TW201144296A - Tetrazolones as inhibitors of fatty acid synthase - Google Patents

Abstract

Provided herein are tetrazolone FASN inhibitors of the formula (I): or a pharmaceutically acceptable form thereof; wherein the variables RA, RB and RC are defined herein. Also provided herein are pharmaceutical compositions of the compounds provided herein as well as methods of their use for the treatment of various disorders such as hyperproliferative disorders, inflammatory disorders, obesity-related disorders and microbial infections.

Description

201144296 VI. Description of the invention: [Prior Art] Fatty acid synthase (FASN) is a key enzyme for the synthesis of long-chain fatty acids from ethylene-coenzyme A (CoA) and propanediyl-CoA, using reduced nicotine Indoleamine adenine dinucleotide phosphate is used as a cofactor. FASN is minimally expressed in the most common human tissues, except for its high degree of performance in liver and adipose tissue. Since FASN expression is significantly increased in several human cancers compared to corresponding normal tissues, and the overexpression of FASN in tumors has been associated with poor prognosis, FASN inhibitors have long been recognized as potential therapeutic agents for the treatment of cancer. FASN inhibitors have also shown promise in the treatment of other FASN-mediated diseases, disorders or conditions, such as obesity, lack of control of your diet, and inflammatory conditions. In addition, FASN has been identified as a target for the treatment of microbial infections. In particular, it has been reported that fatty acid synthesis or fatty acid content is critical in the pathogenesis of the virus. For example, it has been reported that the formation of a new vesicle (i.e., a remodeled golgi apparatus) on the surface of viral RNA replication requires fatty acid biosynthesis (see Cherry et al., Corp. Pai/zogews, 2 (10): el02 (2006)). In addition, fatty acid biosynthesis has been identified as a stem of antiviral therapy using metabolic profiling of the host when the virus is infected (see Munger et al, iVaiwre 26: 1179-1186 (2008)). It has also been reported that inhibition of fatty acid biosynthesis (e.g., inhibition of fatty acid synthase) reduces the replication of human cellular giant virus (HCMV) and influenza A virus (ibid.). The establishment of FASN as a valid target for the treatment of viral infections can be used for 156069.doc 201144296 Multiple viruses. For example, the role of FASN has been implicated in the pathogenesis of enveloped viruses such as human cell giant virus (HCMV), influenza A virus, and hepatitis C virus (HCV) (see Munger et al., #

26: 1179-1186 (2008); Syed et al, Endocrinology and Metabolism, 21: 33-40 (2009) i Sakamoto et al., iVaiMre C/iewc/a/ Price o/ogy, 1: 333-337 (2005) Yang et al., 48: 1396-1403 (2008)). Regarding HCV, it has been reported that higher levels of fatty acid biosynthetic enzymes (including FASN) contribute to hepatic steatosis, resulting in cirrhosis and hepatocellular carcinoma when infected with HCV (Fukusawa et al., 5ζ·ο/. Pharm. Bull) ., 29(9): 1958-1961 (2006)). It has been reported that HCV replication is regulated, inter alia, by fatty acid biosynthesis (Kapadia et al. 'ZVoc. #(3//. *SW., 102(7): 2561-2566 (2005)). Establishing FASN as a target for HCV Other reports of potential host-targets have also been published (see, for example, /ie corpse aio/ogjK, 48: 1396 (2008); jEwi/ocrke Meia Office [, 21: 33 (2010); and 394: 130 (2009)) Regarding other viruses, it has been reported that FASN is increased in cells infected with coxsackievirus B3 (CVB3) (picornavirus), and the replication of CVB3 is by FASN inhibitors. Blocking (see Rassmann et al., jwi/Wra/i Jaearc/z, 76: 150-158 (2007)). FASN is reported to be a lytic virus of Epstein-Barr virus (EBV). Replication is important and suggests that FASN inhibition can be a novel approach to blocking EBV replication (Li et al, JoMrwa/o/Wro/ogj;, 78(8): 4197-4206 (2004)). FASN has also been involved. Role in the replication of dengue virus (dengue 156069.doc 201144296 virus) (see eg Heaton et al., corpse roc.

Acad. 5*cz··, 107(40): 17345-17350 (2010); and Samsa et al., PZoS Ραί/zegews, 5(10): el000632 (2009)). In addition, in addition to being a potential target for antiviral therapy, the role of FASN has been implicated in diabetes or in the general health of the liver (see, for example, Wu et al., /WyiiS1 Wushan 7/〇«, www.pnas. Org/cgi/doi/ 10.1073/pnas.l0025 88108 (2011)). Thus, there is a need for an effective inhibitor of FASN that can potentially be used as a therapeutic agent for microbial infections or other diseases and conditions including, but not limited to, viral infections. SUMMARY OF THE INVENTION Provided herein are four 11 ketone FASN inhibitors of formula (I): 0 〇

Rc (I) or a pharmaceutically acceptable form thereof; wherein the variables ra, rb & rg are defined below and herein. Also provided herein are pharmaceutical compositions comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof. Also provided herein is a method of treating cancer comprising administering at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition thereof, to an individual in need thereof. Also provided herein is a method of treating a microbial infection comprising administering to a subject in need thereof at least one compound of formula (I), or a pharmaceutically acceptable form thereof, 156069.doc -6- 201144296', or a pharmaceutical composition thereof. The details of other or alternative embodiments are set forth in the accompanying implementations and examples set forth below. Other features, objects, and advantages will be apparent from the description and claims. SEQ ID NO. 1 : Homo sapiens FASN amino acid sequence:

MEEVVIAGMSGKLPESENLQEFWDNL1GGVDMVTDDDRRWKAGLYGLPRRSGKLKDL

SRFDASFFGVHPKQAHTMDPQLRLLLEVTYEAIVDGGINPDSLRGTHTGVWVGVSGSET

SEALSRDPETLVGYSMVGCQRAMMANRLSFFFDFRGPSIALDTACSSSLMALQNAYQAI

HSGQCPAAIVGGINVLLKPNTSVQFLRLGMLSPEGTCKAFDTAGNGYCRSEGVVAVLLT

KKSLARRVYATILNAGTNTDGFKEQGVTFPSGDIQEQLIRSLYQSAGVAPESFEYIEAHG

TGTKVGDPQELNGITRALCATRQEPLLIGSTKSNMGHPEPASGLAALAKVLLSLEHGLW

APNLHFHSPNPEIPALLDGRLQVVDQPLPVRGGNVGINSFGFGGSNVHIILRPNTQPPPAP

APHATLPRLLRASGRTPEAVQKLLEQGLRHSQDLAFLSMLNDIAAVPATAMPFRGYAVL

GGERGGPEVQQVPAGERPLWFICSGMGTQWRGMGLSLMRLDRFRDSILRSDEAVKPFG

LKVSQLLLSTDESTFDDIVHSFVSLTAIQIGL1DLLSCMGLRPDGIVGHSLGEVACGYADG

CLSQEEAVLAAYWRGQCIKEAHLPPGAMAAVGLSWEECKQRCPPGVVPACHNSKDTV

TISGPQAPVFEFVEQLRKEGVFAKEVRTGGMAFHSYFMEA1APPLLQELKKVIREPKPRS

ARWLSTSIPEAQWHSSLARTSSAEYNVNNLVSPVLFQEALWHVPEHAVVLEIAPHALLQ

AVLKRGLKPSCTIIPLMKKDHRDNLEFFLAGIGRLHLSGIDANPNALFPPVEFPAPRGTPLI

SPLIKWDHSLAWDVPAAEDFPNGSGSPSAAIYNIDTSSESPDHYLVDHTLDGRVLFPATG

YLSIVWKTLARALGLGVEQLPVVFEDVVLHQATILPKTGTVSLEVRLLEASRAFEVSEN

GNLWSGKVYQWDDPDPRLFDHPESPTPNPTEPLFLAQAEVYKELRLRGYDYGPHFQGI

LEASLEGDSGRLLWKDNWVSFMDTMLQMSILGSAKHGLYLPTRVTAIHIDPATHRQKL

YTLQDKAQVADVVVSRWLRVTVAGGVHISGLHTESAPRRQQEQQVPILEKFCFTPHTEE

GCLSERAALQEELQLCKGLVQALQTKVTQQGLKMWPGLDGAQ1PRDPSQQELPRLLS

AACRLQLNGNLQLELAQVLAQERPKLPEDPLLSGLLDSPALKACLDTAVENMPSLKMK

VVEVLAGHGHLYSRIPGLLSPHPLLQLSYTATDRHPQALEAAQAELQQHDVAQGQWDP

ADPAPSALGSADLLVCNCAVAALGDPASALSNMVAALREGGFLLLHTLLRGHPLGDIV

AFLTSTEPQYGQG1LSQDAWESLFSRVSLRLVGLKKSFYGSTLFLCRRPTPQDSPIFLPVD

DTSFRWVESLKGILADEDSSRPVWLKAINCATSGVVGLVNCLRREPGGNRLRCVLLSNL

SSTSHVPEVDPGSAELQKVLQGDLVMNVYRDGAWGAFRHFLLEEDKPEEPTAHAFVST

LTRGDLSSIRWVCSSLRHAQPTCPGAQLCTVYYASLNFRDIMLATGKLSPDAIPGKWTS 156069.doc 201144296

QDSLLGMEFSGRDASGKRVMGLVPAKGLATSVLLSPDFLWDVPSNWTLEEAASVPVVY

STAYYALVVRGRVRPGETLLIHSGSGGVGQAAIAIALSLGCRVFTTVGSAEKRAYLQAR

FPQLDSTSFANSRDTSFEQHVLWHTGGKGVDLVLNSLAEEKLQASVRCLATHGRFLEIG

KFDLSQNHPLGMAIFLKNVTFHGVLLDAFFNESSADWREVWALVQAGIRDGVVRPLKC

TVFHGAQVEDAFRYMAQGKHIGKVVVQVLAEEPEAVLKGAKPKLMSA1SKTFCPAHKS

YIIAGGLGGFGLELAQWLIQRGVQKLVLTSRSGIRTGYQAKQVRRWRRQGVQVQVSTS

NISSLEGARGLIAEAAQLGPVGGVFNLAVVLRDGLLENQTPEFFQDVCKPKYSGTLNLD

RVTREACPELDYFVVFSSVSCGRGNAGQSNYGFANSAMERICEKRRHEGLPGLAVQWG

A1GDVGILVETMSTNDTIVSGTLPQRMASCLEVLDLFLNQPHMVLSSFVLAEKAAAYRD

RDSQRDLVEAVAHILGIRDLAAVNLDSSLADLGLDSLMSVEVRQTLERELNLVLSVREV

RQLTLRKLQELSSKADEASELACPTPKEDGLAQQQTQLNLRSLLVNPEGPTLMRLNSVQ

SSERPLFLVHPIEGSTTVFHSLASRLSIPTYGLQCTRAAPLDSIHSLAAYYIDCIRQVQPEG

PYRVAGYSYGACVAFEMCSQLQAQQSPAPTHNSLFLFDGSPTYVLAYTQSYRAKLTPG

CEAEAETEAICFFVQQFTDMEHNRVLEALLPLKGLEERVAAAVDLIIKSHQGLDRQELSF

AARSFYYKLRAAEQYTPKAKYHGNVMLLjFlAKTGGAYGEDLGADYNLSQVCDGKVSV

HVIEGDHRTLLEGSGLESIISIIHSSLAEPRVSVREG Definition

The definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified according to the CAS translation 'Handbook of Chemistry and Physics, 75th edition, the Periodic Table of the Elements, and the specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functionalities and reactions Ί·± ^ Organic Chemistry, Thomas Sorrell, University

Science Books, Sausalito, 1999; Smith and March March's 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989 ; Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987. Certain compounds provided herein may contain one or more asymmetric centers '156069.doc 201144296 and thus may exist in multiple isomeric forms, eg, enantiomers and/or diastereomers and/or stereo isomer. The compounds provided herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and or a plurality of stereoisomers. A mixture of thickened bodies. In certain embodiments, the compounds provided herein are enantiomerically pure compounds. In certain other embodiments, a mixture of stereoisomers is provided,

Further 'unless otherwise indicated, certain compounds as described herein may have one or more double bonds' which may exist in the form of cis or trans or a £ or 2 isomer. Also included are compounds which are in the form of individual isomers which are substantially free of other isomers' or in the form of a mixture of isomers, such as the racemic mixture of the £/Z isomer & A mixture of z isomers. The terms "optical enrichment", "enantiomeric enrichment", "enantiomerically pure" and "non-racemic" as used interchangeably herein are intended to mean the following: The term "non-racemic" can be applied more broadly to the weight percent of the body than the amount of the enantiomer of the racemic composition of the racemic mixture (eg, greater than the weight of the dip). A mixture of stereoisomers, diastereomers or olefin penta-Z isomers. For example, the enantiomeric enrichment formulation of the (s)-enantiomer means greater than 50% by weight relative to the (]1)-enantiomer '(S)-enantiomer Such as a compound formulation of at least 75% by weight and even up to such as at least 80% by weight.隹 Some examples can increase the concentration by far more than 80% by weight, thus providing "real only shellfish (study enrichment), substantial enantiomeric enrichment", "substantially enantiomerically pure Or a solid non-racemic formulation, which means at least 85% by weight, such as at least 9% by weight, and such as at least 85% by weight relative to the other enantiomer. A formulation having a composition of at least 95% by weight. In some embodiments, the enantiomeric enrichment composition has a higher potency in terms of therapeutic utility per unit mass compared to the racemic mixture of the constituents. The construct can be isolated from the mixture by methods known to those skilled in the art, including the formation and crystallization of palmitic high pressure liquid chromatography (HPLC) and the palm salt; or the enantiomer can be Prepared by symmetric synthesis. See, for example, Jacques et al., V. (IV)

Racemates and Resolutions (Wiley Interscience, New York, 1981) 'Wilen, SH et al, 33:2725 (1977); EHel, L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and wilen, SH(10)/ With hM/ 沾 第 268 1 (Edited by EL EUel, UnW 〇f

Dame Press, Notre Dame, IN 1972). As used herein, "function" and "dentate", alone or as part of another group, mean fluoro (fluoro, _F), chloro (gas, _α), bromine (bromo, -Br) or Iodine (iodo, _)). As used herein, "alkyl", alone or as part of another group, refers to a monovalent group (CM0 alkyl) having a straight or branched chain saturated hydrocarbon group of 1 to 10 carbon atoms. In some embodiments, The alkyl group has 丨 to ^ carbon atoms (Ci-9 alkyl group). In some embodiments, the alkyl group has from 1 to 8 carbon atoms (Cm alkyl group). In some embodiments, the alkyl group has ^ to ? Carbon atoms (Ci-7 alkyl) In some embodiments, an alkyl group has from 1 to 6 carbon atoms (Ci-6 alkyl group). In some embodiments, an alkyl group has from 1 to 5 carbons] 56069 .doc 201144296 Atom ("Cw alkyl"). In some embodiments, an alkyl group has from 1 to 4 carbon atoms ("Cm alkyl"). In some embodiments, the alkyl group has one carbon atom ("C !-3 alkyl"). In some embodiments, the alkyl group has from 2 to 2 carbon atoms ("Cw alkyl"). In some embodiments, the alkyl group has i carbon atoms ("C! In some embodiments, the alkyl group has 2 to 6 carbon atoms ("c2-6 alkyl group"). The examples of the alkyl group include a mercapto group (c) and an ethyl group (c2). ) Base (C3), isopropyl (C3), n-butyl (c: 4), tert-butyl (c4), second butyl (C4), isobutyl (c4), n-pentyl (c5) , 3_mercapto (c5), pentyl (c5), neopentyl (c5), 3-methyl-2-butyl (c5), third fluorenyl (C5) and n-hexyl (CO. alkyl Other examples include n-heptyl (c7), n-octyl (C8), and the like. Unless otherwise specified, the alkyl groups in each case are independently unsubstituted ("unsubstituted alkyl"). Or substituted by i, 2, 3 ' 4 or 5 substituents as described herein ("substituted alkyl"). In certain embodiments, the alkyl group is an unsubstituted Cl-1 () alkane In some embodiments, an alkyl group is a substituted alkyl group. When a range of values is recited, it is intended to cover various values and subranges within the range. For example, "C丨-6 alkyl" is intended to cover C丨, C2, c3, c4, c5, C6, Ci-6, c丨-5, Cl 4' c丨3, Ci 2, c2 6, c2 5, 4, c3- 6. c3.5, c3.4, c4_6, c4_AC5.6 alkyl. "Perhaloalkyl" as defined herein means all hydrogen having from i to 丨0 carbon atoms The alkyl groups each independently substituted with a dentate, for example, selected from fluorine, bromine, gas or iodine ("Cl-i 〇 perhaloalkyl"). In some embodiments, the alkyl moiety has from 1 to 9 carbons. Atom ("Cl_9") In some embodiments, the alkyl moiety has from 1 to 8 carbon atoms ("Cl_8 all-tooth alkyl"). In some examples 156069.doc -11 - 201144296 Example t, alkane The base moiety has from 丨 to 7 carbon atoms ("Cw perhaloalkyl", in some embodiments, the alkyl moiety has from 6 to 6 carbons perhaloalkyl"). In some embodiments, the alkyl moiety has from 5 to 5 carbon atoms (C<5>) perhaloalkyl). In some embodiments, the alkyl moiety has a ^ to bucket

One carbon atom ("cw a base"). In some embodiments, the thiol moiety has from 1 to 3 carbon atoms ("Ci.3 perhaloalkyl"). In some embodiments, the moiety has (1) carbon atoms (Μ"全基) In some embodiments, all of the hydrogen atoms are each replaced by fluorine. In some embodiments, all of the hydrogen atoms are each replaced by a gas. Examples of the alkyl group include -CF3, -cf2cf3, -CF2CF2CF3, _cci3, _CFCl2, CF2C1, and the like. In some embodiments). In some embodiments). In some embodiments). In some embodiments). In some embodiments

As used herein, alone or as part of another group, a monovalent group of a straight or branched hydrocarbon group of a group of H 2 to 1 carbon atoms and one or more carbon-carbon double bonds ("CL-based" In some embodiments, the group has 2 to 9 carbon atoms ("c2-9 alkenyl has 2 to 8 carbon atoms ("c28 alkenyl has 2 to 7 carbon atoms ("〇2·7 alkenyl) The group has 2 to 6 carbon atoms (re" alkenyl group having 2 to 5 carbon atoms ("C25 dilute group" 7-w" group having 2 to 4 carbon atoms ("C24-based"). In some embodiments the group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, the group has 2 carbon atoms GW groups"). The or more carbon-carbon double bonds; (such as 2-butadienyl hydrazone & ampere &) or terminal % (such as 1 · butenyl). Examples of C2 4 include vinyl, work Λ '-propyl group (C3), 2 - acryl (c3) 156069.doc • 12- 201144296 Butenyl (CO, 2-butenyl (CO, butadienyl π*) and the like. Examples of C2·6 alkenyl include the foregoing c: 2·4 alkenyl and pentenyl (CJ, pentadienyl (C5) And hexenyl (C6) and the like. Other examples of alkenyl groups include heptenyl (C7), octenyl (cs), octatrienyl ((8) and the like. Further, otherwise, the alkenyl group in each case is independently unsubstituted ("unsubstituted alkenyl") or substituted by 1, 2, 3, 4 or 5 substituents as described herein ("substituted Alkenyl" In certain embodiments, alkenyl is unsubstituted C2.丨0 alkenyl. In certain embodiments, alkenyl is substituted C210 alkenyl. As used herein, alone or "Alkynyl" as part of another group refers to a straight or branched chain having from 2 to 10 carbon atoms and one or more carbon-carbon reference bonds: t: a monovalent group of the group ("c2 i〇" In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("CM alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("c27 alkynyl"). In some embodiments, an alkyne group has 2 to 6 carbon atoms ("c2.6 fast radical"). In some implementations Wherein the alkynyl group has 2 to 5 carbon atoms (re"alkynyl). In some embodiments the alkynyl group has 2 to 4 carbon atoms ("C24 alkynyl"). In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C23 alkynyl"). In some embodiments the alkynyl group has 2 carbon atoms ("I alkynyl"). The one or more carbon-carbon bonds may be internal such as 2 - in butynyl) or in the end (such as in 1-butynyl). Examples of c2.4 alkynyl include, but are not limited to, ethynyl (c2), propyl (c3), 2; propyne Examples of soil (C3) 1 - butynyl (C4), 2-butynyl (C4) and the like (C4-6) include the aforementioned C2.4 alkynyl and penta- (C5), hexynyl (C6) 156069.doc -13- 201144296 and similar groups. Other examples of alkynyl groups include heptynyl (cd, octynyl (CO and the like). Unless otherwise specified, alkynyl groups in each case are independently unsubstituted ("unsubstituted alkynyl") Or substituted by 1, 2, 3, 4 or 5 substituents as described herein ("substituted alkynyl"). In certain embodiments, 'silk is unsubstituted c2_10 fast radical. In certain In the examples, an alkynyl group is a substituted C2_1Q alkynyl group. As used herein, "heteroaliphatic group", alone or as part of another group, means having from 2 to 13 carbon atoms and from 1 to 4 selected from a non-cyclic 3 to 14 membered straight or branched chain monovalent group of a hetero atom of oxygen, sulfur, phosphorus, and nitrogen and having a carbon atom attached thereto ("3-14 member heteroaliphatic group", in some embodiments," "Miscellaneous" is a saturated group ("heteroalkyl"). In some embodiments, a "heteroaliphatic group" is a group containing one or more double bonds ("heteroalkenyl") In the % example, the "heteroaliphatic group" is a group containing one or more reference bonds ("heteroalkynyl"). Exemplary heteroaliphatic groups include, but are not limited to, ethers. , such as methoxyethyl (-CH2CH2OCH3), ethoxymethyl (-CH2OCH2CH3), (methoxymethoxy)ethyl (-CH2CH2OCH2OCH3), (methoxymethoxy) fluorenyl (-CH2 〇CH2〇CH3) and (decyloxyethoxy)decyl (-CH2〇CH2CH2〇CH3) and the like; amines such as -CH2CH2NHCH3, -CH2CH2N(CH3)2, -ch2nhch2ch3, -CH2N ( CH2CH3) (CH3) and the like. Unless otherwise specified, the heteroaliphatic groups in each case are independently unsubstituted ("unsubstituted heteroaliphatic") or via 1-5 Substituents described herein are substituted ("substituted heteroaliphatic"). In certain embodiments, the heteroaliphatic group is an unsubstituted 3-14 member heteroaliphatic group " in some embodiments In the example, the heteroaliphatic group is substituted 156069.doc • 14· 201144296 3-14 member heteroaliphatic group β as used herein, alone or as part of another group, “carbocyclic group refers to a group having from 3 to 10 ring carbon atoms (r carbocyclyl) in the aromatic ring system and a non-aromatic cyclic hydrocarbon group of one hetero atom. In some embodiments, the carbocyclic group There are 3 to 9 ring carbon atoms (rC3·9 carbocyclic group). In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("Cw carbocyclic group"). In some embodiments The carbocyclic group has 3 to 7 ring carbon atoms ("Cw carbocyclic group"). In some embodiments, the 'carbocyclic group has 3 to 6 ring carbon atoms ("c3 6 carbocyclic group"). In some embodiments, the carbocyclic group has 3 to 5 ring carbon atoms (& Cm carbocyclic group). In some embodiments, the carbocyclic group has 3 to 4 ring carbon atoms ("C3-4 carbon" Ring base"). In some embodiments, a carbocyclic group has 5 to 1 ring carbon atoms ("C5 iG carbocyclic group"). Examples of C3 6 carbocyclic groups include, but are not limited to, cyclopropyl (c3), cyclobutyl (C4), cyclopentyl (C5), cyclopentyl (C5), cyclohexyl (C6), cyclohexyl Alkenyl (C6), cyclohexanediyl (c6) and the like. Examples of the c3-8 carbocyclic group include the foregoing. "Carbocyclyl and cycloheptane-15. 201144296 wherein the point of attachment is on the carbocyclic ring. Unless otherwise specified, the carbocyclic group in each case is independently unsubstituted ("unsubstituted carbocyclyl") Or substituted by 1, 2, 3, 4 or 5 substituents as described herein ("substituted carbocyclic groups"). In certain embodiments the 'carbocyclyl is an unsubstituted Gw carbocyclyl. In certain embodiments, the carbocyclic group is a substituted c3-10 carbocyclic group. In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclic group having from 3 to 10 ring carbon atoms ("(3,1 〇cycloalkyl)"). In some embodiments, a cycloalkyl group There are 3 to 8 ring ί carbon atoms ("C3-8 ring-based"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("(:3_6 cycloalkyl)" in some embodiments In the above, the cycloalkyl group has 5 to 6 ring carbon atoms ("o% 6 cycloalkyl group"). In some embodiments, the cycloalkyl group has 5 to 1 ring carbon atoms ("Ιμcycloalkyl group" Examples of the Cs_6 cycloalkyl group include a cyclopentyl group (c5) and a cyclohexyl group (C5). Examples of the aryl 3 cycloalkyl group include the aforementioned C% 6 cycloalkyl group and a cyclopropyl group (C3) and a cyclobutyl group (C4). Examples of the C3·8 cycloalkyl group include the aforementioned C3 6 cycloalkyl group and a cycloheptyl group (C7) and a cyclooctyl group (C: 8). Unless otherwise specified, the cycloalkyl group in each case is independently Substituted ("unsubstituted cycloalkyl") or substituted with hydrazine, 2, 3, 4 or 5 substituents as described herein ("substituted cycloalkyl"). In certain embodiments , cycloalkyl is an unsubstituted iCm ring In certain embodiments, a cycloalkyl group is a substituted C31Q cycloalkyl group. As used herein, "heterocyclyl J refers to a ring carbon atom and a hydrazine to 4, either alone or as part of another group. a group of 3 to 14 membered non-aromatic ring systems of a ring hetero atom ("3-14 membered heterocyclic group"), wherein each hetero atom is independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In the heterocyclic group of a plurality of nitrogen or phosphorus atoms, the point of attachment may be carbon, nitrogen or a ruthenium as long as the valence number permits. Heterocyclic group 156069.doc 201144296 is a % ("early ring heterocyclic group" ring夕元 (such as a chelating, bridging or screwing system, such as a two-ring system "cyclospores, forks", or a three-ring system ("three-heterocyclic")), and can be Fully saturated "w contains - or multiple carbon-carbon double bonds or semantics" The second two rings may include one or more heteroatoms. "Heterocyclyl" also includes heterocyclyl rings and one as defined above. Or a polyradically fused ring system wherein the point of attachment is in a carbocyclic or heterocyclylcycloheterocyclyl ring and — or a plurality of aryl or heteroaryl groups

°% of the system 'where the junction is on the heterocyclic ring. In some embodiments, a 'heterocyclic group is a 51-membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms ("5-10 membered heterocyclic group"), which makes each hetero atom system independent. It is selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic group is a 5.8 member non-aromatic ring system having a ring carbon atom and i-4 ring heteroatoms ("indolent heterocyclic fluorene") wherein each hetero atom is independently It is selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the 'heterocyclic group is a non-aromatic ring system having a ring carbon atom and 14 ring hetero atoms ("5-6 member heterocyclic group"), wherein Each hetero atom is independently selected from the group consisting of nitrogen, oxygen, scale, and sulfur. In some embodiments t, the 5-6 membered heterocyclic group has 1-3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 丨_2 ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the '5-6 membered heterocyclyl has one ring heteroatom selected from the group consisting of nitrogen, oxygen, lin and sulfur. Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxiranyl, and thi〇renyl. Exemplary 4-membered heterocyclic groups containing i heteroatoms include, but are not limited to, azetidinyl, oxetanyl and thietane. Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydromanganyl, dihydromanganyl, tetrasulphur 156069.doc -17- 201144296 phenyl, dihydrogen. Sequito, strategy. Base, two gas. Billy and. Bilki _2,5· a glimpse. Exemplary 5-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, dioxane nucleus, oxathiolane, and dithiolane. Exemplary 5-membered bases containing 3 miscellaneous materials include, but are limited to, triazolinyl...oxadiyl (tetra) dibasic. Exemplary 6 membered heterocyclic groups containing one hetero atom include (but are sparingly) a (tetra)yl group, a tetrahydro(tetra)yl group, a dihydroanthracene group, and an anthracenyl group. An exemplary 6-shell heterocyclyl containing 2 heteroatoms is a piperazinyl group, a morpholinyl group, a dithiaalkyl group, and a dioxoalkyl group. Exemplary 6 membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, triazinanyl. Exemplary 7 membered heterocyclic groups containing one hetero atom include, but are not limited to, azepanyl, oxetanyl and thiaheptanyl. Exemplary 8-membered heterocyclic groups containing a hydrazone hetero atom include, but are not limited to, azacyclooctane, oxetan, and thiazine. Exemplary bicyclic heterocyclic groups include, but are not limited to, β porphyrinyl, iso, porphyrinyl, dihydrobenzofuranyl, dihydrobenzo. thiophene, tetrahydrobenzo. thiophene, tetra Hydrogen benzofuranyl, tetrahydro'dyl, tetrahydroindolyl, tetrahydroisoindolyl, decahydrolinyl, decahydroisoquinolinyl, octahydrodecenyl, octahydroisodecene Base, a bite group, octa-nitro-[["cardinal; dimethyl anthracene, naphthalene-mercaptoimine, decyl, decenyl, benzo[e][1'4 Diazepht, M, 5, 7• tetrahydrogen „南和[3,4 succinyl, · 5,6-dihydro-chemical-furo[3,2-13]pyrrolyl, 6 , 7-dihydro 511_furo[3,2-b]piperidyl, 5,7-dihydro·4Η_thieno[2,3<]pyranyl, 2,dehydro-1H-t Each of the secondary bite base, 2,3_di-argon-pyrano[2,3 handsome ratio ^ base, 4'5'6,7-tetrahydro-IH-t each [2,3 external ratio 〇定基, ο , "tetrahydrofur 156069.doc _ 18_ 201144296 carboxy[3,2-c].pyridyl, 4,5,6,7-tetrahydrothieno[3,2-b] ° pyridine, 1'2,3'4-tetrahydro-, 6-acridinyl and the like. Unless otherwise specified, otherwise A ring group is independently unsubstituted ("unsubstituted heterocyclic group") or substituted with 1, 2, 3, 4 or 5 substituents as described herein ("substituted heterocyclic group"). In certain embodiments, a heterocyclyl is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, a heterocyclyl is a substituted heterocyclyl. As used herein, alone or as another An "aryl group" as a part of a group means a monocyclic or polycyclic (eg bicyclic or tricyclic) aromatic ring system having 6 to 14 ring carbon atoms and a hetero atom provided in an aromatic ring system (for example, In the examples, the 'aryl group has 6 ring carbon atoms (A aryl group); for example, I;) In the example, the 'aryl group has 1环 a ring of carbon atoms (, aryl such as 1-naphthyl and 2-naphthyl). In some embodiments, the square has eight " ring carbon atoms ("Ci4 aryl also includes as defined above芳美搢淑斗夕,土)方基" fused ring", in which a plurality of carbocyclic or heterocyclic groups are further reduced, and the contacts are on the aryl ring. Unless otherwise "The cat is replaced by an aryl group") or unsubstituted ("unsubstituted ("substituted aryl). ^, 4 or 5 substituents as described herein." In certain embodiments, the aryl group is unsubstituted. In j, the square group is substituted (: 6_丨4 aryl as used herein refers to a single or another material as herein "Fangyuan" CC6·丨4 aryl substituted as defined herein 156069.doc 201144296 C,-10 yard base 'where the joint is on the base ("Cm. "Aromatic aryl" as used herein, "heteroaryl", alone or as part of another group, refers to a 5-14 membered monocyclic ring having a ring carbon atom and one ring hetero atom provided in an aromatic ring system. Or a polycyclic (e.g., bicyclic or tricyclic) aromatic ring system (e.g., f is shared in a ring array.... or (4)^electron lysing ring ... member heteroaryl group)" wherein each hetero atom system is independently selected from Nitrogen, oxygen, phosphorus and sulfur. In heteroaryl groups containing - or a plurality of nitrogen or phosphorus atoms, the point of attachment may be a carbon, phosphorus or nitrogen atom as long as the valence permits. Heteroaryl polycyclic systems may include - or a plurality of heteroatoms in one or both rings. "Heteroaryl" also includes ring systems wherein the heteroaryl ring is fused to one or more aryl groups, as defined above, wherein the point of attachment is on a square or on a heteroaryl ring; or as defined above A ring system in which a heteroaryl ring is fused to one or more carbocyclic or heterocyclic groups wherein the point of attachment is on the heteroaryl ring. For a polycyclic heteroaryl group having no hetero atom (for example, a fluorenyl group, a quinolyl group, a carbazolyl group and the like), the point of attachment may be on either ring, that is, on a ring with a hetero atom. (for example, 20 bases) or on a ring that does not contain miscellaneous mites (for example, 5_°b). In some embodiments, the heteroaryl is a 5-10 membered aromatic ring system ("5-10 membered heteroaryl") having a ring carbon atom and a 丨4 ring heteroatom provided in a family ring system, wherein Each hetero atom is independently selected from the group consisting of nitrogen, oxygen, scale, and sulfur. In some embodiments 'heteroaryl is a 5-membered ring system heteroaryl having a ring carbon atom and one ring heteroatom provided in an aromatic ring system", wherein each hetero atom is independently selected from nitrogen , 'Oxygen, dish and sulfur. In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system (6-membered heteroaryl group) having a ring carbon atom and a -4 ring hetero atom provided in the aromatic ring system, each of which The heteroatoms are independently selected from the group consisting of nitrogen and oxygen': 156069.doc 201144296 Filled with sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 to 3 ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, but are not limited to, all-radical. Base and sale two. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and η-pyridinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, alkalyl, oxo, and thiorh. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, fluorenyl, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzo Furanyl, benzoisofuranyl, j-imidazolyl, oxazolyloxalyl, benzisoxazolyl, benzooxadiazolyl, benzoxyl, benzoisoindolyl, benzo嗟 嗅 基,. The bow is called the base and not the base. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, acridinyl, acridinyl, quinolinyl, isoquinolinyl, porphyrinyl, quinoxalinyl, pyridazinyl and quinazoline base. Exemplary tricyclic heteroaryl groups include, but are not limited to, morphidinyl, diphenyl sulfonyl, sulfonyl, morphine, morphine, and pyridazinyl. Unless otherwise specified, Otherwise, the heteroaryl group in each case is independently replaced by I56069.doc -21 · 201144296 (S substituted heteroaryl group) or by 2, 3, 4 or 5 substituted filaments as described ( "Substituted heteroaryl") ^ Certain examples, the: square is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl. 'As used herein, alone or as part of another group, "heteroaryl" is substituted by a 5-14 membered heteroaryl group as defined herein, as defined herein: Cm. alkyl, wherein the point of attachment is on the alkyl group. ("cm❶ aralkyl"). As used herein, "covalent bond" or "direct bond" refers to a single bond that connects two. Including at least one double encompasses a square or heteroaryl having multiple meanings. As used herein, the term "partially unsaturated" refers to the ring portion of a bond or a key bond. The term r is partially unsaturated. A ring of unsaturation sites, but is not intended to include a base moiety as defined herein. As used herein, such as a divalent alkyl group, a divalent alkenyl group, a divalent alkynyl group, a divalent heteroaliphatic group, a divalent carbocyclic group, a divalent heterocyclic group, and a divalent aromatic fluorene-indenyl group. A divalent "anthracene group" refers to a group 2 as defined herein:; bis-radical. a soap or divalent alkyl, alkenyl, alkynyl, or heteroaliphatic group as defined in the text; a carbocyclic group, a heterocyclic group, an aryl group, and a heteroaryl group, which are "substituted or substituted". Base, "substituted" or "unsubstituted" alkenyl, substituted or "unsubstituted" alkynyl, "substituted" or "unsubstituted" heteroaliphatic, "substituted" or " Unsubstituted "carbon ring", "altered" or "unsubstituted" heterocyclic group, "substituted" or "unsubstituted aryl, or "substituted" or "unsubstituted" Aryl. General 156069.doc • 22- 201144296 The term "substituted" means that at least one hydrogen present on a group (eg, carbon or nitrogen atom, etc.) is replaced by a permissible substituent, for example, a stable compound is produced upon substitution, for example, A substituent of a compound that spontaneously undergoes conversion, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group may have a substituent at one or more substitutable positions of the group, and when one or more positions in any given structure are substituted, the substitution at each position The base is the same or different. A group referred to as "non-hydrogen" indicates that the group is an exemplary and permissible substituent as described herein. Exemplary substituents include, but are not limited to, halogen (ie, fluorine (-F), bromine (-Br), gas (-C1), and iodine (-1), -CN, -N02, -N3, -S02H , -S03H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, _C(=0)Raa, -C02H, -CHO, -C(ORcc)2, -C02Raa, -0C(=0)Raa, -0C02Raa, -C(=0)N(Rbb)2, -0C(=0)N(Rbb)2, _NRbbC( =0) Raa, -NRbbC02Raa, -NRbbC(=0)N(Rbb)2, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb) N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -S02N(Rbb)2, -S02Raa , -S02ORaa, -0S02Raa, -S(=〇)Raa, -0S(=0)Raa ' -Si(Raa)3 ' -OSi(Raa)3 ' -C(=S)N(Rbb)2 ' - C(=0)SRaa, -C(=S)SRaa, -SC(S)SRaa, -P(=〇)2Raa, •0P(=0)2Raa, -P(=0)(Raa)2 , - 0P(=0)(Raa)2, -0P(=0)(0Rcc)2, -P(=0)2N(Rbb)2, -OP(=〇)2N(Rbb)2 ' -P(=0 )(NRbb)2 > -0P(=0)(NRbb)2 ' -NRbbP(=〇)(〇Rcc)2, -NRbbP(=0)(NRbb)2, -P(Rcc)2 ' -P (Rcc)3 ' -OP(Rcc)2 ' 156069.doc •23· 201144296 -OP(Rcc)3, -B(ORcc)2 or _BRaa(ORcc),=0,=S,= NN(Rbb)2, =NNRbbC(0)Raa,=NNRbbC02Raa,=NNRbbS(0)2Raa, =NRbb, =NORcc, Cm〇alkyl, Cl.10 perhaloalkyl, C2_10 alkenyl, C2.10 alkyne a 3-14 member heteroaliphatic group, <:3-|() carbocyclic group, 3-14 membered heterocyclic group, (:6_]4 aryl group and 5-14 membered heteroaryl group] wherein each alkane The base, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently unsubstituted or substituted with from 1 to 5 Rdd groups; wherein: in each case the Raa is independently selected from Cl-1Q alkyl, Ci_ig perhaloalkyl, C2.1Q alkenyl, C2_1Q alkynyl, 3-14 membered heteroaliphatic, c3_1Q carbocyclyl, 3-14 membered heterocyclyl, C6-M aryl and a 5-membered heteroaryl group wherein each alkyl, alkenyl 'alkynyl, heteroaliphatic, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently unsubstituted or substituted with 1 to 5 Rdd groups; In each case, the Rbb is independently selected from the group consisting of hydrogen, 〇H, _〇Raa, _N(RCC)2, _CN, -C(=0)Raa, _C(= 〇)N(Rcc)2, _c〇2Raa -S02R-. -C(=NRcc)〇R-. .C(=NR-)N(Rcc)2 , -S〇2N(Rcc)2 ^ -S02Rcc,-S020Rcc > -SOR- > _C (=S)N(Rcc)2 > -C( = 〇)SRcc ^ -C(=S)SR",! > (=〇), _p(=〇)(Raa)2, p(=〇)2N(Rcc)2, -P(-〇)(NRcc)2, Cm. Alkyl, Cl_i. Perhaloalkyl, c2 i. Alkenyl,. Hey. a base, a 3-14 membered heteroaliphatic group, a (:3·ιΛ ring group, a 3-14 membered heterocyclic group, an aryl group, and a 5-14 membered heteroaryl group, or two Rbb groups bonded to form a 314 member heterocyclic ring. a group or a 5-14 membered heteroaryl ring, each of the substituents, a dilute group, a block group, a heteroaliphatic group, a carbocyclic group, a heterocyclic group, an aryl group and a heteroaryl group independently unsubstituted or subjected to 1 - 5 Rdd groups are substituted; hydrogen, Ci-ιο alkyl, Cwo perhalogen, Rec is in each case independently selected from 156069.doc -24- 201144296 calcination, C2-1Q dilute, C2-10 a 3-14 membered heteroaliphatic group, a C3.1Q carbocyclic group, a 3-14 membered heterocyclic group, (: 0 heptaaryl and 5-14 membered heteroaryl, or two 11" groups bonded to form 3- a 14-membered heterocyclic or 5- to 14-membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, heteroaliphatic carbocyclyl, heterocyclyl, aryl and heteroaryl are independently unsubstituted or 1_5 One ruler (1<1 group substitution; in each case, the Rdd system is independently selected from the group consisting of a lignin, _CN, -N〇2, _n3, -S02H, -S〇3H, -OH, -ORee, _〇N ( Rff)2, -N(Rff)2

