethane (10ml) and boron tribromide (3ml of a 1M solution in dichloromethane) were combined as described in general procedure IX. The reaction was stirred at-78 ℃ for 90 minutes, then warmed to room temperature and stirred for an additional 1 hour. Water (100ml) was added to the reaction, and the resulting mixture was stirred for 30 minutes. The mixture was then added to a separatory funnel and the organic layers were collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give 570(0.965g, 99%) as a light yellow solid. 1H NMR(DMSO-d6，300MHz)δ2.34(s，3H)，6.96(d，1H)，7.33(d，1H)，7.45(m，2H)，7.58(s，1H)，7.69(s，1H)，10.37(s，1H)。
And B:
compound 570(0.16g, 0.5mmol), potassium carbonate (0.34g, 2.5mmol), compound 470(0.166g, 0.54mmol) and acetone (5ml) were mixed in a round bottom flask and heated to reflux overnight. Water was added and the resulting suspension was filtered and the solid was purified by flash chromatography using 9: 1 dichloromethane: methanol as eluent to give 569 as an off-white solid (0.035g, 13%).1H NMR(DMSO-d6，300MHz)δ2.16(s，3H)，2.3(s，3H)，4.8(s，2H)，7.24(m，3H)，7.46(d，1H)，7.58-7.68(m，6H)，9.29(s，1H)。
Example 234:
step A:
sulfonyl chloride 464(3mmol) was added in portions to a large tube equipped with a stir bar, pyridine (5ml), and 4-methoxybenzylamine (Aldrich, 0.41g, 3.01 mmol). The mixture was stirred for 2 days and then concentrated in vacuo. Water was added to the remaining residue and the mixture was filtered. The filtrate was extracted with dichloromethane and the organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the protected sulfonamide 572(0.16g, 46%).1H NMR(DMSO-d6，400MHz)δ2.06(s，3H)，2.21(s，3H)，3.65(s，3H)，3.83(d，2H)，6.77(dd，2H)，7.08(d，2H)，7.52(m，2H)，7.7(m，1H)，7.87(t，1H)，9.36(s，1H)；LC-MS(ES+)m/z 349(M+H)+，LC-MS(ES-)m/z 347(M-H)-。
And B:
the sulfonamide was dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo to afford 573. The product obtained was used without further purification.
And C:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 573(0.1g, 0.33mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 571(0.070g, 32%): 1H NMR(DMSO-d6，300MHz)δ2.15(s，3H)，3.69(s，3H)，3.87(d，2H)，4.82(s，2H)，6.8(m，2H)，7.1(d，2H)，7.23(d，1H)，7.56(dd，3H)，7.67(m，2H)，7.87-8.03(m，4H)，9.41(s，1H)；LC-MS(ES-)m/z663(M-H)-。
Example 235:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 527(0.1g, 0.34mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 574(0.040g, 18%):1H NMR(DMSO-d6，300MHz)δ2.16(s，3H)，2.8(dd，2H)，3.08(m，2H)，4.81(s，2H)，7.16-7.25(m，3H)，7.53-7.69(m，7H)，7.88(m，2H)，8(m，1H)，8.42(m，1H)，9.4(s，1H)；LC-MS(ES+)m/z 650(M+H)+，LC-MS(ES-)m/z 648(M-H)-。
example 236:
step A:
sulfonyl chloride 464(3mmol) was added in portions to a large tube equipped with a stir bar, pyridine (5ml), and 1- (3-aminopropyl) -4-methylpiperazine (Aldrich, 0.48g, 3.05 mmol). The mixture was stirred for 2 days and then concentrated in vacuo. Water was added to the remaining residue and the mixture was filtered. The filtrate was extracted with dichloromethane and the organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to give the protected sulfonamide 576(0.22g, 20%) which was used without further purification.
And B:
the sulfonamide 576 was then dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo to afford 577. The product obtained was used without further purification.
And C:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 577(0.1g, 0.31mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane, and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 575(0.067g, 32%): 1H NMR(DMSO-d6，300MHz)δ1.47(m，2H)，2.04-2.21(m，16H)，2.73(m，2H)，4.82(s，2H)，7.23(d，1H)，7.45-7.7(m，6H)，7.87(m，2H)，8.01(m，1H)，9.41(s，1H)；LC-MS(ES+)m/z 685(M+H)+，LC-MS(ES-)m/z 683(M-H)-。
Example 237:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 538(0.1g, 0.36mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 77(0.053g, 23%):1H NMR(DMSO-d6，300MHz)δ2.16(s，3H)，4(d，2H)，4.82(s，2H)，7.22-7.31(m，2H)，7.55-7.7(m，6H)，7.88(d，2H)，8.02(m，1H)，8.12(t，1H)，8.41(dd，2H)，9.42(s，1H)；LC-MS(ES+)m/z 636(M+H)+，LC-MS(ES-)m/z 634(M-H)-。
example 238:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 515(0.1g, 0.35mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.4mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 579(0.018g, 8%):1H NMR(DMSO-d6，300MHz)δ1.6(m，4H)，2.17(s，3H)，2.3-2.42(m，6H)，2.81(t，2H)，3.16(m，4H)，4.09(m，1H)，4.81(s，2H)，7.24(d，1H)，7.54-7.69(m，5H)，7.88(d，2H)，8(d，1H)，9.41(s，1H)；LC-MS (ES+)m/z 642(M+H)+，LC-MS(ES-)m/z 640(M-H)-。
example 239:
step A:
sulfonyl chloride 464(3mmol) was added in portions to a large tube equipped with a stir bar, pyridine (5ml), and 2- (2-aminoethyl) -1-methylpyrrolidine (Aldrich, 0.29g, 2.3 mmol). The mixture was stirred at room temperature for 2 days, then concentrated in vacuo. Water was added to the resulting residue and the mixture was filtered. The filtrate was extracted with dichloromethane and the organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the protected sulfonamide 581(0.40g, 51%). 1HNMR(DMSO-d6，400MHz)δ1.25(m，2H)，1.53(m，2H)，1.64(m，1H)，1.76(m，1H)，1.96(m，2H)，2.09(s，3H)，2.10(s，3H)，2.28(s，3H)，2.72(m，2H)，2.86(m，1H)，7.46(s，1H)，7.55(dd，1H)，7.59(s，1H)，7.76(d，1H)，9.42(s，1H)；LC-MS(ES+)m/z 340(M+H)+，LC-MS(ES-)m/z 338(M-H)-。
And B:
the sulfonamide 581 was then dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 deg.C overnight. The resulting solution was concentrated in vacuo to afford 582, which was used without further purification.
And C:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 582(0.1g, 0.34mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 580(0.037g, 17%):1H NMR(DMSO-d6，300MHz)δ1.25(m，2H)，1.47-1.8(m，4H)，1.99(m，2H)，2.1(s，3H)，2.17(s，3H)，2.73(m，2H)，2.9(m，1H)，4.81(s，2H)，7.24(d，1H)，7.46-7.69(m，6H)，7.88(m，2H)，8(m，1H)，9.41(s，1H)；LC-MS(ES+)m/z 656(M+H)+。
example 240:
step A:
sulfonyl chloride 464(3mmol) was added in portions to a large tube equipped with a stir bar, pyridine (5ml), and tetrahydrofurfuryl amine (Aldrich, 0.41g, 3.01 mmol). The mixture was stirred at room temperature for 2 days, then concentrated in vacuo. Water was added and the mixture was filtered to give 584(0.2g, 64%).
1H NMR(DMSO-d6，400MHz)δ1.45(m，1H)，1.7(m，3H)，2.05(s，3H)，2.23(s，3H)，2.69(t，2H)，3.51(m，1H)，3.62(m，1H)，3.72(m，1H)，7.5-7.56(m，3H)，7.69(d，1H)，9.37(s，1H)；LC-MS(ES+)m/z 313(M+H)+，LC-MS(ES-)m/z 311(M-H)-。
And B:
sulfonamide 584 was dissolved in ethanol (10ml) and 1.5N HCl (10ml) and heated to 60 ℃ overnight. The resulting solution was concentrated in vacuo to afford 585, which was used without further purification.
And C:
acid 71 was converted to the acid chloride using general procedure V. As in general procedure VI, aniline 585(0.1g, 0.37mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 583(0.038g, 16%): 1H NMR(DMSO-d6，300MHz)δ1.69-1.88(m，3H)，2.17(s，3H)，2.73(t，2H)，3.51-3.81(m，3H)，4.81(s，2H)，7.24(d，2H)，7.54-7.69(m，6H)，7.88(m，2H)，8.01(m，1H)，9.41(s，1H)；LC-MS(AP+)m/z 629(M+H)+，LC-MS(AP-)m/z 628(M-H)-。
Example 241:
by usingGeneral procedure V, acid 71 was converted to the acid chloride. As in general procedure VI, aniline 541(0.1g, 0.36mmol), acetone (4ml), sodium bicarbonate (0.22g, 2.6mmol) and acid chloride (0.16g, 0.40mmol) were used. After 2 days, the resulting solution was concentrated, redissolved in dichloromethane, and purified by flash chromatography using 98: 2 dichloromethane: methanol as eluent to give 586(0.033g, 14%):1H NMR(DMSO-d6，300MHz)δ2.16(s，3H)，4(d，2H)，4.82(s，2H)，7.24(m，3H)，7.55-7.7(m，5H)，7.89(m，2H)，8.02(m，1H)，8.20(t，1H)，8.44(dd，2H)，9.42(s，1H)；MS(ES+)m/z 636(M+H)+。
example 242:
step A:
as in general procedure II, using compound 568(2g, 7.4mmol), potassium carbonate (5.11g, 37mmol), ethyl bromoacetate (1ml, 9mmol) and acetone (40ml) gave 588(2.73g, crude material) as a yellow/off-white solid.1H NMR(DMSO-d6，400MHz)δ1.14(t，3H)，2.39(s，3H)，4.08(m，2H)，4.78(s，2H)，7.14(d，1H)，7.47(d，1H)，7.58(d，1H)，7.9(m，3H)。
And B:
using ester 588(2.73g, 7.6mmol), ethanol (EtOH, 20ml), water (5ml) and lithium hydroxide monohydrate (0.45g, 10.7mmol) as in general procedure III gave 589(2.45g, 97%) as an orange glass.1H NMR(DMSO-d6，300MHz)δ2.3(s，3H)，4.67(s，2H)，7.1(d，1H)，7.44(d，1H)，7.58(dd，1H)，7.9(m，3H)，13.1(bs，1H)。
And C:
according to general method V, carboxylic acid 589(0.1g, 0.3mmol), oxalyl chloride (0.4ml, 2.0M solution in dichloromethane, 0.8mmol), DMF (2 drops) and dichloromethane (2ml) were used. As in general procedure VI, the acid chloride was dissolved in acetone and added dropwise to aniline 490(0.086g, 0.47mmol), acetone (10ml), sodium bicarbonate (0.15g, 1.8mmol) and water (2 drops). After 4 days, the reaction mixture was concentrated and the product was purified by flash chromatography using 9: 1 dichloromethane: methanol as eluent to give 587(0.046g, 31%). 1H NMR(DMSO-d6，300MHz)δ2.24(s，3H)，2.38(s，3H)，4.85(s，2H)，7.24(d，1H)，7.39(s，2H)，7.49(d，1H)，7.65(dd，1H)，7.81(s，1H)，7.95(m，3H)，8.7(s，1H)，9.71(s，1H)。
Example 243:
step A:
as in general method II, using compound 570(0.75g, 2.3mmol), potassium carbonate (1.7g, 12.3mmol), ethyl bromoacetate (0.3ml, 2.7mmol) and acetone (10ml) gave 591(0.87g, 92%) as a clear low melting solid. The crude product was used without further purification.