-N(〇Ree)Rff, _SH, _SRee, _SSRee, _c(9)Ree, _c〇2H, _c〇2Ree, -〇C(0)Ree, _〇C〇2Ree, _c(〇)N(Rff)2, _〇 c(〇)N(Rff)2, -NRffC(0)Ree, -NRffC02Ree, -NRffC(0)N(Rff)2, C(NRff)〇Ree, _〇c(NRff)Ree, _〇c( NRff) 〇Ree, -C(NRff)N(Rff)2 . -〇C(NRff)N(Rff)2 > -NRffC(NRff)N(Rff)2 > NRffS02Ree, -S〇2N(Rff) 2, _S 〇 2R ", _s 〇 2 〇 Ree, _ 〇 s 〇 2 Ree, S 〇 Ree, - Si (Ree) 3, - 〇 Si (Ree) 3, -C (S) N (Rff) 2, - C(0)SRee, -C(S)SR -SC(S)SRee ^ -P(0)2Ree ' -P(0)(Ree)2 - 〇P(〇)(R )2, -〇P(( 〇)(〇Ree)2, =〇, =s, Cl 6 alkyl, Cl 6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3-14 heteroaryl, c3 i〇 carbocycle a '3-10 membered heterocyclic group, an aryl group, a 5-10 membered heteroaryl group, which is an alkyl group, an alkenyl group, an alkynyl group, a heteroaliphatic group, a carbocyclic group, a heterocyclic group, an aryl group, and a hetero The aryl group is independently unsubstituted or substituted with 1 to 5 Rgg groups; in each case, the Ree is independently selected from the group consisting of CM alkyl, Ci 6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3·14 members heteroaliphatic group, a, carbocyclic group, c6i〇 aryl group, 3-10 a heterocyclic group and a 3-10 membered heteroaryl group in which each alkyl group, alkenyl group, alkynyl group, heteroaliphatic group, carbocyclic group, heterocyclic group, aryl group and heteroaryl group is independently 156069.doc •25 - 201144296 unsubstituted or substituted with 1-5 Rgg groups; in each case Rff is independently selected from hydrogen, Ck alkyl, perhaloalkyl, C2.6 alkenyl, C2.6 alkynyl, 3 a 14-membered heteroaliphatic group, a C3.1Q carbocyclic group, a 3-10 membered heterocyclic group, a C6.1Q aryl group, and a 5-10 membered heteroaryl group, or two Rff groups are bonded to form a 3-14 member. a cyclic or 5-14 membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, heteroaliphatic, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently unsubstituted or substituted - 5 Rgg groups are substituted; and in each case Rgg is independently halogen, -CN, -N〇2, -N3, -S02H, -S03H, -OH, -OCw alkyl, -OISKCk alkyl) , -NCCw alkyl), -N(OC丨_6 alkyl KCu alkyl), -N(OH)(CN6 alkyl), -NH(OH), -SH, -SCCw alkyl), -SSfw Alkyl), -(:(0)((:,.6 alkyl), -C02H, -ccmCw alkyl), -0(:(0)((^.6 alkyl), -occmCw alkyl) , -C(0)NH2, -(:(0)1^((^.6 alkyl) 2, -OC(0)NH(Ci.6 alkyl), -NHC(0)(Ci-6 alkyl), alkyl) ¢: (0)((^.6 alkyl), -NHCOJCutan , -NHC(0)N(C 6 alkyl) 2, -NHCXCONHiCw alkyl), -NHC(0)NH2, -C^Ni^CKCw alkyl), -OC^NHXCu alkyl), 0(:(ΝΗ)0(:〗 6 alkyl, -C(NH)N(Cb6 alkyl) 2, -C^NKONHCCw alkyl), -C(NH)NH2, -OC(NH)N ( Ci.6 alkyl)2, -OC^lSmONi^Cualkyl), -OC(NH)NH2, -NHC(NH)N(Cb6 alkyl)2, -NHC(NH)NH2, -NHSOKCk alkane Base, -SC^l^Cu alkyl)2, -SOzNI^Cw alkyl), -S02NH2, -SOzCu alkyl, -SC^OCu alkyl, -osoeualkyl, -SOCw alkyl, -SKCw 3, -OSKCw alkyl)3, alkyl)2, -C^SWHCCw alkyl), -C(S)NH2, -C(0)S(C丨.6 alkyl), -CeeCu alkyl , -SC^SpCw 156069.doc -26- 201144296 Burning base,,) 2 (Cl.6 burning base), · Ρ (9) (Cl-6 appearance base) 2, _〇p (9) (Ci 6 burning base) 2, -〇 P(〇)(〇Cl-6 alkyl)2, Cl-6 alkyl, Ci 6 all-tooth alkyl, c2 6 alkenyl, C2-6 alkynyl, 3-14 member heteroaliphatic, c3, carbon Cyclic group, C61G aryl group, 3-1 杂环 heterocyclic group, 5-10 membered heteroaryl group, =〇 = 8. These and other exemplary substituents are described in more detail in the context of the embodiments, the examples, and the claims. The term "substituent" is not intended to be limited in any way by the above-described exemplary list of substituents. • "Pharmaceutically acceptable form", as used herein, includes pharmaceutically acceptable salts, hydrates, solvates, prodrugs, tautomers, isomers and/or compounds of the compounds provided herein. Or polymorphs, as defined below and herein. In certain embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salts" is intended to be used in the context of sound medical judgment for contact with humans and tissues of lower animals without undue toxicity, irritation, allergic reactions and the like, φ Salts that match the reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in 丄^/2^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The pharmaceutically acceptable salts of the compounds provided herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are the amine salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and peroxyacids; or organic acids such as acetic acid, oxalic acid, cis Ammonic acid, tartaric acid, citric acid, succinic acid or malonic acid; or an amine salt formed by the use of other methods used in the art, such as the exchange of ions 156069.doc -27 201144296. Other pharmaceutically acceptable salts include hexamethylene salt, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulphate, succinate, butyrate, camphor Acid salt, camphor hydrochloride, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethyl citrate, formate, fumarate, Portuguese Glycolic acid, glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, lauric acid Salt, lauryl sulfate, malate, maleate, malonate, decane sulfonate, 2 naphthalene sulfonate, nicotinic acid salt, nitrate, oleate, oxalic acid Salt, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, Succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from a suitable base include alkali metal, alkaline earth metal, ammonium & n+ (Ci_4 alkyl) 4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, demineralized, hydrazine, hydrazine, and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium: quaternary ammonium and amine cations formed using opposite ions, The relative ions are such as a tooth ion, a hydroxide, a sulphate, a sulfate, a Weigen, a sulphate, a lower alkyl sulfonate and an aryl sulfonate. These examples are solvates. As used herein, the term "hydrate" refers to a compound that is non-covalently associated with one or more water molecules, and in some embodiments, may be crystalline. Similarly, "solvate" refers to a compound that is covalently associated with _ or a plurality of organic solvent molecules, and in some embodiments, may be hydrazine. 156069.doc •28- 201144296 In certain embodiments, the pharmaceutical medicinal uses herein, the term "prodrug: two may be in the form of a prodrug. For example, a parent compound derivative of a compound. The term "prodrug" refers to "prodrug J" The compound is converted to the compound in the form of the disclosed compound or mechanism. The conversion can be by one, such as, but not limited to, hydrolysis in the blood.

r drug = 1! Better than the improved physical and / or transfer properties of the parent compound. ^ J is further evaluated to enhance the medicinal and/or pharmacokinetic properties associated with the parent compound. Exemplary advantages of prodrugs can include, but are not limited to, their physical properties, such as enhanced water solubility compared to the parent compound for parenteral administration at physiological: H values; or enhanced self-digestive tract absorption; It enhances drug stability for long-term storage. For example. If the disclosed compound or the pharmaceutically acceptable form of the compound contains a carboxylic acid functional group, the prodrug may comprise an ester formed by substituting a hydrogen atom of the acid group with a group which is Such as (c丨 alkyl, (CrCu) alkoxycarbonyl group, an alkoxycarbonyl group having 4 to 9 carbon atoms, a fluorenyl group having 5 to 1 carbon atoms (alkanes) An oxyethyl group, an alkoxycarbonyloxymethyl group having 3 to 6 carbon atoms, a 1-(indolyloxycarbonyloxy)ethyl group having 4 to 7 carbon atoms, having 5 to 8 carbon atoms 1_ Mercapto-1-(alkoxycarbonyloxy)ethyl, N-(alkoxyalkyl)aminoindenyl having 3 to 9 carbon atoms, 1 - (having 4 to 1 carbon atoms) Ν_(alkoxycarbonyl)amino)ethyl, 3-bristyl, 4-crotonolactone, γ-butyrolactin-4-yl'di-N,N-(C-C2)alkylamine (C2-C3)alkyl (such as β-dimethylaminoethyl), amine aryl-(Cl_C2)alkyl, hydrazine, Ν-bis(Cl_C2)alkylamine thiol 156069.doc • 29· 201144296 -(Ci-C2)alkyl' and (N-piperidinyl)(C2-C3)alkyl, (N-pyrrole) (C2-C3) An alkyl or (N-morpholinyl)(C2-C3)alkyl group. Similarly, if the disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, the prodrug can be used The group is formed by replacing a hydrogen atom of an alcohol group such as an alkoxymethyl group, a 1-((C-C6) alkoxy group) ethyl group, and an i-methyl group _i_((Cl_c6) Alkenyloxy)ethyl, (CrC6)alkoxycarbonyloxymethyl, N^CrC6)alkoxycarbonylaminomethyl, butyl-aryl, (Ci-C6), a- An amine group (C丨-C4), a aryl group, an aryl group and an α-amino group or an α-amino group-α-amino group, wherein each α-amino group is independently selected From naturally occurring L-amino acids, P(0)(0H)2, -P(0) (Ci-C6), or glycosyl (by removing the semi-acetal form of carbohydrates) a group derived from a hydroxyl group. If the disclosed compound or a pharmaceutically acceptable form of the compound has an amine functional group, the prodrug can be formed by replacing the nitrogen atom in the amine group with a group such as the following: , the group is such as R-carbonyl, R〇-carbonyl, NRR, a few groups, wherein R and R are each independently The ground is (C!-Ci〇) 炫, (C; 3-C·;) cycloalkyl, benzyl or R-repo is a natural α-amino sulfhydryl or natural α-amino aryl- Natural amine sulfhydryl; -(:(011)(:(0)(^1, where γΐ is H, (Ci_c6m or benzyl), -c(oy2)y3 'where Y2 is (c)-c4) An alkyl group, and Y3 is a (Ci_c6) alkyl group, a thiol (Ci_C6) leukoyl group, an amine group (C1-C4) alkyl group or a mono- or sulphonyl group or a di-NWJCi-Ce) alkylaminoalkyl group. ;-C(Y4)y5, where? 4 is a hydrazine or a fluorenyl group, and Y5 is a mono-N-(C-C6)alkylamino group or a bis-n,n_(Ci_C6) succinylamino group, N-morphinyl, brigade bite-1- Base or bite bite _1_ base. In certain embodiments, its pharmaceutically acceptable form is tautomerization 156069.doc • 30· 201144296. As used herein, the term 'tautomer' includes two species that are migrating from at least one of a hydrogen atom and at least one change in valence (eg, a single bond becomes a double bond, a bond becomes a single bond, or vice versa). Kind or two or more compounds which are mutually convertible. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The tautomerization (i.e., the reaction of the tautomeric pair) can be catalyzed by an acid or a base, or can occur without the action or presence of an external reagent. Exemplary tautomerizations include, but are not limited to, keto-ene φ alcohols, guanamine-quinone imines, decylamine-endoimines, enamine-imine, and enamine-(different) enamines Metamerization. In certain embodiments, the pharmaceutically acceptable form is an isomer. As used herein, the term "isomer" includes any and all geometric isomers and stereoisomers. For example, 'isomers' include cis and trans isomers, isomers, and S enantiomers, diastereomers, (D) _ isomers, (L) An isomer, a racemic mixture thereof, and other mixtures thereof which are within the mouth of the present invention. For example, in some embodiments, the isomer/enantiomer provided may be substantially free of the corresponding enantiomer and may also be referred to as "optical enrichment." As used herein, "optical enrichment" means that the compound consists of a significantly larger proportion of one enantiomer. In certain embodiments, the compounds provided herein are comprised of at least about 9% by weight of one enantiomer. In other embodiments, the compound is comprised of at least about 95% by weight, 98% by weight, or 99% by weight of one enantiomer. The enantiomers can be separated from the racemic mixture by any method known to those skilled in the art, including the preparation of palmitic high pressure liquid chromatography (HPLC), the formation and crystallization of palm salts; Prepared by asymmetric synthesis. See, for example, Ic. 156069.doc • 31- 201144296 (Jacques, ed., Wiley Interscience, New York, 1981); Wilen et al., Teira/ze, ow 33:2725 (1977);

Stereochemistry of Carbon Compounds (edited by E.L. Eliel,

McGraw-Hill, NY, 1962), and awe/

Optical Resolutions 26th (E.L. Eliel, ed. Univ. of Notre Dame Press, Notre Dame, IN 1972). In certain embodiments, the pharmaceutically acceptable form thereof is a polymorph. As used herein, "polymorph" means, for example, a compound that is in the solid state.

A compound having more than one crystal structure with a difference in molecular packing and/or molecular configuration. The invention also encompasses isotopically-labeled compounds which are identical to the compounds described herein, but wherein one or more atoms are atomically displaced by atomic mass or mass number different from the atomic mass or mass number normally found in the boundary. Examples of isotopes which may be incorporated into the disclosed compounds include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and gas isotopes such as 2H, 3H, nc, oxime, 15n, 18°, 丨7, respectively. 3] P, 32P, 35S, 丨8F and 36α.

A certain, left isotope-labeled compound (such as a compound of the chemical group and the standard 3) is suitable for compound and/or matrix tissue distribution. P氖(also=) and carbon·14 (ie, mc) isotopes can be used to prepare Ease of use and:::. In addition, substitutions with heavier isotopes such as hydrazine (ie 2h) may be characterized by higher (eg, in vivo half-life extension or dose requirement (iv) 3 . Isotopically labeled compounds -: similar to the example portion of this article The disclosed procedure is prepared by replacing the reagent without the isotopically labeled reagent. 156069.doc • 32- 201144296 [Embodiment] The present invention is based on the following findings: tetrazolone An inhibitor of human fatty acid synthase (FASN) and thus suitable for the treatment of FASN-mediated diseases, disorders or conditions. Furthermore, the compounds provided herein are, in certain embodiments, not limited by the particular theory. Long term t fatty acid elongase (ELOVL) can be inhibited, such as EL0VL 6. Thus, in some embodiments, the compounds provided herein are useful for treating ELOVL mediated diseases, disorders Or a condition. For example, in one aspect, a compound of formula (1) is provided herein:

Or a pharmaceutically acceptable form thereof; wherein: 14 members of a heterocyclic group, a C6.14 aryl group and a 5-14 R group are selected from the group consisting of a C3-10 carbocyclic group and a member heteroaryl group;

Base, 匚3-1〇 cycline, 3-14 membered heterocyclyl, 匸Rc is selected from the group consisting of hydrogen, 〇H, _〇Rci, , -OH, -0Rci, 〖-CHO, _c〇2RCl, - C(=NRC2)N(RC2)2

-C(=0)RC1 '-Cho, -C(=NRC2)ORcl . -cr=NR Α-ιο alkynyl, 3-14 membered heteroaliphatic s'u aryl and 5-14 membered heteroaryl; ~〇N(RC2)2, -N(RC2)2, '-c(=o)n(rC2)2, , -S02RC1, -S(=0)RC1, 156069.doc •33· 201144296 -Si( Rcl) 3, Cw. School base, Cm. All self-alkyl, c2.1()alkenyl, C21()alkynyl, 3-14 membered heteroaliphatic, C3·丨ocarbocyclyl, 3_i4 membered heterocyclyl, C6. η aryl and 5- 14 member heteroaryl; wherein: RC1 in each case is independently selected from C丨·1G alkyl, Cuo perhaloalkyl, C2_1G alkenyl, C2_1()alkynyl, 3-14 membered heteroaliphatic, a c3.1Q carbocyclic group, a 3-14 membered heterocyclic group, a fluorene: 6·14 aryl group, and a 5-14 membered heteroaryl group; and in each case, the RC 2 system is independently selected from the group consisting of hydrogen, 〇H, and 〇RC1 ν -N(RC3)2, -CN, -C(=0)Rcl, -C(=〇)N(RC3)2, -C02RC1, -S02RC1, -c(=nrC3)orC1, _c(= nrC3)n(rC3)2, -so2N(RC3)2, -so2RC3, -so2〇rC3, -S〇Rcl, _c(=s)n(rC3)2, -c(=o)SRC3, -C( =S)SRC3, -P(=〇)2rc丨, _p(=〇)(Rci)2, _p(=〇)2N(rC3)2, -P(=0)(NRC3)2, Cmo-pull, c〗 _10 all-dentate alkyl, C2-10 alkenyl, c2.1q fast radical, 3-14 member heteroaliphatic, (: 3_1 () carbocyclyl, 3-14 heterocyclyl, c6_u aryl and 5- a 14-membered heteroaryl group, or two Rc2 groups joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; or RB and Rc are joined together with the nitrogen (N) atom to which each is attached to form a 5-14 member. ring . Or heteroaryl ring, in one embodiment, the compounds provided herein of formula (I):

156069.doc •34· 201144296 or a pharmaceutically acceptable form thereof; wherein: RA is selected from the group consisting of (6. aryl and 5-14 heteroaryl; RB is selected from C6_M aryl and 5-14) Aryl; RC is selected from -OH, -ORcl, ·〇Ν(γ2)2, _n(rC2)2, _c(=〇)RC1, -CHO, -C02RC1, -C(=〇)n(rC2) 2. -C(=NRC2)〇Rcl, -C(=NRC2)N(RC2)2 ' -S02RC1 . -S(=〇)Rcl > -Si(Rcl)3 > Cj.,0 • Alkyl , Cl_10 perhaloalkyl, C2-10 alkenyl 'C2_10 alkynyl, 3] 4 membered heteroaliphatic, 〇3.1() carbocyclyl, 3-14 membered heterocyclic, (6-6 aryl and 5-14) Heteroaryl, the restriction condition is that Rc is not _CH3; in each case, RC1 is independently selected from Ci iQ alkyl, Ci iq perhaloalkyl, C2_1Q alkenyl, C2_1G alkynyl, 3-14 member heterolipid a group, a C3_1G carbocyclic group, a 3-14 membered heterocyclic group, a C6-14 aryl group, and a 5-14 membered heteroaryl group; in each case, the RC2 system is independently selected from the group consisting of hydrogen, hydrazine, _〇 RC1, -N (RC3)2 ^ -CN ' -C(=〇)Rcl , -C(=〇)N(RC3)2 > -C02RCl , • _s〇2rC丨, -c(=nrC3)orC1,-c(= nrC3)n(rC3)2, -S02N(RC3)2, -S02RC3, -S〇2〇R., _S0RC1, _c(=s)n(rC3)2, c(= 〇) SRC32, _C(=S)SRC3, -P(=〇)2Rcl, _p(=〇)(rci)2, _p(=〇)2N(rC3)2, -P(=0)(NRC3)2 , C2.i 〇 alkyl, c2.H^ _ alkyl, c21G alkenyl, M alkynyl, 3-14 member heteroaliphatic, (: 3.1 () carbocyclyl, 3-14 heterocyclyl, ^ 1 An aryl group and a 5-14 membered heteroaryl group, or two !^2 groups are bonded to form a 3_i4 membered heterocyclic group or a 5-14 membered heteroaryl ring; or R and Rc are bonded to each other (N) The atoms are joined together to form a member ring; 156069.doc -35· 201144296 where: rb is substituted by the following group: -l-rd wherein: L is a covalent bond or a divalent c丨.1 hydrocarbon chain, one of L, Two or three methylene units, optionally and independently, via one or more of -0-, -S-, -NRB8-, -(C=NRB8)-, ·(:(=〇)-, -C (=S)-, -s(=o)-, -s(=o)2-, divalent carbocyclic, divalent heterocyclic, divalent aryl or divalent heteroaryl; RD From -CN, -N〇2, -N3, -S02H, -S03H, -C(=0)RB7, -co2h, -CHO, -C(ORB9)2, -co2rB7, -oc(=o)rB7, -oco2rB7, -c(=o)n(rB8)2, -oc(=o)n(rB8)2, -NRB8C(=0)RB7, -NRB8C02RB7, -NRB8C(=0)N(RB8)2 -C(=NRB8)〇RB7, -〇C(=NR B8) RB7, -OC(=NRB8)ORB7, -C(=NRB8)N(RB8)2, -〇C(=NRB8)N(RB8)2, -NRB8C(=NRB8)N(RB8)2, - c(=o)nrB8so2rB7, -nrB8so2rB7, -so2n(rB8)2, -S02RB7, -S〇2〇RB7, _0S02RB7, -S(=0)RB7, -0S(=0)RB7, -C(=S N(RB8)2, -c(=o)srB7, -C(=S)SRB7, -SC(=S)SRB7, -P(=0)2RB7, -0P(=0)2RB7, -P( =0)(RB7)2, -0P(=0)(RB7)2, -OP(=〇)(〇RB9)2, -P(=〇)2N(RB8)2, -op(=o)2n (rB8)2, -P(=0)(NRb8)2 ' -〇P(=0)(NRB8)2 ' -NRB8P(=0)(0RB9)2 > -NRB8P(=〇)(NRB8)2 , -B(〇rB9)2, -br^orB. And tetrazolyl; in each case, the RB7 is independently selected from the group consisting of Ci-1G alkyl, (:., 〇perhaloalkyl, 〇2_1 decenyl, (:2.1() alkynyl, 3-14 member) Heteroaliphatic, (: 3-1 () carbocyclyl, 156069.doc • 36 · 201144296 3-14 member heterocyclic group, c6.14 aryl group and 5-14 membered heteroaryl group; RB8 in various cases Is independently selected from the group consisting of hydrogen, -OH, -〇rB7, -N(RB9)2, -CN, -C(=0)RB7, -C(=0)N(Rb9)2, -C02RB7, -S02RB7 λ -C(=NRb9)ORB7 ' -C(=NRB9)N(RB9)2' -S02N(RB9)2 > -S02RB9, _s〇2〇RB9, -SORB7, -C(=S)N(RB9) 2, -C (=0) SRB9,

-C(=S)SRB9 - -P(=〇)2rB7 . -P(=〇)(RB7)2 . -P(=0)2N(RB9)2 . -P(=〇)(NRB9)2 Cuo alkyl, Cmo perhaloalkyl, c2-10 alkenyl, c2.10 alkynyl, 3-14 membered heteroaliphatic, (:3.1() carbocyclyl, 3-14 heterocyclyl, c6.i4 aryl And a 5-14 membered heteroaryl group, or two rB8 groups are bonded to form a 3-4 membered heterocyclic group or a 5-14 membered heteroaryl ring; and in each case the rB9 is independently selected from hydrogen, Ci iq Alkyl, Ci iq all-tooth alkyl, C2_1Q alkenyl, C2·]. alkynyl, 3-14 member heteroaliphatic, Cm carbocyclic 3 14-membered heterosemis, C6"4 aryl and 514-member heteroaryl A group or two RB9 groups are joined to form a 3-14 membered heterocyclic group or a 5.14 membered heteroaryl ring. In one embodiment, a compound of formula (1) is provided herein:

Or a pharmaceutically acceptable form thereof; wherein: - 14 membered heterocyclic group, c6_14 aryl group and 5-14 alkyl group are selected from C3 - Q carbon ring-based heteroaryl; 156069.doc 37 · 201144296 RB is selected from Cmo alkyl, c2.1Q alkenyl, C2.1G alkynyl, 3-14 membered heteroaliphatic, C3.1() carbocyclyl, 3-14 membered heterocyclyl, C6.14 aryl and 5- 14-membered heteroaryl; RC is selected from the group consisting of hydrogen, -OH, -〇rc丨, _〇n(RC2)2, _n(RC2)2, -C(=0)Rci, -CHO, _c〇2RC1, - C(=〇)N(RC2)2, -C(=NRC2)〇Rcl, -C(=NRC2)N(RC2)2, -S02RC1, -S( =0)RC1, Si(Rcl)3, Cmo Alkyl, (: 〗 〖〇 perhaloalkyl, c2-10 dilute, C2-10 alkynyl, 3-14 member heteroaliphatic, C3. anthracenyl, 3-14 heterocyclyl, c6 a maryl group and a 5-14 membered heteroaryl group; in each case, the RC1 group is independently selected from the group consisting of an alkyl group, a Ci.1G perhalogen group, a hydrazine 2.1 () alkenyl group, (:2.1 () alkynyl group, 3- 14 member heteroaliphatic, hydrazine: 3_1() carbocyclyl, 3-14 membered heterocyclyl, C6.14 aryl and 5-14 membered heteroaryl; and in each case the RC2 is independently selected from hydrogen , _〇H, -qrCi, -N(RC3)2, -CN, -C(=0)RC1, -C(=0)N(RC3)2, -C02RC1, -S02RC1, -c(=nrC3) 〇rC1, -c(=nrC3)n(rC3)2, -so2n(rC3)2, -S02RC3, -S〇2〇RC3, -SORcl, -C(=S)N(RC3)2, -C( =0) SRC3, -C(=S)SRC3, -P(=0)2RC1, -P(=〇)(Rci)2, -P(=〇)2N(rC3)2, -P(-0) (NRC3)2, c丨.1. Alkyl, Cm. All _ 炫, c2·丨. fluorenyl, c2.10 alkynyl, 3-14 member heteroaliphatic, 〇: 3-1 () carbon a cyclic group, a 3-14 membered heterocyclic group, (: 6.14 aryl and 5-14 membered heteroaryl, or two RC2 groups bonded to form a Hongqiao 4 member heterocyclic group or a 5-14 membered heteroaryl ring; Or RB and Rc are joined together with the nitrogen (N) atom to which each is attached to form a 5-14 ring. Basement Ra 156069.doc -38 - 201144296 As described generally above, RA is selected from Cm carbocyclic groups, 3-14 a heterocyclic group, a C6-14 aryl group, and a 5-14 membered heteroaryl group. In certain embodiments, the ruler is (: 3.1 〇 carbocyclic group. Exemplary carbocyclic groups include, but are not limited to, cyclopropyl Base (CO, cyclobutyl (CJ, cyclopentyl (CQ, cyclopentenyl (C5), cyclohexyl (c6), cyclohexenyl (c6), cyclohexadienyl (c6), cycloheptyl) (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7) and cyclooctyl (C8). In a two embodiment, R is a 3-14 membered heterocyclyl. Exemplary heterocyclic groups include, but are not limited to, aziridine, oxiranyl, thiol, azetidinyl, oxetanyl, thietane, tetrahydrofuran , dihydrofurnanyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, monooxolane, oxathiolanyl, dithiolanyl , piperidine, tetraterpene, dihydron-n-bityl, sulphonyl, sulfonyl, morphinyl, monothiaalkyl, dioxoalkyl, azepanyl, oxacyclo Heptyl, thiaheptanoyl, azacyclooctyl, oxetan, and thiazepine L 〇 in a second embodiment 'aryl. Exemplary aryl groups include, but are not limited to, the benzyl, naphthyl, and anthracenyl groups. In certain embodiments, RA is phenylaryl). In certain embodiments, RA is naphthyl (c10 aryl). △ In a certain embodiment, 'RA is 5·Μ heteroaryl. In certain embodiments, R is a 5-10 membered heteroaryl. In certain embodiments, RA is a 5-6 membered heteroaryl. In certain embodiments, R15,6-bicyclic heteroaryl. The ruler is a 6,6-bicyclic heteroaryl group. - In certain embodiments, R, 5 membered heteroaryl. An exemplary 5-membered heteroaryl package (not limited to) pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, 156069.doc • 39- 201144296 Oxazolyl, isoxazolyl, thiazolylisothiazole Base, triazolyl, oxadiazolyl, thiadiazolyl and tetrazolyl.

In certain embodiments, 11 8 is a 5,6-bicyclic heteroarylheteroaryl group including, but not limited to, i, s „3丨«. Exemplary 5,6-bicyclic heteroaryl groups include (but are not limited to, Η Sulfhydryl, isodecyl, carbazolyl, benzotrienyl, benzo (tetra), hetero (tetra), benzofluorenyl, acetophenone, benzene (tetra), benzofluorenyl , benzoisoindenyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, °zoxazinyl and fluorenyl. In certain embodiments, Ra is a 6,6-bicyclic heteroaryl group. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, n-naphthyl, 嗓α-decyl, eosinophilic, isoindolyl, 4-phenylenyl, quinolin Porphyrinyl, pyridazinyl and quinazolinyl. In certain embodiments, ra is a group of formula (1):

(1) Each of t groups W-R1, W-R2, W-R3, W-R4 and W-R5 independently represents a nitrogen atom (N) or represents C-Ri, C_R2, C-R3, C-R4 or C-R5; I56069.doc 201144296 wherein R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, -CN, -N〇2, Ν3, -S02H, -S03H, - OH, _ORA1, -ON(RA2)2, -N(RA2)2, -N(ORA3)RA3, -sjj, -srM, _ssrA3, -C(=0)RA1, -CO2H, -CHO, -C( 〇RA3)2, -C〇2ra1, -oc(=o)ra1, -oco2ra1, -C(=0)N(RA2)2, -〇C(=〇)N(RA2)2, -NRA2C(= 0) RA1, -NRA2C02RA1, _NRA2C(=0)N(RA2)2, -C(=NRA2)ORA1, -OC(=NRA2)RA1, -0C(=NRA2)0RA1, -C(=NRA2)N( RA2)2, -oc(=nrA2)n(rA2)2, _NrA2C(=nrA2)n(rA2)2, -c(=o)NRA2so2RA1, -NRA2so2RA1' ·δ〇2Ν(κΑ2)2, -so2RA1 -S〇2〇RA1, -0S02RA1, -S(=0)RA1, -〇s(=〇)RA1, -Si(RA1)3, -OSi(RA1)3, -C(=S)N(RA2 2, -C(=〇)SRA1, -C(=S)SRA1, -SC(=S)SRA1 ' -P(=0)2RA1 ' -〇P(=0)2RA1 > -P(=〇 )(RA1)2 x -0P(=0)(RA1)2 ' -0P(=0)(0RA3)2 > -P(=0)2N(Ra2)2 ' -0P(=0)2N(RA2 2, -P(=0)(NRA2)2, -〇P(=〇)(NRA2)2, -NRA2P( =〇)(〇RA3)2, -NRA2P(=〇)(NRA2)2 ' -P(RA3)2, -P(RA3)3, -OP(RA3)2, -OP(RA3)3, _B( ORA3)2, -BRA1 (〇RA3), heteroaliphatic, c3-1() carbocyclyl, 3-14 membered heterocyclyl, c6-14 aryl and 5-14 membered heteroaryl; or R1 and R2, R2 and R3, R3 and R4 or one or more of r4 and R5 are bonded to form a Cm carbocyclic group, a 3-14 membered heterocyclic group, a c6.14 aryl group or a 5-14 membered heteroaryl ring; The RA1 is independently selected from the group consisting of alkyl, (:!, 〇perhaloalkyl~^(7)alkenyl~^(7) fast radicals--vibration heteroaliphatic groups ^^^ carbocyclic groups, 3-14 members a cyclic group, a C6_14 aryl group and a 5-14 membered heteroaryl group; 156069.doc • 41 · 201144296 The RA2 system in each case is independently selected from the group consisting of hydrogen, 〇H, -〇ra1, -N(RA3)2, _cn , -C(=〇)RA1, -C(=〇)N(RA3)2, -C02RA1, -S02RA1, -C(=NRA3)〇RA, , -C(=NRA3)N(RA3)2 , - S02N(RA3)2, -S02RA3, -S020RA3, -SORA1, -C(=S)N(RA3)2, -C(=〇)SRA3, -C(=S)SRA3, -P(=0)2RA丨, _p(=〇)(RA1)2, -P(=〇)2N(RA3)2, -P(=〇)(NRA3)2, Cmo alkyl, Cmo perhaloalkyl, C2-10 alkenyl , C2-〗 G alkynyl, 3-14 member heteroaliphatic, c3-〗 〇 carbocyclyl 3-14 membered heterocyclic group, Ce-w aryl group and 5-14 membered heteroaryl group, or two rA2 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; The RA3 is independently selected from the group consisting of hydrogen, C. 丨Q alkyl, Cniq perhaloalkyl, C2.nonenyl, C2_i decynyl, 3-14 member heteroaliphatic, C3_1G carbocyclyl, The 3-14 membered heterocyclic group, (6. fluorenyl and 5-14 membered heteroaryl, or the two Ra3 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring. In certain embodiments, the group of formula (1) represents a c6-14 aryl group or a 6-14 membered heteroaryl group. In certain embodiments, the group of formula (1) represents a 6-14 membered heteroaryl. In certain embodiments, the group of the formula (丨) represents a c6-14 aryl group. In certain embodiments, the formula (1) (: 6-14 aryl represents phenyl. As used herein, when one or more of Ri, R2, R3, R4, and R5 is referred to as "non-hydrogen", it means R1. One or more of R2, R3, R4 and R5 are independently selected from the group consisting of halogen, _CN, _N〇2, _N3, _s〇2H, -S03H, -OH, -0RA1, _ON (ra2) 2, _n(rA2)2, _n(〇rA3)rA3, -SH, -SRA1, -SSRA3, -C(=〇)RA丨, -c〇2H, -CHO, -C(ORA3)2, - C02RA1, -〇C(=〇) RA1, _〇c〇2Rai, _c(=〇)n(rA2)2, -〇C(=0)N(RA2)2, -NRA2C(=0)RA1,- NRA2C02RA1, 156069.doc -42· 201144296 -NRA2C(=0)N(RA2)2, -C(=NRA2)ORA1, -OC(=NRA2)RA1, -OC(=NRA2)ORA1, -C(=NRA2 N(RA2)2, -OC(=NRA2)N(RA2)2, -NRA2C(=NRA2)N(RA2)2, -C(=0)NRA2S02RA1, -NRA2S02RA1, -S02N(RA2)2, - S02RA1, -so2ora1, -oso2ra1, -s(=o)ra1, -0S(=0)RA1, -Si(RA1)3, -OSi(RA1)3, -C(=S)N(RA2)2 -C(=0)SRA1, -C(=S)SRA1, -SC(S)SRA1, -P(=0)2RA1, -op(=o)2ra1, -p(=o)(ra1)2 -op(=o)(ra1)2, -op(=o)(orA3)2, -P(=0)2N(RA2)2, -0P(=0)2N(RA2)2, -P(= 0) (NRa2) 2, -0 P(=0)(NRa2)2, -NRA2P(=0)(0RA3)2, -NRA2P(=0)(NRA2)2, •P(RA3)2, -P(RA3)3, -OP(RA3 2, -OP(RA3)3, -B(ORA3)2 or -BRA1(ORA3), Cmo alkyl, Cwo perhaloalkyl, C2_idecenyl, C2-10 alkynyl, 3-14 aliquot a group, a C3_1G carbocyclic group, a 3-14 membered heterocyclic group, a C6.14 aryl group, and a 5-14 membered heteroaryl group; or 111 and 112, 112 and 113, 113 and 114 or 114 and 115 or Multiple linkages form (: 3.10 carbocyclyl, 3-14 membered heterocyclyl, (6-6 aryl or 5-14 membered heteroaryl ring. In certain embodiments, R1, R2, R3, R4, and R5) The lines are independently selected from the group consisting of hydrogen, hydroxyl, -CN, -N02, -S02H, -S03H, -OH, -0RA1, -N(RA2)2, -C(=0)RA1, -C02H , -CHO, -C(ORA3)2, -C02RA1, -0C(=0)RA1, -0C02RA1, -C(=0)N(RA2)2, -0C(=0)N(RA2)2, - NRA2C(=0)RA1, -NRA2C02RA1, _NRA2C(=0)N(RA2)2, -C(=NRA2)ORA1, -OC(=NRA2)RA1, -OC(=NRA2)ORA1, -C(=NRA2 N(RA2)2, -OC(=NRA2)N(RA2)2, -nrA2c(=nrA2)n(rA2)2, -c(=o)nrA2so2rA1, -nra2so2ra1, -so2n(rA2)2, - S02RA1, -S020RA1, 156069.doc • 43- 201144296 -〇S02RA1, -S( =0) RA1, -〇S(=0)RA1, Cmo alkyl, Cuo perhalogen 1 base, C2.IQ thin base, C2-1G fast base, 3-14 member heteroaliphatic group, C3-IQ carbon a cyclic group, a 3-14 membered heterocyclic group, a C6.H aryl group, and a 5-14 membered heteroaryl group; or R1 and R2, R2 and R3, R3 and R4 or one or more of R4 and R5 are bonded to form a C3 group. .10 carbocyclic, 3-14 membered heterocyclyl, C6_14 aryl or 5-14 membered heteroaryl ring. In certain embodiments, R, R2, R3, R4, and R5 are independently selected from the group consisting of hydrogen, dentate, -CN, -〇RA丨, -1^2)2, -C02H , CO, 〖,·€(=0)Ν(ΙΙΑ2)2, _s〇2Rai, Ci_i〇alkyl, C2.i〇 alkynyl, 3-14 membered heterocyclic group and C6-14 aryl; or R1 and R2, R2 and R3, R3 and r4 or one or more of R4 and R5 are joined to form a 5-14 membered heteroaryl ring. And R&lt 0) N(Rm)2, -S〇2rA1&3_14 membered heterocyclic group; or ... joined to form a 5-14 membered heteroaryl ring. In certain embodiments, R1 Han K is independently selected from hydrogen , halogen, -0RA1 and · 〇: (=0) Ν (κ Α 2) 2 group; silk 4 5 5 join to form a 5-14 member heteroaryl ring. / In some embodiments, '^, ..., a group is independently selected from the group consisting of ruthenium, dentate, He(tetra))n(rA2)2; and (iv) is joined to form a 5-14 membered heteroaryl ring. In certain embodiments, R2, p4n^^^Al RR, R, and Ruler 5 are independently selected from the group consisting of sputum, dentate, and -ORa 之 selected from the second embodiment of the sputum, R1, R2 , R3,

R and R5 are independently selected from the group consisting of 浒«. Q, which consists of 虱, 、, qi and 〇RA1. In some embodiments, Ri, R2, and R3 4 are independently selected from the group consisting of chlorine, gas, 156069.doc 201144296, chlorine, and -OMe. R5 is independently selected from the group consisting of R1, R2, and R3. In certain embodiments, R1, R2, r3, r4, R, R3, R4 and

Among them, R1, R2, R3, and the group. In some of the preferred free hydrogen and fluorine compositions, R4 and R5 are independently selected from the group consisting of hydrogen and gas. In certain embodiments, the R4 disc R5^拉士士/, κκ </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

Wherein R1, R2, R3, R4 and R5 are as defined above and herein. In certain embodiments, the group of formula (ii) represents Cs丨*aryl. In certain embodiments, the C6_14 aryl group of formula (ii) represents a phenyl group. In certain embodiments, 'RA' is a group of formula (ii) which is monosubstituted, disubstituted or trisubstituted. In certain embodiments, RA is a monosubstituted or disubstituted group of formula (π). In certain embodiments, RA is a monosubstituted group of formula (ii). For example, 'in some embodiments', R is a group of formula (H) substituted by ortho-position, e.g., wherein R--R4 is hydrogen and R5 is non-hydrogen, such as a group of formula (ii-a). In certain embodiments 'rA is a meta-substituted group of formula (ii), for example, 156069.doc • 45- 201144296 wherein R-R and R5 are hydrogen and R4 is non-hydrogen, such as formula (ii-b) Group. In certain embodiments, RA is a para-substituted group of formula (ii), wherein, for example, R1, R2, R4, and R5 are hydrogen and R3 is non-hydrogen, such as a group of formula (u-c).