And B:
as in general procedure III, ester 591(0.87g, 2.1mmol), ethanol (EtOH, 7.5ml), water (2.5ml) and hydrogen and oxygen were usedLithium monohydrate (0.125g, 2.98mmol) gave 592 as a white foam (0.74g, 91%).1H NMR(DMSO-d6，300MHz)δ2.32(s，3H)，4.68(s，2H)，7.08(d，1H)，7.41(d，1H)，7.57(d，2H)，7.67(s，2H)，13.1(bs，1H)。
And C:
according to general method V, carboxylic acid 592(0.1g, 0.26mmol), oxalyl chloride (0.4ml, 2.0M solution in dichloromethane, 0.8mmol), DMF (2 drops) and dichloromethane (2ml) were used. The acid chloride was then dissolved in acetone and added dropwise to aniline 490(0.086g, 0.47mmol), acetone (10ml), sodium bicarbonate (0.15g, 1.8mmol) and water (2 drops) as in general procedure VI. After 5 days, the reaction mixture was concentrated and the product was purified by flash chromatography using 9: 1 dichloromethane to methanol as eluent to give a solid. The solid was dissolved in dichloromethane, washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 590(0.029g, 20%). 1H NMR(DMSO-d6，300MHz)δ2.19(s，3H)，2.3(s，3H)，4.75(s，2H)，7.22(d，2H)，7.43(d，2H)，7.58-7.74(m，6H)，8.68(s，1H)。
Example 244:
step A:
4- (3-bromo-propoxy) -2-methyl-1-nitrobenzene (3.29g, 12mmol), DMF (30ml) and potassium carbonate (7.6g, 55mmol) were combined in a round bottom flask. 3-pyrroline (Aldrich, 1g, 14.5mmol) was added dropwise to the reaction and the resulting solution was stirred overnight at room temperature. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to afford an orange oil594(1.22g, 39%) of substance (g).1H NMR(DMSO-d6，400MHz)δ1.88(m，2H)，2.54(s，3H)，2.69(m，2H)，3.4(s，4H)，4.14(t，2H)，5.78(s，2H)，6.96(dd，1H)，7.03(d，1H)，8.03(d，1H)。
And B:
compound 594(0.65g, 2.5mmol), tin dichloride dihydrate (1.83g, 8.1mmol) and ethanol (10ml) were mixed at room temperature and stirred overnight. Sodium hydroxide (2N) was added and the mixture was extracted with ethyl acetate. The organic layer was collected, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 595(0.26g, 49%) as a brown oil.1HNMR(DMSO-d6，300MHz)δ1.78(m，2H)，2(s，3H)，2.65(m，2H)，3.37(s，4H)，3.83(t，2H)，4.34(bs，2H)，5.76(m，2H)，6.49(s，2H)，6.54(d，1H)。
And C:
according to general method V, carboxylic acid 589(0.2g, 0.6mmol), oxalyl chloride (1.4ml, 2.0M solution in dichloromethane, 2.8mmol), DMF (1 drop) and dichloromethane (5ml) were used. The resulting acid chloride was dissolved in acetone and added dropwise to aniline 595(0.26g, 1.2mmol), acetone (10ml), sodium bicarbonate (0.2g, 2.4mmol) and water (1ml) as in general procedure VI. After 5 days, the reaction mixture was concentrated and the product was purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 593 as an orange glass (0.127g, 38%). 1H NMR(DMSO-d6，300MHz)δ1.86(m，4H)，2.01(s，3H)，2.36(s，3H)，2.76(m，2H)，3.48(m，2H)，3.97(t，2H)，4.7(s，2H)，5.8(s，2H)，6.7(m，2H)，7.12(d，1H)，7.22(d，1H)，7.48(d，1H)，7.65(dd，1H)，7.94(d，2H)，8.99(s，1H)。
Example 245:
compound 593(0.1g, 0.2mmol) was dissolved in dioxane (2ml) and hydrochloric acid (1ml of a 4M solution in dioxane) was added dropwise. The mixture was stirred for 2 days and concentrated in vacuo to give 596(0.071g, 68%) as a black solid.1H NMR(DMSO-d6，300MHz)δ2.02(s，5H)，2.36(s，3H)，3.68(m，2H)，3.95(m，4H)，4.2(m，2H)，4.71(s，2H)，5.93(s，2H)，6.75(m，2H)，7.2(m，2H)，7.49(d，1H)，7.65(d，1H)，7.95(m，3H)，9.06(s，1H)，10.95(bs，1H)。
Example 246:
step A:
DMF (59ml, 762mmol) was added dropwise to a stirred solution of oxalyl chloride (380ml of a 2M solution in dichloromethane, 760mmol) in a 1 l 3-necked round-bottomed flask at 0 ℃. After the addition was complete, the reaction was stirred for 1 hour, then allowed to warm to room temperature and stirred for an additional 2 hours. To the resulting white solid was added 2-aminotoluene-5-sulfonic acid (Aldrich, 50g, 267mmol) in one portion and the resulting reaction mixture was stirred vigorously for 1 hour. The reaction mixture was transferred to a 1 liter round bottom flask and concentrated to give 598 as a brown solid (150.24g, crude product). The crude product can be used without further purification or characterization.
And B:
compound 598(10g, 38mmol) was added to a solution of 4-aminomorpholine (Aldrich, 5g, 49mmol) in THF (40ml) at room temperature and stirred for 2 days. Water and saturated sodium bicarbonate solution were added, and the resulting solution was extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was further purified by flash chromatography using 95: 5 dichloromethane: methanol as eluent to give 599 as an orange glass (0.53g, crude product). The crude product was used without further purification.
And C:
compound 599(0.53g, 1.6mmol), hydrazine dihydrochloride (0.36g, 3.4mmol) and methanol (30ml) were mixed at room temperature and stirred overnight. The reaction was concentrated in vacuo and the product was purified by flash chromatography using 1: 1 methane: ethyl acetate as eluent to give 600 as a white solid (0.075g, 3.3%).1H NMR(DMSO-d6，300MHz)δ2.06(s，3H)，2.5(m，4H)，3.42(m，4H)，5.7(bs，2H)，6.62(d，1H)，7.34(m，2H)，8.23(s，1H)。
Step D:
according to general method V, carboxylic acid 589(0.08g, 0.24mmol), oxalyl chloride (0.4ml, 2.0M solution in dichloromethane, 0.8mmol), DMF (1 drop) and dichloromethane (5ml) were used. The resulting acid chloride was then dissolved in acetone and added dropwise to amine 600(0.07g, 0.26mmol), acetone (10ml), potassium carbonate (0.1g, 0.72mmol) and water (1 drop) as in general procedure VI. After 1 day, the reaction mixture was concentrated, suspended in dichloromethane, filtered and further purified by flash chromatography and TLC preparative plate chromatography using 98: 2 and 95: 5 dichloromethane: methanol, respectively, as eluents to give an off-white solid. The resulting solid was further triturated in dichloromethane and filtered to give 597 as a white solid (0.014g, 10%).1H NMR(CDCl3，300MHz)δ2.34(s，3H)，2.50(s，3H)，2.66(m，4H)，3.64(m，4H)，4.74(s，2H)，5.26(s，1H)，7.08(d，1H)，7.35(d，1H)，7.59(dd，1H)，7.72(s，1H)，7.85(m，4H)，8.19(d，1H)，8.69(s，1H)；LC-MS(AP+)m/z583(M+H)+，LC-MS(AP-)m/z 581(M-H)-。
Example 247:
step A:
compound 623(0.5g, 1.2mmol), cyanide ketone (I) (Aldrich, 0.55g, 6.1mmol), pyridine (4ml, 49.5mmol) and DMF (15ml) were combined in a pressure tube equipped with A stirring rod, nitrogen supplied if necessary and reflux condenser. The mixture was stirred at reflux temperature for 4 days. The mixture was cooled, diethyl ether (150ml) was added and the resulting suspension was filtered through celite, washing with diethyl ether (3X 150 ml). The filtrate was washed with 2: 1 water, concentrated ammonium hydroxide, saturated ammonium chloride and saturated sodium bicarbonate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo. The product was further purified by flash chromatography using 4: 1 hexane: dichloromethane as eluent to give 602 as an off-white solid (0.13g, 35%). 1H NMR(DMSO-d6，300MHz)δ3.65(s，3H)，7.25(d，1H)，7.48(d，1H)，7.66(dd，1H)，8.4(d，2H)，8.71(s，1H)；GC-MS(EI+)m/z 296(M)+。
And B:
anisole derivative 602(0.125g, 0.42mmol), dichloromethane (10ml) and boron tribromide (0.44ml of a 1M solution in dichloromethane) were combined as described in general procedure IX. Stirring at-78 deg.CThe reaction was allowed to warm to room temperature for 1 hour and stirred for an additional 1 hour. Water (50ml) was added to the solution, and the resulting mixture was stirred vigorously for 15 minutes, after which it was added to a separatory funnel. The organic layers were collected, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 603 as a yellow glass (0.12g, 99%).1H NMR(DMSO-d6，300MHz)δ7(d，1H)，7.45(d，1H)，7.52(dd，1H)，8.42(d，2H)，8.7(m，1H)；GC-MS(EI+)m/z 282(M)+。
And C:
compound 603(0.13g, 0.46mmol), potassium carbonate (0.12g, 0.87mmol), compound 470(0.146g, 0.42mmol) and acetone (5ml) were mixed in a round bottom flask at room temperature and stirred overnight. Water (20ml) was added, the suspension filtered and the resulting solid washed with ether and air dried to give 601 as an off-white solid (0.212g, 98%).1H NMR(DMSO-d6，300MHz)δ2.19(s，3H)，4.82(s，2H)，7.24(m，3H)，7.51-7.74(m，3H)，8.5(d，2H)，8.69(m，1H)，9.5(s，1H)；LC-MS(AP+)m/z 508(M+H)+，LC-MS(AP-)m/z 506(MH)-。
Example 248:
step A:
3-methyl-4-nitrophenol (Aldrich, 5.0g, 33mmol), 3-bromopropylphthalimide (8.8g, 33mmol), cesium carbonate (16.1g, 5.0mmol) and anhydrous DMF (60ml) were added to a round bottom flask and heated to 55 ℃ for 2 hours. The reaction was then allowed to cool to room temperature and poured into a mixture of ether and water. The solid obtained is filtered, washed with water and diethyl ether and dried in a vacuum oven at 45 ℃ for 12-16 hours 605(9.5g, 85%) was obtained as a brown solid.1H NMR(DMSO-d6，300MHz)δ8.03(m，1H)，7.87(m，4H)，6.87(m，2H)，4.16(t，2H)，3.79(t，2H)，2.51(s，3H)，2.11(m，2H)。
And B:
605(3.0g, 8.8mmol), hydrazine hydrate (1.6ml, 1.7g, 53mmol) and absolute ethanol (50ml) were charged to a round bottom flask equipped with a stirring rod, reflux condenser and, if necessary, nitrogen gas. The reaction was heated to reflux and stirred for 4 hours, after which the reaction mixture was allowed to cool to room temperature and stirred for an additional 48-60 hours. The resulting heterogeneous mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting solid was washed with dichloromethane, filtered and dissolved in ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 606 as a yellow oil (1.1g, 59%).1H NMR(DMSO-d6，400MHz)δ7.99(d，1H)，6.97(d，1H)，6.91(dd，1H)，4.10(t，2H)，2.63(t，2H)，2.49(s，3H)，1.77(m，2H)。
And C:
606(0.3g, 1.43mmol), dry THF (5ml) and trimethylsilyl isocyanate (0.21ml, 0.18g, 1.57mmol) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as needed. The mixture was stirred at room temperature for 3 hours, after which water (1ml) was added to the heterogeneous solution. The mixture was concentrated under reduced pressure, and the resulting residue was washed with a mixture of ethyl acetate and diethyl ether, filtered and dried to give 607(0.273g, 75%) as a pale yellow solid. 1H NMR(DMSO-d6，400MHz)δ8.00(d，1H)，6.97(d，1H)，6.90(dd，1H)，5.97(t，1H)，5.35(bs，2H)，4.04(t，2H)，3.05(m，2H)，2.44(s，3H)，1.77(m，2H)。
Step D:
607(0.055g, 0.22mmol), ethanol (8ml) and palladium on carbon (0.006g, 10% Pd/C, 10% by weight) were added to a flask equipped with a stir bar. The vessel was placed in a hydrogenation apparatus at 40 p.s.i. When the reaction was judged complete, the reaction mixture was filtered through celite and the solvent was removed under reduced pressure to give 608(0.045g, 92%) as a white solid.1H NMR(DMSO-d6，400MHz)δ6.51(s，1H)，6.46(m，2H)，5.92(t，1H)，5.33(bs，2H)，4.30(bs，2H)，3.75(t，2H)，3.03(m，2H)，1.96(s，3H)，1.67(m，2H)。
Step E:
according to general method V, acid 71(0.17g, 0.45mmol), oxalyl chloride (0.25ml of a 2M solution in dichloromethane, 0.50mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) were used. The resulting acid chloride, aniline 608(0.95g, 0.43mmol), sodium bicarbonate (0.19g, 2.3mmol), acetone (5ml) and water (1ml) were used according to general procedure VI. The resulting solid was washed with diethyl ether, filtered and dried under vacuum at 50 ℃ to give 604(0.115g, 44%) as a white solid: MS (ES)+)m/z 581(M)+；1H NMR(DMSO-d6，300MHz)δ9.10(s，1H)，8.01(d，1H)，7.86(m，2H)，7.67(dd，1H)，7.54(d，1H)，7.22(d，1H)，7.08(d，1H)，6.75(d，1H)，6.69(dd，1H)，5.98(t，1H)，5.37(bs，2H)，4.70(s，2H)，3.91(t，2H)，3.08(q，2H)，1.99(s，3H)，1.76(m，2H)。
Example 249:
step A:
according to general method V, acid 129(0.14g, 0.45mmol), oxalyl chloride (0.25ml of a 2M solution in dichloromethane, 0.50mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) were used. The acid chloride obtained, aniline 608(0.095g, 0.43mmol), sodium bicarbonate (0.19g, 2.3mmol), acetone (5ml) and water (1ml) were used according to general procedure VI. The resulting residue was treated with diethyl ether and the solid precipitated. The solid was purified by flash chromatography eluting with 5% methanol in dichloromethane to give 609(0.015g, 6%) as a white solid: 1H NMR(DMSO-d6，400MHz)δ9.01(s，1H)，8.13(s，1H)，8.03(m，2H)，7.63(m，2H)，7.47(d，1H)，7.18(d，1H)，7.07(d，1H)，6.72(d，1H)，6.65(dd，1H)，5.94(m，1H)，5.34(bs，2H)，4.65(s，2H)，3.87(t，2H)，3.03(m，2H)，1.95(s，3H)，1.76(m，2H)。
Example 250:
step A:
5-fluoro-2-nitrotoluene (1.0g, 6.45mmol), diethylene glycol methyl ether (0.77ml, 0.77g, 6.45mmol), anhydrous DMF (20ml) and potassium carbonate (1.8g, 12.9mmol) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen as required. The reaction mixture was heated to 80 ℃ and stirred for 16-18 h, after which time diethylene glycol methyl ether (1.15ml, 1.16g, 9.67mmol) was added. The reaction was heated to 130 ℃ and stirred for 16-18 hours. When the reaction was judged complete, the reaction was allowed to cool to room temperature and poured into ethyl acetate and water. The organic layer was washed with 5% aqueous sodium hydroxide, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 611(1.07g, 65%) as a yellow oil.1H NMR(DMSO-d6，300MHz)δ8.06(d，1H)，7.08(d，1H)，7.01(dd，1H)，4.24(t，2H)，3.78(t，2H)，3.60(m，2H)，3.48(m，2H)，3.27(s，3H)，2.57(s，3H)。
And B:
611(0.36g, 1.4mmol), ethanol (10ml) and palladium on charcoal (0.036g, 10% Pd/C, 10% by weight) were added to a flask equipped with a stir bar. The vessel was placed in a hydrogenation apparatus at 43 p.s.i. for 2 hours, after which the reaction mixture was filtered through celite. To the filtrate was added 1N HCl and ethyl acetate. The layers were separated and the pH of the aqueous layer was adjusted with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to give 612(0.18g, 57%) as a yellow oil. 1H NMR(DMSO-d6，400MHz)δ6.52(s，1H)，6.46(s，1H)，4.32(bs，2H)，3.86(t，2H)，3.60(m，2H)，3.50(m，2H)，3.39(m，2H)，3.19(s，3H)，1.96(s，3H)。
And C:
according to general method V, acid 71(0.16g, 0.42mmol), oxalyl chloride (0.04ml, 0.058g, 0.46mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) were used. The acid chloride obtained, aniline 612(0.09g, 0.40mmol), sodium bicarbonate (0.176g, 2.1mmol), acetone (7ml) and water (1ml) were used according to general procedure VI. The resulting residue was treated with diethyl ether to give 610 as a white solid (0.061g, 25%): MS (ES)+)m/z 584(M)+；1H NMR(DMSO-d6，400MHz)δ9.06(s，1H)，7.97(d，1H)，7.82(m，2H)，7.63(dd，1H)，7.49(d，1H)，7.18(d，1H)，7.05(d，1H)，6.73(s，1H)，6.66(dd，1H)，4.66(s，2H)，3.98(t，2H)，3.65(t，2H)，3.52(m，2H)，3.40(m，2H)，3.19(s，3H)，1.95(s，3H)。
Example 251:
step A:
according to general method V, acid 496(0.1g, 0.3mmol), oxalyl chloride (0.03ml, 0.042g, 0.33mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) were used. The resulting acid chloride, aniline 612(0.065g, 0.29mmol), sodium bicarbonate (0.126g, 1.5mmol), acetone (10ml) and water (0.5ml) were used according to general procedure VI. The product was purified by flash chromatography using 2% methanol to dichloromethane as eluent, followed by chromatography again using 1: 1 hexane to ethyl acetate as eluent. After standing, crystals formed in the collected fractions. The crystals were collected and dried to give 613(0.012g, 7%) as a pink crystalline solid:1H NMR(DMSO-d6，400MHz)δ9.08(s，1H)，8.09(d，1H)，7.99(s，1H)，7.87(d，1H)，7.63(dd，1H)，7.48(d，1H)，7.17(d，1H)，7.08(d，1H)，6.74(d，1H)，6.67(dd，1H)，4.67(s，2H)，3.99(t，2H)，3.65(t，2H)，3.51(m，2H)，3.40(m，2H)，3.19(s，3H)，1.95(s，3H)。
example 252:
according to general method V, acid 589(0.138g, 0.42mmol), oxalyl chloride (0.04ml, 0.058g, 0.46mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) were used. The acid chloride obtained, aniline 612(0.09g, 0.40mmol), sodium bicarbonate (0.176g, 2.1mmol), acetone (7ml) and water (1ml) were used according to general procedure VI. The product was purified by flash chromatography using 1: 1 hexane: ethyl acetate as eluent followed by treatment with diethyl ether to afford 614(0.048g, 21%) as a beige solid: MS (ES) +)m/z 537(M)+；1H NMR(DMSO-d6，400MHz)δ8.95(s，1H)，7.92(s，1H)，7.86(m，2H)，7.61(dd，1H)，7.45(d，1H)，7.18(d，1H)，7.08(d，1H)，6.74(s，1H)，6.67(m，1H)，4.66(s，2H)，3.99(t，2H)，3.65(t，2H)，3.51(q，2H)，3.40(q，2H)，3.19(s，3H)，2.31(s，3H)，1.96(s，3H)。
Example 253:
step A:
44(0.45g, 1.44mmol), copper (I) cyanide (0.32g, 3.6mmol) and anhydrous DMF (20ml) were placed in a round bottom flask equipped with a reflux condenser, a stir bar and a nitrogen supply if required. The reaction mixture was heated to reflux and stirred for 3 hours. When the reaction was judged complete, the reaction was allowed to cool to room temperature and poured into ethyl acetate and water. The resulting emulsion was filtered, the organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 616(0.2g, 54%) as a yellow solid.1H NMR(DMSO-d6，400MHz)δ10.59(s，1H)，9.17(d，1H)，9.00(d，1H)，8.54(m，1H)，7.48(dd，1H)，7.43(d，1H)，6.95(d，1H)。
And B:
a mixture of 616(0.20g, 0.77mmol), 470(0.237g, 0.77mmol), potassium carbonate (0.213g, 1.5mmol) and sodium iodide (230mg, 1.54mmol) in 8ml acetone was warmed to reflux for 6 hours. When the reaction was judged complete, the reaction was allowed to cool to room temperature and poured into ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was treated with ether, the resulting solid was filtered and recrystallized from acetonitrile to give 615(8mg, 3%).1H NMR(DMSO-d6，300MHz)δ9.48(s，1H)，9.20(d，1H)，9.13(d，2H)，8.64(t，1H)，7.64(m，5H)，7.25(m，3H)，4.81(s，2H)，2.17(s，3H)。
Example 254:
step A:
following general procedure V, using 2-chloro-6-methylisonicotinic acid (1g, 5.8mmol), dichloromethane (20ml), oxalyl chloride (0.56ml, 0.8g, 6.4mmol), and N, N-dimethylformamide (1 drop), 618 was obtained as a red-purple oil (1.1g, > 99%). The product was used in the next step without further purification.