In certain embodiments, 1 is a disubstituted group of (π) groups. For example, in certain embodiments, Ra is a 2,6-disubstituted (π) group, eg wherein R 2 , R 3 , and R 4 are hydrogen and the ruler and rule 5 are non-hydrogen, eg, Π-d). In certain embodiments, RA is a 2,5-disubstituted (丨丨) group, for example wherein R 2 , R 3 and R 5 are hydrogen and R 1 and R 4 are non-hydrogen, eg, a group of formula (H_e) . In certain embodiments, RA is a 2,4-disubstituted (ϋ) group, for example, wherein R2, R3, and R5 are hydrogen and Ri and R3 are non-hydrogen, such as a group of formula (1)-f). In certain embodiments, RA is a 2,3-disubstituted group of formula (ii), for example wherein R, R and R are hydrogen and R4 and r5 are non-hydrogen, such as a radical of the formula. In certain embodiments, RA is a 3,4-disubstituted group of formula (ii), for example wherein R1, R4 and R5 are hydrogen and R2 and R3 are non-hydrogen, such as a group of formula (ii-h). In certain embodiments, RA is a 3,5-disubstituted group of formula (ii), for example wherein r, r and r are chloro and r2 and r4 are non-hydrogen, such as a group of formula (m). 156069.doc •46- 201144296

For example, 'in certain embodiments' RA is a 2,6 disubstituted group as described herein, such as a group of formula (ii-d):

Wherein R1 and R5 are as defined above and herein. In some embodiments, one of Ri and R5 is dentate, cn, _〇rA1, -N(R)2, -C02H, -co2RA1, _c(=〇)n(rA2)2, _s〇 2rA1, Ci alkyl group, c2.10 alkynyl group, 3_14 membered heterocyclic group and aryl group, and the other of Rl&amp;R\ is i, _CN, -〇RAl, ·ν(κα2)2, {〇2Η , _c〇2RA1, _C(=0)N(RA2)2, -S〇2RA1, CU group, C2.1Q alkynyl group, 3_14 member heterocyclic group and (:6_14 aryl group 156069.doc -47- 0 201144296 '-ORA1 &gt; c,., one of which is halogen, in some embodiments 'Ri and R5' is a halogen hospital or -c di)n(rA2)2' and in Rl and r5 -ORA1, p, Kl〇alkyl or -c(=o)n(rA2)2. 1 In certain embodiments, 'R丨 and r5 are each independently dentate. For example, R and R are each independently selected from the group consisting of fluorine and gas. In certain embodiments, the ruler is a trisubstituted group of formula (ii). For example, in certain embodiments, rA is a 2,4,6-trisubstituted group of formula (1)), wherein, for example, r2 and r4 are hydrogen and R1, R3, and R5 are non-hydrogen, eg, formula (ii) -j) Group. In certain embodiments, ra is a 2,3,6-trisubstituted group of (π) groups such as wherein R 2 and R 3 are hydrogen and Ri, "and rule 5 is non-hydrogen, eg, a group of formula (ii_k) In certain embodiments, RA is a 2,4,5-trisubstituted group of formula (ii), for example wherein R2 and R5 are hydrogen and Ri, R3 and r4 are non-hydro', eg, formula (1). In certain embodiments, RA is a 2,3,4-trisubstituted group of formula (ii), wherein, for example, R and R are hydrogen and R, R 2 and R 3 are non-hydrogen, eg, a group of (ii-m). In certain embodiments, 'RA is a group of formula (ii) substituted with 3,4,5-trisubstituted, for example wherein R1 and R5 are hydrogen and R2, R3 and R4 are non-hydrogen, For example, a group of the formula (ii_n). R1 D1 p1

(ii-l) 156069.doc -48- 201144296 R2

I IV R2

In certain embodiments, a heteroaryl group of 5-6 membered heteroaryl, 5,6-bicyclic heteroaryl or 6,6-bicyclic heteroaryl.

a In certain embodiments, R, 6 membered heteroaryl. In certain embodiments, ... is a 6 membered heteroaryl selected from pyridyl. In certain embodiments, it is considered to be 2_° than the bite base, 3 to ° ratio π base or 4 to n ratio bite. In certain embodiments, RA is 2-pyridyl, wherein W-Ri is N, and W-R2, W-R3, W-R4, and W-R5 are C-R2, C-R3, C-R4, respectively. And C-R5' such as the group of formula (iii). In certain embodiments, RA is 3-pyridyl, wherein W-R2 is N' and W-R1, W-R3, W-R4, and W-R5 are C-R1, C-R3, C-R4, respectively. And C-R5 ' is, for example, a group of the formula (iv). In certain embodiments, RA is 4- to pyridine, wherein W-R3 is N, and W-R1, W-R2, W-R4, and W-R5 are C-R1, C-R2, and C, respectively. -R4 and C-R5, for example a group of the formula (v).

(iii) (»v) (v) 156069.doc • 49- 201144296 where..., ^~ as defined above and herein. In some embodiments, the mono is substituted or disubstituted. In some embodiments, RA is monosubstituted. Than the base. Wherein 3, in certain embodiments, RA is monosubstituted, the R, R4, R5 are hydrogen and R2 is non-hydrogen, for example, a formula (mm group. wherein 2 in certain embodiments '^ Is a monosubstituted formula (ii(tetra)), R, R4, R5 are hydrogen and R3 is non-hydrogen, such as a group of formula (iH-b). wherein 2 in certain embodiments, Ra is monosubstituted (10)定. Fixing, R, R3, R5 are hydrogen and R4 is non-hydrogen, such as a group of formula (D). 2 In some embodiments, RA is a monosubstituted formula (10), a bite group, RR, RS hydrogen And r5 is a non-hydrogen group, such as a group of the formula (m_d).

3 In certain of the four embodiments, R, monosubstituted 〇V" is more than fluorenyl, wherein R hydrogen U1 is non-hydrogen, such as a group of formula (iv-a). In certain embodiments, H Monosubstituted formula (d) (d) base, straight R, R4, R5 are hydrogen and R3 is non-hydrogen, a group of formula (W_b). 1 In a certain 3: in the embodiment 'RA is a single-substituted (four) bite a group wherein RR is hydrogen J_R4 is a non-hydrogen group such as a group of formula (w_e). In certain embodiments, 'RA is a monosubstituted formula (IV), a bite group of which 156069.doc 201144296, for example, formula (iv-d) The group.

R1, R3, R4 are hydrogen and R5 is non-hydrogen. In certain embodiments, 'ra is a monosubstituted (7) mouth-bite group, wherein R2, R4, R5 are hydrogen and R1 is non-hydrogen, for example, formula (v_a) ) the group. In certain embodiments, RA is a monosubstituted group of formula (7)(d) wherein R, R, R are hydrogen and R2 is non-hydrogen, such as a radical of the formula.

In certain embodiments, the disubstituted base is used. In certain embodiments, RA is a disubstituted formula wherein D and R are hydrogen and RW is non-hydrogen, such as a group of formula (1) and e). In certain embodiments, Ra is a disubstituted formula (IV). ratio. The base 'where R and R are hydrogen and RW is money, such as a group of the formula. In certain embodiments, 'is a disubstituted formula (ni) m, wherein R and R are hydrogen and R is non-hydrogen, such as a group of formula ((1)). In certain embodiments, Ra is a disubstituted formula (iii) D is a pyridyl group, wherein R and R are hydrogen and R &amp; is non-hydrogen, such as a group of formula ((1) VII. In certain embodiments Wherein, Ra is a disubstituted pyridyl group, wherein 156069.doc -51 · 201144296 R and R 5 are hydrogen and R 2 and R 3 are non-hydrogen, for example, a group of formula (1). In certain embodiments, R, is substituted by a dentate group, wherein R2 and R5 are hydrogen and R3 and R4 are non-hydrogen, such as a group of formula (πΗ).

In certain embodiments, 'RA' is a disubstituted formula, wherein R and R are hydrogen and R and r are non-hydrogen, such as a group of formula (b). In certain embodiments, RA is a disubstituted formula (IV). The bases R and R are hydrogen and r and R are non-hydrogen, such as a group of the formula (dip). In the case of &amp;, 'RA is a disubstituted formula (wherein R and R are hydrogen and R1 and R3 are non-hydrogen, such as a group of formula (iv-g). 1 In certain embodiments a group of a disubstituted formula ((7) a thiol group, wherein R and R are hydrogen and RjR5 is non-hydrogen, for example, 〇vh). In some embodiments, '1^ is a disubstituted formula, Wherein R and R are hydrogen and r &amp; R4 is a non-hydrogen group such as a formula (diazepam). &amp; [In some embodiments, 'RA is a disubstituted formula than a bite group, of which 156069.doc • 52 · 201144296 R1 and R3 are hydrogen and R4 and R5 are non-gas, R1

For example, the group of formula (iv-j) R4

(&gt;v-f)

(iv-e)

(•v-g)

In certain embodiments, RA is a group wherein R4 is hydrogen and R1 and R5 are non-hydrogen, e.g., ^, formula (ν-c). In certain embodiments, the pyridyl group of formula (V) and R5 are hydrogen-substituted and R1 and R2 are non-hydrogen, such as, for example, a group of formula (v-d). In certain embodiments, 'RA is a formula (V) substituted by a 5~. ratio. The group and R5 are hydrogen and R1 and R4 are non-hydrogen groups such as formula (v-e). In some embodiments, the ruler is face _ and han 5 is hydrogen and (iv) is non-hydrogen; and: is replaced by a formula (tree base wind such as a group of formula (vf). Substituting formula (V) &quot; Pyridyl, wherein R2 wherein R4 wherein R2 wherein R1 R2

(v-e) (v-f) In certain embodiments, 'RA is 5 6 -, 6, bicyclic heteroaryl. For example, 'in some embodiments φ T ' RA is a 5,6-bicyclic heteroaryl 156069.doc •53·201144296 base of the formula (Vi), which is a subgroup of the group of formula (ii-g): R2

Where R1! ^,! ^3 is as defined above and herein, and R4 is bonded to R5 to form a 5-membered heteroaryl ring; X, Y and Z are independently selected from CRA4, Ο, S, N or NRA5; in each case RA4 is independently Selected from hydrogen, halogen, -CN, -N〇2, -N3, -S02H, -S03H, -OH, -ORA6, _ON(RA7)2, -N(RA7)2, -N(ORA6)RA8,- SH, -SRA6, -SSRA8, -C(=0)RA6, -C02H, -CHO, -c(orA8)2, -co2rA6, -oc(=o)ra6, -0C02RA6, -C(=0)N (RA7)2, -0C(=0)N(RA7)2, -NRA7C(=0)RA6, -nrA7co2rA6, -nrA7c(=o)n(rA7)2, -C(=NRA7)ORA6, -OC (=NRA7)RA6, -OC(=NRA7)ORA6, -C(=NRA7)N(RA7)2, -OC(=NRA7)N(RA7)2, -nrA7c(=nrA7)n(rA7)2, -C(=0)NRA7S02RA6, -NRA7S02RA6, -S02N(RA7)2, -S02RA6, -so2orA6, -0S02RA6, -S(=0)RA6, -0S(=0)RA6, -Si(liA6)3, -OSi(RA6)3, -C(=S)N(RA7)2, -C(=0)SRA6, -C(=S)SRA6, SC(=S)SRA6, -P(=0)2RA6, -〇P(=〇)2RA6, -P(=〇)(RA6)2, -0P(=0)(Ra6)2, -OP(=〇)(〇RA8)2, _p(=〇)2n( rA7)2, -0P(=0)2N(RA7)2, -P(=〇)(NRA7)2, -OP(=〇)(NRA7)2, 156069.doc -54· 201144296 -NRA7P(=〇 )(〇RA8)2, -NRA7P(=〇)(NRA7)2, -P(RA 8)2, -P(RA8)3, -〇P(RA8)2, _〇P(RA8)3, _B(〇RA8)2 or -BRA6(ORA8), Cl-ίο burning base, Cl-ίο Il burning base, C2-1. Dilute, C2. IG alkynyl, 3-14 membered heteroaliphatic, Cm carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl and 5-14 membered heteroaryl; RA6 series in each case independent Is selected from the group consisting of C^oalkyl, Cwq perhaloalkyl^^alkenyl^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 5-14 member heteroaryl; in each case RA5 and RA7 are independently selected from the group consisting of hydrogen, 〇H, _〇rA6, -N(RA7)2, _CN, -C(=0)RA6, -C( =〇)N(RA7)2, -C02RA6, -S02RA7 . -C(=NRA3)〇RA6 &gt; -C(=NRA7)N(RA7)2 ' -so2N(nA3)2, -S02RA6, -S〇 2〇RA8, _S0RA6, _c(=s)n(rA7)2, -C(-〇)SR, ·cpSWRA8, ·Ρ(=〇)2βΑ6, _p(=〇)(rA6)2, -P(= 〇) 2N(R~)2, _P(=0)(nrA8)2, Ci i. Unified basis, Ci i. All (10) group, C2-1G alkenyl, C2.1Q alkynyl, 3-14 membered heteroaliphatic, C3"G carbocyclyl, 3·14 membered heterocyclic, aryl and 5-14 membered heteroaryl, or The two RA7 groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; in each case the RA8 group is independently selected from the group consisting of gas, Ci, affiliation, % all-dentate alkyl, C2.1Q dilute a c2_i decynyl group, a 3-14 membered heteroaliphatic group, a C3 i〇 carbocyclyl group, a 3-U membered heterocyclic group, a C6.i4 aryl group, and a 5-14 membered heteroaryl group, or two rA8 groups are bonded to form a 3: 1 collar heterocyclyl or 5-14 heteroaryl ring; and the dotted line represents a double bond or a single bond. In certain embodiments, Ri is hydrogen. In certain embodiments, r2 is hydrogen. In certain embodiments &apos;R3 is hydrogen. In certain embodiments, Ri, RjR3 156069.doc • 55- 201144296 is hydrogen β. In certain embodiments, ra is a heteroaryl group of the formula ('^_3) or *b*&gt;:

Wherein R1, R2, R3 are as defined above, and X and Z are independently selected from the group consisting of ruthenium, S and NRA5. Some embodiments in which RA is a heteroaryl group of formula (vi-a) or (vi-b) Wherein X and z are 0 (i.e., benzoxazolyl) &lt;» In certain embodiments, X and Z are S (i.e., benzothiazolyl). In certain embodiments, X and Z are NRA5 (i.e., imidazolyl). In certain embodiments, RA is a heteroaryl group of formula (vi-c) or (vi-d):

Wherein R1, R2' R3 are as defined above, and the oxime is independently selected from the group consisting of ruthenium, S and NRA5. In certain embodiments of the aryl group of the formula (Wc) or (vi-d), X is 0 (i.e., benzoxime groups. In certain embodiments, 乂 is 8 (i.e., Benzo 156069.doc • 56· 201144296 base). In certain embodiments, χ is nrA5 (ie, in some embodiments, RA A + ) is of the formula (vl-e), (vi-f) or (4) Heteroaryl:

Wherein R1, R, R3 and RA4 are as defined above, and X Y and Z are independently selected from the group consisting of Ο, S and NRA5. In certain embodiments of the heteroaryl group wherein R is of the formula (vl-e), (VUf) or (vi_g), Y is hydrazine (i.e., benzofuranyl or isobenzopyranyl). In certain embodiments, Y is S (i.e., benzoindolyl or isobenzobenzophenyl). In certain embodiments 'Y is NRA5 (i.e., fluorenyl or isodecyl). In certain embodiments, RA is a heteroaryl group of formula (w-h):

R2

Wherein R, R, R3 are as defined above, and the gamma is independently selected from the group consisting of ruthenium, S and NRA5. In certain embodiments of the heteroaryl group of formula VIII (vi-e), γ is 〇 (i.e., benzene 156069.doc • 57·201144296 and oxadiazolyl). In certain embodiments, γ is s (i.e., benzo is di-salt). In certain embodiments, Y is nrA5 (ie, benzotrisal). Base buck rb As described generally above, Rb is selected from the group consisting of Cmo alkyl, c2-1G alkenyl, C2.lc alkynyl, 3-14 membered heteroaliphatic, C 3. ίο carbocyclyl, 3-14 member Heterocyclyl, c6 aryl and 5-14 membered heteroaryl; or rb and Rc are joined together with the nitrogen (N) atom to which they are attached to form a 5-14 membered ring.

In certain embodiments, the RB is selected from the group consisting of Cl-1 alkyl, C2 i nonenyl, CM. Alkynyl 3-14 member heteroaliphatic, c3_! indenocarbocyclyl, 3-14 membered heterocyclyl, c6j aryl and 5-14 membered heteroaryl. In certain embodiments, rb is an acyclic group, that is, selected from Ci i alkyl,

Alkenyl, (: 2-10 alkynyl and 3-14 membered heteroaliphatic. In certain embodiments, hydrazine is 匚丨·丨0 alkyl. In certain embodiments, rB is substituted alkyl, For example, a Cwo aryl group. In certain embodiments, ^ is a c _2 aryl group, such as a silky or unsubstituted aryl group, or a substituted or unsubstituted phenylethyl group ( C2 aralkyl). In certain embodiments, RB is Cm. Heteroaryl Groups In certain embodiments, RB is an alkenyl group. In certain embodiments, Rb is a block basis. In certain embodiments, RB is a 3.14 member heteroaliphatic group. In certain embodiments of the stone mountain, the RB is a cyclic group, that is, a C3-10-based, 3-U membered heterocyclic group. ... aryl and 5_i4 member heteroaryl. In the second embodiment, rb^Cw. Carbocyclyl or η# member heterocyclic group. (Examples of the RB&lt;1G carbocyclic group) Exemplary carbocyclic groups include = limited to propyl propyl (C3), cyclobutyl (C4), cyclodecyl (6), cyclophosphazene 5-cyclohexyl ( C6), cyclohexenyl (c6), cyclohexadienyl (6), ring I56069.doc • 58· 201144296 base (C5) 'cyclohexyl (c6), cyclohexenyl (c6), cyclohexadienyl Cycloheptyl (C:7), cycloheptadienyl (C7), cycloheptatrienyl ((:7) and cyclooctyl. In certain embodiments '^3_14 member heterocyclyl. Illustrative hetero Silk includes, but is not limited to, aziridine, oxiranyl, thiol, azetidinyl, oxetanyl, thietane, tetrahydrofuranyl, dihydrogen = south Base, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, dioxane; thiol, oxathione, L 裒 二 • • 咬 咬 咬 、 、, tetrazo (tetra) , dichloroheptyl ratio, mercapto group, pyridyl group, phenanthrenyl, di-m-m, aziridine, oxetan, thiopyranyl, azacyclonon Alkyl, oxirane, and thialate. In some implementations, r, c6_14 aryl or 5-14 members Aryl. In certain embodiments 'RB is c6-u aryl. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, and anthryl. In certain embodiments, rB aryl). In certain embodiments, Rb is naphthyl (c10 aryl). 6 • 纟 In certain embodiments, it is a 5-14 membered heteroaryl. In certain embodiments, #为5-1() Aryl. In certain embodiments, rB45_6 is heteroaryl. In certain embodiments 'RB is 5,6-bicyclic heteroaryl. In certain embodiments, RB is 6,6-bicyclic heteroaryl In certain embodiments 'RB is a 5-membered heteroaryl. Exemplary 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl' pyrazolyl, oxazolyl, Isoxazolyl, thiazolyl, isoxazolyl, triazolyl, oxazolyl, thiadiazepine and tetrazolyl. In certain embodiments, RB is 6 membered heteroaryl. Exemplary 6 members Heteroaryl package 156069.doc • 59· 201144296 includes, but is not limited to, a bite base, a zirconium group, a dimethyl group, a D thiol group, a triazinyl group, and a tetramethyl group. In certain embodiments, Rb is a 5,6-bicyclic heteroaryl group. An exemplary 5,6-bicyclic hybrid Aryl groups include, but are not limited to, fluorenyl, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzene And imidazolyl, benzoxazolyl, benzoisoxazolyl, benzoheptyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, pyridazinyl and fluorenyl. In certain embodiments 'rb is a 6,6-bicyclic heteroaryl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, acridinyl, acridinyl, quinolinyl, isoquinolinyl 4, benzyl, quinoxalinyl, pyridazinyl and quinazolinyl. In certain embodiments, rb is substituted with: -L-Rd wherein: [is a covalent bond or a divalent C]-anhydrocarbon chain, wherein one, two or three methylene units of L Depending on the situation and independently, one or more -〇-, -S-, -NRB8-, -(C=NRB8)·, _c(=〇)_, _c(=s)-, -S(:=〇 ), _s(=〇)2·, a divalent C3-丨0 carbocyclic group, a divalent 3-14 membered heterocyclic group, a divalent C6-14 aryl group or a divalent 5-14 membered heteroaryl group; And rD is selected from the group consisting of -CN, -N02, -N3, -S02H, -so3h, -c(=o)rB7, -C02H, -CHO, -C(ORB9)2, -co2rB7, -〇c(=〇 rB7, -0C02RB7, -c(=o)n(rbV-oc(=o)n(rB8)2, -nrB8c(=〇)RB7, -nrB8co2rB7, -NRB8C( = 〇)N(RB8)2 _c(=nrB8)〇rB7, _〇C(=NRB8)RB7, 156069.doc •60- 201144296 -OC(=NRB8)〇RB7, -C(=NRB8)N(RB8)2, -OC(=NRB8 N(RB8)2, -nrB8c(=nrB8)n(rB8)2, -c(=o)nrB8so2rB7, -nrB8so2rB7, -so2n(rB8)2, -so2rB7, -so2orB7, -oso2rB7, -S(= 0) RB7, -〇S(=0)RB7, -C(=S)N(RB8)2, -C(=0)SRB7, -C(=S)SRB7, -SC(=S)SRB7,- P(=0)2RB7, -OP(=〇)2RB7, -P(=0)(RB7)2, -OP(=〇)(RB7)2, -OP(=〇)(〇RB9) 2, -P(=0)2N(RB8)2, -OP(=〇)2N(RB8)2, -P(=0)(NRB8)2, -0P(=0)(NRb8)2' -NRb8P (=〇)(〇RB9)^-NRB8P(=0)(NRB8)2 '-B(〇RB9)2, -brB7(orB9) and tetrazolyl; in each case, RB7 is independently selected from the group consisting of Cuo Base, Cuo perhaloalkyl, c2.1()alkenyl, C2_1G alkynyl, 3-14 membered heteroaliphatic, C3-1G carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl and 5- 14-membered heteroaryl; RB8 in each case is independently selected from the group consisting of hydrogen, 〇H, -〇RB7, -N(RB9)2, _CN, -C(=〇)RB7, -C(=0)N (RB9)2, -C02RB7 ' -S02RB7. -C(=NRB9)〇RB7&gt; -C(=NRB9)N(RB9)2' -S02N(RB9)2 , S02RB9, _s〇2〇RB9, _S0RB7, _C (=S)N(RB9)2, _c(=〇)srB9, •c(=s)srB9, -p(=〇)2RB7, _p(=o)(rB7)2, -p(=o)2N (RB9)2, _P(=〇)(NRB9)2, Cmo alkyl group, Cl.10 perhaloalkyl group, C2 l〇 dilute group, c 2-l decynyl group ^-卩 member heteroaliphatic group '^ a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring formed by a carbocyclic group - a "membered heterocyclic group, an aryl group, and a 5-14 membered heteroaryl group, or a two RB8 group; And in each case RB9 is independently selected from the group consisting of hydrogen, CiiG alkyl, CiiG perhaloalkyl, alkenyl, C 2" g alkynyl group, 3_14 member heteroaliphatic group, Cy. Carbocyclyl, 3-14 membered heterocyclyl, C014 aryl, and 5-14 membered heteroaryl, or two ^9 156069.doc -61 · 201144296 group attached to form a 3.14 membered heterocyclic group or 5.14 member Heteroaryl ring β In certain embodiments, L is a covalent bond. And R. .&gt;-(c=NRB8)-, -C(=〇).-C(=S).&gt;-S(=0)--S(=0)2.&gt; 4 shell anti-cyclic group, A mussel heterocyclic group, a divalent aryl group or a divalent heteroaryl group is substituted. And R. · '-(C=NRB8)-' -C(=〇)-' -C(=S)-&gt; -S(=0)-^S(=0)2., Divalent c3_1() carbon ring Base, divalent 3-14 membered heterocyclic group, divalent fluorenyl aryl group or divalent 5-14 membered heteroaryl group. As generally described above, rd is selected from the group consisting of: _CN, -no2, -so2h , -S03H, -C(=0)RB7, -C〇2H, -CHO, -C(ORB9)2, -co2rB7 . -0C(=0)RB7 , -oco2RB7 . -C(=0)N(RB8 ) 2 ^ -0C(=0)N(RB8)2 , -NRB8C( = 0)RB7, -NRB8C02RB7, -NRB8C(=0)N(RB8)2, -C(=NRB8)〇RB7, -〇C (=NRB8) RB7, -0C(=NRB8)0RB7, -C(=NRB8)N(RB8)2' -〇C(=NRB8)N(RB8)2, -NRB8C(=NRB8)N(RB8)2 -C(=0)NRB8S02RB7, -nrB8so2rB7,,so2n(rB8)2, -so2RB7, -so2orB7, -oso2rB7, -s(=o)rB7, _os(=o)rB7, -c(=s)n (rB8)2, -c(=o)srB7, -C(=S)SRB7, -SC(=S)SRB7, -P(=〇)2RB7, -〇P(=〇)2RB7, -P(= 0) (RB7)2, -0P(=0)(RB7)2, -op(=o)(orB9)2, -P(=0)2N(RB8)2, -0P(=0)2N(RB8 ) 2, -p(=o)(nrB8)2, -0P(=0)(NRB8) 2'-NRb8P(=0)(0RB9)2^-NRB8P(=0)(NRB8)2' 156069.doc -62- 201144296 -b(orB9)2, -brB7(orB9) and tetrazolyl. However, in certain embodiments, Rd is not _c〇2RB7 (e.g., c〇2Me, C02Et, C02«Pr, C02zPr, or C02iBu), but may be selected from any of the other substituents listed above. In certain embodiments, rd is not -c(=〇)rB7, but may be selected from any of the other substituents listed above. In certain embodiments, rD is not -CHO, but may be selected from any of the other substituents listed above. In certain embodiments, RD is not -C(ORB9)2, but may be selected from any of the other substituents listed above. In certain embodiments, RD is not, but may be selected from any of the other substituents listed above. In certain embodiments, rD is not _n〇2, but may be selected from any of the other substituents listed above. In some embodiments, R is not -SO2H, -S03H, _S〇2N(RB8)2, _nrB8so2rB7, -S02RB7, -S〇2〇RB7, -〇S〇2RB7, -S(=0)RB7 or - 〇s (= 〇) rB7, but may be selected from any of the other substituents listed above. In certain embodiments, RD is not -0C(=0)RB7, -〇C〇2RB7, -0C(=0)N(RB8)2, -NRB8C(=0)RB7, -NRB8C02RB7, -NRB8C( =0) N(RB8)2, -〇C(=NRB8)RB7, -〇C(=NRB8)〇RB7, -oc(=nrB8)n(rB8)2 or _NrB8C(=nrB8)n(rB8) Any of 2, but may be selected from any of the other substituents listed above. In some embodiments, RD is not any of -C(=S)N(RB8)2, -C(=0)SRB7, -C(=S)SRB7, or -SC(=S)SRB7 , but may be selected from any of the other substituents listed above. In some embodiments, RD is not -P(= 〇)2RB7, _〇P(= 〇)2rB7, -P(=0)(RB7)2, -〇P(=〇)(RB7)2, -op(=o)(orB9)2 , -P(=0)2N(RB8)2 &gt; -〇P(=〇)2N(RB8)2 ' -P(=0)(NRB8)2 , -0P (=0)(NRB8)2, _NRB8p(=〇)(〇RB9)2 or -nrB8p(=o)(nrB8)2 156069.doc -63- 201144296 'but can be selected from the above Any other substituent listed. In certain embodiments, 'RD is not any of _B(0RB9)2 or ·βιιΒ7(〇κΒ9), but may be selected from any of the other substituents listed above. In certain embodiments, RD is not a tetrazolyl group, but may be selected from any of the other substituents listed above. In certain embodiments 'RD is selected from the group consisting of -CN, -N〇2, -S02H, -S03H, C(= 〇)RB7, _c〇2H ' · εΗ〇, c〇2rB7, c( = 〇)n (rB, -C(=NRB8)〇RB7 . -C(=NRB8)N(RB8)2 &gt; -C(=0)NRB8S02RB7 ' S02N(RB8)2, -S02RB7, -S〇2〇RB7, _s(=〇)rB7, -C(=S)N(RB8)2, -C( = 〇)SRB7, -C(=S)SRB7, -P(=〇)2rB7, -P(=〇)( RB7)2, -P(=0)2N(RB8)2, _P(=〇)(NRB8)2, _b(〇rB9)2, •BR, R, and tetrasal. In some embodiments, L is a covalent bond. In certain embodiments, the RD is selected from the group consisting of _c(=0)rB7, _c〇2H, _CH〇, C〇2RB7, -C(=〇)N(RB8)2, -C (=NRB«)〇RB7, -c(=nrB8)n(rB8)2, -c(=0)nrB8S〇2rB7, _c(=s)n(rB8)2

• c (which R- and -C(=S)SR~ In some embodiments, L is a covalent bond. In certain embodiments, the RD is selected from the group consisting of &lt;( = 〇)κΒ7, _eHQ and -C〇2RB7. In certain embodiments, L is a covalent bond. In certain embodiments, RD is an even H. In certain embodiments, L is a covalent bond. In r^-l-rd In some embodiments of the substitution, the RBit_ step is substituted with: -R1 wherein: re is selected from the group consisting of halogen OH ' -orbio on(Rb,,) 2^ -N(RB1*)2 156069.doc -64 - 201144296 -N(ORB12)RB12, -SH, -SRB10, -ssrB12, -oc(=o)rB10, -0C02RB1°, -0C(=0)N(Rb,1)2, -NRB11C(=0) RB10, -NRB11C02RB1° ' -NRB11C(=0)N(RB11)2 ' -OC(=NRb1,)Rb1° ' -OC(=NRb,1)〇RB10 , -〇C(=NRB11)N(RB11) 2, -NRB11C(=NRB11)N(RB11)2, _NRB11so2RB10, _OS02RB1〇, -0S(=0)Rb, ° ' -Si(RB10)3 &gt; -OSi(RB,0)3 ' -SC(S ) SRB1° ' -0P(=0)2RB, °, -OP(=〇)(RB10)2, -〇P(=〇)(〇Rb,2)2, -0P(=0)2N(RB11) 2 ^ -OP(=〇)(NRB11)2 ' -NRB11P(=0)(0RB,2)2 ' NRB11P(=0)(NRB11)2, -p(RB12)2, -P(RB12)3, -0P(rB12)2, -0?(1^12)3, 3-14 membered heterocyclic group and 5-14 membered heteroaryl group, of which 3-1 The attachment point of the 4-membered heterocyclic group or the 5-14 membered heteroaryl group is on the nitrogen atom; in each case, the RB1G system is independently selected from the group consisting of Cl_1()alkyl, Cl_lG perhaloalkyl, C2.1Galkenyl, C2 -1Q alkynyl group, 3-14 membered heteroaliphatic group, C3_1Q carbocyclic group, 3-14 membered heterocyclic group, C6-14 aryl group and 5-14 membered heteroaryl group; RBU is independently selected in each case From hydrogen, -OH, _〇rB丨〇, _N(RB12)2, -CN, -C(=〇)RB1., -C(=〇)N(RB12)2, -co2rB10, -S02RB1° ' - C(=NRB12)〇RB1° . -C(=NRB12)N(RB12)2 &gt; -S02N(RB12)2, -S02RB12, -S〇2〇RBi2, _s〇rB10, -C(=S)N (RB12)2, -C(=〇)SRB12, -C(=S)SRB丨2 ' -P(=〇)2RB丨0, -P(=O)(RB10)2 ^ -P(=0) 2N(RB12)2 , -P(=〇)(NRB12)2 ^ Cl.10^ base, C!-10 perhalogenated group, C2-10 fluorenyl group, c2_10 alkynyl group, 3-14 member heteroaliphatic group , Cn. a carbocyclic group, a 3-14 membered heterocyclic group, a C6-M aryl group, and a 5.14 membered heteroaryl group, or two RBn groups joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; · 156069.doc 201144296 RB12 in each case is independently selected from the group consisting of hydrogen, Cuo alkyl, Ci.10 perhaloalkyl, (: 2.10 alkenyl, (: 2-10 alkynyl, 3-14 member heteroaliphatic, (: 3.10 carbocyclic group, 3-14 membered heterocyclic group, c6-I4 aryl group and 5-14 membered heteroaryl group, or two RB12 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 member heterocyclic group. In some embodiments, the RE is selected from the group consisting of dentate, 〇H, -〇RB10, -ON(Rb&quot;)2, Ν(Κβη)2, _n(〇rB12)rB12, .SH , _srb1〇, -SSRB12, _Si(RB1°)3, _〇si(RB1°)3, _p(rB12)2, _p(RBi2)3, -OP(RB12)2, _〇P(rbi2)3, a 314 membered heterocyclic group and a 514 membered heteroaryl group wherein the 3-14 membered heterocyclic group or the 5-14 membered heteroaryl group is bonded to the nitrogen atom. In certain embodiments, the re is selected from the group consisting of halogen, 〇H, _〇rbi〇, -N(RB11)2, 3·14 membered heterocyclic group and 5-14 membered heteroaryl group, wherein the connection point of 314 member heterocyclic group or 5-14 member heteroaryl group is on the nitrogen atom. Some embodiments RE is selected from the group consisting of dentate, _〇11810, and _n(rB丨)) 2. In some embodiments, Re is a halogen. In some embodiments, rE is &quot;0R. In some implementations In the examples, RE is -N(RB11)2. In certain embodiments, -L-RD and -RE are ortho-rb substituents (ie, two adjacent atoms attached to the group R; for example, Adjacent to each other). In certain embodiments, -L-RD and _re are ortho to each other. In certain embodiments, -L-RD and _Re are not o-position 8 substituents (ie, not connected) Two adjacent atoms on the group RB; for example, in position or para position with each other. In some embodiments, _L_rD and _rE are in position with each other. In some embodiments '-L-RD and _1^ is in a position to compete with each other. In some implementations, rb is a group of formula (5): 156069.doc -66 - 201144296 R7