And B:
using acid chloride 618(1.1g, 5.8mmol), N, O-dimethylhydroxylamine hydrochloride (1.1g, 11.6mmol), triethylamine (1.6ml, 1.2g, 11.6mmol) and chloroform (50ml) according to general procedure VII, 619(1.3g, > 99%) was obtained as a red-purple oil. The product was used in the next step without further purification.1H NMR(DMSO-d6，300MHz)δ7.42(s，1H)，7.38(s，1H)，3.54(s，3H)，3.24(s，3H)。
And C:
according to general method VIII, amide 619(1.3g, 5.8mmol), n-butyllithium (4ml of a 1.6M solution in hexane, 6.4mmol), 2-bromo-4-chloroanisole (0.8ml, 1.3g, 5.8mmol) and diethyl ether (25ml) are used. Purifying the product by flash chromatography using 3: 2 hexane: ethyl acetate as eluent to obtainTo 620 as a pale yellow solid (0.2g, 12%).1H NMR(DMSO-d6，300MHz)δ7.67(dd，1H)，7.50(d，1H)，7.42(s，1H)，7.38(s，1H)，7.24(d，1H)，3.65(s，3H)，2.51(s，3H)。
Step D:
using anisole 620(0.2g, 0.68mmol), boron tribromide (1.4ml of a 1.0M solution in dichloromethane, 1.4mmol) and dichloromethane (5ml) according to general procedure IX, 621(0.163g, 85%) was obtained as a yellow solid. The product was used without further purification.1H NMR(DMSO-d6，400MHz)δ10.56(s，1H)，7.47(dd，1H)，7.41(s，1H)，7.38(m，2H)，6.93(d，1H)，2.47(s，3H)。
Step E:
a mixture of 621(0.08g, 0.28mmol), 470(0.086g, 0.28mmol), potassium carbonate (0.077g, 0.56mmol) in 10ml acetone was warmed to reflux for 1.5 h. When the reaction was judged complete, the reaction was allowed to cool to room temperature and poured into ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was treated with methanol and the resulting solid was filtered to give 617(0.007g, 5%): MS (ES) +)m/z 508(M)+；1HNMR(DMSO-d6，400MHz)δ9.38(s，1H)，7.64(m，1H)，7.61(s，1H)，7.56(s，2H)，7.50(m，2H)，7.45(s，1H)，7.20(m，3H)，4.75(s，2H)，2.42(s，3H)，2.13(s，3H)。
Example 255:
step A:
a solution of 1, 3, 5-tribromobenzene (3.0g, 9.53mmol) in 50ml diethyl ether was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (4.2ml of a 2.5M solution in hexane, 10.5mmol) was added dropwise over 10 minutes. The resulting mixture was stirred at-78 deg.C for an additional 10 minutes, then 183(2.0g, 9.53mmol) was added in small portions over 10 minutes. The reaction mixture was removed from the cold bath, allowed to warm to room temperature and stirring was continued for 1.5 hours. The mixture was poured into water and extracted with ether. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting orange residue was treated with methanol, filtered and dried to give 623(2.03g, 53%) as a yellow solid:1H NMR(DMSO-d6，400MHz)δ8.12(m，1H)，7.71(m，2H)，7.60(dd，1H)，7.43(d，1H)，7.20(d，1H)，3.63(s，3H)。
and B:
using anisole 623(0.2g, 0.49mmol), boron tribromide (1ml of a 1.0M solution in dichloromethane, 1mmol), and dichloromethane (8ml) according to general procedure IX, 624 was obtained as a yellow solid (0.176g, 92%). The product was used without further purification.1HNMR(DMSO-d6，400MHz)δ10.46(s，1H)，8.10(m，1H)，7.74(m，2H)，7.43(dd，1H)，7.35(d，1H)，6.93(d，1H)。
And C:
a mixture of 624(0.12g, 0.31mmol), 470(0.095g, 0.31mmol), potassium carbonate (0.086g, 0.62mmol), sodium iodide (0.093g, 0.62mmol) in 10ml acetone was warmed to reflux for 12-16 h. When the reaction was judged complete, the reaction was allowed to cool to room temperature and poured into ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was treated with diethyl ether, the resulting solid was filtered and dried to give a yellow solid 622(0.04g, 21%):1H NMR(DMSO-d6，00MHz)δ9.35(s，1H)，8.07(t，1H)，7.83(m，2H)，7.60(m，4H)，7.47(d，1H)，7.20(m，3H)，4.77(s，2H)，2.14(s，3H)。
example 256:
step A:
sulfonyl chloride 464(11.5g, 0.046mol) and THF (250ml) were added to a round bottom flask equipped with a stir bar and gas dispersion tube and the mixture was cooled to 0 ℃. Methylamine gas was bubbled through the reaction mixture for 0.5 hour, after which the mixture was poured into ethyl acetate and water, and the pH of the aqueous layer was adjusted to 7 with concentrated hydrochloric acid. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting orange residue was treated with diethyl ether, filtered and dried to give 626(5.32g, 48%):1H NMR(DMSO-d6，300MHz)δ9.46(s，1H)，7.80(d，1H)，7.58(m，2H)，7.34(m，1H)，2.41(d，3H)，2.32(s，3H)，2.13(s，3H)。
and B:
626(6.2g, 0.026mol), ethanol (250ml) and 1.5N (75ml) were added to a round bottom flask equipped with a stir bar, reflux condenser and nitrogen supply if necessary. The mixture was heated to reflux and stirred for 6 hours. When the reaction was judged complete, the reaction was allowed to cool to room temperature and poured into cold saturated sodium bicarbonate solution. Extracting the mixture with several portions of ethyl acetate, drying the organic layer over magnesium sulfate, filtering and concentrating under reduced pressure to obtain627(3.6g, 69%) of yellow solid:1H NMR(DMSO-d6，400MHz)δ7.23(m，2H)，6.82(m，1H)，6.59(d，1H)，5.62(bs，2H)，2.26(d，3H)，2.03(s，3H)。
and C:
using acid 71(0.237g, 0.63mmol), oxalyl chloride (0.35ml of a 2M solution in dichloromethane, 0.69mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) according to general procedure V gave the acid chloride. The acid chloride, aniline 627(0.12g, 0.60mmol), sodium bicarbonate (0.264g, 3.2mmol), acetone (7ml) and water (1ml) were used according to general procedure VI. The resulting residue was treated with ether and filtered to give 625(0.158g, 45%) as a white solid: MS (ES) +)m/z 558(M)+；1H NMR(DMSO-d6，400MHz)δ9.38(s，1H)，7.97(d，1H)，7.84(m，2H)，7.62(m，2H)，7.55(m，1H)，7.50(m，2H)，7.30(m，1H)，7.19(d，1H)，4.77(s，2H)，2.34(d，3H)，2.13(s，3H)。
Example 257:
step A:
2-aminotoluene-5-sulfonic acid (10g, 0.053mol), methylene chloride (120ml), an aqueous solution (120ml) of sodium carbonate (22.3g, 0.21mol) and benzyl bromide (14.3ml, 20.5g, 0.12mol) were charged to a round bottom flask equipped with a stir bar, reflux condenser and, if necessary, nitrogen gas. The reaction mixture was warmed to reflux and stirred for 72 hours. When the reaction was judged complete, ethanol was added to the reaction mixture and the solvent was evaporated under reduced pressure to give 629(27.4g, > 100%) as a brown oil. The product was used in the next step without further purification.
And B:
629(20.6g, 0.053mol) and anhydrous DMF (200ml) were added to a round bottom flask equipped with a stir bar and supplied with nitrogen if necessary. The mixture was cooled to 0 ℃ and thionyl chloride (11.7ml, 19.0g, 0.16mol) was added dropwise over 15 minutes after which the reaction mixture was warmed to room temperature and stirred for a further 2 hours. When the reaction was judged complete, the mixture was poured into ice water and stirred for 30 minutes. The aqueous mixture was extracted with ethyl acetate, the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 630(5.0g, 24%) which was used without further purification.
And C:
dimethylamine (11.6ml of a 5.6M solution in ethanol, 0.065mol) was placed in a round-bottomed flask equipped with a stirring rod and supplied with nitrogen gas if necessary and cooled to 0 ℃. Sulfonyl chloride 630(5.0g, 0.013mol) was added in portions over 10 min and the reaction mixture was stirred at 0 ℃ for 30 min. When the reaction was judged to be complete, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was filtered through a pad of silica gel using dichloromethane as eluent and the filtrate was concentrated under reduced pressure to give 631(1.0g, 20%) as a yellow oil.1H NMR(DMSO-d6，400MHz)δ7.47(d，1H)，7.22(m，11H)，7.05(d，1H)，4.13(s，4H)，2.48(s，6H)，2.44(s，3H)。
Step D:
631(0.330g, 0.85mmol), toluene (10ml) and palladium on charcoal (50mg of 10% wt Pd/C) were added to a plastic coated reaction vessel equipped with a stir bar. The vessel was placed in a hydrogenation apparatus at 40 p.s.i.. When the reaction was judged complete, it was filtered through celite and the filtrate was washed with saturated sodium bicarbonate and water. The organic layers were collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure to give 632(120mg, 67%) as a beige solid.1HNMR(DMSO-d6，400MHz)δ7.19(m，2H)，6.64(d，1H)，5.74(bs，2H)，2.44(s，6H)，2.04(s，3H)。
Step E:
according to general method V, acid 71(0.222g, 0.59mmol), oxalyl chloride (0.32ml, 2M solution in dichloromethane, 0.65mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) were used. The resulting acid chloride, aniline 632(0.12g, 0.56mmol), sodium bicarbonate (248mg, 3.0mmol), acetone (7ml) and water (1ml) were then used as in general procedure VI. The resulting residue was treated with ether and filtered to give 628 as a white solid (0.142g, 42%): MS (ES) +)m/z 572(M)+；1H NMR(DMSO-d6，400MHz)δ9.37(s，1H)，7.96(d，1H)，7.83(m，2H)，7.73(d，1H)，7.62(dd，1H)，7.50(m，3H)，7.19(d，1H)，4.78(s，2H)，2.53(s，6H)，2.17(s，3H)。
Example 258:
step A:
according to general procedure V, picolinic acid (3g, 0.015mol), dichloromethane (50ml), oxalyl chloride (1.5ml, 2.2g, 0.017mol) and N, N-dimethylformamide (4-5 drops) were used. According to general procedure VII, the acid chloride obtained, NO-Dimethylhydroxylamine hydrochloride (2.9g, 0.03mol), triethylamine (4.2ml, 3.0g, 0.03mol) and chloroform (50ml) gave 634(3.7g, > 99%) as a yellow oil. The product was used without further purification:1H NMR(DMSO-d6，400MHz)δ7.83(m，1H)，7.72(m，1H)，7.59(d，1H)，3.61(s，3H)，3.21(s，3H)。
and B:
according to general method VIII, amide 634(3.7g, 0.015mol), n-butyllithium (6.4ml of a 2.5M solution in hexane, 0.016mol), 2-bromo-4-chloroanisole (2.1ml, 3.3g, 0.015mol) and dehydrated ether (20ml) are used. The product was purified by flash chromatography using 9: 1 hexane: ethyl acetate as eluent followed by recrystallization from methanol to afford 635 as a white solid (2.25g, 46%).1H NMR(DMSO-d6，400MHz)δ7.90(m，3H)，7.55(dd，1H)，7.44(d，1H)，7.17(d，1H)，3.58(s，3H)。
And C:
according to general procedure IX, using anisole 635(0.227g, 0.85mmol), boron tribromide (1.7ml of a 1.0M solution in dichloromethane, 1.7mmol) and dichloromethane (15ml), 636(0.069g, 26%) was obtained as a yellow solid. The product was used in the next step without further purification. 1H NMR(DMSO-d6，400MHz)δ10.40(s，1H)，7.88(m，3H)，7.43(m，2H)，6.99(d，1H)。
Step D:
a mixture of 636(0.07g, 0.22mmol), 482(0.081g, 0.23mmol), potassium carbonate (0.061g, 0.44mmol) in 10ml acetone was heated to reflux. When the reaction was judged to be complete, it was allowed to cool to room temperature and poured intoEthyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting solid was washed with warm acetonitrile, filtered and dried to afford 633(0.027g, 23%) as a white solid: MS (ES)+)m/z 540(M+H)；1H NMR(DMSO-d6，400MHz)δ9.23(s，1H)，7.88(m，3H)，7.56(m，5H)，7.23(m，3H)，4.66(s，2H)，2.09(s，3H)。
Example 259:
step A:
635(0.750g, 2.3mmol), sodium cyanide (0.225g, 4.6mmol), copper (I) iodide (0.078g, 0.41mmol) and acetonitrile (10ml) were added to a round bottom flask equipped with a stirring bar, supplied with nitrogen and a reflux condenser if necessary. A stream of nitrogen was bubbled through the reaction mixture for 5 minutes, after which tetrakis (triphenylphosphine) palladium (1.0g, 0.89mmol) was added and the mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature and poured into ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The orange residue was treated with diethyl ether and the resulting solid was filtered and dried to give 638(321mg, 51%) as a pale yellow solid. 1H NMR(DMSO-d6，300MHz)δ8.23(m，3H)，7.63(dd，1H)，7.51(d，1H)，7.22(d，1H)，3.59(s，3H)。
And B:
according to general method IX, anisole 638(0.32g, 1.17mmol), boron tribromide (2.3ml of 1.0M in dichloromethane) were usedSolution, 2.3mmol) and dichloromethane (15 ml). The resulting residue was recrystallized from methanol to give 639(0.046g, 15%) as an orange solid.1H NMR(DMSO-d6，400MHz)δ10.39(s，1H)，8.20(m，3H)，7.45(m，2H)，6.90(d，1H)。
And C:
a mixture of 639(0.045g, 0.17mmol), 482(0.064g, 0.18mmol), potassium carbonate (0.047g, 0.34mmol) in 10ml acetone was heated to reflux. When the reaction was judged to be complete, it was allowed to cool to room temperature and poured into ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting solid was recrystallized from acetonitrile, filtered and dried to give 637(19mg, 23%) as a light yellow solid: MS (ES) M/z 484 (M)+)；483(M-H)-；。1H NMR(DMSO-d6，400MHz)δ9.31(s，1H)，8.20(m，3H)，7.57(m，5H)，7.20(m，3H)，4.64(s，2H)，2.10(s，3H)。
Example 260:
step A:
copper (II) bromide (5.36g, 0.024mol) and acetonitrile (100ml) were charged to a round bottom flask equipped with a stir bar and supplied with nitrogen gas as needed. The reaction mixture was cooled to 0 ℃ and tert-butyl nitrite (3.8ml, 3.3g, 0.032mol) was added dropwise over 15 minutes. 2-amino-5-bromotrifluorotoluene (5g, 0.021mol) was added dropwise over 15 minutes and the resulting mixture was stirred further at 0 ℃ for 1.5 hours. The mixture was allowed to warm to room temperature and stirred for a further 16-18 hours. When the reaction was judged to be complete, the mixture was concentrated to 1/2 original volume and poured into 1N HCl and extracted with ether. Collecting organic layer, concentrating under reduced pressure to obtain 641 as a yellow oil (5.5g, 86%).1H NMR(DMSO-d6，400MHz)δ7.96(s，1H)，7.78(m，2H)。
And B:
a solution of 641(5.5g, 18mmol) in 60ml of diethyl ether was cooled to-78 ℃ in a dry ice/acetone bath. N-butyllithium (9.2ml of a 2.5M solution in hexane, 23mmol) was added dropwise over 10 min. The resulting mixture was stirred at-78 ℃ for another 10 minutes, then 183(3.8g, 18mmol) was added in small portions over 10 minutes. The reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was collected, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash chromatography using 2% ethyl acetate in hexane as eluent to give 642(1.7g, 24%) as a yellow oil:1HNMR(DMSO-d6，400MHz)δ8.03(d，1H)，7.88(m，1H)，7.65(dd，1H)，7.60(d，1H)，7.36(d，1H)，7.16(d，1H)，3.47(s，3H)。
and C:
using anisole 642(0.5g, 1.27mmol), boron tribromide (2.5ml of a 1.0M solution in dichloromethane, 2.5mmol) and dichloromethane (10ml) according to general procedure IX, 643(0.4g, 83%) was obtained as a yellow oil.1H NMR(DMSO-d6，400MHz)δ10.71(s，1H)，8.03(s，1H)，7.92(d，1H)，7.50(m，3H)，6.90(d，1H)。
Step D:
a mixture of 643(0.400g, 1.05mmol), 470(0.322g, 1.05mmol), potassium carbonate (0.290g, 2.1mmol) and sodium iodide (0.315g, 2.1mmol) in 15ml acetone was warmed to reflux and stirred for 16 h. When the reaction was judged to be complete, the mixture was allowed to cool to room temperature and poured into ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography using 3% methanol to dichloromethane as eluent to give a yellow solid. The solid was recrystallized from acetonitrile, filtered and dried to give 640 as a white solid (16mg, 3%): 1H NMR(DMSO-d6，400MHz)δ9.31(s，1H)，8.01(s，1H)，7.90(d，2H)，7.66(m，5H)，7.47(d，1H)，7.24(m，3H)，4.67(s，2H)，2.23(s，3H)。
Example 261:
step A:
642(0.250g, 0.64mmol), sodium cyanide (0.063g, 1.3mmol), copper (I) iodide (0.023g, 0.12mmol) and acetonitrile (10ml) were added to a round bottom flask equipped with a stir bar, supplied with nitrogen and a reflux condenser if necessary. A stream of nitrogen was bubbled through the reaction mixture for 5 minutes, after which tetrakis (triphenylphosphine) palladium (0.086g, 0.08mmol) was added and the mixture was heated to reflux for 6 hours. The reaction mixture was allowed to cool to room temperature and the resulting precipitate was filtered. The precipitate was dissolved in ethyl acetate and washed with water. The organic layer was collected, filtered through a pad of celite, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange residue. The residue was treated with ether, filtered and dried to give 645 as a white solid (57mg, 26%).1HNMR(DMSO-d6，300MHz)δ8.27(s，1H)，8.16(d，1H)，7.71(dd，1H)，7.64(d，1H)，7.56(d，1H)，7.22(d，1H)，3.54(s，3H)。
And B:
according to general method IX, anisole 645(0.126g, 0.37mmol), boron tribromide (0.74ml of a 1.0M solution in dichloromethane, 0.74mmol) and dichloromethane (15ml) were used. The resulting residue was treated with ether and filtered to give 646(0.077g, 64%) as a pale yellow solid.1H NMR(DMSO-d6，400MHz)δ10.80(s，1H)，8.25(s，1H)，8.16(d，1H)，7.64(d，1H)，7.55(dd，1H)，7.45(d，1H)，6.95(d，1H)。
And C:
a mixture of 646(0.077g, 0.24mmol), 482(0.089g, 0.25mmol), potassium carbonate (0.066g, 0.48mmol) in 10ml acetone was heated to reflux. When the reaction was judged to be complete, it was allowed to cool to room temperature and poured into ethyl acetate and water. The organic layer was collected, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue obtained was treated with diethyl ether to give a yellow solid. The solid was recrystallized from acetonitrile, filtered and dried to give 644 as a pale yellow solid (11mg, 3%): 1H NMR(DMSO-d6，400MHz)δ9.31(s，1H)，8.18(s，1H)，8.05(d，1H)，7.64(m，6H)，7.23(m，3H)，4.69(s，2H)，2.17(s，3H)。
Example 262:
step A:
using phenol 477(0.345g, 1.2mmol), potassium carbonate (0.326g, 2.4mmol), ethyl bromoacetate (0.14ml, 0.207g, 1.3mmol) and acetone (10ml) according to general procedure II gave 648(0.46g, > 99%) as an orange oil. The product is free ofUsed with further purification:1H NMR(DMSO-d6，400MHz)δ8.28(t，1H)，8.04(d，1H)，7.98(t，1H)，7.58(dd，1H)，7.47(d，1H)，7.11(d，1H)，4.73(s，2H)，4.07(m，2H)，1.11(m，3H)。
and B:
using ester 648(0.46g, 1.2mmol), THF (4ml), water (1ml), ethanol (1ml) and lithium hydroxide (0.128g, 3.1mmol) according to general procedure III, 649(0.25g, 60%) was obtained as a yellow foam. The product was used without further purification:1H NMR(DMSO-d6，400MHz)δ13.1(bs，1H)，8.27(s，1H)，8.06(s，1H)，8.00(s，1H)，7.57(dd，1H)，7.45(d，1H)，7.08(d，1H)，4.63(s，2H)，4.07(m，2H)，1.11(m，3H)。
and C:
according to general method V, acid 649(0.120g, 0.34mmol), oxalyl chloride (0.04ml, 0.06g, 0.48mmol), N-dimethylformamide (1 drop) and dichloromethane (7ml) were used. The resulting acid chloride, aniline 490(0.064g, 0.34mmol), sodium bicarbonate (0.14g, 1.7mmol), acetone (7ml) and water (1ml) were used according to general procedure VI. The resulting residue was purified by flash chromatography using 3% methanol to dichloromethane as eluent to give 647(0.01g, 6%) as a pale yellow solid. MS (ES)+)m/z：519(M+)：1H NMR(400MHz，DMSO-d6)δ9.72(s，1H)，8.66(s，1H)，8.26(s，1H)，8.12(s，1H)，8.04(s，1H)，7.75(d，1H)，7.62(dd，1H)，7.50(d，1H)，7.34(s，2H)，7.20(d，1H)，4.81(s，2H)，2.20(s，3H)ppm。
Example 263:
according to general procedure V, acid 649(0.1g, 0.3mmol) was converted to the acid chloride and coupled with 5-amino-6-methyl-2-pyridinesulfonamide (0.06g, 0.33mmol, 1.1eq.) as described in step E of the synthesis of compound 503 in example 206 to afford 650. LCMS (ES) +)520m+1/z。1H NMR(DMSO-d6)δ9.65(br s，1H，NH)，8.3(s，1H，Ar)，8.1(m，2H，Ar)，8.0(s，1H，Ar)，7.7(d，1H，Ar)，7.6(dd，1H，Ar)，7.5(d，1H，Ar)，7.32(bs，2H，NH2)，7.2(d，1H，Ar)，4.8(s，2H，CH2)，2.3(s，3H，CH3)。
Example 264:
step A:
the same procedure as used to prepare compound 139 was used with 4- (3-bromo-propoxy) -2-methyl-1-nitrobenzene (1g, 3.6mmol) and 1, 2, 4-triazole (Aldrich, 0.25g, 3.6 mmol). Compound 652(0.45g, 48%) was obtained as an oil.1H NMR(DMSO-d6，400MHz)δ2.4(br s，4H)，2.45(s，3H)，4.1(t，2H)，6.9(dd，1H)，6.92(d，1H)，7.9(d，2H)，8(d，1H)。
And B:
compound 652 was used in the same manner as in the preparation of compound 140. Aniline 653(0.33g, 84%) was obtained as an oil. The compound was used without further purification.
And C:
according to general method VUsing acid 71(0.26g, 0.7mmol), oxalyl chloride (0.09ml, 1mmol), DMF (1 drop) and dichloromethane, the desired acid chloride was obtained. The acid chloride, aniline 653(0.16g, 0.7mmol), sodium bicarbonate (0.3g, 3mmol), acetone (8ml) and water (0.3ml) were used according to general procedure VI. The crude product was purified by flash column chromatography on silica gel eluting with 2% methanol in dichloromethane to give 651 as a white solid (0.05g, 12%).1H NMR(DMSO-d6，400MHz)δ1.9(s，3H)，2.1-2.2(m，2H)，3.8(t，2H)，4.3(t，2H)，4.66(s，2H)，6.6(dd，1H)，6.7(d，1H)，7.03(d，1H)，7.2(d，1H)，7.5(d，1H)，7.6(dd，1H)，7.8-7.82(m，2H)，7.9(s，1H)，8(d，1H)，8.5(s，1H)，9.02(s，1H)。
Example 265:
according to general method V, acid 49(0.14g, 0.4mmol), oxalyl chloride (0.2ml, 2mmol), DMF (1 drop) and dichloromethane were used. The resulting acid chloride, aniline 653(0.1g, 0.4mmol), sodium bicarbonate (0.17g, 1.7mmol), acetone (5ml) and water (0.1ml) were used according to general procedure VI. The crude product was purified by flash column chromatography on silica gel eluting with 2% methanol in dichloromethane to give 654(0.04g, 18%) as a white solid. 1H NMR(DMSO-d6，400MHz)δ1.9(s，3H)，2.1-2.2(m，2H)，3.8(t，2H)，4.3(t，2H)，4.7(s，2H)，6.6(dd，1H)，6.7(d，1H)，7.08(d，1H)，7.2(d，1H)，7.3-7.4(m，2H)，7.42-7.6(m，3H)，7.9(s，1H)，8.5(s，1H)，9(s，1H)。
Example 266:
using acid 71(1.4g, 3.6mmol), thionyl chloride (1.3ml, 18mmol), DMF (1 drop) and dichloromethane according to general procedure V gave the desired acid chloride. According to general method VI, using the acyl radicalChlorine, aniline 595(0.84g, 3.6mmol), sodium bicarbonate (1.36g, 16mmol), acetone (50ml) and water (1 ml). The crude product was purified by flash column chromatography on silica gel eluting with 5% methanol in dichloromethane to give 655(0.53g, 25%) as a solid.1H NMR(DMSO-d6，400MHz)δ1.7-1.8(m，2H)，1.95(s，3H)，2.6-2.7(m，2H)，3.4(br s，4H)，3.9(t，2H)，4.66(s，2H)，5.7(s，2H)，6.6(dd，1H)，6.7(d，1H)，7.0(d，1H)，7.2(d，1H)，7.5(d，1H)，7.6(dd，1H)，7.8-7.82(m，2H)，8(d，1H)，9.02(s，1H)。
Example 267:
step A:
the same procedure as for the preparation of compound 139 was used, using 4- (3-bromo-propoxy) -2-methyl-1-nitrobenzene (1g, 3.6mmol) and thiazolidine (Aldrich, 0.34ml, 4.3 mmol). Compound 657(0.45g, 48%) was obtained as an oil, which was used without further purification.