Wherein each of the groups W-R6, W-R7, W-R8, w_r9 and w_Rl〇 independently represents a nitrogen atom (N) or represents C-R6, C-R7, C-R8, C-R9 or C-R10, respectively. · and • where ",", "," and ... are independently selected from the group consisting of: 致, 素, -CN, -N〇2, _N3, -SO2H, -S〇3h, _OH, _ 〇rbi -on(rB2)2, _n(rB2)2, -N(ORB3)rB3, _SI1, -SrB1, _ssrB3, -C(=0)RB1 ' -C02H ' -CHO ' -C(〇RB3)2 &gt; -C02RB1 -0C(=0)Rb1 ' -0C02RB1 ' -C(=0)N(RB2)2 s -0C(=0)N(RB2)2 n -NRB2c(=〇)RB1 &gt; -nrB2co2rbi -NRB2C(=0)N(RB2)2 -C(=NRB2)ORb1, -OC(=NRB2)RB1, -〇C(=NRB2)〇RB1, -C(=NRB2)N(RB2)2 -〇C(=NRB2)N(RB2)2, -NRB2C(=NRB2)N(RB2)2, • -C(=0)NRB2S02RB1, -NRB2so2RB1, -so2N(RB2)2, -so2RB&gt;, -S02ORB1 , -0S02RB1, -S(=0)RB1, -os(=o)rb1, -Si(RB1)3, -OSi(RB1)3, -C(=S)N(RB2)2, -C(= 0) SRB1, -C(=S)SRB1, -SC(S)SRB1, -P(=〇)2RB1, -〇p(=〇)2RB1, _p(=0)(rbi)2, -op(= o) (rb1)2, -op(=o)(orB3)2, -p(=o)2n(rB2)2, -0P(=0)2N(Rb2)2, -P(=0)(NRB2 ) 2, -0P (=0) (NRb2) 2 , -NRB2P (=0) (0RB3) 2, - NRB2P(=0)(NRB2)2, -P(RB3)2., -P(RB3)3, -OP(RB3)2, -〇P(RB3)3, -b(orB3)4 -BRB1(〇 RB3), 匸1.10 alkyl, (31-10 perhalogenyl, €2-10 alkenyl, 〇2-10 alkynyl, 3-14 negative-67-156069.doc 201144296 heteroaliphatic, Cno carbocycle a 3-14 membered heterocyclic group, a C6_14 aryl group, a 5-14 membered heteroaryl group, -L-RD, and -RE; or a combination of ",", "," and "or" with 1110 Or a plurality of linkages to form a C3-i〇 carbocyclic group, a 3-14 membered heterocyclic group, a C6·!4 aryl group or a 5-14 membered heteroaryl ring; or r1〇 is bonded to Rc to form a 3-14 membered heterocyclic group or 5-14 membered heteroaryl ring; in each case, RB1 is independently selected from the group consisting of Cl-丨G alkyl, Cl lG perhaloalkyl, C2-1()alkenyl, C2.1Q alkynyl, 3-14 a heteroaliphatic group, a C3-1Q carbocyclic group, a 3-14 membered heterocyclic group, a C6.14 aryl group, and a 5-14 membered heteroaryl group; in each case, the RB2 system is independently selected from hydrogen, 〇H , -〇rBi, -N(RB3)2, _CN, -C(=0)RB1, -C(=〇)N(RB3)2, -C02RB1, -S02RB1, -C(=NRB3)〇RB1, _c (=NRB3)N(RB3)2, _so2n(rB3)2, -S02RB3, -S〇2〇RB3, -SORB1, -C(=S)N(RB3)2, -C(=0)SRB3, - C(=S)SRB3, -P(=0)2RB1, _p(=0)( Rbi)2, _ρ(=〇)2Ν(κβ3)2, -P(=0)(NRB3)2, Cm. Alkyl, (^.,.all-alkyl, Cn., ketone, c2.1 decynyl, 3-14 membered heteroaliphatic, C3.1Q carbocyclyl, 3-14 membered heterocyclyl, c ^6-14 aryl and 5-14 membered heteroaryl, or two groups attached to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring; in each case the rB3 is independently selected from the group consisting of hydrogen and Cl. , alkyl, perhalogenated, (: 2.1 () alkenyl, (: 2.1 () alkynyl, 3-14 membered heteroaliphatic, (: 31 () carbocyclic, 3-14 membered heterocyclic , a Cn4 aryl group and a 5-14 membered heteroaryl group, or two ^3 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; and L, RD are as defined above and herein. When one or more of R6, R7, R«, R9 and Ri〇 are referred to as "non-hydrogen", it means that one or more of R6, R7, R8, R9 and Ri〇 are 156069. Doc •68· 201144296 The site is selected from the group consisting of: halogen, -CN, -N〇2, -N3, -S02H, -so3h, -OH, -ORB1, -ON(RB2)2, -N(RB2) 2. -N(ORB3)RB3, -SH, -SRB1, -SSRB3, -C(=〇)Rb1, -C02H, -CHO, -C(ORB3)2, -co2rb1, -OC(=0)RB1, -〇C02RB1, -C(=0)N(RB2)2

-0C(=0)N(Rb2)2, -NRB2C(=0)RB1, -NRB2C02RB1, -NRB2C(=0)N(RB2)2^-C(=NRB2)〇RB1 . -〇C(=NRB2 ) RB,, -OC(=NRB2)ORB1, -C(=NRB2)N(RB2)2, -〇C(=NRB2)N(RB2)2, -NRB2C(=NRB2)N(RB2)2, - C(=0)NRB2S02RB1, -NRB2S02RB1' -S02N(RB2)2&gt; -S02RB1' -S〇2〇RB1' -0S02RBl s -S(=0)Rb, &gt; -OS(=〇)RB1 &gt; - Si(RB1)3 ^ -OSi(RB1)3 . -C(-S)N(RB2)2, -C(=〇)SRB1, -C(=S)SRB1, -SC(=S)SRBl, - P(=〇)2RB1, -〇p(=〇)2RB1, _P(=〇)(rbi)2, _〇p(=〇)(rB1)2, -0P(=0)(0RB3)2 . P(=0)2N(RB2)2 . -0P(=0)2N(RB2)2 x -P(=0)(NRB2)2 . -0P(=0)(NRB2)2 ^ -NRB2P(=〇 )(〇rB3)2 _NRB2p(=0)(NRB2)2, -P(RB3)2, -P(RB3)3, _OP(rb3)2

-〇P(RB3)3, _B(〇RB3)2, _brB1(〇rB3 DE ll-ίο alkyl, q-丨. all-alkyl, c2_lQ alkenyl, C21Q alkynyl, 3-14 heteroaliphatic, Cwo carbocyclyl, 3-14 membered heterocyclic, 丨4 aryl and 5-14 membered heteroaryl | or wherein RkR7, r, r8, R8 and R9 or R9 are linked to - or more in r1q to form C3. Carbocyclyl, 3-14 M heterocyclyl, % aryl or 5·14 member heteroaryl: two or in which the ruler 1. is bonded to Rc to form a 3 to 14 membered heterocyclic group or a 5 to 14 membered heteroaryl R9 and R10 is &gt; In certain embodiments, R6, in certain embodiments, R6, R7, R8, as defined above and as defined herein, -L-Rd 156069.doc -69· 201144296 ^, ... One is a group as defined herein. In certain embodiments, the group of formula (IV) represents a % aryl group or a 614 membered heteroaryl group. In certain embodiments, the group of formula (vii) is represented 6·ΐ4Μheteroaryl. In certain embodiments, the group of formula (IV) represents a % aryl group. In certain embodiments, the group of formula (vii) represents phenyl. In some real _ 'W_R6 'W_R8, 医9 and like 10 denote C-R6, C-R7, C_r8, (10) or c_Ri0, respectively. In some cases in terms of embodiments, RB is the formula (viii) the group: R7

Wherein R6, R7, R8, R9 and R1. As defined above and herein. And R6, R, R, R At least one of R and R10 is a group -rE as defined herein. In certain embodiments, the group of formula (viii) represents a C6i4 aryl group. In certain embodiments, the C6.丨4 aryl group of formula (viii) represents phenyl. In certain embodiments, RB is a mono-, di- or tri-substituted group of formula (viii). In certain embodiments, rb is a monosubstituted or disubstituted group of formula (viii). In certain embodiments, RB is a monosubstituted group of formula (viii). For example, in certain embodiments, Rb is an ortho-substituted formula (viii) 156069.doc • 70· 201144296, wherein, for example, R6_R9 is hydrogen and R1〇 is non-hydrogen, eg, formula (viii_a) Group. In certain embodiments, rB is a meta-substituted group of formula (viii), for example wherein R and R are deuterium and R9 is non-hydrogen, such as a group of formula (viii-b). In certain embodiments, RB is a para-substituted group of formula (viii), wherein, for example, R6, R7, R9, and Ri〇 are hydrogen and R8 is non-hydrogen, such as group of formula (vm-c).

R8 R10 (viii-a) (viii-b) (viii-c) In certain embodiments, it is a disubstituted formula (viii) group. For example, in certain embodiments, Rb is a 2,6-disubstituted oxime group, wherein, for example, R7, ..., and 9 are hydrogen and r6 and R10 are non-hydrogen, such as formula (viii) a group of -d). In certain embodiments, RB is a 2,5-disubstituted formula ("group, for example, wherein R6, R8, and R9 are hydrogen and r7 and Ri" are non-hydrogen, for example In certain embodiments, RB is a disubstituted group of formula (viii), for example, wherein R6, R7, and R9 are hydrogen and are non-hydrogen, such as a group of formula (1). In some embodiments, RB is a 2,3_disubstituted group of formula (viii), wherein, for example, R6, R7 and R« are hydrogen and RjR1〇 is non-hydrogen, for example, 156069.doc •71 of formula (vu(iv)) 201144296 A broadly substituted group of formula (viii), Example 9 is a non-hydrogen 'for example (Wii-h). In certain embodiments, RB is 3,4-wherein R6, R7 and R10 are hydrogen and r ^r group. In certain embodiments, RB is a 3,5•disubstituted formula &amp; group, such as a group in which &quot; and hydrogen is considered to be non-hydrogen.

R7

In certain embodiments, 1 is a trisubstituted group of formula (viii). For example, 'in certain embodiments, rb is a group of formula (viii) substituted by 2,4,6_, such as where RW is hydrogen and r6, R^Rio are non-hydrogen, eg, formula (viii- j) The group. In certain embodiments 'RB is a 2,3,6-trisubstituted group of formula (viii), for example wherein R and R are hydrogen and R1, R4 and R5 are non-hydro', eg, (v_k) ) The group. In certain embodiments, RB is a 2,4,5-trisubstituted group of formula (Viii), 156069.doc • 72· 201144296, for example, (viii... wherein, for example, R8 and R9 are hydrogen and R6, R7 and R 丨 0 is a non-hydrogen group. In certain embodiments, the RB is a 2,3,4-trisubstituted group of formula (viii) wherein, for example, R 6 and R 9 are argon and R 7 , R 8 and R 〇 It is a non-hydrogen, earthy group.

In certain embodiments, Rb is a 3,4,5-trisubstituted (v) group, for example, wherein R6 and R10 are hydrogen and R7, R8A r9 are non-aeromeric, such as a group of formula (5) (d) R7

R8 (viii-m) (viiUn) In certain embodiments, RB is a heteroaryl selected from 5-6 membered heteroaryl, 5,6-bicyclic heteroaryl or 6,6-bicyclic heteroaryl. In certain embodiments, Rb is a 6 membered heteroaryl. In certain embodiments, ra is a 6 membered heteroaryl selected from pyridyl. In some embodiments, 妒 is 2_. Ratio to pyridine, 3- to η-based or 4- to 2-bit base. And Rs. - w· c- w- c- R1Q, for example group e of formula (ix) In certain embodiments 'RBa pyridyl, wherein W_R7 is N, and R6, W-R8, W-R9 and W_R丨0 Respectively c r6, C_R8, C-R9 and Rl&lt;), for example a group of formula (x). In certain embodiments, RB is 4-pyridyl, wherein W_R8 is N and R is 6. And W-R7, W-R9 and W_R10 are respectively c_r6, C_R7, C_R\RlG ', such as a group of the formula (xi). R7 〇7

Wherein R6, R' R, R9 and R1. As defined above and herein. For example, R7 R8 R7 R7 is in some embodiments 'R 6, R7, R8, R9 and R1. At least - the above = and the group _l_rD as defined herein. In certain embodiments, at least one of R R &amp; R10 is a group -Re as defined herein. In certain embodiments, &apos;RB is a monosubstituted or disubstituted, biting group. In certain embodiments 'RB is a monosubstituted pyridyl group. In some 9 real. In the examples, RB is a monosubstituted (8) pyridyl group, wherein R is hydrogen and R is non-hydrogen, such as a group of formula (ix-a). In some 9 real. In the examples, 'Rb is a monosubstituted form such as a butyl group, wherein R is hydrogen and r8 is non-hydrogen, such as a group of formula (ix-b). In some 8 embodiments, RB is monosubstituted. Formula (4)-, wherein R is hydrogen and R9 is non-hydrogen, such as a group of formula (ix-c). I56069.doc • 74- 201144296 wherein in certain embodiments, RB is 铿罝 &amp; /., L # q Early substituted formula (IX) pyridyl group R7, R8, R9 is hydrogen and R10 is non-fluorene, 7 l ^ η opening 例如 ', for example, a group of formula (ix-d).

In certain embodiments, hydrazine is a monosubstituted group of formula (1)(d) wherein R8, R9, R10 are hydrogen and R6 is non-hydrogen, such as a group of formula (^). In certain embodiments, hydrazine is a monosubstituted formula (1), wherein R6, R9, R丨0 are hydrogen and R8 is non-hydrogen, such as a group of formula (x-b). In certain embodiments, RB is a monosubstituted (1) bite group, wherein R6 'R8, R10 are hydrogen and R9 is non-hydrogen', such as a group of formula (x-c). In some embodiments,! e is a monosubstituted formula (1), wherein R6, R8, and R9 are hydrogen and R1 is non-hydrogen, such as a group of formula (10).

In certain embodiments, ... is a monosubstituted group of (5) (d), wherein R6, R7, R9 are hydrogen and π is non-hydrogen, such as a group of formula (4) (4). In certain embodiments, RB is a monosubstituted formula (_&amp; base, wherein R6, R7, R) is an atmosphere and V is a non-hydrogen group, such as a group of formula (μ). 156069.doc • 75 - 201144296

In certain embodiments, rbS is disubstituted pyridyl. In certain embodiments, RB is a disubstituted pyridyl group of formula (ix) wherein R8 and R9 are hydrogen and R7 and Rio are non-hydrogen, such as a group of formula (ix-e). In certain embodiments, RB is a disubstituted pyridyl group of formula (ix) wherein R and R9 are hydrogen and R8 and r1g are non-hydrogen, such as a group of formula (ix-f).

In certain embodiments, rb is a disubstituted pyridyl group of formula (ix) wherein R and R8 are hydrogen and R9 and R10 are non-hydrogen, such as a group of formula (ix-g). In certain embodiments, &apos;118 is a disubstituted pyridyl group, wherein R and R are deuterium and R and R9 are non-hydrogen, such as a group of formula (ix-h). In certain embodiments, RBg is disubstituted by (ix) n is a pyridyl group, wherein R and R are hydrogen and R and R8 are non-hydrogen, such as a group of formula (jx-j).

In certain embodiments, rb is a disubstituted formula (ix) D is a pyridyl group, wherein R and R are deuterium and R and R9 are non-hydrogen, such as a group of formula (丨x_j). R7

156069.doc 76· 201144296

A disubstituted formula (X) pyridyl group such as a group of the formula (x-e). The disubstituted formula (X)» is a group such as a group of the formula (x-f). A disubstituted formula of the formula (X)-pyridinyl group is a group of the formula (x-g). Disubstituted formula (X). A pyridine group such as a group of the formula (x-h). The disubstituted formula (X)D is a group of the formula (x-i). - Substituting formula (X). A pyridine group such as a group of the formula (x-j).

In certain embodiments, RB is and R9 is hydrogen and R6 and R1. Non-hydrogen, in certain embodiments, RB is via and R10 is hydrogen and R6 and R9 are non-hydrogen. In certain embodiments, Rb is and R1G is hydrogen and R6 and R8 are non-hydrogen, at some In some embodiments, RB is hydrogen and R9 is hydrogen and R8 and R丨❶ are non-hydrogen. In certain embodiments, rb is and R is hydrogen and R8 and R9 are non-hydrogen, in certain embodiments , RB is and R8 is hydrogen and R9 and R10 are non-hydrogen, 156069.doc, wherein R8 1 wherein R8 wherein R9 wherein R6 wherein R6 wherein R6

77· 201144296 In certain embodiments 'RB is a disubstituted formula (10)-specific bite group, wherein R7 and R9 are hydrogen and R^Rl° is money, such as a group of formula (xi-c). In certain embodiments, 'RB is a disubstituted formula (5) biting group, wherein R and R7 are hydrogen and R9 and R1. It is a non-hydrogen group such as a group of the formula (4)-d). In certain embodiments, Rb is a disubstituted formula (10) pyridyl wherein R and R8 are hydrogen and R7 and R10 are non-hydrogen, such as a group of the formula (heart). In certain embodiments, 0 is a disubstituted s(xi)npyridinyl group, wherein R and R10 are hydrogen and R7 and R9 are non-hydrogen, such as a formula group.

In certain embodiments, RB is of the formula (xii) (:5- 〇 carbocyclyl or 5-1 杂 heterocyclyl:

Wherein: X is N, NR30, Ο, S or CR31R32; P is 0, 1 or 2; in each case R2丨, R22, R23, R24, R25, R26, R2?, r28 156069.doc -78· 201144296 R29, R31 and R32 are independently selected from the group consisting of hydrogen, halogen, _CN, -N02, -N3, -so2h, _so3h, _〇H, -〇RB1, _ON(RB2)2, _N(RB2)2, -N( ORB3) RB3, -SH, -SRB1, -SSRB3, -C(=0)RB1, -co2h, _CHO, _C(ORB3)2, -C02RB1,_0C(=0)RB1, -0C02RB1, -C(=0 N(RB2)2, -〇c(=〇)N(RB2)2, -nrB2c(=o)rB1, -NRB2C02RB1, _NRB2C(=0)N(RB2)2, -C(=NRB2)ORB1 -OC(=NRB2) RB1, _〇c(=NRB2)〇RB1, -C(=NRB2)N(RB2)2, φ -〇c(=nrB2)N(RB2)2, -NRB2C(=NRB2) N(RB2)2, -C(=0)NRB2S02RB1, -NRB2S02RB1' -S02N(RB2)2&gt; -S02RB1' -S〇2〇RB1' -oso2rb, ' -S(=0)RB1, -〇S( =〇) RB1, -Si(RB1)3, -〇Si(RB1)3, -C(=S)N(RB2)2, -C(=0)SRB1, -C(=S)SRB1, -SC (=S) SRB1, -P(=0)2RB1, -0P(=0)2RB1, _P(=〇)(rbi)2, _〇p(=〇)(rbi)2, -0P(=0) (0RB3)2 . -P(=〇)2N(RB2)2 ' -OP(=0)2N(RB2)2 ' -P( = 0)(NRB2)2, -〇p( = 〇)(NRB2) 2, _NRB2p ( = 〇) (〇 RB3) 2, -nrB2p (= o) (n rB2)2, ·ρ(π)2,·ρ(κβ3)3, _〇p(rB3)2, • -〇p(rB3)3, -B(〇RB3)2 or -brb1(0rB3), Cl_i0 Affiliation, Ci 1〇 whole functional alkyl, C2.1Q alkenyl, (: 2·1() alkynyl, 3-14 member heteroaliphatic, c3-1Q carbocyclic, 3-14 heterocyclyl , (6-14 aryl, 5-14 membered heteroaryl, 丄_1^ and ·^; or R29 and R21, R22 and R23, R2&gt; R31, ^ and ^, ^ and ^, R28 and R29 Or R26 is bonded to one or more of R29 to form a double bond or a (1) carbocyclic group, a 3-14 membered heterocyclic group, a (6-indenyl group or a 5-14 membered heteroaryl ring; optionally wherein X is Ν, then Ν and R23 or Ν are connected to R25 to form a double bond; R30 is selected from hydrogen, -OH, -〇 RB1, _N(RB3)2, _CN, c(=〇)rBi, -C(=0)N (RB3)2 ^ -C02RB1 ' -S02Rb, &gt; -C(=NRB3)〇RB, 156069.doc -79- 201144296 -C(=NRB3)N(RB3)2, -S〇2N(rB3)2 _s〇2rB3, _s〇2〇rB3, S(-0)R . -C(=S)N(RB3)2 , -C(=〇)SRB3 ' -C(=S)SRB3, -P(=o ) 2RB1' -p(=o)(rb1)2, _p(=〇)2N(rB3)2 p(=〇)(nrB3)2

Cwo alkyl, Cl-10 total alkenyl, c2 1 nonenyl, C2 1 decynyl, 3-14 heteroaryl, C3_1() carbocyclyl, 3_M heterocyclyl, c6 14 aryl and 514 Heteroaryl, depending on the situation, the Han and the ruler "or Han ^ and the rule ^ are connected to form a heterocyclic ring or a 5-14 member heteroaryl ring; among them: rb in each case is independently selected From Ci iG alkyl, ^ t-tooth alkyl, C2-1G alkenyl, c2_1 () alkynyl, 3-14 heteroaliphatic, c3 1G carbocyclyl, 3 14 mer, C: 6- M aryl and 5_i4 member heteroaryl; in each case, the RB2 is independently selected from the group consisting of hydrogen, OH, _〇rBi, -N(R)2. _CN '-C(=〇)rb&gt; . -C(= 0) N(RB3)2 &gt; -C〇2RB1 &gt; -SOW丨, _C(=NrB3)〇rB1, _c(=nrB3)n(rB3)2, _s〇2n(rB3)2, -SO#, _S〇2〇rB3, _s〇rB1, _c(=s)n(rB3)2, _c(=〇)srB3, -C(=S)SRB3, -P(=0)2RB1, _p(=〇)( rB1)2, _p(=〇)2N(rB3^, -P(=0)(NRB3)2, Cmo alkyl, (: 1-1 〇 all-tooth alkyl, c2 i-alkenyl, q alkynyl, 3-14 member heteroaliphatic, c3l() carbocyclyl, 3-14 membered heterocyclyl, q &quot; aryl and 5-14 membered heteroaryl, or two rb2 groups joined to form 3_14 Heterocyclyl or 5-14 membered heteroaryl ring; in each case RB3 is independently selected from the group consisting of hydrogen, c丨丨q alkyl, c. All-alkyl, C2-1Q alkenyl 'C2, alkyne a 3,14 member heteroaliphatic group, a C3, a carbocyclic group, a 3-14 membered heterocyclic group, a C6·&quot; aryl group and a 5-14 membered heteroaryl group, or two groups of 2 groups are bonded to form a 3-14 member. a cyclic group or a 5-14 membered heteroaryl ring; 156069.doc • 80- 201144296 and L, RD and REW are as defined above and herein. In certain embodiments, R21, R22, R23, R24, R25, R26 And at least one of R27, R28, R29, R3Q, R31 and R32 is a group _L-RD as defined above and herein. In certain embodiments, R21, R22, R23, R24, R25, R26 And at least one of R27, R28, R29, R30, R31 and R32 is selected from the group -RE as defined herein. In certain embodiments, p is 〇. In certain embodiments, 'P is 1 In certain embodiments, p is 2. In certain embodiments, X is N. In certain embodiments, X is NR 30. In certain embodiments, X is Ο. In certain embodiments In the middle, X is S. In certain embodiments, X is CR31R32. In certain embodiments, RB is a Cs.io carbocyclic group of formula (xiii) or a 5-1 membered heterocyclic group:

Where: X is N, NR30, 0, S or CR31R32; P is 0, 1 or 2; in each case R21, R22, r23, r24, r25, r26, r27, r28 R, R31 and R32 are independently selected From hydrogen, odont, _CN, _n〇2, 156069.doc 201144296 -so2h, -so3h, -OH, -ORB1, -ON(RB2)2, -N(RB2)2, -N(ORB3)RB3, -SH, -SRB1, -SSRB3, -c( = o)rb1, -C02H, -CHO, -C(ORB3)2, -C02RB1, -0C(=0)RB1, -0C02RB1, -c(=o) n(rB2)2, -oc(=o)n(rB2)2, -NRB2C(=0)RB1, -nrB2co2rB1, -nrB2c(=o)n(rB2)2, -C(=NRB2)ORB1, - OC(=NRB2)RB1 ' -OC(=NRB2)ORB, ' -C(=NRB2)N(RB2)2 ' , OC(=NRB2)N(RB2)2,,NRB2C(=NRB2)N(RB2) 2. -C(=0)NRB2S02RB1, -NRB2so2RB1, -so2n(rB2)2, -so2RB1, -so2〇RB1, -〇so2RB1, -S(=0)RB1, -〇S(=0)RB1, - Si(RB1)3, -〇Si(RB1)3, -C(=S)N(RB2)2, -c(=o)srb1, -C(=S)SRB1, -SC(=S)SRB1 -P(=0)2RB1 ' -0P(=0)2RB1 ' -P(=0)(Rb,)2 λ -〇P(=〇)(Rb1)2 . -0P(=0)(0RB3)2 , -P(=0)2N(RB2)2, _〇p(=〇)2N(rb2)2, -p(=o)(nrB2)2 ' -〇p(=〇)(nrB2)2, _nrB2p (=〇)(〇rB3)2, -NRB2P(=〇)(NRB2)2, -P(RB3)2,·ρ( 33)3, _〇p(rB3)2, -〇P(RB3)3, -B(〇RB3)e-BR, ORBV Ci 1 〇alkyl, Ci 1〇-toothed-alkyl, C2_I()alkenyl , C2-1Q alkynyl, 3-14 member heteroaliphatic, c31 () carbocyclyl, 3-14 membered heterocyclic, C6_丨4 aryl, 5-14 membered heteroaryl, _l_re^_rE; Or R29 and R21, R22 and R", R3&gt; R23, r, r25, r26 and r27 are linked to one or more of R29 and R26 and R29 to form a double bond or a c3i〇 carbocyclic group, a 3-H member a cyclic group, a c6_14 aryl group or a 5-14 membered heteroaryl ring; optionally wherein X is N, then N is bonded to R21 or N to form a biguanide; and R30 is selected from the group consisting of hydrogen, -OH, -ORB1, _n(rB3) 2. CN, _c(=〇)rBi, -C(=0)N(RB3)2 . -C02RB1 , -so2rb, -C( = NRB3)N(RB3)2, _s〇2N(rB3)2, _s 〇2RB3, s〇2〇rB3,

C(=NRB3)〇R I56069.doc -82- 201144296 -s(=o)rbi,_c(=s)N(RB3)2, -C(=0)SRB3,_c(=:s)srB3, - P(=〇)2Rb, '-P(=0)(RB1)2' -P(=0)2N(Rb3)2' -P(=0)(NRB3)2 'Cmo alkyl, Cmo all litan , C2-10 alkenyl, C2-10 alkynyl, 3-14 membered heteroaliphatic, C3-1G carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl and 5-14 heteroaryl, or R22 Joining R3G or 113() with Han23 to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; wherein: • In each case, the RB1 is independently selected from alkyl, Cmq all-tooth alkyl, C2- 1()alkenyl, C2_1G alkynyl, C3-1G carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl and 5-14 membered heteroaryl; in each case the RB2 is independently selected from hydrogen , _0H, -〇rB丨, -N(RB3)2, _CN, -C(=0)RBl, _C(=0)N(RB3)2, _c〇2rB1, •S02RB1, _c(=NRB3)ORB1 -C(=NRB3)N(RB3)2, -S02N(RB3)2, -S02RB3, -S〇2〇RB3 ' -S(=〇)RB1 . -C(=S)N(RB3)2 - - C(=〇)SRB3, -C(=S)SRB3, _p(=〇)2Rbi, _p(=〇)(rbi)2, • _p(=0)2N(rB3)2, -p(=〇) (NRB3) 2, Cmo alkyl, Cl_10 functional alkyl, C2-10 alkenyl, C2_n) alkynyl, 3-14 member heteroaliphatic, c3.1Q a cyclic group, a 3-14 membered heterocyclic group, a C6_u aryl group, and a 5-14 membered heteroaryl group, or two groups bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; in each case rB3 Is independently selected from the group consisting of hydrogen, Ci ig alkyl, Ci ig perhaloalkyl, C: 2-1G alkenyl, C 2 · decynyl, 3-14 heteroaliphatic, (^(9) carbocyclyl, 3-14 a heterocyclic group, a (:6]4 aryl group and a 5-14 membered heteroaryl group, or two rB3 groups bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; and L, RD &amp; RE As defined above and herein. 156069.doc 83 - 201144296 In some embodiments, at least one of RU, R22, R23, R24, R25, r26, r27, R, R29, R3G, ruler 31, and ruler 32 Is a group -L-RD as defined above and herein. In certain embodiments, R21, R22, r23, r24,

And at least one of R29, R30, R31 and R32 is selected from _RE as defined herein. In certain embodiments, p is 〇. In certain embodiments, p is one. In some embodiments, p is two. In certain embodiments, X is N. In certain embodiments, X is NR30. In some embodiments 'X is zero. In certain embodiments, X is S. In certain embodiments 'X is CR31r32. For example 'In some embodiments, X is 〇. In certain embodiments, R is a 5-1 member heterocyclic group of formula (xii-a) or (xiii_a):

Wherein p, R21, R22, R23, r24, r25, r26, r27, caliper 28 and R29 are as defined above and herein. In certain embodiments, the enthalpy is NR30. For example, in certain embodiments, R is a heterocyclic group of formula (xii-b) or (xiii_b): 156069.doc -84· 201144296

Wherein p, R21, R22, R23, R24, R25, R26, R27, r28, r29 and r3Q are as defined above and herein. In certain embodiments, χ is Cr3 rr3, for example, in some embodiments 'RB is a formula (xii_c) 2C5l 〇 carbocyclyl:

Wherein p, R21, R22, R23, R24, R25, R26, R27, r28, r29, R31 and R32 are as defined above and herein. The base faces RB and # of the connection are as generally described above. In some embodiments, rb and Rc are joined together with the nitrogen (N) atoms to which they are attached to form a 5 _ 丨 4 member ring. For example, in some embodiments, RyRC is joined together with the nitrogen (N) atom to which each is attached to form a member ring of the formula (χ ν). 156069.doc -85- 201144296

Wherein: Q is N, NR40, Ο, S or CR41R42; m is 0, 1 or 2; and in each case R41, R42, R43, R44, R45, R46, R47, R48, R49 and R50 are independently selected From hydrogen, halogen, -CN, -N02, -N3, -S02H, -so3h, -OH, -ORF1, -ON(RF2)2, -N(RF2)2, -N(ORF3)RF3, -SH, -SRF1, -SSRF3, -C(=0)RF1, -C02H, -CHO, -C(ORF3)2, -co2rf1, oc(=o)rf1, -oco2rf1, -c(=o)n(rF2) 2. -0C(=0)N(RF2)2, -NRF2C(=0)RF1, -NRF2C02RF1, -NRF2C(=0)N(RF2)2, -C(=NRF2)ORF1, -〇C(= NRF2)RF1, -OC(=NRF2)ORF1, -C(=NRF2)N(RF2)2, -OC(=NRF2)N(RF2)2, -NRF2C(=NRF2)N(RF2)2, -C (=0)NRF2S02RBC1, -NRF2S02RF1, -so2n(rF2)2, -S02RF1, -S020RF1, -0S02RF1, -s(=o)rf丨, -0S(=0)RF1, -Si(RF1)3,- OSi(RF1)3, -C(=S)N(RF2)2, -c(=o)srf1, -C(=S)SRF1, -SC(=S)SRF1, -p(=o)2rf1 -op(=o)2rf1, -P(=0)(RF1)2, -op(=o)(rf1)2, -op(=o)(orF3)2, -P(=0)2N(RF2 2, -op(=o)2n(rF2)2, -p(=o)(nrF2)2, -0P(=0)(NRF2)2 ' -NRF2P(=0)(0RF3)2' -NRF2P (=0)(NRF2)2 ' P(RF3)2, _P(RF3)3, -〇P(RF3)2, -〇P(RF3)3, -B(ORF3)2 156069.doc 86 - 201144296 BR (OR), c Shushu. Alkyl, c丨丨. Perhaloalkyl,. 2_丨. Alkenyl, C2丨. Alkynyl, 3-14 membered heteroaliphatic, (^^ carbocyclyl, 314 membered heterocyclyl, aryl, 5-14 membered heteroaryl, ·l_rd&amp;_rE; or r47 and r49, ruler 48 and ruler 5〇, R and R, R and R42, R4&gt; R45, Han 42 and &amp; 46, R45 and ruler 43 and ruler 46 are connected to one or more of the rulers to form a double bond or a ruthenium 3.10 carbocyclic group, 3- a 14-membered C6-14 aryl or a 5-14 membered heteroaryl ring; optionally wherein N is N, then N and R_49 or N are bonded to R46 to form a double bond; R40 is selected from the group consisting of hydrogen, -OH, - 〇RF1, _N(RF3)2, _CN, _c(=〇)rF1, -c(=o)n(rF3)2, _c〇2RF1, _s〇2RF1, _c(=nrF3)〇rF1, -C(= NR-)N(R-)2 , -S02N(Rf3)2 . .s〇2RP3 ^ _s〇2〇rF3 ^ -C(=S)N(RF3)2 . -C(=〇)SRF3 . -C (=S)SRF3 ^

SOR1 P(-0)2R ' -P(=0)(Rf,)2 . -P(=〇)2N(RF3)2. _P(=0)(-NRF3^ %

Cmo alkyl, Cl.1〇M alkyl, c2.i〇 dilute 'C2i〇 block, 3-14 member heteroaliphatic, carbocyclic, 3-14 heterocyclyl, Q 14 aryl and 514 aryl a group, wherein, depending on the case, a ring or a ruler and a ruler are attached to form a heterocyclic group or a 5-14 membered heteroaryl ring; wherein: in each case, the RF1 is independently selected from a Ci iQ alkyl group. , Ci, fully functional alkyl, C2_1Q alkenyl, C2.1Q alkynyl, c3 lG carbocyclyl, 3-14 heterocyclyl, C6-H aryl and 5-14 membered heteroaryl; rF2 in each case Independently selected from hydrogen, 〇Η,, -N(RF3)2 . . . CN ^ -C(=〇)Rfi . -C(=〇)N(RF3)2 ^ .c〇2RF1 -SO#,- C(=NR")0rF1, _c(=nrF3)n(rF3)2, _s〇2n(2rF3)2, -so2rF3, _so2〇rf3, _s(=〇)rF1, _c(=s)n(rF3 2, 156069.doc -87 - 201144296 -C(=0)SRF3, _C(=S)SRF3,·ρ(=〇)2κ/丨, _p(=〇)(rfi)2, -P(=0 2N(RF3)2, -P(=0)(NRF3)2, Ci 1 alkyl group, Ci 1 〇 all-dentate alkyl group, C2-1G alkenyl group, C2-1Q alkynyl group, 3-14 member heteroaliphatic group , C31❶ carbocyclic group, 3·14 membered heterocyclic group, C6-M aryl group and 5-14 membered heteroaryl group, or two ft. groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 member heterocyclic group. An aryl ring; in each case the rF3 is independently selected from the group consisting of hydrogen, Ci iQ alkyl, Ci iq perhaloalkyl, C2.1G alkenyl, c2_1Q alkynyl, 3-14 heteroaliphatic, C31G carbocyclyl, a 3-14 membered heterocyclic group, a C6^4 aryl group and a 5-14 membered heteroaryl group, or two groups of 3 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; and L, RD And rew as defined above and herein. In some embodiments, at least one of R40, R41, R42, R43, R44, r45, r46, R7, R48, R49 and R5G is as above and a group -L-RD as defined herein. In certain embodiments, at least one of r40, r41, r42, r43, r44, R, R46, R47, R48, 1^9, and r5〇 is selected from, for example, -RE as defined herein. In certain embodiments, m is 〇. In some embodiments, the jaw is 丨. In certain embodiments, m is 2. In certain embodiments, Q is N. In certain embodiments, 〇 is 1 ^ 4 〇. In certain embodiments, Q is 〇. In certain embodiments, 〇 is s. In certain embodiments, Q is CR41R42. In certain embodiments, R47 is joined to R49 to form a double bond, and R48 is joined to R5〇 to form C. 6. M aryl or 5-14 membered heteroaryl, for example, in certain embodiments, RB and Rc are joined together with the nitrogen (Ν) atom to which they are attached to form a formula 5-14 Member Ring: 156069.doc •88· 201144296 R7

Wherein Q, m, W, R41, R42, R43, R44, R45, r46, R6, R7, R8 and R9 are as defined above and herein. In certain embodiments, Q is CR41R42, R49 is joined to r4i to form a double bond, and R5() is joined to R42 to form a C6-M aryl or a 5-14 membered heteroaryl. For example, in certain embodiments, RB&amp;RC is joined together with the nitrogen (N) atom to which each is attached to form a group of formula (xvi):

Wherein m, W, R43, R44, R45, R46, Rule 47 and R48 are as defined above and herein; and wherein R66, R67, R68 and R69 are independently selected from the group consisting of: hydrogen, halogen, -CN, -N02, -N3, _S〇2h, -S03H, -OH, _〇rf4, -ON(RF5)2, -N(RF5)2, -N(〇RF6)rF6, _SH, -SRF4, _SSRF6 -C (=0)RF4 ' -C02H &gt; -CHO . -C(〇RF6)2 ' -C〇2rF4 ^ 156069.doc •89· 201144296 -0C(=0)RF4,-0C02RF4, -C(=0) N(RF5)2, -〇C(=0)N(RF5)2, -NRF5C(=0)RF4, -NRF5C〇2RF4, -NRF5C(=0)N(RF5)2, -C(=NRF5) ORF4, -〇C(=NRF5)RF4, -0C(=NRF5)0RF4, -C(=NRF5)N(RF5)2, -〇C(=NRF5)N(RF5)2, -nrF5c(=nrF5) n(rF5)2, C(=0)NRF5S02RF4, -NRF5S02RF4, _so2N(RF5)2, -S02RF4, -so2orF4, -oso2RF4, -s(=o)RF4, -0S(=0)RF4, -Si( RF4)3, -OSi(RF4)3, -C(=S)N(RF5)2, -C(=〇)SRF4, -C(=S)SRF4, -SC(S)SRF4 ' -P(= 0)2RF4 ' -0P(=0)2RF4 - -P(=0)(RF4)2 ' -op(=o)(rF4)2 , -op(=o)(orF6)2 , -P(=〇 2N(RF5)2, -OP(=0)2N(RF5)2, -P(=〇)(NRF5)2, -op(=o)(nrF5)2, -NRF5P(=〇)(〇RF6 ) 2, -NRF5P (= 〇) (NRF5) 2, _p (rF6) 2, -P (R F6)3, -OP(RF6)2, -〇P(rF6)3, ·Β(〇κ^)2 or _brF4(〇rF6),

Cl-ίο alkyl, C _ 10 perhaloalkyl, c 2-10 alkenyl, C 2-10 alkynyl, 3-14 heteroaliphatic, C 3 .10 carbocyclyl, 3-14 membered heterocyclyl, c6_14 An aryl group, a 5_i4 membered heteroaryl group, -L-RD and -RE; or R" is bonded to one or more of R67, 67 and 68, and 68 and R69 (: 3-10 carbocyclic, 3- 14 membered heterocyclic group, (: 6_14 aryl or 5-14 membered heteroaryl ring; in each case, RF4 is independently selected from the group consisting of Cl-1G alkyl, Ci iG functional alkyl, c2. 丨Q alkenyl , c2-decynyl, 3·14 member heteroaliphatic, c3”q carbocyclyl, 3-14 membered heterocyclic, c6-14 aryl and 5-14 membered heteroaryl; RF5 is independently selected from the group consisting of hydrogen, 〇H, _〇RF4, -N(RF6)2, -CN, -C(=〇)RF4, -C(=〇)N(RF6)2, _c〇2RF4, -so2rF4, -c(=nrF6)orF4, _C(=NRF6)N(RF6)2, -S〇2N(RF6)2, -S02RF6, -S〇2〇RF6, -SORF4, -C(=S) N(RF6)2, -C(=〇)SRF6, 156069.doc •90· 201144296 -c(=s)srF6,·Ρ(=0)2π, _p(=〇)(rF4)2, _p(= 〇), RF6)2, -p(=〇KNRF6)2, Ci i. Alkyl, Cl 丨. Totally dentate alkyl, c21. Alkenyl, do alkynyl 3-14 member heteroaliphatic, Cm carbocycle Base, 3_i4 Heterocyclic agricultural #甘你, 16-14方土 and 5-14 member heteroaryl, or two RF5 groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; and in each case The RF6 is independently selected from the group consisting of hydrogen, Ci alkyl, 1-1 〇 all-alkyl, Cm alkenyl, Cm alkynyl, 3-14 heteroaliphatic, 3·ι〇carbocyclyl, and heterocyclyl a Cw4 aryl group and a 5-membered heteroaryl group, or two "6 groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring. In certain embodiments, R43, R", r45 And at least one of R46, r47, r48^, R67, R68 and R69 is a group -LR as above and in this D. In some embodiments, R43, r44, r45, 46, ruler, R48, At least one of R66, R67, ultra 68, and R69 is selected from -RE as herein. π 疋 In some embodiments, m is 〇. In some embodiments, U is 1. In certain embodiments Where m is 2. Aryl group Rc As generally described above, the RC is selected from the group consisting of hydrogen, 〇H, _〇RC1, _〇n(rC2)2, -n(rC2)2, -c(=〇 )rC1, -cho, -co2rC1, _c(=:0)n(rC2)2, -C(=NRC2)〇Rci, _c(=nrC2)n(rC2)2, _s〇2RC1, s(four))rCi, _Si (Rcl) 3, Cl-10, Cl_10 perhaloalkyl, C2_i〇, C2 i〇 fast radical, 3-14 member heteroaliphatic, (^(7) carbocyclyl, 3-14 heterocyclyl, c6_i4 aryl And 5-14 membered heteroaryl; wherein: 156069.doc -91· 201144296 Rci in each case is independently selected from Ci i() alkyl, Ci iQ functional alkyl, C2_1Q alkenyl, c21() alkyne a group, a C31 fluorene carbocyclyl group, a 314 membered heterocyclic group, a C6-]4 aryl group, and a 5-14 membered heteroaryl group; and in each case, the system is independently selected from the group consisting of hydrogen, 〇H, _〇rCi, -N (RC3)2 ^ -CN &gt; -C(=〇)Rc* . .C(=〇)N(RC3)2 . -C〇2Rcl . -S02RC1 &gt; -C(=NRC3)0RC1. -C( =NRC3)N(RC3)2. -S〇2N(RC3)2 ^ S02RC3, -S020RC3, _SORci, _c(=s)n(rC3)2, _c(4))srC3, C(=S)SRC3 ^ -P( =〇)2rCi . .P(=〇)(rc,)2 x _P(=〇)2N(rC3)2 x

-P(=0)(NRC3)2, Cmo alkyl group, Cm. All-alkyl, c2]G alkenyl, c2 i decynyl, 3-14 membered heteroaliphatic, C31Q carbocyclyl, 3_M heterocyclyl, Q aryl and 5-14 membered heteroaryl, or The two rC2 groups are joined to form a 3_i4 membered heterocyclic group or a 5-14 membered heteroaryl ring; or RB and Rc are joined together with the nitrogen (N) atom to which each is attached to form a 5-14 membered ring. In certain embodiments, the &apos; Rc is selected from the group consisting of Cn 〇 alkyl, Ci i〇 functional alkyl, C2-1G alkenyl, Cn. Alkynyl, 3-14 membered heteroaliphatic, &lt;:31() carbocyclyl, 3-14 heterocyclyl, C6^4 aryl and 5-14 membered heteroaryl. In certain embodiments, R.sup.c is an unsubstituted group, for example, selected from unsubstituted (:, decyl, unsubstituted Cm alkenyl, unsubstituted C2 i decynyl, Unsubstituted 3-14 member heteroaliphatic, unsubstituted c. (7) carbocyclyl, unsubstituted 3-14 membered heterocyclic group, unsubstituted C6 m aryl group and unsubstituted 5-14 membered heteroaryl. However, in certain embodiments, rC is an unsubstituted group 'wherein -CH3 and -CH2CH3 are excluded. In certain embodiments, 'Rc is 2 or 2 The above carbon atom group 156069.doc -92- 201144296 group is, for example, selected from the group consisting of C2.10 alkyl, c2 i〇 all-toothed base, c2 w thin base, : base, 3-14 member heteroaliphatic group, c3•丨Carbocyclyl, 3-14 membered heterocyclyl, 14 aryl and 5·14 membered heteroaryl. In certain embodiments, RC is an unsubstituted group having 2 or 2: upper carbon atoms. However, in certain embodiments, the group of carbon atoms 'where · CH2CH3 is excluded. In certain embodiments, 'an group having 3 or more carbon atoms' is selected, for example, from c3-10 alkyl. , c3 i〇 full tooth burning base, c3 i a dilute group, a Cw group, a 3,14 membered heteroaliphatic group, a C31Q carbocyclic group, a 3-14 M heterocyclic group, a 4 aryl group, and a 5-14 membered heteroaryl group. In certain embodiments, Rc has 3 Or 3 unsubstituted groups 1 of carbon atoms, in some embodiments, R is 3 or more carbons "Early and evening, outside. - Atomic group'... H (CH is fine in a certain example t 'R is a group having 4 or more carbon atoms', for example, selected from the group consisting of 'alkylene-total", &amp; dilute, c4i. alkynyl , (5) a heteroaliphatic group, a C5 iq carbocyclic group, an anthracene heterocyclic group, a C... square group, and an anthracene heteroaryl group. In some embodiments, 'RC is 4 or more carbon atoms Unsubstituted group. In certain embodiments, hydrazine is a non-cyclic group, for example selected from the group consisting of C", dilutyl, C2-1 decynyl, and 3-14 heteroaliphatic. In the examples, R is an unsubstituted acyclic group, for example, selected from unsubstituted Cl.10, unsubstituted c2.10, unsubstituted C2 i〇 block and Substituted 3-H member heteroaliphatic group. However, in certain embodiments, rC is non- a group in which hydrazine; and _CH2CH3 are excluded. 156069.doc • 93· 201144296 In certain embodiments, Rc is C^oalkyl. In certain embodiments, RC is unsubstituted alkyl. In certain embodiments, Rc is c]w alkyl, wherein -CH3 is excluded. In certain embodiments, Rc is alkyl, wherein -CHAH3 is excluded. In certain embodiments, R(^ Cii oxime, wherein -CH(CH3)2 is excluded. In certain embodiments, Rc is Cm danyl, for example selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, t-butyl, t-butyl, isobutyl, n-pentyl, pentyl 3-yl, pentyl, neopentyl, 3-methyl-2-butyl, third amyl and n-hexyl. In certain embodiments, R.sup.c is an unsubstituted alkyl group. In certain embodiments, Rc is C2_1 decyl, wherein _CH2CH3 is excluded. In certain embodiments, Rc is (: 2_1 decyl, wherein _CH(CH3)2 is excluded. In certain embodiments, Rc is C: 3&quot; alkyl, for example selected from n-propyl, iso Propyl 'n-butyl, tert-butyl, t-butyl, isobutyl, n-pentyl, pent-3-yl, pentyl, neopentyl, 3-methyl-2-butyl, third pentyl And in certain embodiments 'Rc is an unsubstituted C3_10 alkyl group. In certain embodiments, RC is C3 〇alkyl, wherein _CH(CH3)2 is excluded. In the examples, r, c4 i is an alkyl group, for example selected from the group consisting of n-butyl, hexanedibutyl, t-butyl, isobutyl, n-pentyl, pent-3-yl, pentyl, neopentyl 3methylbutyl 'tripentyl and n-hexyl. In certain embodiments, Rc is unsubstituted C4•decyl.

In certain embodiments, r, C2 i〇 alkenyl. In certain embodiments, rC is a C2.10 alkenyl group substituted with no &apos;. In certain embodiments, RC is C2.nonenyl selected from the group consisting of dilute propyl groups.

In a second embodiment, 'RC is (7) fast base. In certain embodiments, rC 156069.doc •94· 201144296 is an unsubstituted c2-IG alkynyl group. At some. In some embodiments, 1 is a 3-14 member heteroaliphatic group. In certain embodiments, RC is an unsubstituted 3-14 membered heteroaliphatic group. In a second embodiment, r is a cyclic group, for example selected from the group consisting of a carbocyclic groups, 3-14 members. Heterocyclyl, c614 aryl and 5-14 heteroaryl. In certain embodiments R is an unsubstituted cyclic group, for example selected from unsubstituted C3•丨〇

* 3-14 membered heterocyclic group, unsubstituted C6_丨4 aryl group and unsubstituted 5-14 membered heteroaryl group. . In a certain embodiment 'C3 i. Carbocyclic group. In certain embodiments, R is a % carbocyclyl. In certain embodiments, Rc is a cw carbon ring group. In certain embodiments 'V is &amp; carbocyclyl. And R. Hexyl (C6), cyclohexenyl (6), cyclohexadiene = (c6), cycloheptyl (c7), cycloheptyl (6), cycloheptyl (5) octyl (c8). In some embodiments, 'rC is a carbocyclic group selected from the group consisting of cyclopentyl and cyclohexyl. In certain embodiments, unsubstituted ^, _, in the examples, a 3 to 14 membered heterocyclic group. In the examples, = 10 mole%. In certain embodiments, Rc is a 5.6 membered heterocyclic group. In the case of Ί, 'Rc is a 3-14 member heterocyclyl selected from the group consisting of: aziridine 2 Ring rolling ethane group, thiol group, azetidinyl group, oxetanyl group, thietane group, tetrahydro group, dihydroanthracene, tetrahydrothiol, oxygen furnace: &amp; ° ratio of base, dihydrogen ratio of each group, dioxolane, pentyl group, dithiol group, butyl group, tetrahydropyranyl, 156069.doc -95- 201144296 Dihydropyridinium, pyridyl, piperazinyl, morphinyl, dithiadiyl, dioxo, azepine a group, an oxetanyl group, a thiaheptane group, an azacyclononyl group, an oxetan group, and a thiene group. In some embodiments, 'R is selected from the group consisting of four A 3-14 membered heterocyclic group of a hydrogen-based group. In certain embodiments, 'Rc is an unsubstituted 3-14 membered heterocyclic group.

In some embodiments, RC is a C6-]4 aryl group. In certain embodiments, rC is a C6·!4 aryl group selected from the group consisting of stupid, naphthyl, and anthracenyl. In certain embodiments, RC is C6_&quot; aryl selected from phenyl. In certain embodiments, the ruler (: is an unsubstituted Ce-14 aryl group. In some embodiments, 1^ In the case of a tablet, R is a 5-1 member heteroaryl. In certain embodiments, RC In certain embodiments, RC is a 5-membered heteroaryl group, for example selected from 2 = Base &quot; thiophene, μ, fluorenyl, isomeric, fluorenyl, iso (tetra), tris (tetra), stil, red, and tetra. Base, for example, selected from n to bite base, health

In the examples, in some embodiments, Re is an unsubstituted 5-14 membered heteroaryl group. Exemplary combinations of groups RA, RB, and Rc Various combinations of RA, RB, and/or RC are encompassed herein and are described in more detail below and herein. For example, in some embodiments, 'B c ϋΒ / ^ .re ^ 』 TK Xing 11 is cyclic, that is, R is selected from the group consisting of C3-1Q carbocyclic groups, 3-14 arylene groups, and RC systems. It is selected from the group consisting of 〇3.10 carbocyclic group μ...a 4-membered heterobasic group, C...aryl group and 5_14j gan, Q —-14 member heterocyclic group, c6. group and 5-14 membered heteroaryl group” In the second embodiment, RC is a group having two carbon atoms of 156069.doc -96·201144296 or more. In certain embodiments, RC is a group having three or more carbon atoms. In certain embodiments, Rc is a group having 4 or more carbon atoms. In certain embodiments, it is preferably an unsubstituted cyclic group. In certain embodiments, the ring is ring-shaped and Rc is acyclic, that is, selected from the group consisting of a 6-丨0 carbocyclic group, a 3-14 membered heterocyclic group, a fluorene 4 aryl group, and a 514 membered heteroaryl group. And Rc is selected from -OH, -ORCi, -0N(RC2)2, _n(rC2)2, φ -C(=0)RC1 ' -CHO ' -C02Rc1 &gt; -C(=0)N(RC2 ) 2 x -C(=NRC2)〇rc1 . -C(=NRC2)N(RC2)2, -S02RC1, -S(=0)RC1, _si(RC1)3, Ci i〇alkyl, Cb10 perhalogen Alkyl, C2_10 alkenyl, C2. decynyl, 3-14 membered heteroaliphatic, wherein RC1 and RC2 are as defined above and herein. In certain embodiments 'R' is an acyclic group having 2 or more carbon atoms. In some embodiments, 'R is an acyclic group having 3 or more carbon atoms. In certain embodiments, Rc is an acyclic group having 4 or more carbon atoms. In certain embodiments, R.sup.c is an unsubstituted acyclic group. • In certain embodiments, the ^ and # are independently selected from the group consisting of C6-14 aryl and 5-14 membered heteroaryl. In certain embodiments, the ruler is a C6_14 aryl group and the ^^ is a c614 aryl group or a 5-14 membered heteroaryl group. In certain embodiments, the ruler is a 5-14 membered heteroaryl&apos; and RB is a C6_u aryl or a 5-14 membered heteroaryl. In certain embodiments, RA is aryl or 5-14 membered heteroaryl, and 1 is (6-14 aryl. In certain embodiments, RA is CVu aryl or 5-14 member Aryl, and rb is a 5-14 membered heteroaryl. In certain embodiments, both 1 and 1 are c614 aryl. In certain embodiments, 'R and R are both stable (Cearyl) In certain embodiments, rA is 匸6 14 156069.doc •97· 201144296 aryl and rb is c3_丨〇 carbocyclyl. In certain embodiments, RAS C6-M aryl and RB are 5-14 membered heteroaryl. In certain embodiments, ... is 6- to 4 aryl and 1 is 3-14 membered heterocyclyl. In certain embodiments, 11 is (6- 14 aryl and RB&amp;RC are joined together with the nitrogen (N) atom to which each is attached to form a 5-14 membered ring. In certain embodiments, both 1 and 118 are 5-14 membered heteroaryl groups. In some embodiments, the ruler is a 5-14 membered heteroaryl group and is a heptacarbyl group. In certain embodiments, the ruler is a 5-14 membered heteroaryl group and is a &quot;aryl group. In certain embodiments, Rg 5-14 is heteroaryl and rb is a 3-14 membered heterocyclyl. η In certain embodiments, 1^ is 5-14 membered heteroaryl, and rB&amp;rC and each The nitrogen (N) atoms to which they are attached are joined together to form a 5-14 membered ring. In certain embodiments, the 'compound is a compound of formula (U):

Or a pharmaceutically acceptable form thereof; wherein Rc, WR^WR^WR, Wj4 w ^ 'W-R5' W-R6 - W-R7, W-R8, W_r9 and W-RiQ are as described above and herein definition. In certain embodiments, the rule 6, (11), R, R8, R9, and R10

The lesser one is as defined above and herein. The group I-L-Rh is in some embodiments 156069.doc •98. 201144296, in the Chinese version of the formula (11), r7, r8, r^r10 At least one of them is additionally selected from the group _rE as defined above and herein. In certain embodiments, the compound is a compound of formula (Π-a), (ΙΙ-b) or (II-c): R2

R2

R2

(II-c) or a pharmaceutically acceptable form thereof; wherein Rc, W-R1, W-R2, W-R3, W-R4, W-R5, W-R7, W-R8, W-R9 and W-R1G is as defined above and herein. In certain embodiments, at least one of formula (II-a), (II_b) or (11_magic ruler 7, R9 156069.doc.99. 201144296 and R10 is as defined above and herein. a group _lrD. In certain embodiments, at least one of the formula (Π-a), (ΙΙ-b) or (II-C) &lt; R7, R8, ul. 9 and R 丨 is additionally selected from, for example The groups defined above and herein are: in certain embodiments, the compound is a compound of formula (III):

Or a pharmaceutically acceptable form thereof; wherein Rc, R1, R2, R3, R4, r5, W_R6 w r7 w_r8, W-R9 and W-R1G are as defined above and herein. In certain embodiments, at least one of r6, R7, r8, R9, and r1〇 of the compound of formula (III) is a group _lrD as defined above and herein. In certain embodiments, R6, r7, r8, r9&amp;r1 (^2s: one of the compounds of formula (III) is additionally selected from the group _rE as defined above and herein. In certain embodiments The compound is a compound of the formula (I„-a), (in_b) or (m_c):

156069.doc •100- 201144296

R2

R2

Or a pharmaceutically acceptable form thereof; wherein RC, R1, R2, R3, r4, r5, wr7, wr8, WR9 and W-R1G are as defined above and herein. In certain embodiments, at least one of Formula (HKa), (I] tI_b), or (iii_c) 2R7, R8, R9, and R10 is a group _lrd as defined above and herein. And X. rE. In a practical example: the compound is a compound of formula (IV):

156069.doc •101 - 201144296 or a pharmaceutically acceptable form thereof; wherein RC, ruler, 2 - R R, R, R5, R6, R7, r8, RlRi are as defined above and herein. i In some embodiments, R6, R7, R8, mRi of the formula (!V). To the extent that the group is _l rD as defined above and herein. In certain embodiments, at least one of R6, r7, r8 9 R, and R of formula (IV) is additionally selected from the group consisting of the radicals rE as defined herein. In certain embodiments, it is independently H, Cl•Wiki, Cm. Alkoxy groups &quot;aryloxy, cn, _s〇2n(rA7)2, _s〇2RAi_s〇2C)rA6; rG is unsubstituted % alkyl or unsubstituted carbocyclic group; MU is independently selected From H, Cmo alkyl, (: 丨... alkoxy, (: 6_14 aryloxy, c〇〇H and _c〇2RA6. In certain embodiments, RLR5 is independently HH methoxy, (3) and SOzMe; Rc is an unsubstituted Ci_3 alkyl or unsubstituted cycloalkyl; and R6-R10 are independently selected from H, methyl, methoxyphenoxy, c〇〇h and C02Me. In some embodiments, the compound is a compound of formula (IV_a), (IV_b), (Iv_c) or (IV-d): R2

R8 156069.doc -102- 201144296

(iV-d) wherein R1, R2, R3, or a pharmaceutically acceptable form thereof; R, R5, R6, R7, R8, R9 and R10 are as defined above and herein.

In certain embodiments, at least one of the 去ίτν , 7 R 八 UV-a), (IV_b) 4 (IV, c) 2R7, r8, R9, and R10 is a base as defined above and herein. Group LR ° In certain embodiments, R, R, R9 and Ri of formula (IV-a), (iv_b), or (iV-d). At least one of them is additionally selected from the group -RE as defined above and herein. 156069.doc • 103· 201144296 In one embodiment, provided herein is a compound of formula (IV-d) or a pharmaceutically acceptable form of C thereof. In one embodiment of the compound of formula (IV-d), R is hexadecyl or c: 3-1 carbon ring. In one embodiment, it is preferably ethyl, isopropyl, cyclopentyl or cyclohexyl. In another embodiment of the compound of formula (IV-d), R1&amp;R2 are each independently hydrogen, halogen, _CN, _0RA丨 or _S02RA1, wherein RA is broad

Oxy, -CN or -S02CH3.

Base or phenoxy. In certain embodiments, the compound is a compound of formula (V):

Or a pharmaceutically acceptable form thereof; R, R8, R9 and R10 wherein Rc, X, γ, z, Ri, R2, R3, r6 are as defined above and at least one of e R9 and R10 as defined herein. In some embodiments

In certain embodiments, R6, R7, r8, . of formula (V) is a group as defined above and herein, _l_rD 156069.doc -104· 201144296, R6, r7 of formula (v) At least one of r8, r9 and Ri〇 is additionally selected from the group consisting of the base-rE as defined above and herein. In certain embodiments, the compound is of the formula (v-a), (v-b) or (). Object:

R2

R2

Or pharmaceutically acceptable wherein Rc, X, Y, z, and herein are as defined herein. Forms; 玟1, H2, R3, R7, r8 R9 and R1() as above 156069.doc ' 105. 201144296 In certain embodiments, r7, R8 of formula (Va), (Vb) or (Vc), At least one of r9 and R10 is a group _lrD as defined above and herein. In certain embodiments, at least one of R7 'R8, uldent 9 and R of formula (Va), (yb) or (Vc) is additionally selected from the group -RE 如 as defined above and herein In the examples, the compound is a compound of formula (VI):

(VI) or a pharmaceutically acceptable form thereof; wherein RC, Y, R1, R2, R3, R6, r7, r8, R&gt; R10 are as defined above and herein. In certain embodiments, at least one of R6, R7, R8, R9, and R10 of formula (VI) is a group as defined above and herein. In certain embodiments, at least one of R6, R7, R8, R9 &amp; r10 of formula (VI) is additionally selected from the group _RE as defined above and herein. And R. 2〇rA6; rC is an unsubstituted alkyl group or an unsubstituted Gw carbocyclic group; and "汛^ is independently selected from h, Cl_10, CM alkoxy, c6-丨4 aryloxy , COOH and -C02RA6. In certain embodiments, RLR3 is independently corrected, methyl, methoxy, and cn; 156069.doc •106- 201144296

Rc is an unsubstituted C5.6 cycloalkyl group; and r6_Rig is independently selected from the group consisting of fluorene, methyl, decyloxy, phenoxy, COOH and CO2Me. In certain embodiments, the compound A - WX7T, ^ von (VI_a), (VI-b) or (VI-c):

R2

R2

R8 or its pharmaceutically acceptable form; Gan τ4·» T&gt; C -w.

Where R is defined. In certain embodiments, formula (VI_a),

R3, R7, R8, r9 and R1I are as defined above and herein as defined above and at least one of R7, R8, 156069.doc • 107· 201144296 R and R of (VM&gt;) or (VI_c) Group-L-Rd. In certain embodiments, at least one of formula (vl_a)' (vi_b) or (vi_#r7, R, R, and R towels is additionally selected from the group -RE as defined above and herein. Exemplary compounds are exemplified The compounds are illustrated in the examples and are listed in Tables, Tables 2, 3 and 4 provided therein. In certain embodiments, the compound of formula (1) is selected from the list, Table 2, Table 3 or Any of the compounds provided in Table 4. In certain embodiments, the compound of formula (1) is selected from any of the compounds provided in Table 1. In certain embodiments, Formula (1) is selected from Table 2. Any of the compounds provided. In certain embodiments, the compound of formula (I) is selected from any of the compounds provided in Table 3. In certain embodiments, the compound of formula (I) is selected from those provided in Table 4. Any compound. In certain embodiments, the compound of formula (1) is selected from any of the compounds provided in Table 2 or Table 3. In certain embodiments, the compound of formula (1) is selected from Table or Table 2. Any of the compounds provided. In certain embodiments, the η of formula (1) is known to be selected from any of the compounds provided in Table 1 or Table 3. In certain embodiments, the 'compound of formula (I) is selected from any of the compounds provided in Table! or Table 4. In certain embodiments, the compound of formula (I) is selected from Table 2 or Table 3. Any of the compounds. In certain embodiments, the compound of formula (1) is selected from any of the compounds provided in Table 2 or Table 4. The activity provided by the FASNNADPH depletion assay is in Tables, Tables 2, 3, and Tables. 4 is indicated by an asterisk (*), where t "A*" means that 仏 is 6〇_ or less. "B*" means that iCm is 6〇nM to include 25〇nM. 156069.doc 201144296, "C*" means that the IC50 is a compound including 25 〇 nM or more to 1000 nM 'D*' means that the ICsg is a compound including 1 〇〇〇 nM or more to 10 000 nM, and "E" *" means 1 (:5() is 1〇, the compound above, as measured by the assay. The activity provided by the FASN flashing near Fiashplate assay is provided in Table 1, Table 2, Table 3 and Table 4. "A" means 1 (5 〇 is a compound of 15 nM/mL or less, "B" means iCw is a compound including 15 nM to 1 〇〇 nM, and "C" means IC 5〇 is a compound including 1〇〇nM or more to 2〇〇nM, and “D” means 1 (:5〇 is a compound including 2〇〇nM or more to 5〇〇〇nM; and “E” system Refers to a compound above nM, as determined by the assay. In some embodiments, the compound of formula (I) is active as "A", "A*", "B" provided in Table 2 or Table 3. Any compound of "B*", "C" or "c*". In certain embodiments, the compound of formula (1) is active "A" or "provided" in Table 丨, Table 2 or Table 3. Any compound of A*". In certain embodiments, the compound of formula (I) is any compound having activity "B" or "B*" as provided in Table 丨, Table 2 or Table 3. In certain embodiments, the compound of Formula (I) is any compound having activity rc" or "c*" as provided in Table 1, Table 2, or Table 3. In certain embodiments, the compounds provided herein include Any compound which is substituted by the group _l_rD as defined above and herein and which has the activity "A", "a*", "B" or "B*" provided in Table 丨, Table 2 or Table 3. For example, in certain embodiments, the compound of formula (I) is a compound selected from the group consisting of: 156069.doc 201144296

156069.doc •110- 201144296

156069.doc -Ill - 201144296

156069.doc 112- 201144296

N(S02Me)2

156069.doc -113 - 201144296

MrCC N=N / , 〇Me

Et

C(0)NHEt

156069.doc •114- 201144296

156069.doc -115- 201144296

F

156069.doc •116· 201144296

Ν=Ν λΛ

iPr • C(0)NH2

156069.doc •117· 201144296

156069.doc • 118· 201144296

C〇2Bn

PhO, F

156069.doc -119- 201144296

156069.doc -120- 201144296

156069.doc -121 - 201144296

ο

F

OMe

156069.doc •122· 201144296

F

OMe

F

O _ OnBu ΛΛ N=N / OMe Et

C02H 156069.doc •123· 201144296

F

F

156069.doc •124· 201144296

F F

156069.doc -125- 201144296 or its pharmaceutically acceptable form. In certain embodiments, the compound of formula (I) is a compound selected from the group consisting of:

156069.doc -126- 201144296

F F

F

156069.doc 127- 201144296 In other embodiments the compound of formula (i) is a compound selected from the group consisting of:

156069.doc -128 201144296

F

Or a pharmaceutically acceptable form thereof.

2. Pharmaceutical Compositions and Formulations In certain embodiments, provided herein are pharmaceutical compositions comprising at least a compound of formula (I) or a pharmaceutically acceptable pharmaceutically acceptable excipient thereof. $式和-或夕夕 In some embodiments, the singer + one is for a pharmaceutical composition, which includes the medical doctor: the second is = 3 or the table 4: the provided formula (1) (4) In other embodiments: two: a plurality of pharmaceutically acceptable forms, at least one of the pharmaceutical compositions of Table I, comprising the activity provided by Table 2 or Table 3, "a, 156069.doc • 129. 201144296 "A*", "B" or "B*" of the formula (1) or its pharmaceutically acceptable form and/or a variety of pharmaceutically acceptable excipients: In this case, provided - A pharmaceutical composition comprising, as defined in Table 2 or Table 3, an active "A" or "/, such as Table 1, or a pharmaceutically acceptable form thereof, and/or a plurality of medicines Excipients. As described above, the pharmaceutical compositions provided herein may comprise an acceptable excipient. As used herein, it includes any solvent and diluent suitable for the particular agent. Or other liquid vehicle, dispersion or suspension, surfactant, isotonic agent, _ or emulsifier, preservative, solid binder, Slip agents and the like. Pharmaceuncal Sciences, , £ w ^ PUbllShmg C〇., Ε_η, Pa., 1 _) discloses various pharmaceutically acceptable excipients for the preparation of pharmaceutically acceptable compositions and preparation thereof Known technology. Unless any conventional excipient medium is incompatible with the compounds provided herein, such as to produce any undesirable biological effects or otherwise otherwise deleteriously interact with any other component of the pharmaceutically acceptable composition. The use of an excipient; the letter is enclosed in the fan of the present invention. Some examples of pharmaceutically acceptable excipients include, but are not limited to, ionomers, oxidized acid; stearic acid; egg phosphatase, such as human serum albumin; a buffer substance such as phosphate, glycine, sorbic acid or potassium sorbate; a mixture of saturated plant fatty acids, water, salts or electrolytes, such as protamine su, Disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc 156069.doc 201144296 salt; colloidal cerium oxide; magnesium tridecanoate; polyvinylpyrrolidone; polyacrylate, wax, polyethylene-polyoxypropylene Block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and horse starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and acetate Powder; tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppositories; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, eucalyptus oil, corn oil and soybean oil; , such as propanol or polyethylene glycol; esters, such as ethyl oleate and ethyl laurate oxime agar: buffers, such as magnesium hydroxide and aluminum hydroxide, alginic acid, non-pyrogenic water, isotonic physiology Saline solution, Ringer's solution (8) to ~SQluti〇n), ethanol and acid salt buffer solution; and other non-toxic compatibility (four) agents, such as sodium lauryl sulfate and magnesium stearate; and according to the judgment of the blender, Coloring

Agents, release agents, coated enamels, sweeteners, flavoring and flavoring agents, preservatives and antioxidants may also be present in pharmaceutically acceptable compositions C