And B:
657(1g, 3.5mmol) of the nitro group was reduced under catalytic conditions (H2, 10% Pd/C in ethanol). Using acid 71(1.3g, 3.5mmol), thionyl chloride (1.3ml, 18mmol), DMF (1 drop) and dichloromethane according to general procedure V gave the desired acid chloride. The crude aniline obtained, acid chloride, sodium bicarbonate (1.4g, 16mmol), acetone (50ml) and water (1ml) were used according to general procedure VI. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate: hexane (7: 3) to give 656(0.14g, 7%) as a white solid. 1H NMR(DMSO-d6，300MHz)δ1.7-1.8(m，2H)，2(s，3H)，2.4(t，2H)，2.8(t，2H)，3(t，2H)，3.9-4(m，5H)，4.7(s，1H)，6.6(dd，1H)，6.7(d，1H)，7.0(d，1H)，7.2(d，1H)，7.5(d，1H)，7.6(dd，1H)，7.8-7.82(m，2H)，8(d，1H)，9.02(s，1H)。
Example 268:
step A:
to a solution of copper (II) bromide (5.36g, 24mmol) and acetonitrile (100ml) was added dropwise tert-butyl nitrite (3.8ml, 32mmol) at 0 ℃ followed by dropwise addition of 3-amino-5-bromotrifluorotoluene (5g, 21 mmol). The mixture was stirred at 0 ℃ for 1.5 hours and then at room temperature for 16 hours. The mixture was concentrated in vacuo to half its original volume and then poured into 1N HCl (120ml) and the mixture extracted with ether (100 ml). The organic layer was washed with 1n hcl, dried (sodium sulfate), filtered and concentrated in vacuo (note: the product was fairly volatile and should not be exposed to high vacuum for a long time) to give 659(5.12g) as a brown oil, which was used without further purification.1H NMR(CDCl3，400MHz)δ7.82(s，1H)，7.67(s，2H)。
And B:
659(5.12g), N-methyl-N-methoxy-2-methoxy-5-chlorobenzamide (3.6g, 16.8mmol) and N-butyllithium (8.76ml of a 2.7M solution in heptane) were treated according to the method outlined in example 2 part A to give 660(3.36g) which was used without further purification.1H NMR(CDCl3，400MHz)δ8.02(s，1H)，7.89(d，2H)，7.46(dd，1H)，7.38(d，1H)，6.92(d，1H)，3.66(s，3H)。
And C:
following general procedure A, using 660(3.36g, 8.55mmol), sodium cyanide (838mg, 17mmol), copper (I) iodide (325mg, 1.7mmol) and tetrakis (triphenylphosphine) palladium (O) (987mg,. 86mmol), purification on silica gel (10% ethyl acetate/hexane) gave 661(1.35 g). 1HNMR(CDCl3，400MHz)δ8.19(s，1H)，8.13(s，1H)，8.04(s，1H)，7.50(dd，1H)，7.43(d，1H)，6.94(1H)，3.65(s，3H)。
Step D:
661(1.35g, 3.98mmol) was treated according to the method for the synthesis of compound 4 to give 662(1.29g, > 99%) as a yellow oil which was used without further purification:1H NMR(CDCl3，300MHz)δ11.49(s，1H)，8.20-8.16(m，3H)，7.59(dd，1H)，7.38(d，1H)，7.15(d，1H)。
step E:
following the procedure of example 197, step D, treatments 662(487mg, 1.5mmol) and 470 gave the crude product, which was purified by silica gel chromatography (8: 1 dichloromethane/ethyl acetate/methanol) and triturated with ether to give 658(315mg) as an off-white solid.1H NMR(DMSO-d6，400MHz)δ9.41(s，1H)，8.56(s，1H)，8.45(s，1H)，8.27(s，1H)，7.66-7.52(m，5H)，7.19(m，3H)，4.76(s，2H)，2.12(s，3H)；MS(ES-)：m/z 550(M-H)-。
Example 269:
step A:
a mixture of 3-methoxythiophene (1.14g, 10mmol), aluminium chloride (2.67g, 20mmol) and benzoyl chloride (1.16ml, 10mmol) in 50ml dichloromethane was heated to reflux for 20 h. The reaction mixture was then poured into ice and stirred at room temperature for 5 hours, after which the aqueous layer was separated and extracted with 20ml of dichloromethane. The combined organic layers were then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.897g of an orange oil. Purification by flash chromatography using 5-7% ethyl acetate: hexanes as eluent gave 664(0.823g, 40%) as a yellow crystalline solid:1H NMR(CDCl3，400MHz)δ12.35(s，1H)，7.92(dd，2H)，7.56-7.46(m，4H)，6.83(d，1H)。
and B:
a solution of o-toluidine (2.67ml, 25mol) and pyridine (2.2ml, 27.5mmol) in 200ml chloroform was cooled to 0 ℃ in an ice bath. Bromoacetyl bromide (2.4ml, 27.5mmol) was added dropwise over 7 min and the resulting mixture was slowly warmed to room temperature and stirred for 24 h. The reaction mixture is then poured into 150ml of water. The aqueous layer was separated and extracted with 100ml dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 665(5.86g, quantitative): 1H NMR(CDCl3，400MHz)δ8.10(br s，1H)，7.81(d，1H)，7.20-7.17(m，2H)，7.10-7.06(m，1H)，4.04(s，2H)，2.27(s，3H)。
And C:
a mixture of 664(0.204g, 1.0mmol), 665(0.235g, 1.03mmol) and potassium carbonate (0.622g, 4.5mmol) in 10ml of acetone was heated to reflux for 6 hours and then stirred at room temperature for a further 16 hours. Then the reaction mixture is mixedPoured into 30ml of water and extracted with two portions of 30-ml each of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.448g of crude material. Purification by flash chromatography using 35% ethyl acetate/hexanes as eluent gave 663(0.272g, 77%): MS (ES +): m/z 352(M + H);1H NMR(CDCl3，400MHz)δ8.53(br s，1H)，7.81-7.79(m，2H)，7.59(d，1H)，7.42-7.38(m，3H)，7.19-7.16(m，2H)，7.10-7.07(m，1H)，6.93(d，1H)，4.73(s，2H)，2.19(s，3H)。
example 270:
a mixture of 664(0.218g, 1.07mmol), 470(0.338g, 1.1mmol) and potassium carbonate (0.622g, 4.5mmol) in 10ml acetone was heated to reflux for 5 hours. The reaction mixture was then poured into 30ml of water and extracted with 30ml of ethyl acetate. The pH of the aqueous layer was adjusted to 7 with 3M HCl and then extracted with 30ml of ethyl acetate. The combined organic layers were filtered to remove a yellow solid, dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.360g of crude material. This material was suspended in dichloromethane and acetone and filtered, then suspended in methanol and filtered to give 666(0.076g, 17%): MS (ES +): m/z 431(M + H); 1H NMR(CDCl3，400MHz)δ9.29(s，1H)，7.96(d，1H)，7.77(d，2H)，7.67(d，1H)，7.62(d，1H)，7.58(dd，1H)，7.50(t，1H)，7.43-7.48(m，2H)，7.23(br s，2H)，7.15(d，1H)，4.83(s，2H)，2.16(s，3H)。
Example 271:
step A:
a mixture of 3-methoxythiophene (1.14g, 10mmol), aluminum chloride (2.70g, 20.2mmol) and 3, 5-difluorobenzoyl chloride (1.18ml, 10mmol) in 50ml dichloromethane was heated to reflux for 20 h. Then stirred at room temperature for 27 hours. The reaction mixture was then poured onto ice and stirred at room temperature for 40 minutes, after which the aqueous layer was separated and extracted with 20ml of dichloromethane. The combined organic layers were then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.214g of a brown solid. Purification by flash chromatography using 2% ethyl acetate/hexanes as eluent gave 668(0.518g, 22%) as a yellow solid:1H NMR(CDCl3，400MHz)δ12.04(s，1H)，7.57(d，1H)，7.43(dd，2H)，7.02-6.97(m，1H)，6.84(d，1H)。
and B:
a mixture of 668(0.192g, 0.80mmol), 665(0.188g, 0.82mmol) and potassium carbonate (0.498g, 3.6mmol) in 10ml acetone was heated to reflux for 6 hours. The reaction mixture was then poured into 30ml of water and extracted with two portions of 30-ml each of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude material. Purification by flash chromatography using 35-40% ethyl acetate/hexanes as the eluent gave 667(0.069g, 22%) as a yellow solid: MS (ES +): m/z 388(M + H); 1H NMR(CDCl3，400MHz)δ8.75(br s，1H)，7.74(d，1H)，7.66(d，1H)，7.36-7.32(m，2H)，7.23-7.21(m，2H)，7.15-7.10(m，1H)，6.99(d，1H)，6.96-6.89(m，1H)，4.80(s，2H)，2.32(s，3H)。
Example 272:
a mixture of 668(0.192g, 0.80mmol), 470(0.252g, 0.82mmol) and potassium carbonate (0.498g, 3.6mmol) in 10ml acetone was heated to reflux for 6 hours. The reaction mixture is then poured into 30ml of water and extracted with two portions of 30-ml each of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.272g of crude material. Purification by flash chromatography using 35-50% ethyl acetate/hexanes as eluent gave 669 as a yellow solid (0.103g, 28%): MS (ES +): m/z 467(M + H);1H NMR(CDCl3，400MHz)δ9.47(br s，1H)，8.06(d，1H)，7.72-7.52(m，3H)，7.50-7.40(m，3H)，7.26(br s，2H)，7.17(d，1H)，4.89(s，2H)，2.23(s，3H)。
example 273:
step A:
a mixture of 3-methoxythiophene (1.14g, 10mmol), aluminium chloride (2.78g, 20.8mmol) and 284(10mmol) in 50ml dichloromethane was heated to reflux for 24 h. Then stirred at room temperature for 15 hours. The reaction mixture was then poured onto ice and stirred at room temperature for 1 hour, after which the aqueous layer was separated and extracted with 35ml dichloromethane. The combined organic layers were then dried over magnesium sulfate, filtered and concentrated in vacuo to give 2.239g of a brown oil. Purification by flash chromatography using 5% ethyl acetate/hexanes as eluent gave 671(0.195g, 9%):1H NMR(400MHz，CDCl3)δ12.04(s，1H)，8.19(s，1H)，8.13(d，1H)，7.83(d，1H)，7.64-7.58(m，2H)，6.86(d，1H)。
and B:
a mixture of 671(0.164g, 0.72mmol), 665(0.168g, 0.74mmol) and potassium carbonate (0.448g, 3.24mmol) in 12ml acetone was heated to reflux for 15 hours and then stirred at room temperature for a further 5.5 hours. Since the reaction mixture had dried overnight, a further 10ml of acetone were added, the mixture was heated to reflux for 6 hours and then stirred overnight at room temperature, and the reaction was allowed to proceed The mixture was poured into 50ml of water and extracted with two portions of 35-ml each of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.251g of a brown oil. Purification by flash chromatography using 30-40% ethyl acetate/hexanes as eluent gave 670(0.033g, 12%) as a yellow solid: MS (ES +): m/z 377(M + H);1HNMR(CDCl3，400MHz)δ8.63(br s，1H)，8.07(s，1H)，8.01(d，1H)，7.73-7.68(m，2H)，7.65(d，1H)，7.55(t，1H)，7.20-7.18(m，2H)，7.09(t，1H)，6.97(d，1H)，4.76(s，2H)，2.27(s，3H)。
example 274:
step A:
(reference: Synthesis, 1984, 847). Sulfonyl chloride (2ml, 25.5mmol) was added to a stirred mixture of methyl 3-methoxy-2-thiophenecarboxylate (Avocado, 4g, 23.2mmol) in chloroform (40ml) and after concentration the reaction mixture was stirred gently for 4-6 hours. The concentrate was dissolved in glacial acetic acid and HCl gas was bubbled through. The resulting mixture was allowed to stand for 48 hours. After solvent extraction, flash column chromatography on silica gel eluting with dichloromethane afforded 673(2.8g, 58%) as a white solid.1H NMR(DMSO-d6，300MHz)δ3.7(s，3H)，3.9(s，3H)，7.3(s，1H)。
And B:
according to general procedure III 673(1g, 4.8mmol), lithium hydroxide dihydrate (1g), ethanol (10ml) and water (10ml) were used. After treatment, is obtained as674(0.59g, 64%) as a light brown solid.1H NMR(DMSO-d6，300MHz)δ3.9(s，3H)，7.2(s，1H)，12.6(br s，1H)。
And C:
carbonyldiimidazole (0.5g, 3.1mmol), N, O-dimethylhydroxylamine hydrochloride (0.45g, 4.65mmol) and a catalytic amount of N, N-dimethylaminopyridine were added to a solution of 674(0.59g, 3.1mmol) in THF (10 ml). The reaction mixture was stirred at room temperature under argon for 24 hours. The mixture was then diluted with ethyl acetate and washed with water. After drying (magnesium sulfate), the solvent was removed and the crude product was purified by flash column chromatography on silica gel eluting with 5% methanol in dichloromethane to give 675 as an off-white solid (0.36g, 49%). 1H NMR(DMSO-d6，300MHz)δ3.1(s，3H)，3.7(s，3H)，3.9(s，3H)，7.2(s，1H)。
Step D:
according to general method VIII, 675(0.36g, 1.5mmol), 3, 5-dibromotoluene (Avocado, 0.34g, 1.4mmol) and n-butyllithium (1.1ml, 1.5mmol of a 1.4M solution in hexane) in diethyl ether are used. After work-up, flash column chromatography on silica gel eluting with dichloromethane afforded 676(0.3g, 58%) as a white solid.1H NMR(DMSO-d6，300MHz)δ2.3(s，3H)，3.8(s，3H)，7.4(s，1H)，7.5(s，1H)，7.6(s，1H)，7.62(s，1H)。
Step E:
according to general method IX676(0.3g, 0.9mmol), boron tribromide (1.7ml, 1.7mmol) and dichloromethane (10ml) were used. 677(0.26g, 87%) was obtained as a solid.1H NMR(DMSO-d6，400MHz)δ2.3(s，3H)，6.8(s，1H)，7.46(s，1H)，7.6(s，1H)，7.62(s，1H)，11.6(s，1H)。
Step F:
a mixture of 677(0.26g, 0.8mmol), 470(0.24g, 0.8mmol) and potassium carbonate (0.6g, 4mmol) in DMF (10ml) was stirred for 12 h. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate extract was further washed with water, brine and dried (magnesium sulfate). After removal of the solvent, the crude product was flash column chromatographed on silica gel eluting with 5% methanol in dichloromethane to give impurity 672 which was recrystallized from ethyl acetate to give 672 as a white solid (0.016g, 4%).1H NMR(DMSO-d6，300MHz)δ2.2(s，3H)，2.3(s，3H)，4.9(s，2H)，7.2(s，1H)，7.4(s，1H)，7.5-7.8(m，7H)，9.4(s，1H)。
Example 275
Inhibition of viral replication
HeLa cell assay
HeLa cell assays were performed according to the modified method of Kimpton J. and Emerman M. (Detection of prevention-replication and pseudotyped human immunological virus with a reactive cell line of an integrated β -galactosidase gene, J.Virol.66: 2232-2239(1992)), in which HIV-1 infection is integrated by activation into CD4 +The HIV-LTR driven beta-galactosidase reporter gene in the genome of the HeLa cell line. Quantification of β -galactosidase can be accomplished by measuring the activation of a chemiluminescent substrate (Tropix). The concentration required for each compound to inhibit 50% of the HIV-1 induced β -galactosidase signal (IC) was determined for each genetically purified recombinant virus relative to untreated controls50)。
A. Test method
Growth and maintenance of the CD4-HIV LTR-. beta. -gal HeLa cell line.
HeLa-CD 4-LTR-. beta. -gal cells were obtained from NIH AIDS Research and Reference Reagent Program. Cells were propagated in DMEM containing 10% fetal calf serum, 0.2mg/ml geneticin and 0.1mg/ml hygromycin B. When the cells reached 80% confluence (approximately every 2-3 days), the cells were routinely lysed by trypsinization.
Construction of HIV-1 Reverse Transcriptase (RT) mutants
The DNA encoding HIV-1 reverse transcriptase was subcloned from the M13 phage into the usual shuttle vector, pBCSK +, as an approximately 1.65kbp EcoRI/HindIII cut (ended) DNA fragment. The HIV DNA insert pRT2 of the resulting plasmid was fully sequenced on both strands and then used for site directed mutagenesis experiments. Specific amino acid substitutions were performed using Stratagene Quick Change reagent and mutagenized oligonucleotides (from Oligos). After mutagenesis, the complete coding sequence of the mutant RT was verified by sequencing the DNA duplex.
C. Construction of Gene purified HIV-1 RT mutant viruses
HIV-1 mutants were isolated by a modified recombinant virus assay (Kellam P. and Larder B. recombinant virus assay: a rapid, phenotypic assay to evaluate drug susceptibility of human immunodeficiency type 1 virus isolates, antibiotic Agents and chemotherapeutics, 38: 23-30, 1994). EcoRI/HindIII digested mutant RT plasmid and Bst EII-digested HIV-1 in the presence of DMRIE-C transfection reagent (Gibco) according to the supplier's recommendationsHXB2ΔRTDNA cotransfection 1X 107Jurkat T-cells (maintained in RPMI containing 10% fetal bovine serum, dividing 1: 5 every 5-6 days). Each mutant RT coding sequence was hybridized into the RT-deleted HIV-1 viral DNA backbone by in vivo homologous recombination. Transfected cell cultures were expanded and monitored until syncitia formation and CPE spread. The virus was harvested by clarified centrifugation of culture supernatant (clear spin) and frozen as the original stock at-80 ℃. For recombinant progeny virusSequencing in the RT region to confirm the genotype of the mutant. Infected Jurkat cells further expanded the virus stock, harvested and stored as frozen aliquots. The stock was titrated in HeLa MAGI cells for assay.
D. Titration of viral stocks
Titration of HIV-1 in the Hela MAGI assay SystemHXB2Mutants, to determine relative light units per ml (RLU), a measure of infectivity associated with the assay system. Viral stocks were serially diluted 2-fold in DMEM containing 10% fetal bovine serum plus 20. mu.g/ml DEAE-dextran and assayed as described in the protocol section below.
E. Test protocol
3X 10 in 100. mu.l DMEM with 10% fetal bovine serum3A96-well microtiter plate (Costar #3598) was inoculated with HeLa-CD 4-LTR-. beta. -gal. The microtiter plates were placed in a humidified incubator at 37 ℃ and 5% carbon dioxide overnight. The next day, the mutant virus stock was thawed in a water bath at room temperature and diluted in DMEM containing 10% fetal bovine serum and 20. mu.g/ml DEAE-dextran to obtain an input of 1500-2000 RLU/ml. The whole medium was removed with an 8-channel multi-head aspirator and 35. mu.l (50-70 total RLUs) of diluted virus was added to each well to allow virus adsorption. The plates were placed in a humidified incubator at 37 ℃ and 5% carbon dioxide for 1.5-2 hours.
Compound titer plates were prepared at a final concentration of 1.35X during virus adsorption. The compounds were automatically titrated in a 5-fold stepwise manner in the range from 2.7. mu.M (2. mu.M final concentration) to 1.35pM (1pM final concentration). This protocol allows 8 test compounds per 96-well plate and 10 dilution spots per compound (n ═ 1) for 2 controls. The compound was titrated into DMEM containing 10% fetal bovine serum plus 0.135% DMSO (0.1% final concentration). 100 μ l of the titrated compound was removed from each well of the titer plate and added to the viral adsorption plate. The plates were placed in a 37 ℃ humidified incubator with 5% carbon dioxide for 72 hours.
After incubation, from each well, as described aboveThe supernatant was aspirated and 100. mu.l phosphate buffered saline was added. PBS was then aspirated as above and 15. mu.l lysis buffer (Tropix) was added. The plate was maintained at room temperature for 10 minutes, during which time the chemiluminescent substrate (Tropix) was diluted 1: 50 into substrate dilution buffer (Tropix) at room temperature. Then, 100. mu.l of the diluted substrate was added to each well. Plates were incubated for 1-1.5 hours at room temperature. After incubation, the chemiluminescence values of each well were determined using a Dynatech plate reader under the following settings:
parameter(s) Value of
Operation of Circulation of
Data of All of
Gain of Is low in
Period of time 1s
Pausing 2s
Row board abcdefgh
Temperature of At room temperature
Stirring the mixture Is free of
Analyzing the output raw data, RLUs, by non-linear regression to determine IC50Values (see data analysis section below).
F. Data analysis
Relative Light Units (RLU) are expressed as% control:
(RLU in the Presence of Compound [ ]/RLU in the absence of Compound). times.100 ═ control
By the following nonlinear regression model obtained from the ROBOSAGE software package:
Y＝Vmax×(1-(Xn/(Kn+Xn)))
determination of the concentration of Compound that inhibits 50% Signal production by untreated samples (IC)50)。
This equation describes a sigmoidal inhibition curve with a zero baseline. X is inhibitor concentration and Y is response to inhibition. V maxIs the limiting response when X is close to zero. When X increases infinitely, Y tends towards its lower limit, zero. IC with K as inhibition curve50That is, when X ═ K, Y equals 50% of Vmax。
The results of Table 1 are representative of IC50And (6) reporting the value.
MT4 cell assay
A. Test protocol
Antiviral HIV activity and compound-induced cytotoxicity were determined in parallel in the human T-cell lymphotropic virus transfected cell line MT4 by a propidium iodide (propidium iodide) based method. Aliquots of test compounds were serially diluted with CetusPro/Pette in medium (RPMI 1640, 10% Fetal Calf Serum (FCS) and gentamicin) in 96-well plates (Costar 3598). Exponentially growing MT4 cells were harvested and centrifuged in a Joean centrifuge (model CR 412) at 1000rpm for 10 minutes. The cell pellet was resuspended at a density of 5X 105 cells/ml in fresh medium (RPMI 1640, 20% FCS, 20% IL-2)And gentamicin). Aliquots of diluted HIV-1 (strain IIIB) infected cells were added to give a virus multiplicity of infection of 100 XTCID 50. Similar cell aliquots were diluted with medium to provide mock-infected controls. Cell infection was performed in a tissue culture incubator with a humid 5% carbon dioxide atmosphere for 1 hour at 37 ℃. After 1 hour of incubation, the virus/cell suspension was diluted 6-fold with fresh medium and 125 μ l of cell suspension was added to each well of the plate containing each dilution of compound. The plates were then placed in a tissue culture incubator with humidified 5% carbon dioxide for 5 days. At the end of the incubation period, 27 μ l of 5% Nonidet-40 was added to each well of the plate. After thorough mixing with a Costar multiheaded pipette, 60. mu.l of the mixture was transferred to a filter-bottomed 96-well plate. The plate was analyzed in an automated tester (Screen Machine, Idexx Laboratories). The control and standard used in each assay were 3 '-azido-3' -deoxythymidine at concentrations ranging from 0.01 to 1 μ M tested. IC for 3 '-azido-3' -deoxythymidine 50The desired range of values is 0.04-0.12. mu.M. The assay uses propidium iodide staining to estimate the DNA content in each well.
B. Analysis of
The antiviral effect of the test compound is reported as IC50I.e., to produce an inhibitory concentration that reduces HIV-induced cytopathic effects by 50%. This effect was measured by the amount of test compound required to restore cell growth to 50% of HIV-infected MT4 cells compared to the uninfected MT4 cell control. IC (integrated circuit)50Calculated by RoboSage, auto-generated curve fitting program (version 5.00, month 10-7-1995).
For each assay plate, the results of wells containing uninfected cells or infected cells without compound were averaged (relative fluorescence units, rfU), respectively. For the determination of compound-induced cytotoxicity, results from wells containing various concentrations of compound and uninfected cells were compared to the average of uninfected cells that were not treated with compound. The percentage of remaining cells was determined by the following formula:
residual cell percentage (compound-treated uninfected cells, rfU/untreated uninfected cells) x 100.
Residual cell percentage levels at or below 79% indicate that the level of compound direct-induced cytotoxicity was significant for this concentration of compound. When this occurs, the results obtained with compound-treated infected wells at this concentration are not included in the IC 50In the calculation of (2).
To determine the antiviral activity of the compounds, results from wells containing various concentrations of the compounds and infected cells were compared to the average of uninfected cells and infected cells not treated with the compounds. The percent inhibition of the virus was determined by the following formula:
percent inhibition of virus ═ 1- ((mean of untreated uninfected cells-treated infected cells)/(mean of untreated uninfected cells-mean of untreated infected cells)) × 100
Reference documents:
averett, d.r., evaluation of anti-HIV compounds by two new high efficiency assays, j.virol.methods 23: 263-276, 1989.
Schwartz, o. et al, a rapid and simple colorimetric test for anti-HIV drug research, AIDS res.and Human Retroviruses 4 (6): 441-447, 1988.
Daluge, s.m. et al, 5-chloro-2 ' 3 ' -deoxy-3 ' fluorouridine (935U83), a selective anti-human immunodeficiency virus drug with improved metabolic and toxicological profiles. Anti, Agents and Chemother.38 (7): 1590-1603, 1994.
Domsife, R.E., et al, Anti-human immunological virus synergy byzidovudine (3' -azidothymidine) and didedanosine (dideoxynosine) coherent with the additive inhibition of normal human marrow promoter cells, Anti-microbial Agents and Chemotherm.35 (2): 322-3281991.
The results in Table 1 are shown as representative ICs50And (3) a range.
TABLE 1
Compound number virus type IC50(nM) range*Measurement of
1 HIV-1 C MT4
NEV-R D MT4
5 HIV-1 B MT4
NEV-R C MT4
8 HIV-1 B MT4
NEV-R C MT4
9 HIV-1 B MT4
NEV-R C MT4
62 HIV-1 A MT4
HIV-2 D MT4
NEV-R A MT4
E138K A HeLa
G190A A HeLa
G190E A HeLa
K101E A HeLa
K103N A HeLa
K103N/G190A B HeLa
K103N/L1001 A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C B HeLa
L1001 A HeLa
P225H A HeLa
P236L B HeLa
V106A B HeLa
V106A/Y181C B HeLa
V1061 A HeLa
V1061/Y181C B HeLa
V1081 A HeLa
V1081/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
Y188C A HeLa
78 HIV-1 A
NEV-R A
E138K A HeLa
G190A A HeLa
G190E A HeLa
K101E A HeLa
K103N A HeLa
K103N/G190A B HeLa
K103N/L1001 A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L1001 A HeLa
P225H A HeLa
P236L A HeLa
V106A B HeLa
V106A/Y181C B HeLa
V1081 A HeLa
V1081/Y181C B HeLa
WTRVA A HeLa
Y181C A HeLa
Y188C A HeLa
79 HIV-1 A MT4
HIV-2 D MT4
NEV-R A MT4
K103N A HeLa
K103N/Y181C A HeLa
103 HIV-1 B MT4
NEV-R C MT4
K103N B HeLa
120 HIV-1 B MT4
NEV-R B MT4
K103N B HeLa
K103N/Y181C C HeLa
WTRVA B HeLa
Y181C B HeLa
122 HIV-1 A MT4
NEV-R B MT4
K103N B HeLa
K103N/Y181C D HeLa
WTRVA B HeLa
Y181C C HeLa
239 HIV-1 A MT4
NEV-R A MT4
E138K A HeLa
G190A A HeLa
G190E A HeLa
K101E A HeLa
K103N A HeLa
K103N/G190A B HeLa
K103N/L1001 A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C B HeLa
L1001 A HeLa
P225H A HeLa
P236L A HeLa
V106A B HeLa
V106A/Y181C C HeLa
V1061 A HeLa
V1061/Y181C A HeLa
V1081 A HeLa
V1081/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
Y188C A HeLa
257 HIV-1 A MT4
NEV-R A MT4
E138K A HeLa
G190A A HeLa
G190E A HeLa
K101E A HeLa
K103N A HeLa
K103N/G190A B HeLa
K103N/L1001 A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L1001 A HeLa
P225H A HeLa
P236L A HeLa
V106A B HeLa
V106A/Y181C B HeLa
V1061 A HeLa
V1061/Y181C B HeLa
V1081 A HeLa
V1081/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
Y188C A HeLa
338 HIV-1 A MT4
NEV-R B MT4
K103N B HeLa
K103N/Y181C C HeLa
WTRYA A HeLa
Y181C B HeLa
387 HIV-1 A MT4
NEV-R B MT4
K103N A HeLa
K103N/Y181C B HeLa
WTRVA A HeLa
Y181C B HeLa
435 HIV-1 A MT4
NEV-R B MT4
K103N A HeLa
K103N/Y181C C HeLa
WTRVA A HeLa
Y181C B HeLa
448 HIV-1 A MT4
HIV-2 D MT4
NEV-R A MT4
E138K A HeLa
G190A A HeLa
G190E A HeLa
K101E A HeLa
K103N A HeLa
K103N/G190A B HeLa
K103N/L1001 A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C B HeLa
L1001 A HeLa
P225H A HeLa
P236L B HeLa
V106A B HeLa
V106A/Y181C B HeLa
V1061 A HeLa
V1061/Y181C B HeLa
V1081 A HeLa
V1081/Y181C A HeLa
Y181C A HeLa
Y188C A HeLa
453 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K101E A HeLa
K103N A HeLa
K103N/G190A B HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L1001 A HeLa
P225H A HeLa
P236L B HeLa
V106A C HeLa
V106A/Y181C B HeLa
V1061 A HeLa
V1061/Y181C B HeLa
V1081 C HeLa
V1081/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
Y188C A HeLa
491 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A B HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L1001 A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V1061 A HeLa
V1061/Y181C B HeLa
V1081 A HeLa
V1081/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
564 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L1001 A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V106I/Y181C A HeLa
V1081/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
587 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V108I A HeLa
K103N/Y181C A HeLa
L100I A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V106I/Y181C B HeLa
V108I A HeLa
V108I/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
475 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L100I A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V106I/Y181C B HeLa
V108I A HeLa
V108I/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
478 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L1001 A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V1061/Y181C A HeLa
V108I A HeLa
V108I/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
498 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L100I A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V106I/Y181C B HeLa
V108I A HeLa
V108I/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
593 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V108I A HeLa
K103N/Y181C A HeLa
L100I A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V106I/Y181C B HeLa
V108I A HeLa
V108I/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
483 HIV-1 B MT4
NEV-R A MT4
K103N C HeLa
V106A/Y181C C HeLa
V106I A HeLa
V106I/Y181C B HeLa
WTRVA B HeLa
Y181C C HeLa
637 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L100I A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V106I/Y181C A HeLa
V108I/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
503 HIV-1 A MT4
NEV-R A MT4
G190A A HeLa
K103N A HeLa
K103N/G190A A HeLa
K103N/P225H A HeLa
K103N/V1081 A HeLa
K103N/Y181C A HeLa
L100I A HeLa
P225H A HeLa
P236L A HeLa
V106A/Y181C A HeLa
V106I A HeLa
V106I/Y181C A HeLa
V108I A HeLa
V108I/Y181C A HeLa
WTRVA A HeLa
Y181C A HeLa
601 HIV-1 A MT4
NEV-R A MT4
K103N A HeLa
WTRVA A HeLa
Y181C A HeLa
V106A A HeLa
*A represents an IC of 10nM or less50
B denotes an IC between 11nM and 100nM50
C denotes an IC between 101nM and 1000nM50
D represents the IC between 1000nM and 3000nM50

Claims (12)

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof
Wherein:
R1is C which may be optionally substituted by one or more substituents selected from the group consisting of6-14Aryl: halogen, -CF3、C1-8Alkyl radical, C1-8Alkylamino, alkoxy, C3-6Cycloalkyl radical C2-6Alkenyl radical、C6-14Aryl radical C2-6Alkenyl, -CN, -NO2、-NH2、-SR6、-S(O)2R6、-S(O)R7、-S(O)2R7、-C(O)R7C which may be optionally substituted by a substituent selected from the group consisting of hydroxy, halogen, aryl and heterocycle2-6Alkenyl and may be selected from hydroxy, halogen, aryl, C3-6Cycloalkyl and heterocyclic substituents optionally substituted C2-6An alkynyl group;
R6is selected from hydroxy, halogen, -CF3C optionally substituted by one or more substituents of aryl and heterocycle1-8An alkyl group;
R7is selected from hydroxyl, halogen, aryl, C3-6C wherein one or more substituents of cycloalkyl and heterocycle are optionally substituted1-8An alkyl group; -NH2(ii) a Or a heterocycle;
R2is hydrogen, halogen or C1-8An alkyl group;
R3and R4Can be formed of C6-14Aryl optionally substituted heterocycle, said C6-14The aryl group may be substituted by one or more groups selected from C1-8Alkyl and-NO2The substituent(s) is optionally substituted;
provided that when R is1Is unsubstituted C6-14When aryl is present, then R3R4Is substituted;
R5is hydrogen, halogen, C1-8Alkyl, -NO2、-NH2、C1-8Alkylamino radical, CF3Or an alkoxy group.
2. A compound of formula (II) according to claim 1, wherein R is 1Is C substituted by halogen6-14An aryl group; r2Is hydrogen; r3And R4Can be formed of C6-14Aryl optionally substituted heterocycle, said C6-14The aryl group may be substituted by one or more groups selected from C1-8Alkyl and-NO2The substituent(s) is optionally substituted; r5Is halogen.
3. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a viral infection in a mammal.
4. The use of claim 3, wherein the viral infection is an HIV infection.
5. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting HIV reverse transcriptase.
6. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of HIV infection.
7. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection.
8. Use of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a viral infection.
9. The use of claim 8, wherein the viral infection is an HIV infection.
10. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A pharmaceutical composition according to claim 10 in the form of a tablet or capsule.
12. A pharmaceutical composition according to claim 10 in liquid form.
HK05111885.0A 1999-09-04 2006-01-16 Benzophenones as inhibitors of reverse transcriptase HK1080455A (en)

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