In some embodiments, the compound of formula (1) is from about 0.01 mg/kg to about 2 mg/kg, such as about (M mg/kg to about 1 Torr, further such as from about 5 mg/kg to about 50 mg/kg. The “individuals” that are intended to be cast include (but are not limited to) humans (ie males or women of any age group, such as pediatric individuals (eg infants, children, youth or adult individuals (eg young people, middle-aged Human or elderly)) and/or other primates (eg, stone crab, wolf, wolf); mammals, including related mammals, such as cattle, pigs, horses, sheep, goats, and /or dogs; and/or poultry 'including commercially relevant poultry such as chicken, duck, goose and / 156069.doc 131 · 201144296 Formulations of the pharmaceutically acceptable compositions described herein may be in pharmacological techniques Prepared by any method known or developed in the future. In general, the methods of preparation comprise the steps of associating a compound of formula (I) with one or more pharmaceutically acceptable excipients, if necessary and / Or forming and/or packaging the product as needed Single or multiple dose units. The pharmaceutical compositions provided herein can be prepared, packaged, and/or sold in bulk in a single unit dosage form and/or in a single unit dosage form. As used herein, "unit dose" is intended to include The individual amount of the pharmaceutical composition of at least one compound of formula (I). The amount of the compound of formula (I) is generally equal to the dose of the compound of formula (I) to be administered to the individual and/or a suitable fraction of such dose, such as One-half or one-third of the dosage. The relative amounts of the compound of formula (I), pharmaceutically acceptable excipients and/or any other ingredients in the pharmaceutical compositions provided herein will depend on the identity, body size and And/or the condition varies, and further varies depending on the route the composition is intended to be administered. For example, the composition may comprise from 0.1% to 100% (w/w) of the compound of formula (I). In some embodiments, The pharmaceutically acceptable excipient is at least 95%, 96%, 97%, 98%, 99% or 100% pure. In some embodiments, the excipient is approved for human use and for use by livestock. In some embodiments, excipients It has been approved by the United States Food and Drug Administration. In some embodiments, the excipient is of pharmaceutical grade. In some embodiments, the excipient meets the United States Pharmacopoeia (USP), European Pharmacopoeia (EP), British Pharmacopoeia and / 156069.doc -132 - 201144296 or International Pharmacopoeia standards. Pharmaceutically acceptable excipients for the manufacture of pharmaceutically acceptable compositions include, but are not limited to, inert diluents, dispersing agents and/or granulating agents, surfactants and/or emulsifiers, Degreasers, binders, preservatives, buffers, lubricants and/or oils. One or more such excipients may optionally be included in the formulation. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and perfuming agents may be present in the pharmaceutically acceptable compositions, as judged by the formulator. Exemplary pharmaceutically acceptable excipients include, but are not limited to, diluents such as carbonic acid, sodium carbonate, calcium citrate, dibasic phosphate, sulfuric acid, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, fiber , microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and the like, and combinations thereof. Exemplary granulating and/or dispersing agents include, but are not limited to, horse macadamia starch, corn house powder, tapioca starch, sodium starch glycolate 'clay, alginic acid, guar gum, citrus pulp (citrus) Pulp), fat-filled, bentonite, cellulose and wood products, natural sponges, cation exchange resins, carbonates, citrates, sodium carbonate, cross-linked poly(vinylpyrrolidone) (crospovidone) Carboxymethyl starch sodium (sodium starch glycolate), carboxymethyl cellulose, croscarmellose sodium (croscarmellose), methyl cellulose, pregelatinized starch ( Starch 15〇〇), microcrystalline powder, water-insoluble starch, slow-base cellulose, magnesium alumite (Veegum), sodium lauryl sulfate, quaternary compound, etc., and combinations thereof 0 156069.doc -133- 201144296 Exemplary surfactants and / or emulsifiers include, but are not limited to, natural emulsifiers (such as acacia, agar, alginic acid, sodium alginate, tragacanth, kudu Chondrux, cholesterol, sanxian gum (xanth An), pectin, gelatin, egg yolk, casein, lanolin, cholesterol, wax and lecithin), colloidal clay (eg bentonite [aluminum citrate] and vegas [magnesium citrate]), long-chain amine Base acid derivatives, high molecular weight alcohols (such as stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate Ester and propylene glycol monostearate, polyvinyl alcohol), carbomer (such as carboxy xy polymethylene, polyacrylic acid, acrylic polymer and carboxyvinyl polymer), horn Carrageenan, cellulose derivatives (such as sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), Sorbitan fatty acid esters (eg, polyoxyethylene sorbitan early lauric acid from [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Spail 4〇], dehydrated sorbus Sugar alcohol monostearate [Span 60], sorbitan tristearate [Span 65], glycerol monooleate, sorbitan monooleate [Span 80], polyoxyethylene Esters (eg polyoxyethylene monostearate [Myrj 45], polyoxyethylene ratified cannabis oil, polyethoxylated sesame oil, polyglycolic stearic acid and Solutol), sucrose fatty acid esters, polyethylidene Glycol fatty acid esters (eg Cremophor), polyoxyethylene ethers (eg polyoxyethylene lauryl ether [BHj 3〇]), poly(vinyl pyrrolidone), diethylene glycol monolaurate, triethanolamine Oleic acid ester, sodium oleate, oleic acid, ethyl oleate, oleic acid, lauric acid vinegar, 156069.doc -134- 201144296 sodium lauryl sulfate, Pluronic F 68, Poloxamer 188 'Citrimonium Bromide), cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and the like and/or combinations thereof. Exemplary binders include, but are not limited to, starch (eg, corn starch and starch paste), gelatin, sugar (eg, sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural And synthetic gums (such as gum arabic, sodium alginate, irish moss extract, panwar gum, ghatti gum, isapol husk mucus, carboxy thiol Cellulose, mercapto cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), Magnesium aluminum citrate (Vigm) and pine polysaccharide (larch arabogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic salt, agglomerate, polyacrylic acid vinegar, hydrazine, water , alcohols, and the like, and combinations thereof. Exemplary preservatives can include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary anti-deuteration agents include, but are not limited to, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyphenyl ether, butylated hydroxytoluene, monothioglycerol, metabisulfite Potassium, propionic acid, propyl gallate, sodium ascorbate, sodium hydrogen sulfite, sodium metabisulfite and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, ethylenediaminetetraethanoin, ethylenediaminetetraacetic acid, edetic acid, and antibutanic acid. , benzoic acid, phosphoric acid, sodium edetate, tartaric acid and 156069.doc • 135· 201144296 Ethylene diamine tetraacetate. Exemplary antimicrobial preservatives include, but are not limited to, benzyl chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetyl chloride Pyridine, chlorhexidine, oxybutanol, gas cresol, chloroxylen〇l, cresol, ethanol, glycerol, heptetidine (hexetidiny, imidazolidinyl (imidurea), Phenol, phenoxyethanol, phenylethanol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, Ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate and sorbic acid. Exemplary alcohol preservatives include but are not limited to Ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, butyl alcohol, hydroxybenzoate and phenylethanol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E ,β-carotene( Beta-carotene), citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid and phytic acid. Other preservatives include (but are not limited to) Shengyue Hope, B Ssl age, and acid deferoxime mesylate ), &gt; scented bismuth, butylated benzoyl sulphate (bha), butylated trans-toluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate ( SLES), sodium hydrogen sulfite, sodium metabisulfite, sulfite desulfurization, metabisulfite slant, Glydant P1US, Phen〇nip, decyl hydroxybenzoate, Germall 115, Germaben „, Ne〇1〇ne In some embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. Exemplary buffers include, but are not limited to, citrate buffer solution, acetic acid 156069.doc -136- 201144296 Salt buffer solution, phosphate buffer solution, ammonium sulfate, calcium carbonate, calcium chloride, sputum acid, calcium glubionate, calcium gluceptate ), gluconic acid, D-gluconic acid, glycerol acid, calcium lactate, propionic acid Calcium levulinate, valeric acid, acid-storing, acid-filling, acid-feeding, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium Mixture, hydrogen phosphate, If, dihydrogen phosphate, phosphoric acid clock mixture, sodium acetate, sodium bicarbonate, sodium vapor, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium sulphate mixture, blood-supplement Oxymethamine, oxyhydrin, aluminum hydroxide, alginic acid, non-pyrogenic water, isotonic saline, Ringer's solution, ethanol, etc., and combinations thereof. Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, cerium oxide, talc, malt, glyeeryl behanate, hydrogenated vegetable oil, polyethylene glycol, Sodium benzoate, sodium acetate, sodium sulphate, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and the like, and combinations thereof. Exemplary oils include, but are not limited to, almond oil, almond oil, avocado oil, babassu oil, lemon oil, biack current seed oil, sorghum, juniper oil, golden chrysanthemum Oil, canola oil, coriander oil, brazil palm oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, eucalyptus oil, eucalyptus oil Evening primrose oil, fish oil, linseed oil, geranyl oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba (j〇j〇ba) oil , kukui nut oil, lavenderin oil, lavender oil, lemon 浐 156069.doc -137- 201144296 oil, litchi cubeba oil (macademia nut) oil, broccoli Cai Oil, Mango Xuan Oil, white awning flower (meadowfoam seed) oil, Shao oil, meat and vegetable oil, olive oil, orange oil, orange roUghy oil, palm oil, standard oil, Peach kernel oil, peanut oil, poppy seed oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, Sandalwood oil, camellia oil, savoury oil, sea buckthorn oil, sesame oil, shea butter oil, polyoxygenated oil, soybean oil, sunflower oil, tea tree oil, eucalyptus oil, tsubaki oil, vetiver Oil, walnut oil and wheat germ oil. Exemplary oils include, but are not limited to, succinate stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, diterpene Oxygen 360 (dimethicone 360), isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, polyoxyxylene oil, and combinations thereof. Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, micro-solutions, solutions, suspensions, syrups and granules. In addition to the compound of formula (I), the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, Benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethyl decylamine, oil (in detail, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil) , glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the combinations provided herein are mixed with the following solubilizing agents: such as Cremophor, alcohol, oil, modified oil, 156069.doc 201144296 alcohol, polysorbate , cyclodextrins, polymers and combinations thereof. For example, in certain embodiments, an oral suspension can comprise at least one compound of formula (1) and carboxymethylcellulose. In some embodiments, the oral suspension can comprise at least one compound of formula (1), carboxymethylcellulose, and DMSO. In one embodiment, the oral suspension can comprise a compound of formula (I) and 0.5. / 〇 carboxymethyl cellulose / 5% DMSO / 0.5% Tween (PKPD #5). In another embodiment, the oral suspension may comprise a compound of formula (1) and about G1% h% of slow methylcellulose. • The 'primary preparations (eg sterile injectable aqueous or oily suspensions) can be suitably dispersed according to known techniques. Or humectants and suspending agents to prepare. The bacterium can be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in u butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution (U'S.P.) and isotonic sodium solution. In addition, sterile non-volatile oils are conventionally employed as a solvent or suspending medium. For this purpose, any mild, non-volatile oil may be employed, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The beta priming formulation can be sterilized, for example, by filtration through a bacterial dressing filter or by sterilizing in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile prior to use. Injectable medium. The injectable compound may contain from about 1 to about 5% w/w of the formula (1). Compound 0 is a prolonged drug action, and it is often desirable to slow the absorption of the substance from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material having a poor water solubility. The absorption rate of the drug depends on the dissolution rate of the substance 156069.doc • 139· 201144296, and the dissolution rate may be determined by the crystal size and the crystalline form, or the delayed absorption of the parenterally administered drug form may be This is achieved by dissolving or suspending the drug in an oil vehicle. Compositions for rectal or vaginal administration are usually suppositories which can be prepared by admixing the conjugates provided herein with a suitable non- irritating excipient such as cocoa butter, polyethylene glycol or suppository wax. The suppositories are solid at ambient temperature but are liquid at body temperature and thus melt in the rectum or vaginal cavity and release the compound of formula (I). Solid dosage forms for oral administration include capsules, lozenges, pills, powders and granules. In such solid dosage forms, the compound of the formula is admixed with at least one pharmaceutically acceptable inert excipient such as sodium citrate or dicalcium phosphate and/or below: a) a filler or extender such as starch, Lactose, sucrose, glucose, mannitol and citric acid; b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain salts and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption enhancers such as quaternary ammonium compounds ;g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene Glycol, sodium lauryl sulfate, and mixtures thereof. The dosage form may contain a buffer in the case of capsules, troches, and pills. A unit dosage formulation (e.g., a tablet) may contain from about 0. 05% to about 95% by weight of a solid composition of a similar type of Compound 0 of Formula (I) useful as a pharmaceutically acceptable ingredient 156069.doc • 140· 201144296 Soft and hard-filled fillers in gelatin capsules such as nipples and still molecular weight polyethylene glycols and the like. The solid dosage forms of the spinners, dragees, capsules, pills, and granules prepared may have coatings and shells such as enteric coatings and other coatings well known in the art. The solid dosage forms may optionally comprise an opacifying agent and may have a composition which only releases the compound of formula (I). In some embodiments, the compound of formula (1) can be released in a delayed manner as appropriate in a certain sigma file of the intestine. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose and high molecular weight polyethylene glycols and the like. The compound of formula (I) may be in microencapsulated form with one or more pharmaceutically acceptable excipients as described above. In such solid dosage forms, the compound of formula (1) is mixed with: &gt; an inert diluent such as sucrose, lactose or starch. These dosage forms may contain, in addition to inert diluents, other substances, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, according to common practice. In the case of capsules, lozenges and pills, the dosage form may comprise a buffer. Dosage forms for topical and/or transdermal administration of a compound of formula (1) as provided herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. In general, the compound of formula (j) is admixed under sterile conditions with one or more pharmaceutically acceptable excipients and/or any preservatives and/or buffers which may be required. In addition, the use of transdermal patches is encompassed herein, and such transdermal patches often have the added advantage of controlling the delivery of the compound of formula (1) 156069.doc-141 - 201144296 to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispersing a compound of formula (1) in a suitable medium, by providing a rate controlling film and/or by dispersing a compound of formula (1) in a polymer matrix. And / or in the gel to control the rate. Suitable devices for the delivery of the pharmaceutically acceptable intradermal compositions described herein include a needle device such as that disclosed in U.S. Patent Nos. 4,886,499, 5,519,521, 5,328, 4,83, 5,527,288, 4,270,537, 5,015,235, 5,141,496, 5,417,662. Narrator. The intradermal composition can be administered by a device that limits the effective penetration length of the needle into the skin, such as those described in PCT Publication No. 99/3485, and its functional equivalents. A jet injection device is suitable which delivers a liquid vaccine to the dermis via a liquid jet injector and/or via a needle that pierces the stratum corneum and produces a jet that reaches the dermis. Jet injection devices are described, for example, in U.S. Patents 5,480,381, 5,599,302, 5,334,144, 5,993,412, 5,649,912, 5,569,189, 5,704,911, 5,383,851, 5,893,397, 5,466,220 '5,339,163 &gt; 5,3 12,335 '5,503,627 '5,064,413 '5,520,639, 4,596,556, 4,790,824, 4,941,880, 4,940,460 and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particle transfer devices are suitable which use a compressed gas to promote the passage of the vaccine in powder form through the outer layer of the skin to the dermis. Alternatively or additionally, conventional syringes can be used in the traditional mantoux method of intradermal administration. Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as elixirs, lotions; oil-in-water and/or water-in-oil emulsions such as creams, ointments and/or pastes. And/or a solution; and/or a suspension which may be administered topically may, for example, comprise from about 1% to about 10% (w/w) of formula (I) compound 156069.doc.142. 201144296 However, the concentration of the compound of formula (i) can be as high as the solubility limit of the compound of formula (i) in a solvent. In some embodiments, a formulation that can be administered topically can comprise, for example, about 1°/. Up to about 9% (W/W) of a compound of formula (I), such as from about ^ to about (iv) (w/w), further such as from about 1% to about 7% (w/w), further such as about j 0/〇 Up to about 6% (w/w), further such as from about 1% to about 5% (w/w), further such as from about 1% to about 4% (w/w), further such as from about 1% to about 3% ( w/w) and further such as about 1. /. To about 2. /. a compound of the formula (w/w). For partial investment

The formulation may further comprise one or more other pharmaceutically acceptable excipients as described herein. The pharmaceutical compositions provided herein can be prepared, packaged, and/or sold in a formulation suitable for administration to the lung via the buccal cavity. Such a formulation may comprise dry particles comprising a compound of formula (I) and having a diameter of from about 5 to about 7 nanometers, such as from about 2 to about 6 nanometers, further such as from about 2 to about 5 nanometers and further such as about 3 To, the force is not within the range of 4 meters. The pharmaceutical compositions are preferably in the form of a dry powder for administration using a device comprising a dry powder reservoir which can be introduced into a propellant stream to disperse the powder and/or using an auto-propelled solvent/powder dispensing container, such as containing dissolution and/or suspension. The attack of the compound of formula (1) in a low hysteresis propellant in a sealed container. The powders comprise particles in which at least 98% of the particles (by weight) have a diameter greater than 〇5, a a-r _ , no ..., to 95 〇 / 〇 particles (in number) having a diameter less than 7 Nai Lai. The formula is ··, in the "one, 乂95 ° / ❶ particles (by weight) diameter greater than 1 nm and at least 90% of the zipper (in number) diameter is less than 6 nm. Dry powder combination The material may include a liquid removal agent... including a solid fine powder diluent (such as sugar) and may be provided in a unit dosage form. The liquid low boiling point propellant having a boiling point below 65 T at dry m is generally included at atmospheric pressure 156069.doc • 143· 201144296 In general, the 'propellant may constitute from 5% to 99.9% (w/w) of the pharmaceutical composition' and the active ingredient may constitute 〇 to (w/w) of the pharmaceutical composition. The propellant may further comprise other Excipients, such as liquid nonionic surfactants and/or solid anionic surfactants and/or solid diluents (which may be of the same size as the particles comprising the compound of formula (I)). The pharmaceutical composition for pulmonary delivery may provide a compound of formula (1) in the form of a solution and/or suspension droplets. The formulation may comprise an aqueous and/or dilute solution of the compound of formula (I) and/or Or suspension (as the case may be (4)) , packaged and/or sold, and may be administered using any spray and/or nebulizing device. The formulations may further comprise one or more other excipients, including (but not (iv)) flavoring agents (such as sugar (4) ), a volatile oil, a buffer, a surfactant, and/or a preservative (such as methyl benzoate). The droplets provided by this route of administration may have an average diameter in the range of from about 10 to about 200 nm. The formulations described herein as suitable for pulmonary delivery are suitable for intranasal delivery of the pharmaceutical compositions provided herein. Another formulation suitable for intranasal administration is a coarse powder which comprises a compound of formula (1) and has an average particle size. It is about 2 to 5 micrometers. Such a formulation is administered, for example, by rapid inhalation through the nasal passages from a powder container held close to the nostrils. Formulations suitable for nasal administration may, for example, contain about a few 1% (w/d to drive (W/w) a compound of formula (1), and may comprise - other excipients as described herein. The pharmaceutical compositions provided herein may be suitable for blending with 唆 frequency Preparation, packaging and/or sale of the form. Such as the use of conventional methods of money and / or oral form, and can be, for example, 156069.doc • 144 · 201144296 匕a.1 to 20 / 〇 (w / w) of the formula (1) compound, the rest contains oral a soluble and/or degradable composition and optionally one or more other pharmaceutically acceptable excipients as described herein. In some embodiments, suitable for transposition and inclusion may comprise Powders and/or aerosolized and/or atomized ☆ liquids and/or suspensions of the compounds of formula (1). The powdered, aerosolized and/or atomized formulations may have a dispersion of from about 1 to about 1 when dispersed. The average particle size and/or droplet size in the range of about 2 nanometers, and may further comprise - or a plurality of other pharmaceutically acceptable excipients as described herein. The pharmaceutical compositions provided herein can be prepared, packaged, and/or sold in a form suitable for administration to the eye. Such formulations may, for example, be in the form of eye drops, including, for example, 0_i/丨·0% (w/w) of a solution and/or suspension of a compound of formula (1) in an aqueous or oily liquid carrier. The drops may further comprise a buffer, a salt and/or one or more other pharmaceutically acceptable excipients as described herein. Other suitable formulations for ocular administration include formulations containing a compound of the formula in the form of a microcrystalline form and/or a liposome formulation. Ear drops and/or spring or eye drops are encompassed within the mouth of the present invention. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st Edition (Lippincott Williams &amp; Wilkins, 2005). While the description of the pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to all classes of animals. Modification of pharmaceutical compositions suitable for administration to humans to facilitate their suitability for administration to a variety of animals is well understood, and general veterinary pharmacologists may use only conventional (if any) 156069.doc • 145-201144296 Design and/or perform this modification. Further provided herein are kits comprising one or more compounds of formula (1) (or a pharmaceutically acceptable form thereof) and/or a pharmaceutical composition as described above. The kit is usually supplied in a suitable container (for example, a septum, plastic or cardboard package). In some embodiments, the kit can include - or a plurality of pharmaceutically acceptable excipients, pharmaceutical additives, therapeutically active agents, and the like as described herein. In certain embodiments, the kit can include components for proper administration, such as measuring cups, syringes, needles, cleaning aids, and the like. In certain embodiments, the kit can include instructions for proper administration and/or preparation for proper administration. The instructions will instruct the consumer or medical staff to administer the dosage form according to the mode of administration known to those skilled in the art. These kits can be packaged and sold in single or multiple kit units. An example of such a kit is the so-called foam package blister pack which is well known in the packaging industry and is widely used for encapsulating pharmaceutical unit dosage forms (tablets, sacs and the like). The blister pack is generally comprised of a sheet of relatively hard material covered by a drop of a preferred transparent plastic material. In the packaging process, a recess is formed in the plastic pig piece. The recess has the size and shape of the key or capsule to be packaged. Next, the toner or capsule is placed in the recess and the sheet of relatively hard material is sealed against the gusset on the opposite side of the plastic tab from the direction in which the recess is formed. Thus, the tablet or capsule is sealed in a recess between the plastic box and the sheet. The strength of the sheet allows pressure to be applied to the recess by hand, thereby forming an opening in the sheet at the recess, thereby removing the key or capsule from the blister pack. The tablet or capsule can then be removed via the opening. It may be necessary to provide a memory aid on the kit, for example, in the form of a key agent 156069.doc 201144296...etc. The second week, Monday, week or wins the digital form, whereby the numbers and The number of days (4) for the ingestion of the specified lozenge or capsule should be. Another example of such a memory aid is a print on a card, for example, as follows: "First week, Monday, star, etc. Memory aid--", "丨", 3⁄4 publications ^ His variations will be obvious. "Day Dose" may be intended to take a single-day lozenge or capsule or a number of pills or capsules.

3 &gt; Uses and treatments 7 7 As used herein, unless otherwise specified, the term "treatment" encompasses an action performed by an individual in the event of a specified disease, disorder or condition, which reduces the disease, condition or disease. The severity of the condition' or delay or slow the progression of a disease, condition or condition. As used herein, unless otherwise specified, the term "prevention" encompasses the action taken by an individual prior to the onset of a specified disease, disorder or condition which inhibits or reduces the severity of the disease's condition or condition. As used herein and unless otherwise specified, the term "management" encompasses preventing a disease, disorder, or condition in a given disease from recurring in an individual who has already suffered the disease, disorder, or condition, and/or prolonging the disease, condition, or condition. The individual of the condition is in a state of remission. These terms encompass the modulation of the threshold, development and/or duration of a disease or condition, or the manner in which an individual responds to a disease, disorder or condition. As used herein, &quot;inhibiting&quot; and &quot;inhibitor&quot; and the like terms refer to the ability of a chemical to reduce, slow, interrupt, or prevent the activity of a particular biological process in a cell (e.g., WFASN activity) relative to a vehicle. In certain embodiments, 156069.doc • 147- 201144296 inhibition reduces activity by 5%, 丨〇%, 15%, 20%, 25%, 30%, 35%, 4 compared to activity not inhibited. 〇%, 45%, 5%, 6%, 70%, 80%, 90% or more. As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound is sufficient to provide a therapeutic benefit in the treatment or management of a disease, disorder or condition, or to delay one or more symptoms associated with a disease, disorder or condition or Minimize these symptoms. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of a disease, disorder or condition. The term "therapeutically effective amount" can encompass an amount of a modified overall therapy that reduces or eliminates the symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent. As used herein and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder or condition or one or more symptoms associated with a disease, disorder or condition, or to prevent recurrence thereof. By prophylactically effective amount is meant an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder or condition. The term “preventive effective” can be used to improve the overall prevention or enhance the preventive efficacy of another preventive agent. 3 · 2 Examples In one embodiment, provided herein are methods of treating, preventing, and/or managing a fasn-mediated condition, disease, or condition comprising administering to a subject in need thereof at least one of a therapeutically or prophylactically effective amount A compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1) or a pharmaceutically acceptable form thereof. 156069.doc 201144296 In another embodiment, provided herein is a method of inhibiting FASN in an individual comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable form thereof Or a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable form thereof. In another embodiment, provided herein is a method of inhibiting FASN pathway activation in vitro or ex vivo, comprising reacting a FASN protein with at least one compound of Formula (I), or a pharmaceutically acceptable form thereof, or comprising at least one formula ( I) The pharmaceutical composition of the compound or a pharmaceutically acceptable form thereof is contacted in an amount sufficient to reduce activation of the FASN pathway. In another embodiment, provided herein is the use of at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, For treating a FASN-mediated condition, disease or condition in an individual. In another embodiment, provided herein is the use of at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (A) or a pharmaceutically acceptable form thereof, Used to make pharmaceuticals. In certain embodiments, the agent is suitable for treating a FASN mediated condition in an individual. The compound of formula (I) supplied herein may be an inhibitor of FASN. &quot;FASN mediated condition&quot; as used herein refers to a disease, disorder or condition that can be treated by inhibiting FASN activity. FASN-mediated conditions include, but are not limited to, hyperproliferative disorders; inflammatory conditions; obesity-related disorders such as, but not limited to, type 2 diabetes and fatty liver disease; microbial infections such as, but not limited to, morbid, Bacteria, fungi, parasites and protozoal infections; and their complications. 156069.doc 201144296 In certain embodiments, the FASN-mediated condition is a hyperproliferative disorder. In certain embodiments, the hyperproliferative disorder is cancer. To date, abnormal FASN activity has been observed in a variety of hyperproliferative disorders including, but not limited to: (i) Bladder cancer (see Visca et al, Jwiz'cancer Λα. (2003) 23:335- 339); (ii) Brain cancer (eg meningioma, see Haase et al., (2010) Advance Access 20 published on February 5, 10, 1-11; for example, glioma, see Zhao et al, 5r. 乂 Cancer (2006) 95: 869-878; for example, neuroblastoma, see Slade et al., and (2003) 23:1235-1243); (iii) breast cancer (see Alo et al., Cancer (1996) 77:474- 482; Pizer et al., Cawcer Λα. (1996) 56: 2745-2747; Pizer et al., Cawcer (2000) 60: 213-218; Milgraum et al., C7z·”. Cawcer /?1 to (1997) 3 : 2115-2120 ; Lupu and Menendez, V. (2006) 147: 4056-4066; Alo et al., Oncol. Rep. (2000) 7: 1383-1388; Wang et al., Cawcerle &quot; (2001) 167:99- 104; Liu et al., Mo/· Ciiwcer 77zer. (2008) 7:263-270; and Kuhajda et al., PAMS (2000) 97: 3450-3454; for example breast cancer, see Hennigar et al., 5/oc/n 'm. (1998) 1392:85-10 0 and Alii et al. (2005) 24:39-46); (iv) Colorectal cancer (see Rashid et al., 乂Ραί/ζο/. (1997) 150:201-208; Huang et al., fFoWfi? J (JaWroewiero/. (2000) 6:295-297; Zhan et al, C/zw· Cancer Res. (2008) 156069.doc -150- 201144296 14:5735-5742); (v) Esophageal cancer (see Nemoto) Et al., corpse (2001) 69:297-303); (vi) endometrial cancer (see Pizer et al., C&lt;3«cer (1998) 83:528-537; Pizer et al., /«ί. « /· Gy^ieco/· Ραί/ζσ/· (1997) 16:45-51 ; Lupu and Menendez, (2006)

147:4056-406; and Sebastiani et al., (9 «co/og_y (2004) 92:101-105); (viii) gastric cancer (see Kusakabe et al., (2002) 40:71-79); (ix) Gastrointestinal stromal tumors (see Rossi et al., 乂 α αί/ζο/. (2006) 209: 369-375); (X) Kidney cancer (eg Wilms' tumor), see Camassei et al., Med. corpse ei/iair. (2003) 40:302-308); (xi) liver cancer (see Evert et al., Invest. (2005) 85:99-108); (xii) lung cancer (see Piyathilake) Et al., Ραί/ζσΛ (2000) 31:1068-1073; and Visca et al., Λα. (2004) 24:4169-4173); (xiii) mesothelioma (see Gabrielson et al., Ca«cer Research (2001) 7:153-157); (xiv) multiple myeloma (see Wang et al., 乂Z/ze Sci B (2008) 9:441-447); 156069.doc -151 - 201144296 (χν) neuroblasts Tumors (see Slade et al., and ei. (2003) 23:1235-1243); (xvi) Oral cancer (see Krontiras et al., //eac/iVecA: (1999) 21:325-329; and Agostini et al. Oral Oncol. (2004) 40:728-735; see also oral squamous cell carcinoma (OSCC): Silva, etc. Human, (2007) 14: 376-382); (xvii) Insect cancer (see Pizer et al., Cawcer Λα. (1996) 56: 1189-1193; Alo et al., (9 «co/· and 叩. 2000) 7:1383-1388; Wang et al., (2005) 24:3574-3582; Gansler et al., Hum. Pathol. (1997) 2S:6S6-692 y AZhou^A&gt; Cancer Res. (2007) 2964- 2971); (xviii) Pancreatic cancer (eg, pancreatic adenocarcinoma, pancreatic ductal mucinous neoplasm (IPMN), see Walter et al., Cawcer V. Bz'omarAreri· Prev. (2009) 18:23 80-23 85 (xix) Vulvar Pagets disease (see Alo et al.'/ηί. J. Gynecol. Pathol. (2005) 24:404-408); (xx) Prostate cancer (see Pizer et al.) /Voc Jw. Career

Res. (2000) 41:655; Swinnen et al., /«,· J. Cancer (2002) 98:19-22; Epstein et al., t/ro/ogy (1995) 45:81-86; De Schrijver et al. Person, Cancer Λβ·?. (2003) 63:3799-3804; Pizer et al., /Vojiaie (2001) 47:102-110; Furuya et al., Λα. (1997) 17:4589-4593; Shurbajif A &gt; Hum. Pathol. (1996) 27:917-921; Migita et al.,··· (2009) 101:519-532; Rossi et al., Mo/. Cawcer (2003) 156069.doc -152- 201144296 1:707 -715; AShahf A » Hum. Pathol. (2006) 37:401-409); (xxi) retinoblastoma (see Camassei et al., /nvesiig. Opthalmol. Vis. Sci. (2003) 44:2399-2403 And Slade et al, Anticancer Res. (2003) 23:1235-1243); (xxii) soft tissue sarcoma (eg malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, See Takahiro et al., C&quot;«. Λα. (2003) 9:2204-2212);

(xxiii) Skin cancer (eg melanoma, see Innocenzi et al., ··· Cutan. Pathol. (2003) 30:23-28; Kapur et al., Modern Ραί/ιο/ο幻; (2005) 18:1107- 1112; and Carvalho et al., 乂 Cancer (2008) 123: 2557-2565); Bl (xxiv) thyroid cancer (see Vald et al., Ραί/ζ. (1999) 12:70A; Sekiguchi et al., P/mrmacoi/ Ier. (2001) 5 5:466-474; for example, papillary thyroid carcinoma (PTC), see Uddin et al, J. Clin. Endocrinol. Metab. (2008) 93: 4088-4097) ° Expected abnormal FASN activity in other It plays a role in hyperproliferative disorders. Exemplary hyperproliferative diseases, disorders, conditions, or cancers include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, angiosarcoma (eg, lymphangiosarcoma, lymphatic endothelial sarcoma, angiosarcoma), benign single gamma globulin Lesions, cholangiocarcinoma (eg cholangiocarcinoma), bladder cancer, breast cancer (eg breast adenocarcinoma, breast papillary carcinoma, breast cancer, breast medullary cancer), brain cancer (eg meningioma; glioma, eg astrocytes) Tumor, oligodendroglioma; neuroblastoma), bronchial carcinoma (eg bronchial carcinoma), cervical cancer (eg cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (eg, colon 156069.doc • 153· 201144296 intestinal adenocarcinoma), epithelial cancer, to perimembranous tumor, endothelial sarcoma (such as Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), intrauterine Membrane cancer, esophageal cancer (eg, esophageal adenocarcinoma, Barrett's adenocarinoma), Ewing sarcoma, familial eosinophilia, Gastric cancer (eg gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer, heavy chain disease (eg alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell temple Powdery degeneration, renal cancer (such as nephroblastoma (also known as Wilhelm's tumor), renal cell carcinoma), liver cancer (such as hepatocellular carcinoma (HCC), such as hepatocellular carcinoma, malignant liver cancer), lung cancer ( For example, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, white disease (such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia ( CML), chronic lymphocytic leukemia (CLL), lymphoma (eg Hodgkin lymphoma, non-Hodgkin lymphoma 'NHL), follicular lymphoma , diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), leiomyosarcoma (LMS), mastocytosis (eg, systemic mastocytosis), multiple myeloma (MM), bone marrow Dysplasia syndrome (mdS), Skin tumor, spinal cord proliferative disorder (MPD) (eg, polycythemia vera (pV), essential thrombocythemia (ET), unexplained bone marrow cell metaplasia (amm) (also known as myelofibrosis (MF)) , chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (Cnl), eosinophilic syndrome (HES), neuroblastoma, neurofibromatosis (eg type 1 Or type 2 neurofibromatosis (NF), schwannofibroma 156069.doc • 154- 201144296 (schwannomatosis), neuroendocrine carcinoma (eg gastrointestinal pancreatic neuroendocrine tumor (GEP-NET), carcinoid), osteosarcoma, Oral cancer (eg, oral squamous cell carcinoma (OSCC)), ovarian cancer (eg, cystadenocarcinoma, ovarian embryonal cancer, ovarian adenocarcinoma), vulvar Paget's disease, penis Paget's disease, papillary adenocarcinoma, Stem cancer (eg, glandular adenocarcinoma, intraductal papillary spotted tumor (IPMn)), pineal tumor, primitive neuroectodermal tumor (PNT), prostate cancer (eg, prostate adenocarcinoma), rhabdomyosarcoma, retina Blastoma, saliva Adenocarcinoma, skin cancer (such as squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma), small intestine cancer (such as appendix cancer), soft tissue sarcoma (such as malignant fibrous histiocytoma) (MFH) 'Heat sarcoma, malignant peripheral nerve sputum tumor (MPNST), chondrosarcoma, fibrosarcoma, mucinous sarcoma), sebaceous gland cancer, sweat gland cancer, synovial tumor, testicular cancer (eg, seminoma, testicular embryo cancer), Sickle adenocarcinoma (such as papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid cancer), and WaldenstrijoVs macroglobulinemia (&quot;WaldenstrijoVs macroglobulinemia). • In certain embodiments, the hyperproliferative disorder is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, endometrial cancer, gastric cancer, gastrointestinal matrix tumor, kidney cancer, liver cancer, lung cancer, mesothelial Tumor, multiple myeloma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, vulva, retinoblastoma, soft tissue sarcoma, skin cancer or squamous cell carcinoma. In certain embodiments, the cancer is selected from the group consisting of mesothelioma, multiple myeloma, neuroblastoma, Paget's disease, retinoblastoma, leukemia, myelodysplastic syndrome, or soft tissue sarcoma. 156069.doc -155- 201144296 In certain embodiments, the brain cancer is a meningioma, a glioma, or a neuroblastoma. In certain embodiments, the oral cancer is oral squamous cell carcinoma. In certain embodiments, the pancreatic cancer is a pancreatic adenocarcinoma or an intrapancreatic papillary mucinous tumor. In certain embodiments, the soft tissue cancer is a malignant fibrous histiocytoma, a liposarcoma, a malignant peripheral nerve sheath tumor, or a chondrosarcoma. In certain embodiments the 'skin cancer is melanoma. In certain embodiments, the thyroid cancer is papillary thyroid cancer. In certain embodiments, the FASN mediated condition is an inflammatory condition. The term "inflammatory condition" refers to a disease or condition characterized by one or more of the following symptoms: pain 'fever, redness, swelling, and loss of function." Inflammatory conditions are intended to cover inflammation associated with immune system disorders and associated with non-immune system disorders. Inflammation. Inflammatory conditions are intended to cover acute inflammation and chronic inflammation. To date, abnormal FASN activity has been observed in inflammatory bowel disease such as ulcerative colitis (see Consolazio et al., eg plus corpse plus h/ogy (2〇〇6) 126.113118).

Rashid et al. 乂 乂. J• Household Plus 0/· (1997) 150:201-208). Expected abnormal FASN activity plays a role in other inflammatory conditions. Exemplary inflammatory conditions include, but are not limited to, acne-associated inflammation, anemia (eg, regenerative anemia, hemolytic autoimmune anemia), asthma, arteritis (eg, polyarteritis, arteritis, nodular arteries) Periflammation, Takayasu's arteritis, arthritis (eg, crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and reed Arthritis (Reher, s 156069.doc • 156· 201144296 arthritis), ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune disease, allergies or allergic reactions, Alzheimer's disease ( Alzheimer's disease), atherosclerosis, bronchitis, bursitis, cancer, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, dermatomyositis, diverticulitis, diabetes (eg I Type 2 diabetes, type 2 diabetes), dermatitis, eosinophilic leukorrhea gastrointestinal disorders (eg eosinophilic eosinophilic esophagitis, eosinophilic eosinophilic gastritis Eosinophilic globulin gastroenteritis, eosinophilic leukemia, eczema, endometriosis, gastrointestinal bleeding, gastritis, gastroesophageal reflux disease (G〇RD or its synonym GERD), Ge-Bayi Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, allergies, headache (eg migraine, tension headache), intestinal obstruction (eg surgery) Post-intestinal obstruction and intestinal obstruction during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis, inflammatory bowel disease (IBD) (eg Crohn's disease, ulcerative colitis, collagen) Colitis, lymphocytic colitis, ischemic colitis, diversi〇n colitis, Behcet's syndrome, undetermined colitis, inflammatory bowel syndrome (IBS) , lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, renal disease, pemphigus vulgaris, pernicious anemia, peptic ulcer, psoriasis, polymyositis, primary Biliary cirrhosis, Parkinson's disease, pelvic inflammatory disease, reperfusion injury, localized enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, scler〇d〇ma, meat Sedative disease, spondyloarthropathy, Sjogren's syndrome, thyroid gland, 156069.doc -157- 201144296 Transplant rejection, tendonitis, trauma or injury (eg frostbite, chemical irritants, toxins, Scars, burns, physical damage), vasculitis, leukoplakia and Wegener's granulomatosis 0 In one embodiment, the inflammatory condition is selected from the group consisting of anemia, asthma, arteritis, arthritis, chronic obstruction Sexual lung disease, dermatitis, gastroesophageal reflux disease, Crohn's disease, inflammatory bowel syndrome, multiple sclerosis, psoriasis and autoimmune diseases. It has also been observed that inhibition of FASN activity reduces body weight (e.g., by blocking the body's ability to convert carbohydrates into fat) and inhibits chyme (see Loftus et al. 'science (2000) 288: 2379-23 81). . Reduced storage fat is expected to provide a variety of primary and/or secondary benefits in an individual (eg, in an individual diagnosed with complications associated with obesity), such as an increase in insulin reactivity (eg, in an individual diagnosed with type 2 diabetes) Middle); lowering of hypertension; lowering cholesterol levels; and/or ischemic heart disease, arterial vascular disease, colic; muscle infarction, stroke, migraine, heart failure, deep vein thrombosis, pulmonary embolism, Gallstones, gastroesophageal reflux disease, obstructive sleep apnea, obesity insufficiency syndrome, asthma, gout, poor mobility, back pain, erectile dysfunction, urinary incontinence, liver damage (eg fatty liver disease, cirrhosis) alcohol Sexual cirrhosis, endotoxin-mediated liver damage) or chronic renal failure (or reduced risk or slowed progression). Thus, in some embodiments the disclosed methods are applicable to obese individuals, diabetic individuals, and alcoholic individuals, and are generally applicable as part m to treat obesity-related disorders or complications thereof. As used herein, "obesity-related disorders" include, but are not limited to, obesity, non-I56069.doc 201144296 desired weight gain (eg, drug-induced weight gain, due to cessation of smoking) and overeating (eg bulimia, bulimia) Symptoms, compulsive eating or lack of appetite control, each may cause undesired weight gain or obesity depending on the situation). As used herein, "obesity" refers to class I obesity, π-type obesity, sputum obesity, or pre-obesity (e.g., "overweight") as defined by the World Health Organization. In some embodiments, 'obesity-related disorders include, but are not limited to, π-type diabetes' blood pressure, high cholesterol, ischemic heart disease, arterial vascular disease, colic, myocardial infarction, stroke, migraine, congestive Heart failure, deep vein thrombosis, pulmonary embolism, gallstones, gastroesophageal reflux disease, obstructive sleep apnea, obesity insufficiency syndrome, asthma, gout, poor mobility, back pain, erectile dysfunction, urinary incontinence, liver Injury, fatty liver and chronic renal failure. In some embodiments, the treatment of an obesity-related disorder or a complication thereof involves reducing the weight of the individual. In some embodiments, the treatment of an obesity-related disorder or a comorbidity thereof involves controlling an individual's appetite. • In other embodiments, provided herein are methods of treating, preventing, and/or managing a microbial infection (eg, a bacterial infection, a viral infection, a fungal infection, or a parasite or protozoal infection) comprising administering to the individual a therapeutically or prophylactically effective amount At least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable form thereof. Also provided herein is the use of at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, for use in therapy, Prevent and/or manage microbial infections in individuals. 156069.doc •159· 201144296 Also provided herein is the use of at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable form thereof It is used to manufacture agents suitable for the treatment, prevention and/or management of microbial infections. FASN has been identified as a target for the treatment of microbial infections such as viral infections, such as infection by enveloped viruses such as herpes viruses (eg human cell giant virus (HCMV), herpes simplex virus l (HSV-l), simple Herpesvirus 2 (HSV-2), varicella zoster virus (VZV), Epstein-Barr virus, influenza A virus and hepatitis C virus (HCV) (see Munger et al., TVaiwre 5k (10) (2008) 26 : 1179-1186 ; Syed et al., Trends in Endocrinology and Metabolism [2QQ9] 21:33-40 ; Sakamoto et al., iVaiwre (2005) 1:333-337; Yang et al., (2008) 48:1396-1403) Or a small RNA virus such as Coxsackievirus B3 (CVB3) (see Rassmann et al., 3«ίζ·-νζ·&quot;α/ Λαβαπ/ζ (2007) 76:150-158). Other exemplary viruses include, but are not limited to, hepatitis A virus; HIV; poxvirus; hepadavirus; retrovirus; and RNA viruses such as flavivirus, togavirus, coronavirus, Hepatitis D virus, positive mucus virus, paramyxovirus, baculovirus, bunyavirus, and filovirus. In some embodiments, the virus infects a human. In other embodiments, the virus infects a non-human animal. In another embodiment, the virus infects a primate (eg, a stone crab macaque, a rhesus monkey); a mammal, including a commercially relevant mammal such as a cow, pig, horse, sheep, goat, cat, and/or dog. ; and / 156069.doc •160- 201144296 or poultry, including commercially relevant poultry such as chicken, duck, geese and/or turkey. In certain embodiments, the virus is a enveloped virus. Examples include, but are not limited to, as a hepadnavirus family, a herpesvirus family, an iridovirus family, a poxvirus family, a flavivirus family, a chlamyvirus family, a retrovirus family, a coronavirus family, a filovirus A virus of a family, a baculovirus family, a budding virus family, a positive mucus virus family, a paramyxovirus family, and a member of the arenavirus family. Other examples include, but are not limited to, hepadnavirus type hepatitis B virus (HBV), woodchuck hepatitis virus, ground squirrel (hepatovirus) hepatitis virus, duck hepatitis B virus, heron hepatitis B Virus, herpesviruses are herpes simplex virus type 1 and 2 (HSV), varicella zoster virus, cell giant virus (CMV), human cell giant virus (HCMV), mouse cell giant virus (MCMV), guinea pig cells are huge Virus (GPCMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV variants A and B), human herpesvirus φ 7 (HHV-7), human herpesvirus 8 (HHV-8), card Boss' sarcoma-related therapeutic virus (KSHV), type B virus is vaccinia virus, variola virus, acne virus, wolfpox virus, vaccinia virus, road plague virus, ectromelia virus, mousepox Virus, rabbitpox virus, raccoon pox virus, infectious soft-dead virus, sheep variola virus, milker's nodes virus, cow's hyaline stomatitis virus, sheep pox virus, goat virus, painful skin Disease virus, fowlpox virus , canarypox virus, acne virus, vaginal pox virus, myxoma virus, rabbit fibroma virus, rabbit fibroma virus, squirrel fibroid virus, swine mark virus, tacropod virus (tanapox 156069.doc -161 - 201144296

Virus), Yababox virus, flavivirus dengue virus, hepatitis C virus (HCV), GB hepatitis virus (GBV-A, GBV-B and GBV-C), West Nile virus ), yellow fever virus, St. Louis encephalitis virus, Japanese encephalitis virus, Powassan virus, tick-borne encephalitis virus, Kosanur forest disease Virus (Kyasanur Forest disease virus), chlamy virus, Venezuelan equine encephalitis (VEE) virus, chikungunya virus, Ross River virus, Mayaro virus ( Mayaro virus), Sindbis virus, rubella virus, retrovirus type 1 and type 2 human immunodeficiency virus (HIV), type 1, type 2 and type 5 human T cell leukemia virus (HTLV), small Murine breast tumor virus (MMTV), Rous sarcoma virus 'RSV', lentivirus, coronavirus, severe acute respiratory syndrome (SARS) virus, filovirus Ebola virus, Marburg virus, Metapneumovirus 'MPV (such as human interstitial pneumonia virus (HMPV)), baculovirus rabies virus, vesicular stomatitis virus , Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, La Crosse virus, Hantaan virus, Positive mucus virus, influenza virus (type A, type B and type C), paramyxovirus, parainfluenza virus (type 1, type 2 and type 3 PIV), respiratory fusion virus (type A and type B), measles virus, Mumps virus, arenavirus, lymphocytic choriomeningitis virus, Junin virus (Junin 156069.doc -162- 201144296

Virus), Machupo virus, Guanarito virus, Lassa virus, Ampari virus, Flexal virus, Ipvirus (Ippy virus), Mobala virus, Mopeia virus, Latino virus, Parana virus, Pichinde virus, Pong Punta toro virus (PTV), Tacaribe virus, and Tamiami virus. In some embodiments, the virus is a non-membrane virus, i.e., the virus does not have a envelope and is a naked virus. Examples include, but are not limited to, as a small virus family, a circovirus family, a polyoma family, a papilloma virus family, an adenovirus family, an iridescent virus family, a reovirus family, and a biRNA virus (birnavirus). A virus of the family, the calicivirus family, and members of the picornavirus family. Specific examples include, but are not limited to, canine parvovirus, small virus B1 9, porcine type 1 and type 2 circovirus, BFDV (Beak and Feather Disease virus), chicken anemia virus, polyoma virus (Polyomavirus), simian virus 40 (SV40), JC virus, BK virus, Budgerigar fledgling disease virus, human papilloma virus, bovine papillomavirus (BPV), cottontail rabbit Papillomavirus, human adenovirus (HAdV-A, HAdV-B, HAdV-C, HAdV-D, HAdV-E and HAdV-F), avian adenovirus A, bovine adenovirus D, frog adenovirus, resuscitation Solitary virus, human circovirus, human coltivirus, mammalian reovirus, bluetongue virus, rotavirus A, rotavirus (group B to group G), heat of the monument in Colorado Virus 156069.doc -163- 201144296 (Colorado tick fever virus), aquatic reovirus A (aquare〇virus A), polyhedrosis virus l (cyP〇virUS 1), Fijidisease virus, rice Dwarf virus, rice wrinkle dwarf virus, insect source reovirus Uidnoreovirus 1) , fly reovirus 1 (myc〇re〇virus 〇, double RNA virus, bursal disease virus, pancreatic necrosis virus, calicivirus, swine herpes virus, rabbit hemorrhagic disease virus, novo Norwalk virus, Sapp〇r〇virus, small rna virus, human poliovirus (1-3), human coxsackie virus A1_22, human

24 (CAl-22 and CA24, CA23 (echovirus 9)) Coxsackie virus (Bl-6 (CBl-6)), human Echo virus 17, 9, 1127, 29-33, dimension Rish virus (5) yuish virus), simian enterovirus MWSEVMS), porcine enterovirus ^ (and 丨7), bovine enterovirus liver virus, heart virus, 1-2 (BEV1-2), hepatitis A virus, rhinovirus, aphthous virus And the Eco virus. In certain embodiments, the virus is a therapeutic virus, such as Bribe, Lin_2, and C. In another embodiment, the virus is v. In another embodiment, the virus is livertn phie virus. In another embodiment, the virus is an influenza virus. In this case, the virus is HIV. In certain embodiments, the viral hepatitis virus. In a particular embodiment, the virus is in some embodiments, the virus is a Kaposi's sarcoma-associated (four) poison (KSHV). In some implementations, the virus is a smallpox virus. In the main example, the virus is a dengue virus. In other embodiments, the virus is a SARS virus. In one embodiment, the virus is an Ebola virus. In some embodiments, the virus Aemu+± is a Marburg virus. In certain embodiments, the 156069.doc* 164 - 201144296 virus is an atopic virus. In a specific embodiment, the 5 virus is a cancer virus. In some embodiments, the virus is varicella zoster virus (VZV). In some embodiments, the virus is a small RNA virus. In certain embodiments, the virus is a rhinovirus. In certain embodiments, the virus is not a rhinovirus. In some embodiments, the virus is an adenovirus. In a particular embodiment, the virus is a Coxsackie virus (e.g., Coxsackie virus B3). In some embodiments, the virus is a rhinovirus. In certain embodiments, the virus is human papillomavirus (HPV). In certain embodiments, the virus is a DNA virus. In other embodiments, the virus is an RNA virus. In one embodiment, the virus is a DNA or RNA virus having a single-stranded genome. In another embodiment, the virus is a DNA or RNA virus having a double-stranded genome. In some embodiments, the virus has a linear genome. In other embodiments, the virus has a circular genome. In some embodiments, the virus has a segmented genome. In other embodiments, the virus has a non-segmented genome. In some embodiments, the virus is a positive strand RNA virus. In other embodiments, the virus is a negative strand RNA virus. In one embodiment, the virus is a segmented negative strand RNA virus. In another embodiment, the virus is a non-segmented negative strand RNA virus. In some embodiments, the virus is an icosahedral virus. In other embodiments, the virus is a spiral virus. In other embodiments, the virus is a complex virus. In some embodiments, the virus is a hepatitis C virus. In certain embodiments, the viral line is selected from the group consisting of: herpes virus, such as HSV-1, HSV-2, VZV, EBV, CMV (HCMV, MCMV, GPCMV), 156069.doc-165-201144296 HMCV, CVB3, HHV- 6 and HHV-8; influenza viruses, such as influenza A and influenza B viruses; respiratory viruses such as RSV, PIV (type 1, type 2 and type 3), aphrodisiac virus, rhinovirus, adenovirus, HMPV and S ARS virus, positive cancer · virus, such as vaccinia virus, vaccinia virus, mousepox virus, wolf disease virus and rabbit pox virus; hepatitis virus, such as HBV and HCV; papova virus, such as papilloma virus (such as cotton-tailed rabbit papilloma virus and human papilloma virus) and BK virus; or other viruses such as VEE virus, Rift Valley fever virus, takab virus, yellow fever virus, West Nile virus, dengue virus , PTV and Pichind virus. In one embodiment, the virus is HSV-1. In another embodiment, the virus is HSV-2. In another embodiment, the virus is VZV. In another embodiment, the virus is EBV. In another embodiment, the virus is HCMV. In another embodiment, the virus is MCMV. In another embodiment, the virus is GPCMV. In another embodiment, the virus is HHV-6. In another embodiment, the virus is HHV-8. In one embodiment, the virus is an influenza A virus. In another embodiment, the virus is an influenza B virus. In one embodiment, the virus is an RSV. In another embodiment, the virus is PIV-3. In another embodiment, the virus is a measles virus. In another embodiment, the virus is a rhinovirus. In another embodiment, the virus is an adenovirus. In another embodiment, the virus is HMPV. In another embodiment, the virus is a SARS virus. In one embodiment, the virus is a vaccinia virus. In another embodiment, the virus is a vaccinia virus. In another embodiment, the virus is a murine virus. At 156069.doc •166·201144296 __ &gt; / j , I , , ' virus is wolfpox virus. In another embodiment, the virus is a rabbit pox virus. In one embodiment, the virus is HBV. In another embodiment, the virus is HCV. In one embodiment, the virus is a cottontail rabbit papilloma virus. In another example, the main stalks 4 and t are human papillomaviruses. In another embodiment, the virus is a BK virus. In a single embodiment, the virus is a VEE virus. In another embodiment, the beta poison is a Rift Valley fever virus. In another embodiment, the virus is a takab virus. In another embodiment, the virus is a yellow fever virus. In another embodiment, the poison is West Nile Disease #. In another embodiment, the virus is a dengue..., a disease t. In another embodiment, the virus is a PTV. In another embodiment the virus is Pichind virus. In the embodiments, the at least one compound of the formula (1) provided herein or a pharmaceutical composition thereof in the form of an acceptable form or comprising at least one compound of the formula (1) or a pharmaceutically acceptable form thereof can be treated by An infection caused by a type of disease. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, can be treated by two or Two or more types of viruses cause one or more infections at the same time. In other embodiments, at least one of the compounds of formula (1) or a medically acceptable form thereof, or a pharmaceutical composition comprising at least one of the compounds of formula (1) or a pharmaceutically acceptable form thereof, may be treated by Three or more types of viruses cause it at the same time - or more. In other embodiments, 56069.doc • 167- 201144296, at least one compound of formula (i), or a pharmaceutically acceptable form thereof, or at least one compound of formula (1) or a pharmaceutically acceptable form thereof, as provided herein S &amp; f I plants can treat one or more infections simultaneously by four or more types of viruses. In other embodiments, at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, as provided herein, is treatable One or more infections are caused by five or more types of viruses simultaneously. In other embodiments, at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, is Six, seven, eight, nine, ten, fifteen, twenty or twenty types of viruses simultaneously cause one or more infections. In certain embodiments, the microbial infection can encompass diseases associated with prion infection, such as scrapie, mad cow disease, and any modified form thereof. In some embodiments, microbial infections encompass prion diseases affecting humans. It is contemplated that a compound of formula (I) provided herein, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, will also be suitable for the treatment of other microbial infections, such as bacteria. Infection, fungal infections and parasitic infections. In certain embodiments the 'microbial infection is a bacterial infection. Examples of bacterial infections include, but are not limited to, infections caused by mycobacteria (eg, Mycobacterium tuberculosis, Mycobacterium bovis (from έον/ί), Mycobacterium uberis (from, Mycobacterium phlei ( From, for example, and mycobacteria (M ayWcrflwww), rickettsia, emblem 156069.doc -168- 201144296 mycoplasma, chlamydia and legionella » Other examples of bacterial infections include, but are not limited to, infections caused by Gram positive bacillus (eg, Listeria (I(6)er(4); Bacillus (5) 10/Wj), such as Bacillus anthracis (square; Phytophthora (five &quot; gram-negative bacteria (Gram negative bacillus) (eg, genus Patong, B. genus, genus genus (Camp; y/o6acier), Enterobacter

, genus Escherichia (heart c/zehc/πίζ), genus Travia (Francbe/(4), Haemophilus, Klebsiella, Morganella, Proteus (Proiew), Providencia, Pseudomonas, Salmonella (heart/wo„e//a), Serratia, Shigella (from /gW/a), Vibrio (打^/〇) and Yarrowia (Raima), spirochete bacteria (such as Borrelia (such as rre (8)), including Borrelia burgdorferi causing Lyme disease (5〇^心和r/ Πθ), anaerobic bacteria (eg Actinomyces (m·such as w;; cei) and Clostridium (C/i^rishan*mw)), Gram-positive and Gram-negative cocci, Enterococcus (Ewieroeoccws), Staphylococcus (^SVrepioco+ccw·?), Pneumococcal (PwewmococcM·?), Staphylococcus (ΧίαρΑ少/wcwi) and Neisseria {Neisseria,. Specific examples of infectious bacteria Including (but not limited to): Helicobacter pylori (Hencohcrier sputum...), Borrelia burgdorferi, Legionnella vulgaris (Zeg/o«e//a please noisy; „_heart), knot Mycobacteria, Mycobacterium avium, Mycobacterium intracellulare (from, Mycobacterium kansii (from 156069.doc • 169- 201144296, Mycobacterium gordon (M. gor), Staphylococcus aureus ( &amp;αρ;ζ/ococcw aMreWs), Neisseria gonorrhoeae o«orr/zoeae, Neisseria meningitidis (TVWjja/a, Listeria monocytogenes (Lbierio mowoc^ioge heart) y), Streptococcus pyogenes (Are/^ococcMi /^0ge«ei) (group A streptococci), Streptococcus agalactiae (Sire/^ococcw·? group of key bacteria), Streptococcus viridans, Streptococcus / (aeca / h), Bovineococcus (^Vrepiococcws ftovb), Streptococcus pneumoniae, Haemophilus influenzae ' ^ ^ ® {corynebacterium diphtheriae) ' Red spot erysipelas Bacillus (·£&gt;&gt;^ζ·/7β/οί/ζΓΖ·Λ: r/7M5iopai/n'ae), Clostridium perfringers, Clostridium perfringens (C/osiric^wm ieiawz) ·), Enterobacter aerogenes (jE «iero6crcier aerogewej), Klebsiella pneumoniae (foot /> «ewwo«iae), more Pasteurella multocida {Pasturella mw/ioc/ί/α), Fusobacterium nucleatum (Fwso acierz.ww nucleatum), Streptobacillus moniliformis, Treponema pallidum (7&gt;e/?o^ 7e/wa ρβ//ζ·山'wm), snail snail (7Ve_po«ewa /Jeriewwe), squid, rickettsia and Israeli actinomycete ZiSr&lt;3e&quot;z). In one embodiment, the bacterial infection is caused by M. tuberculosis. In certain embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, is One type of 156069.doc -170- 201144296 Bacterial infection. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, may be treated by two or Two or more types of bacteria cause one or more infections at the same time. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, may be treated by three or three The above types of bacteria cause at the same time - or a variety of infections. In other embodiments, at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, may be treated by four One or more types of bacteria cause one or more infections at the same time. In other embodiments, at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, as provided herein, is treatable One or more infections are caused by five or more types of bacteria simultaneously. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, can be treated by six species, Seven, eight, nine, ten, fifteen, twenty or twenty types of bacteria simultaneously cause one or more infections. In certain embodiments, provided herein are methods of treating, preventing, and/or managing a disease, disorder, or condition caused by a fungal infection. Examples include, but are not limited to, aspergilliosis, crytococcosis, sporotrichosis, coccidioidomycosis, Brazil 156069.doc -171 - 201144296 coccidioidomycosis ), histoplasmosis, blastomycosis, zygomycosis, and candidiasis. In certain embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, is treatable by one type The infection caused by the fungus. In other embodiments, at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, can be treated by two One or more types of fungi cause one or more infections at the same time. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1) or a pharmaceutically acceptable form thereof can be treated. __ or multiple infections caused by three or more types of true (four). In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, can be treated by four or More than four types of fungi cause at the same time - or multiple infections. In other embodiments, at least one compound of formula (1) or a pharmaceutically acceptable form thereof, or a compound of formula (1), or a pharmaceutical thereof, and I. T. An acceptable form of the pharmaceutical composition can treat one or more of the infections by five or five rare+, five or more types of fungi. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable formula thereof, or a pharmaceutical composition comprising at least one JU'/τχ compound or a pharmaceutically acceptable species thereof (1) The substance can be treated by 156069.doc • 172· 201144296 /, seven, eight, nine, ten, fifteen, twenty or twenty types of fungi simultaneously cause one or more infections. In certain embodiments, provided herein are methods of treating, preventing, and/or managing a disease, disorder, or condition caused by a parasitic or protozoal infection. Examples of parasitic or protozoal diseases and conditions include, but are not limited to, diseases, conditions, and conditions caused by parasites such as, but not limited to, Plasmodium falciparum (doors and /c doors), Plasmodium falciparum (Huttuva va/e), Plasmodium vivax WVM), Plasmodium falciparum (Ρ·ma/an•如), Dussian Leishman body (1• office, infant Leishman Body (I.), Ethiopian Leishman body aei/n'op/ca), great Leishman body ([• (4), tropical Leishman body (especially iropz'ca), Mexican Leishman body (Yi咖咖.,Brazil Leishman body (Yubu mountain (9)...), Gangdish Leishman body (r G〇w mountain 〇, tiny worm (7) mzcron), divergent cokeworm (reverse colonic cocci (7) c〇 / 〇, human worm (B. /? 〇所mu), small cryptic larvae (C, Cayetta Cyclospora (C. (7) state (four) (four) (4), fragile dual-core amoeba (Ζλ介邮, dissolved tissue Amoeba (£· /n.iio/yika), Beet's and other spores (7 hearts//ζ·), Manson's blood sucking A (S. mansonii), Egyptian blood sucking (s haemat〇bium) , Trypanosoma ssp., 3 argon {Tox〇plasma ssp , A螓i Green gas (O. vo/vw/wi). Other diseases, disorders and conditions include, but are not limited to, diseases, disorders and conditions caused by: Bovine worms (5 hearts to 6 〇) 1;), dog cocci, C. sinensis, Bosnoitia dariingi, cat vine, C (Cytauxz〇〇n (4), Eimeria ssp., Hammond蝱 讲 (4) (4) "Chemical ssp", canine bow first! Ιί Θ Γ (Γ. C 细 · ί), 绦 ( (Cesioda, also known as tapeworm) and Taylor 156069.doc -173- 201144296 Protozoa. Specific diseases. Symptoms and conditions include, but are not limited to, dysentery, babesiosis, trypanosomiasis, American trypanosomiasis (also known as geiger's disease), leishmaniasis (leishmaniasis), toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isosporiasis ), cyclosporiasis, microsporidiosis, ascariasis is Trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis, trichinosis, lymphatic filariasis, iris Onchocerciasis, filariasis, schistosomiasis, and dermatitis caused by animal schistosomiasis. In one embodiment, the parasitic or protozoal disease is malaria. In another embodiment, the parasitic or protozoal disease is leishmaniasis. In another embodiment, the parasitic or protozoal disease is coccidiosis. In another embodiment, the parasitic or protozoal disease is toxoplasmosis. In another embodiment, the parasitic or protozoal disease is trypanosomiasis. In certain embodiments, at least one compound of formula () or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1) or a pharmaceutically acceptable form thereof, is treatable by An infection caused by one type of parasite. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, may be 156069.doc • 174 - 201144296 Treatment of one or more infections caused by two or more types of parasites simultaneously. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, can be treated by three or More than one type of parasite simultaneously causes - or multiple infections. In other embodiments, at least one of the compounds of formula (1), or a pharmaceutically acceptable form thereof, provided herein, is a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable form thereof. Treatment is caused by one or more infections of four or more types of parasites simultaneously. In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1) or a pharmaceutically acceptable form thereof, may be treated by five or More than five types of parasites cause one or more infections at the same time. In other embodiments, at least one compound of Formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of Formula (I), or a pharmaceutically acceptable form thereof, provided herein Treatment consists of six, seven, eight, nine, ten, fifteen, twenty or twenty types of parasites simultaneously causing one or more infections. In some embodiments, the compounds provided herein treat an infection caused by any combination of viruses, bacteria, fungi, and parasites. By way of example, in certain embodiments t, the compounds provided herein treat infections caused by one or more viruses and one or more fungi. In other embodiments, the compounds provided herein treat infections caused by one or more viruses and one or more bacteria. In other embodiments, the compounds provided herein treat infections caused by one or more fungi and one or more bacteria. In other examples of 156069.doc-175-201144296, the compounds provided herein treat infections caused by one or more viruses and/or a plurality of parasites. In other embodiments, the compounds provided herein treat infections caused by one or more fungi and one or more parasites. In other embodiments, the compounds provided herein treat infections caused by - or a plurality of bacteria and/or a plurality of parasites. In other embodiments, the compounds provided herein treat infections caused by one or more viruses, one or more fungi, and/or a plurality of bacteria. In other embodiments, the compounds provided herein treat infections caused by one or more bacteria, one or more fungi, and one or more parasites. In other embodiments, the compounds provided herein treat infections caused by one or more viruses, one or more fungi, and one or more parasites. In other embodiments, the compounds provided herein treat infections caused by one or more viruses, one or more bacteria, and one or more parasites. The compounds provided herein are inhibitors of FASN. Thus, in certain embodiments, the compounds provided herein can be used to treat and/or manage other FASN-related disorders, examples of which include, but are not limited to, diabetes and general health of the liver, such as treatment, prevention, and/or management Fatty liver. In certain embodiments, the compound is an inhibitor of palmitate synthesis. As used herein, &quot;inhibition&quot; and &quot;inhibitor&quot; and the like terms refer to the ability of a compound to reduce, disrupt, or prevent the activity of a particular biological process in a cell (e.g., FASN activity, palmitate synthesis) relative to the vehicle. In other embodiments, provided herein are methods of inhibiting EL〇VL in an individual comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (1) or a pharmaceutically acceptable form thereof. 156069.doc • 176- 201144296 In another embodiment, provided herein is the use of at least one compound of formula (i) for treating an ELOVL mediated disorder in a subject. In another embodiment, provided herein is the use of at least one compound of formula (I) for the manufacture of a medicament. In certain embodiments, the agent is suitable for treating an ELOVL mediated disorder. As used herein, &quot;ELOVL mediated condition&quot; refers to a disease, disorder, or condition that can be treated by inhibiting ELOVL activity. In general, ELOVL-mediated disorders are substantially similar to FASN-mediated disorders. Thus, ELOVL mediated disorders include the FASN mediated disorders described herein above. Examples include, but are not limited to, hyperproliferative disorders, inflammatory conditions, obesity-related disorders and their complications, diabetes, and general health of the liver, such as treating, preventing, and/or managing fatty liver. In one embodiment, the ELOVL mediated disorder is a hyperproliferative disorder. In another embodiment, the ELOVL mediated condition is an inflammatory condition. In another embodiment, the ELOVL mediated condition is obesity. In another embodiment, the ELOVL mediated condition is diabetes. In another embodiment, the ELOVL mediated condition is fatty liver. In one embodiment, the ELOVL mediated disorder is an ELOVL6 mediated disorder. 4. Administration of a pharmaceutical composition of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, may be administered in any amount effective for treatment and any administration Ways to vote. The compounds provided herein are usually formulated in unit dosage form for ease of administration and at a uniform dosage of 156069.doc -177-201144296. However, it should be understood that the total daily usage of the compounds provided herein will be determined by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose for any particular individual will depend on a number of factors, including the disease, condition, or condition being treated. The condition and its severity, the activity of the particular compound used; the particular composition used; the species, age, weight, general health, sex and diet of the individual; the time of administration, the route of administration and the rate of excretion of the particular compound used; duration of treatment a drug that is combined or used in combination with a particular compound used; and similar factors well known in the art of medicinal techniques. A therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, as disclosed herein, may be treated by a compound Effectiveness to measure. The compound of formula (I) can be administered at a dose of about 1 about 200 mg/kg per day; such as from about 1 叩/kg to about 150 mg/kg, from about 1 mg/kg to about 200 mg/kg, about 1 pg/ Kg to about 1 mg/kg, about 1 to /" to about 1 mg/kg, from about 50 Mg/kg to about 200 mg/kg, from about 10 Mg/kg to about i mg/kg, about 10 pg/ From kg to about 100 pg/kg, from about 100 to about i mg/kg, and from about 5 〇〇 Mg/kg to about 50 mg/kg. In certain embodiments, for one or more administrations per day 7 A therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, of 〇0 adult may comprise per unit A dosage form of from about 0.0001 mg to about 1 000 mg of the compound. It is to be understood that the dosage range as described herein provides a pharmaceutical composition 4 which is in turn associated with an adult. The amount to be administered, for example, to a child or adolescent can be obtained by a medical practitioner or a practitioner. The technician determines and can be lower than the amount of adult to be administered or the same as the amount of adult 156069.doc •178- 201144296. Can be used twice a day, once a day, every other day The desired dose is delivered every two or two weeks every two weeks, two weeks or weeks. In some embodiments, multiple administrations may be used (eg, two, three, four, five, six, seven, Eight, nine, ten, eleven, twelve, thirteen, fourteen or fourteen times to deliver the required dose. In a uniform example, the disclosed formula (I) The therapeutically effective amount of the compound or a pharmaceutically acceptable form thereof or a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable form thereof is sufficient to establish from about 1 μΜ to about 100 μΜ. For example, the maximum plasma wave amplitude in the range of about i μΜ to about 2 μμΜ. The preliminary dose is determined, for example, according to an animal test, and the agent for human administration is based on a technically recognized specification. The dose can be initially estimated from the cell culture assay. The dose can be formulated in an animal model to achieve a circulating plasma concentration range that includes, for example, a cell culture assay or an ICW as determined in an animal model, ie, a therapeutic agent concentration that achieves a half-maximal symptom suppression. The amount in plasma can be measured, for example, by high performance liquid chromatography. The effect of any particular dose can be monitored by a suitable bioassay. Examples of dosages are: about O.bWw, about x5xIC5❶, about lxic50 , about 5xIC50, i〇XIc5〇, about 5〇xIc5〇, and about 1〇〇xIC5〇. The therapeutically effective dose achieved in one animal model can be converted for use in another animal using conversion factors known in the art. , including humans (see, eg, Freireich et al, C (10) Chemother. Reports 5 0 (4): 219-244 (1966), and Table A for equivalent surface area dose factors). 156069.doc -179- 201144296 Table A Mouse (2〇g) Rat (150 g) Monkey (3.5 kg) Canine (8 kg) ~~ (60 kg) Mice 1 1/2 1/4 1/6 iTIF&quot; Rat 2 1 1/2 1/4 ~ϊ/7 Monkey 4 2 ΊΓ 3/5 173' - Canine 6 4 ΊΓ 5 1 U2 --- Human 7 Ύ 2 1 ----^ In some embodiments a pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable form thereof or comprising at least one compound of the formula (Ϊ) or a pharmaceutically acceptable form thereof, administered via a variety of routes, including oral, intravenous , intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, transrectal, intravaginal, intraperitoneal, topical (eg, by powder, ointment, cream, and/or drops), Transmucosal, nasal,. Intratracheal instillation, bronchial instillation and/or inhalation; and/or in the form of oral sprays, nasal sprays and/or aerosols. Particularly contemplated routes are systemic intravenous injection, regional administration via blood and/or lymphatic supply, and/or direct administration to affected areas. In general, the most appropriate route of administration will depend on a variety of factors, including the nature of the agent (e.g., its stability in the gastrointestinal environment), the condition of the individual (e.g., whether the individual is able to tolerate oral administration), and the like. Currently, oral and/or nasal spray and/or aerosol routes are most commonly used to deliver therapeutic agents directly to the lungs and/or respiratory system 4, possibly taking into account the progress of the drug (4) delivery science, by any appropriate Routes of delivery of pharmaceutical compositions are also covered in this article. It should also be understood that 'the above formulas and formulas thereof are as described above and in the formula (I) or in the form of a compound of the formula (1). Or a pharmaceutical composition in the form of an acceptable form can be administered in combination with - or a variety of other therapeutic agents 156069.doc 201144296. "Combination with" does not imply that the medicament must be administered and/or dispensed at the same time for delivery, although such delivery methods are indeed within the scope of the present invention. A pharmaceutical composition of the compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, may be preceded, preceded or preceded by - or a plurality of other therapeutically active agents It was later invested. In general, each agent will be administered at a dose and/or a daily schedule determined for the agent. It will be further appreciated that another therapeutically active agent for use in this combination may be administered together in a single-composition form or separately in separate compositions. The particular combination employed in the course of treatment will take into account the compatibility of the compound of formula (1) with another therapeutically active agent and/or the desired therapeutic effect to be achieved. In some embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or other therapeutically active agent comprising at least one of the compounds of formula (1) or a pharmaceutically acceptable form thereof, will be used in combination. Do not invest more than the amount of its individual use. In some embodiments, the amount of ® used in the combination will be less than the amount used individually. "Therapeutic active agent", "therapeutic agent", "agent" or "active agent" means any substance suitable for use in therapy (including prophylactic and therapeutic treatment). Also included herein are pharmaceutical compositions and combinations of agents that improve their bioavailability reduction and/or improve their metabolism, inhibit their excretion, and/or improve their distribution in the body. It will also be appreciated that the therapy used may have a desired effect on the same condition (for example at least one compound of formula (I) or a pharmaceutically acceptable form thereof or a medicament comprising at least one compound of formula (1) or a pharmaceutically acceptable form thereof. The composition may be administered in combination with an anti-inflammatory agent, an anxiolytic agent and/or an antidepressant, etc., 156,069.doc 201144296, and/or it may achieve a different effect (eg, control (4) any adverse by-products, an exemplary therapeutically active agent, including ( But not limited to) anticancer agents, antibiotics, anti-obesity agents, antiviral agents, anesthetics, anticoagulants, enzyme inhibitors, steroids, anti-inflammatory agents, antihistamines, immunosuppressants, antibiotics, antigens, Vaccines, antibodies, decongestants, sedatives, opioids, pain relievers, analgesics, antipyretics, enhancers, hormones, prostaglandins, progestational agents, antiglaucoma agents, ophthalmic agents, anticholinergic agents, antibiotics Depressants, antipsychotics, hypnotics, tranquilizers, anticonvulsants, muscle relaxants, antispasmodics, muscle contractions, channel blockers, miotic agents, antisecretory agents, antithrombotics, anticoagulation Agent, anticholinergic agent, β-adrenergic blocker, diuretic, cardiovascular active agent, vasoactive agent, vasodilator, antihypertensive agent, angiogenesis agent, cell-extracellular matrix interaction Inhibitors/intercalators of modulators (eg, cytostatics and anti-adhesive molecules) or DNA, RNA, protein/protein interactions, protein-receptor interactions, etc. Active agents include small organic molecules, such as pharmaceutical compounds (eg, compounds approved by the Food and Drug Administration, such as the Code of Federal Regulations (c〇de 〇f Fedei&gt;al

Regulations, CFR), antibodies, peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nuclear proteins, mucins, lipoproteins, synthetic peptides or proteins, small molecules linked to proteins, glycoproteins, Steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense nucleotides, lipids, hormones, antibodies, vitamins and cells, and combinations thereof. In certain embodiments the therapeutically active agent is an anticancer agent. Exemplary anticancer agents include, but are not limited to, radiation therapy, interferon (eg, interferon alpha, interferon 156069.doc -182. 201144296)

γ), antibodies (eg HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (Panidan) Antibiotic (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab), antiestrogens (eg tamoxifen, raloxifene) And megestrol), LHRH agonists (such as goscrclin and leuprolide), antiandrogens (such as flutamide and bicalutamide) Bicalutamide)), photodynamic therapeutics (eg verteporfin (BPD-MA), phthalocyanine, photosensitizer Pc4 and demethoxy-hypocrellin A (2BA) -2-DMHA)), nitrogen mustard (eg cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine) Estramustine) and melphalan, subunits such as carmustine (BCNU) and lovastatin (lomustine, CCNU)), yoghurt vinegar (such as busulfan and treasulfan), triazine (such as dacarbazine, temozolomide), Ming compounds (such as cisplatin, carboplatin, oxaliplatin), vinca flower bioassay (such as vincristine, vinblastine, vindesine) And vinorelbine, taxoid (eg paclitaxel, albumin-bound paclitaxe ABRAXANE, nab-pacific paclitaxel, docetaxel 156069.doc • 183· 201144296 (docetaxel), taxol (taxol), epipodophyllin (eg etoposide, etoposide citrate)

Phosphorus te), teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, Cristnatol, mytomycin C, antimetabolite, DHFR inhibitor (eg, methotrexate, dichloromethotrexate, triterpenoid) (trimetrexate), edatrexate, IMP dehydrogenase inhibitors (eg mycophenolic acid, tiazofurin, ribavirin and EICAR), ribonucleoside Glycosidate reductase inhibitors (eg hydroxyurea and deferoxamine)

(deferoxamine)), urinary mouth bite analogs (eg 5-fluorourine) (5-FU), floxuridine, doxyl fluoride (doxifluridine), raltitrexed (ratitrexed), methane Gas bite-tegafur-uracil, capecitabine, cellulite analogs (such as cytarabine (ara C), cytosine arabinoside and cytosine arabinoside) Fludarabine, purine analogues (eg, mercaptopurine and Thioguanine), vitamin D3 analogues (eg EB 1089, CB 1093 and KH 1060), isovaler An isoprenylation inhibitor (such as lovastatin), a dopaminergic neurotoxin (such as 1-methyl-4-phenylpyridinium), a cell cycle inhibitor ( For example, staurosporine, actinomycin (such as actinomycin D (dactinomycin), bleomycin (^'J 156069.doc 201144296 such as Bolemycin) A2, bleomycin B2, Peplomycin), anthracycline (anthracycline) (eg daunorubicin, little red

Doxorubicin, polyethylene glycol, liposome cranberry, idarubicin, epirubicin, pirarubicin, zorubicin, rice Mitoxantrone, MDR inhibitors (eg verapamil), Ca2+ ATPase inhibitors (eg thapsigargin), imatinib, thalidomide , lenalidomide, tyrosine kinase inhibitors (eg axitinib (AG013736), bosutinib (SKI-606), cedianib (cediranib, RECENTINTM, AZD2171) ' dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571) ), lapatinib (TYKERB®, TYVERB®), lantatinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®) , semaxanib (semaxinib, SU5416), sunitinib (smaxinib) Sunitinib, SUTENT®, SU11248), tocilanib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), van tarani (vatalanib, PTK787, PTK/ZK), trastuzumab Anti-(HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (ranibizumab) , Lucentis®), Nilotinib (TASIGNA®), Solafi 156069.doc -185- 201144296 Nie (sorafenib, NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (alemtuzumab, CAMPATH®), gemtuzumab oz omegastar (gemtuzumab ozogamicin, MYLOTARG®), sirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovedibine lactate (dovitinib) Lactate, TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ- 26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, Tivozanib (AV-95) 1), OSI-930, MM-121, XL-184, XL-647 and/or XL228), proteasome inhibitors (eg bortezomib (VELCADE)), mTOR inhibitors (eg rapamycin (eg rapamycin) Rapamycin), sirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis) , XL765 (Sanofi Aventis) 'PF-4691502 (Pfizer) ' GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), olimerson (oblimersen), gemcitabine (gemcitabine), erythromycin (carminomycin) ), leucovorin, pemetrexed, ring-filled amine, dacarbazone, procarbizine, prednisolone, dexamethasone, hi Tree pathology (campathecin), plicamycin, asparaginase, aminopterin, methoterin, phytomycin 156069.doc • 186· 201144296 ( Porfiromycin), melphalan, leur〇sidine, leurosine Chlorambucil, trabectedin (trabectedin), prop-card bar hydrazine (procarbazine), Dermot to Meredith (disc〇derm〇lide), magenta neomycin, methotrexate and six amino Yue melamine.

Suitable for cancer treatment (also known as "anticancer treatment regimen") and may be combined with at least one compound of formula (I) or a pharmaceutically acceptable form thereof or comprising at least one compound of formula (I) or pharmaceutically acceptable Exemplary combinations of therapeutically active agents used in combination with pharmaceutical compositions in their form include, but are not limited to:

ABVD AC BEACOPP

BEP CA CAF CAV CBV ChlVPP/EVA CHOP CHOP-R or R-CHOP COP or CVP CMF COPP EC Adriamycin (cranberry), bleomycin, vinblastine, dacarbazine doxorubicin (small Cranberry), cycloheximide bleomycin, etoposide, doxorubicin (cranberry), ring-filled amine, oncovin (vincristine) 'c' barley, predni Prednisone bleomycin, etoposide, platinum (cisplatin) cyclophosphamide, doxorubicin (small red each) (same as AC) cyclodextrin, doxorubicin (small red per) Fluorouracil (5_fu) Cyclophosphamide, doxorubicin (cranberry), vincristine cyclophosphamide, BCNU (carmustine), VP-16 (etoposide) butyl butyrate Jie, Changchun Xinzheng (Ankeping), procarbazine, prednisone, etoposide, vinblastine, doxorubicin (small red each) ring-shaped amine, hydroxydoxorubicin (small red Raspberry), Vincristine (Ancorpine), Prednisone CHOP + Rituximab Cyclophosphamide, Ankepin (Changchun Xinzheng), Prednisone Cyclophosphamide, Methamidine, Fluorouracil (5-FU) Cyclophosphamide, amphetamine (vincristine), Carbaryl, prednisone, epirubicin, cyclophosphamide 156069.doc •187- 201144296 ECF epirubicin, cisplatin, fluorouracil (5_FU) EP etoposide, medicinal (cisplatin) EPOCH etoposide , prednisone, ancordone, cyclophosphamide and hydroxy daunorubicin FEC FL (also known as Mayo) fluorouracil (5-FU), epirubicin, cyclophosphamide fluoride urinary mouth Bite (5-FU), 曱醯tetrahydrofolate (acid folic acid) FOLFOX fluorouracil. Ding (5-FU), formazan tetrahydrofolate (folate), oxaliflorin 'FOLFIRI fluorourine, &quot;5-FU, formazan tetrahydrofolate (acid folic acid), irinotecan ICE Cyclohexamine, carboplatin, etoposide (VP-16) ICE-R ICE + rituximab m-BACOD methotrexate, bleomycin, doxorubicin (cranberry), ring structure Amine, Anke Ping (Changchun Xinzheng), Dexamethasone MACOP-B Methotrexate, Formazantetrahydrofolate (luic acid), Doxorubicin (Cranberry), Cyclophosphamide, Ankepine (Vincristine), prednisone, bleomycin MOPP, dichlorinated diethylamine (mechlorethamine), ancordine (vincristine), procarbazine, prednisone PCV, procarbazine, CCNU Mistin), vincristine ProMACE-MOPP Amidoxime, doxorubicin (cranberry), cyclophosphamide, etoposide + MOPP ProMACE-CytaBOM prednisone, Xiaohong per (doxorubicin) , Cycloheximide, Etoposide, Cytarabine, Bleomycin, Ankepin (Changchun Xinzheng), Amidoxime, Betatetrahydrofolate R-FCM Rituximab, Fluoride Rabin, cyclamate, mitox brewing Stanford V Cranberry, diclofenac diethylamine, bleomycin, vinblastine, vincristine, etoposide, prednisone Thal/Dex Shali sinensis, dexamethasone TIP Pacific paclitaxel, isocyclic phosphonium Amine, platinum (cisplatin) VAC vincristine, actinomycin, cyclophosphamide VAD Changchun new test, doxorubicin (small red each), dexamethasone VAPEC-B Changchun new test, doxorubicin (small Cranberry), prednisone, etopo 156069.doc 188· 201144296 glycosides, cyclic guanamine, bleomycin etoposide, isocyclic guanamine, platinum (cisplatin)

In other embodiments, the therapeutically effective agent is an antiviral agent. Exemplary antiviral agents include, but are not limited to, Abacavir, Aciclovir, Acyclovir, Adefovir, Amantadine, Ampu Amprenavir, Ampligen, Arbidol, Atazanavir, Atripla, BI201335, Boceprevir, BMS-858 (See, eg, Gao et al., iWziwre, 465(6): 96-102 (2010)), BMS-790052 (see, eg, Gao et al., iVaiwre, 465(6): 96-102 (2010)), Cidford Cidofovir, Combivir, Danoprivir (ITMN-191; RG-7227), Darunavir, Delavirdine, Didanosine ), TCA, Doxanol, EI-1 to EI-12 (see, for example, Baldick et al.

6(9)el001086: 1-14 (2010)), ethiravir

(Elvitegravir), Efavirenz, Emtricitabine, Enfuvirtide, Entecavir, Etravirine, Famciclovir, Fosanavir Fosamprenavir), foscarnet, fosfonet, ganciclovir, GSK-572, Ibacitabine, Imunovir, Idoxuridine, °Imiquimod, Indinavir, Inosine, interferon (eg type III interferon, II 156069.doc -189· 201144296

Interferon, type I interferon, peginterferon a-2a (Peginterferon alfa-2a), peginterferon alpha-2b (Peginterferon alpha-2b), standard interferon a-2a, standard interference A-2b, consensus interferon, complex a. Interferon alfacon-1, ALBUFERON, ω interferon, interferon γ-lb, lymphoblastic interferon τ), pull Lamivudine, Lopinavir, Loviride, Maraviroc, Moroxydine, Methisazon, MK-2048, Nai Nelfinavir, Nevirapine, Nexavir, Oseltamivir (Tamiflu), Penciclovir, Peramivir, Pu Pleconaril, Podophyllotoxin, Raltegravir, virus. Sitting, Rimantadine, Ritonavir, and β-meter. Pyraidine, Saquinavir, Stavudine, Tenofovir (eg Tenofovir disoproxil), Tela Telaprivir, Tipranavir, Trifluridine, Trizivir, Tromantadine, Truvada, Valaciclovir (Valtrex), Valganciclovir, vaccines (eg VZV vaccines such as Variivax and Zostavax), Vicaliviroc, Azerbaijan Vidarabine, Viramidine, Zalcitabine, Zanamivir (Relenza), Zidovudine and 156069. Doc -190- 201144296 Other small molecule antiviral agents as described in Herker et al, Me Hsu, Advance Online Publication d〇i: 10.1038/nm2238: 1-4 (January 10, 2010) combination. Examples of other antiviral agents include, but are not limited to, interleukin 2, interleukin 6, interleukin 12 (a compound that enhances the development of type 1 helper cell reaction), interfering RNA, antisense RNA, _啥Mott, 5'-phosphate myocyte dehydrogenase inhibitor, amantadine and rimantadine. Other examples include, but are not limited to, those described in WO 2009/023059, the entire disclosure of which is incorporated herein by reference. In one embodiment, the antiviral agent is an interferon. In another embodiment, the antiviral agent is telaprevir. In one embodiment, a combination of two or more antiviral agents is further used in combination with the compounds provided herein. In certain embodiments, the antiviral agent is a protease inhibitor. Exemplary protease inhibitors include, but are not limited to, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosanavir , telanavir and darunavir. In certain embodiments, the antiviral agent is an integrase inhibitor. Exemplary integrase inhibitors include, but are not limited to, raltevir, ethiravir, and MK-2048, GSK-572. In certain embodiments, the antiviral agent is a reverse transcriptase inhibitor (eg, a nucleoside analog reverse transcriptase inhibitor (NRTI), a nucleotide analog reverse transcriptase inhibitor (NtRTI), a non-nucleoside reverse transcriptase Inhibitor (NNRTI)).

Exemplary nucleoside analog reverse transcriptase inhibitors (NRTIs) include (not available) zidovudine, darnoxine, zalcitabine, stavudine, lamivudine Y 156069.doc • 191 · 201144296 Abacavir, emtricitabine, entecavir and acyclovir (partial nucleoside structure). Exemplary nucleotide analog reverse transcriptase inhibitors (NtRTIs) include, but are not limited to, tenofovir and adefovir. Exemplary non-nucleoside reverse transcriptase inhibitors (NNRTIs) include, but are not limited to, efavirenz, nevirapine, delavirdine, and etravirine. In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, and/or The antiviral agent is further used in combination with an enhancer. As used herein, an "enhancer" is an agent that, when used in combination with a compound and/or an antiviral agent provided herein, is used in the absence of an enhancer, or a compound of formula (I) provided herein, or The treatment, prevention or management of a microbial infection is provided in a pharmaceutically acceptable form or treatment comprising at least one pharmaceutical composition of formula (I) or a pharmaceutically acceptable form thereof and/or an antiviral agent. Exemplary enhancers include, but are not limited to, chloroquine, quinoline antimalarial ' grapefruit juice, hydroxyurea, leflunomide, mycophenolic acid, resveratr〇i And ritonavir. In one embodiment, the antiviral agent is an antiviral agent described in U.S. Publication No. 2011/0064698, which is incorporated herein in its entirety by reference. Exemplary antiviral agents include, but are not limited to, IP-501, Merimebodib VX-497, IDN-6556, XTL-002, HCV/MF59, CIVACIR, ZADAXIN, CEPLENE, VX 950/LY 570310, ISIS 14803, JTK 003, Tarvacin, HCV-796, CH-6, ANA971, ANA245, CPG 10101, Rituximab, NM 283, HepXTM-C, IC41, Medusa interferon, El, 156069.doc •192· 201144296 Multiferon, BILN 2061, TMC435350, Telaprevir, Posipuvir, ACH-1625, ABT-450, BI-201335, PHX-1766, VX-500 , MK-7009, R7227, Narlaprevir, Alinia, ABT-072, ABT-333, Filibuvir, VCH-916, R7128, IDX 184, R7128, R1626, MK-328 PSI-785 ANA 598, BI-207127, GS9190, VCH-759, Clemizole, A-832, BMS-790052, ITX 506 GS-9450, ANA773, CYT 107, SPC3649, Other examples of Debio 25, SCY-635 and combinations thereof include (but are not limited to) AZD-7295, BI207127, BIT225, BM824383, BMS65032, BMS791325, G S-9256, IDX 375, INX-189, PPI-461, PSI-938, PSI-7977, TMC435, TMC649128, VX-222, VX-759, VX-916 and combinations thereof. These agents are currently in various clinical trials. Stages and information are easy to use for those skilled in the art. In one embodiment, provided herein is a method of treating, preventing, and/or managing a hepatitis C virus (HCV) infection, comprising administering a therapeutically or prophylactically effective amount of at least one compound of formula (I) provided herein or A pharmaceutically acceptable form or a pharmaceutical composition comprising at least one compound of formula (I), or a pharmaceutically acceptable form thereof, is combined with one or more other therapeutic agents provided herein.

Examples of such therapeutic agents include compounds having anti-HCV activity, for example by inhibition such as, but not limited to, HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, SCVNS4B protein, HCV 156069.doc -193- 201144296 Function of entry, HCV assembly, HCV release, HCVNS5A protein and IMPDH target.

In other embodiments, at least one compound of formula (1), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (1), or a pharmaceutically acceptable form thereof, as provided herein, can be combined with at least one Other therapeutic agents having anti-HCV activity are used in combination, including but not limited to, Aini (Nitazoxanide), Bavituximab, and Belerofon. , Chronvac-C, Civacir, clemizole, Fluvastatin, Glycoferon, Hepavaxx C, HuMax-HepC , Lenocta (sodium gluconate SSG), Locteron, pegylated interferon, ribavirin, Suvius, telaprevir (VX-950), Zadaxin - thymalfasin, ZALBIN (Albuferon, abinterferon a-2b), A-837093, ABT-072, ABT-333, ABT-450, ACH-1095, ACH-1625, ACH-2684, ACH-2928, AN 025-1, ANA598, ANA773, A TI-0810 (formerly known as PG301029), AVL-181, AVL-192, AZD7295, BI 201335, BI 207127, BIT225, BMS-650032, BMS-790052, BMS-791325, BMS-824393, CB5300, CB-183872 (original IB657), CF102, CSL123, CTS-1027, CYT107, Debio 025, ECH18, EDP-239, GEA007.1, GI 5005, GNI-103, GNI-104, GS 9190, GS 9256, GSK625433, IC41, ID- 12, IDX184, IDX320, IDX375, IMO-2125, IMMU 105, ITMN-191 156069.doc -194- 201144296 R7227 (RO5190591), ITX2155, ITX4520, ITX5061NS5A inhibitor, JKB-122, KPE02001003, KPE00001113, MBL-HCV MDX-1106 (ONO-4538), Mito-Q, MK-0608, MX3235 Celgosivir, NOV-205, PF-868554, PF-487869, PHX1766, PYN17 'PYN18 'PPI-461 'PPI-1301 'PRO-206 ' PSI-7977 &gt; PSI-938INX08189, R7128 (RO5024048), REP 9C, RG7348, SCV-07, SCY-635, SD-1CH, SIRNA-034, SP-30, SPC3649, TG4040, TT033, VCH-759, VX -222, VX-500, VX-813 and VX-985. In one embodiment, the additional therapeutic agent is an interferon. In one embodiment, the interferon is a sputum interferon, a type II interferon, a type I interferon, a pegylated interferon a-2a, a pegylated interferon a-2b, a standard interferon a-2a , standard interferon a-2b, complex interferon, complex alpha interferon-1, ALBUFERON, omega interferon, interferon gamma-lb, lymphoblastoid interferon τ or a combination thereof. In another embodiment, the interferon is interferon alpha-2a, interferon alpha-2b, PEGylated davina-2a, pegylated interferon a-2b, consensus interferon or lymphoblast Interferon τ. In another embodiment, the additional therapeutic agent is a viral sputum. In another embodiment, at least one compound of formula (I), or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable form thereof, Used in combination with ribavirin and interferon. In one embodiment, the interferon is a type III interferon, a type II interferon, a type I interferon, a pegylated interferon a-2a, a pegylated interferon a-2b, a standard interferon a-2a , standard interferon a-2b, complex interference 156069.doc -195- 201144296 prime, complex alpha interferon _ 丨, ALBUFER 〇 N, ω interferon, interferon pib, lymphoblastoid interferon 1, or a combination thereof. In another embodiment, the interferon is interferon alpha-2a, interferon alpha-2b, pegylated interferon alpha-2a, pegylated interferon alpha-2b, consensus interferon or lymphoblastic interferon antiviral Antiviral assays for assays for screening for compounds that are efficacious for a particular virus are well known in the art and are described, for example, in WO 2009/023059, which is incorporated herein in its entirety by reference. Exemplary antiviral assays are provided below. S.1 herpes simplex virus (HSV) The mouse type 1 or 2 herpes simplex virus (118¥_1 or 118¥_2) model can be used to assess the in vivo antiviral activity of test compounds. Balb/c mice are typically used' but other suitable susceptible mouse strains can also be used. # Inoculate mice at various rates with appropriate bribe infection rates, followed by test compounds and placebo. For intraperitoneal (i.p.) vaccination, HSVd replicates in the intestine, liver and spleen and spreads to the CNS. For intranasal (in) inoculation 'HSV_w nasopharynx replication and spread to CNS 1 test any suitable route of administration (eg oral, sputum, sputum, systemic and 'nasal), frequency of administration and dose to determine use The optimal dose and treatment regimen for the test compound in combination with other therapies. / In the mouse HSV-2 reproductive disease model, female Swiss Webster mice (swiss Webster mics) were vaginally inoculated with HSV_14HSV_2 and vaginal scrapings (vagina! swab) were obtained to assess the effect of therapy on viral replication (see For example, Cmte et al. (10) (8), 2〇〇2, 8:386 391). For example, viral power is determined from a vaginal scraper by viral plaque assay. U.S. Patent 56069.doc 201144296 The mouse HSV-1 model for studying skin lesions using SKH-1 mice, an immunologically competent hairless mouse strain, is also described in the art (see, for example, Crute^ AJ Nature Medicine, 2002, ^: 3^6-391; ABolger^, 1997, 35: 157-165). The guinea pig HSV model has also been described (see, for example, Chen et al., Wro/J., November 23, 2004, 1:11). Statistical analysis is usually performed to calculate the significance of antiviral activity. 5.2 Human Cell Huge Virus (HCMV) Since HCMV is generally not infected with laboratory animals, a mouse model of murine CMV (MCMV) infection can be used to characterize the in vivo antiviral activity of test compounds. For example, a MCMV mouse model of BALB/c mice can be used to characterize in vivo antiviral activity of a test compound when administered to an infected mouse, as described, for example, by Kern et al., dgewh C/zemoi/zer. 2004, 48:4745-4753. Using a standard virus plaque assay Mouse embryonic fibroblasts (MEF) were used to test tissue homogenates isolated from infected mice treated with test compound or treated with no test compound. Statistical analysis is usually performed to calculate the significance of antiviral activity. Alternatively, human tissue (i.e., retinal tissue or fetal thymus and liver tissue) is implanted into SCID mice, and subsequently infected with HCMV, preferably at a tissue transplant site (see, for example, Kern et al, C/zemoi/ Ier., 2004, 48:4745-4753). The pfu of the HCMV used for inoculation varies depending on the visual experiment and the virus strain. Any suitable route of administration (e.g., oral, topical, systemic, and nasal), frequency of administration, and dosage can be tested to determine the optimal dosage and treatment regimen for the test compound to be used in combination with other therapies. Implanted tissue homogenate isolated from infected mice treated with test compound treatment or untested compound at various time points using human viral foreskin fibroblasts (HFF) 156069.doc -197- 201144296 using standard viral plaque assays . Statistical analysis is then typically performed to calculate the significance of antiviral activity. The guinea pig CMV model used to study antiviral agents has also been described, for example.

Bourne et al., 2, 47: 103-109; Bravo et al., 2003, 60: 41-49; and Bravo et al., 乂/w/灿晴 Dzjeases·, 2006, 193:591 -597. 5.3 Routine Viruses Animal models such as ferrets, mice and chickens developed for testing antiviral agents against influenza viruses have been described, for example, in Sidwel et al., such as h., 2000, 48: 1-16 and McCauley et al. Human, Fine, 1995, 27. 179-186. For the mouse influenza model, non-limiting examples of parameters that can be used to assay the antiviral activity of test compounds administered to influenza-infected mice include pneumonia-related death, increased serum alpha 1 -acid glycoprotein, animal body weight, agglutination by blood cells Pulmonary virus assayed by hemaggiutinin, pulmonary virus as determined by viral plaque assay, and histopathological changes in the lung. Statistical analysis is usually performed to calculate the significance of antiviral activity. It can check the changes of the nasal bone and tracheal epithelium and subepithelial inflammation. It can be used to examine bronchiole epithelial changes and peribronchial inflammation in the large, medium and small or terminal bronchioles of the lung. The inflammatory changes in the alveoli were also assessed. The medium bronchioles are graded on a scale of 0 to 3 + as follows: 正常 (normal: lining up to a high columnar epithelial cell with a ciliated top border and a basal pseudostratified nucleus; minimal inflammation); 1+ The cortex is columnar and even proliferates only slightly on the contours; cilia are still visible on many cells; 2 + (the protrusion in the epithelial layer 156069.doc •198· 201144296 changes in the range of decline to significant proliferation) Internal; cells are disordered and the contour of the layer at the boundary of the lumen is irregular; and 3+ (the epithelial layer is significantly damaged and disordered, necrotic cells are visible in the lumen; some bronchioles are degraded and others undergo significant reactive hyperplasia). The trachea was graded on a scale of 0 to 2.5 + as follows: 正常 (normal: lining from a ciliated top border, a basal pseudostratified nucleus, etc. to a tall columnar epithelial cell. The cytoplasm is visible between the apical border and the nucleus. Occasionally small lesions with squamous cells; ι+ (follicular squamous metaplasia in the epithelial layer); 2+ (diffuse squamous metaplasia in the upper epithelium, cilia can be seen in the lesion) and 2· 5 + (diffuse squamous metaplasia, rarely cilia). Virus-specific immunohistochemical analysis using virus-specific monoclonal antibodies (eg Νρ, Ν* ΗΝ specific monoclonal antibodies). Staining on 〇 to 3 + Graded as follows. 〇 (no infected cells); 〇.5+ (very few infected cells); 1+ (very few infected cells, widely separated individual cells); 15+ (very few infected cells, widely separated) Single cell form and in small clusters; 2+ (medificate number of infected cells, usually affecting adjacent cell clusters in the epithelial portion of the bronchiole lining, or small leaflets in the alveoli Under the lesion) ; and 3+ (many infected cells, affecting most of the epithelial layer of the bronchioles, or in the large sublobular lesions throughout the alveoli 5.4 hepatitis B virus (jjBV) «曰' is 1.3.46 HBV The transgenic mouse model (official name, 1-3 genome) Chi46) has been previously described and can be used to test in vivo antiviral activity of test compounds as well as administration and administration protocols (see, for example, Cavanaugh et al., 1997, 71:3236_3243; and Guid〇tti 156069.doc -199- 201144296 et al., 乂Firo/., 1995, 69:6158-6169). In these HBV transgenic mice, a high degree of viral replication is present here. It occurs in the hepatic parenchymal cells of the transgenic mice and in the proximal tortuous tubules of the kidney, to the same extent as in the infected liver of patients with chronic HBV hepatitis. The age of the test compound or placebo can be used. (i.e., 6-10 weeks), gender (i.e., male), and HBV transgenic mice whose serum levels of hepatitis B surface antigen (HBsAg) have been matched, followed by antiviral activity analysis to assess the activity of the test compound Can be tested for this Non-limiting examples of assays performed with compound treated and untreated compound-treated mice include Southern analysis for measuring HBV DNA in the liver, and quantitative reverse transcriptase for measuring HBV RNA in the liver. PCR (qRT-PCR), immunoassay for measuring hepatitis E antigen (HBeAg) and HBV surface antigen (HBsAg) in serum, immunohistochemical analysis for measuring HBV antigen in liver, and Quantitative PCR (qPCR) of serum HBV DNA was measured. Visual inspection of the eye and microscope can be performed as needed. 5.5 Human Deprived Virus (HIV) An established animal model well known in the art can be used in vivo to assess the safety and efficacy of test compounds against HIV. For example, Trigamma mouse HIV-1 infection models have been developed by reconstituting irradiated normal BALB/c mice with murine SCID bone marrow and implanted human peripheral blood mononuclear cells (see Ayash). -Rashkovsky et al., 5*£5 乂, 2005, 19:1149-1151). These mice were injected intraperitoneally with T cell phagocytosis and macrophage phagocytic HIV-1 laboratory virus strain. After infection with HIV, rapid loss of human CD4+ T cells, decreased CD4/CD8 ratio, and increased T cell activity were observed in the 156069.doc •200-201144296. Test compounds can be administered to such mice, and the ability of the virus to replicate in animals treated with or without the compound can be determined using standard assays known in the art. Non-limiting examples of such assays include the COB AS AMPLICORTM RT-PCR assay (Roche Diagnostics, Branchberg, NJ) to determine plasma viral load (HIV-l RNA copy/ml); active HIV-1 viral replication assay, In this assay, human lymphocytes recovered from infected trichimeric mice are co-cultured with target T cells (ΜΤ-2 cells) and examined for HIV-dependent fusion formation; and self-infected tri-complexes Mouse-recovered human lymphocytes were co-cultured with cMAGI indicator cells, wherein HIV-1 LTR-driven β-galactosidase transactivation was measured. The amount of anti-HIV-1 antibody produced in these mice can also be measured by ELISA. The in vivo antiviral activity of test compounds can also be tested using other established mouse models described in the art (see, for example, Mosier® A &gt; Semin. Immunol., 1996, 8: 255-262; Mosier et al. People, i/ojp. Praci. (Official Edition)., 1996, 31: 41-48, 53-55, 59-60; Bonyhadi et al., Mo/. Med. 1997, 3: 246-253; Jolicoeur ^ A » Leukemia, 1999, 13:S78-S80 » Browning^ A * Proc. Natl. Acad. Sci. USA, 1997, 94:14637-14641; and Sawada et al., 丄5 jcp. Mec/·, 1998, 187: 1439-1449). The simian immunodeficiency virus (SIV) non-human primate model has also been described, for example, in Schito et al., Cwrr. 2006, 4:379-386. 5.6 Extracorporeal screening test 5.6.1 The general procedure for the detection of sore virus is to quickly screen out any of the herpes viruses that are inactive or too toxic without the 156069.doc -201 - 201144296 method of evaluation of the sample 'usually the initial use is not expensive fast Assays (such as semi-automated CPE inhibition assays) are used to screen for negatives. Typically, all screening assays are performed in low passage human cells&apos; and each assay system contains a positive control (ACV, GCV, CDV) and a negative control (AZT). Efficacy is demonstrated by at least two different assay systems that detect functional biological activity and should be confirmed using low passage clinical isolates and drug resistant mutants (as long as they are available). In the case of EBV, a hybridization assay for quantitative DNA synthesis was used to confirm the efficacy against EBV. Toxicity is determined using quiescent and proliferating human fibroblasts and proliferating lymphoblasts, and toxicity in human bone marrow and erythrocyte sputum cells is assessed for selected compounds.

5.6.1.1 HSV-1, HSV-2, CMV, and VZV select all screening assay systems utilized to demonstrate biological function, ie, specific inhibition of cytopathic effect (cpE) in susceptible human cells. In CPE inhibition assays, test compounds are added one hour before infection so that the assay system will have maximum sensitivity and detect early replication steps (such as adsorption or penetration) and inhibitors of later events. To rule out non-specific inhibition of viral-cell binding, a traditional viral plaque reduction assay was used to confirm that all compounds exhibiting reasonable activity in the assay were added to the assay for (6) hours of addition of compound m blocking attachment. The positive result will be in the CPE assay, see, but may be negative in the viral plaque assay. Under this condition, the compound added before the infection with the virus was repeatedly subjected to virus plaque inspection. The system can also be manipulated by increasing the pretreatment time, and the system displays antiviral activity by using oligodeoxynucleotide and/or form and by delaying the addition of the drug after infection. Information on which step in the life cycle of the virus (ie, early function versus late function) can be obtained. In all assays used for primary screening, a minimum dose of six compounds is included. The concentration of the core is increased by 5 times, for example, 丨〇〇 gg/ml to 〇 to measure the efficacy. S These data obtain a dose response curve. A computer software program such as VI.N. Prichard, KR Asaltine, and C. Shipman, Jr., ersity 〇f Michigan, Ann Arbor, Michigan's MacSynergy # Π is used to calculate a dose that inhibits viral replication by 50% (effective concentration 50). ; EC50). The same compound, Hando, was also used for the uninfected cells in each assay to determine the toxicity of each test compound. The concentration of the compound cytotoxic to the cells (cytotoxicity concentration 50; CC50) determined by the inability to absorb the neutral dye of the living dye was determined as described above. In some embodiments, the compounds used to treat herpes virus infection are for systemic diseases such as neonatal herpes, CMV, and disseminated VZV, and may require parenteral administration. Therefore, the toxicity of the test substance to the dividing cells was measured at the very early stage of the test. In this aspect, a cell proliferation assay using HFF cells can be an extremely sensitive assay for detecting the toxicity of a compound to dividing cells&apos; and a compound concentration (ICso) that inhibits cell growth by 5% can be calculated as described above. Compared with the four human diploid cell lines and ver〇 cells, hff cells are the most sensitive and predict the toxicity to bone marrow cells. To determine whether each compound has sufficient antiviral/linguality beyond its toxicity level, the selectivity index (SI) is calculated from CCso/ECm. This index, also known as the /σ treatment private number, is used to determine whether a compound is approved for further study. Typically, compounds that are "1 〇 or greater than 1 评估 are evaluated in other assay systems. 156069.doc • 203 - 201144296 For HSV-1 and HSV-2, use the viral plaque reduction assay to confirm the display of activity in the CPE inhibition assay. Compounds. Determination of susceptibility of selected strains of other strains (including laboratory passage isolates and clinical isolates) to selected compounds. A set of ACV-resistant HSV strains may also be utilized. For CMV, a viral plaque reduction assay is used in HFF. Compounds demonstrating activity in the CPE inhibition assay are identified in the cells. A variety of laboratory, clinical, and GCV resistant isolates can also be used for testing. For VZV, compounds active in the CPE assay are further evaluated in the viral plaque reduction assay. 5.6.1.2 Epstein-Barr Virus (EBV) The initial system to be used to determine the antiviral activity against EBV may be to generate VCA in Daudi cells using ELISA assays, using coverage ranging, for example, from 50 pg/ml to 0.03 pg/ml. Six drug concentrations. EC5G can be calculated using results obtained from untreated and drug-treated cells. The test has good activity against EB V VCA and is non-toxic. The ability of selected compounds to inhibit EBV DNA synthesis. In each assay system utilized, the drug is incorporated into uninfected cells to obtain as much toxicity data as possible. In some embodiments, for calculating SI, for toxicity The data is generally at least as reliable as the efficacy results. One example of a toxicity assay is the colorimetric method using MTS. In the hybridization assay measuring the amount of EBV DNA produced by cells infected with P3HR-1, it is confirmed that the SI is greater than, for example, in the screening assay. All compounds of 10. A wide range of compound concentrations can be utilized so that accurate EC50 can be calculated. Untreated control cells treated with compounds are also used as another measure of drug toxicity. In some cases, use for VC A production and DNA synthesis 156069.doc •204· 201144296 The results obtained may not be relevant, as the two events may be independent. 5.6.1.3 Human herpesvirus HHV-6 and HHV-8 Screening for HHV-6 Cord blood lymphocytes (CBL) and human T-cell lymphoblastoid cell lines HSB-2 and SupT-Ι were used in the process. CBL was isolated from fresh heparinized cord blood and HHV was used. The Z29 strain of -6 was infected. The body cavity-based B cell lymphoma cell line BCBL-1 was used for screening against HHV-8. There are two HHV-6 variants, called type A variants or type B variants. The type A HHV-6 variant is, for example, a GS strain that is propagated in HSB-2 or SupT-Ι cells. The type B HHV-6 variant is, for example, Z29 grown in CBL as a stock solution (ATCC, Rockville, Md). ·). HHV-8 was propagated in a latent state in the BCBL-1 cell line. The lytic growth of HHV-8 can be induced by the addition of phorbol ester TPA. Six concentrations of each drug in the range of, for example, 100 pg/ml to 0.03 pg/ml of the drug were tested to obtain EC5〇, EC9〇, CC5〇, and IC5〇 values. The initial assay for HHV-6 was flow cytometry analysis of HHV-6 antigen in HSB_2 cells (HHV-6A), CBL (HHV-6B) or SupT-1 (6A or 6B). For HHV-8&apos;, lytic infection of the virus will be performed in BCBL-1 cells as described above. The initial assay for HHV-8 was a flow cytometric analysis of HHV-8 antigen in BCBL-1 cells. For other herpes virus assays, these assays contain positive controls (infected and untreated cells) and negative controls (uninfected or uninduced cells treated with the compound) required for effective assays and cytotoxicity assays. 156069.doc •205· 201144296 5.6.2 In Vitro Laboratory Procedure for Herpes Virus Assay 5.6.2.1 Preparation of Human Foreskin Fibroblasts for Efficacy of HSV-1, HSV-2, CMV and VZV: From the University of Alabama Medicine Newborn human foreskin is obtained as soon as possible after circumcision at the University of Alabama School of Medicine (UAB) or Brookwood Hospital (Birmingham, Alabama), and placed in a vancomycin (vancomycin) ), amphotericin B, penicillin, and gentamicin in minimal essential medium (MEM), maintained at room temperature for 4 hours. The medium is then removed and the foreskin is cut into small pieces and washed repeatedly until red blood cells are no longer present. The tissue was then trypsinized with 0.25% trypsin for 15 minutes at 37 ° C in a CO 2 incubator with continuous stirring. At the end of each 15 minute period, the tissue was allowed to settle to the bottom of the flask. The supernatant containing the cells was poured into a flask containing MEM and 10% fetal calf serum (FBS) through sterile thick cotton cloth. The flask containing the medium was kept on ice throughout the trypsin treatment procedure. After each decantation of the cells, the thick cotton cloth was washed with a small amount of serum-containing MEM. Fresh trypsin was added to the foreskin sheet each time and the procedure was repeated until the cells were no longer available. The cell-containing medium was then centrifuged at 1 000 RPM for 10 minutes at 4 °C. The supernatant liquid was discarded and the cells were resuspended in a small amount of MEM with 10% FBS. Cells were counted using a Coulter Counter and then placed in an appropriate number of 25 cm2 tissue culture flasks. As the cells became confluent and required trypsin treatment, they were gradually expanded into 175 cm2 flasks. The cells were maintained on vancomycin and amphotericin B for passage three times. Use for mycoplasma DNA 156069.doc -206- 201144296

Hoechst fluorescent dyes periodically test for the presence of mycoplasma contamination of cell lines. Cells up to the 10th generation are usually used. Cytopathic effect inhibition assay: low passage (3_ 1 〇) human foreskin fibroblasts (HFF) were trypsinized 'counted and seeded in 96-well tissue culture plates at a cell concentration of 2.5 x 1 〇 4 cells Added to MEM with 1% fbs. The cells were then incubated at 37 ° C for 24 hours in a 5% C〇2-950/〇 air, 90% moisture-containing atmosphere. The medium was then removed and 1 μl of MEM containing 2% FBS was added to all wells except the first column. In the first column, 125 μL of the medium containing the test compound was added to the triple assay well. Add medium alone to the cells and virus control wells. The compound was then serially diluted 1:5 in the remaining wells of the first column of wells by transferring 25 μl using a Beckman Bio-Mek liquid handler. The plates were then incubated for 6 min and 100 μM of the appropriate concentration of virus was added to each well except for the control wells receiving 1 μl of MEM. For HSV-1 and HSV-2 assays, the virus concentration used was 1000 viral plaque forming units per well (pFUp for CMV and VZV assays) added virus concentrations of 2500 PFU and 1000 PFU per well, respectively. The plates were incubated for 3 days (for HSV-1 and HSV-2), 10 days (for VZV) or 14 days (for CMV) in a C〇2 incubator under C. After the incubation period, 'suck the medium' and use 〇 • 1% crystal violet fumarine (f〇rmalin) solution stained the cells for 4 hours. Then remove the dye and rinse the tray with tap water until all excess dye was removed. Dry the tray for 24 hours and use Bi〇Tek The disc type automatic reader measures the amount of CPE in each column. The EC5Q and IC5G values are determined by comparing the treated cells with the untreated cells using a computer program. The virus plaque production test of HSV-1 and HSV-2: Two days before use, 156069.doc -207- 201144296 HFF cells were trypsinized, counted, and applied to a 6-well plate and incubated at 37 ° C, 5% (: 〇 2 and 90% humidity). Prepare a compound in 2 χ MEM at a concentration twice the desired degree, then Serial dilutions of 1:5 in 2X MEM. The concentration of the compound used is usually 200 pg/ml as low as 〇.〇6 pg/m b will be used in MEM containing i〇〇/0 FBS. The virus was diluted to the desired concentration, thereby obtaining 2 〇 3 病毒 virus plaques per well. Then the medium was aspirated from the wells and 〇 2 ml of virus was added to each well in triplicate' and 0.2 ml of medium was added. The drug was toxic in the wells. The plate was then incubated for 1 hour under a 15 minute shake. After the incubation period, an equal amount of 0/〇 agarose was added to an equal volume of each compound dilution. This was provided at 1 〇〇pg/ The final compound concentration starting at 0.03 pg/ml and the final agarose coating concentration at 5% 5%. The compound agarose mixture was applied to each well in a 2 ml volume and the dish was incubated for three days. The cells were stained with 中5〇/. Neutral red solution. At the end of the 4-6 hour incubation period, the dye was aspirated and the viral plaques were counted using a stereomicroscope at ι〇χ magnification. Spot generation test: the program is almost the same as the program provided for Hsv' There are a few minor changes. The agarose used in the initial overcoat and the two subsequent overcoats is 0.8°/. instead of 1%. The test is incubated for 14 days, on the 4th and 8th days, other lml overcoats are applied. Layer vzv virus plaque production assay: The procedure is essentially the same as that described for HSV virus plaque assay with the following possible exceptions: after compound addition, the dishes are incubated for 1 day; days 3 and 6 Day, add another one with the same amount of 2 χ MEM and 1% agarose! Ml overcoat. Viral plaque reduction assay: In some cases, some of the larger or higher charge molecules active in the cpE inhibition assay 156069.doc -208- 201144296 may be inactive in viral plaque assays because The compound did not diffuse through the agarose overcoat. Therefore, confirmation can be made using a modified virus plaque assay in which the overlying medium is liquid rather than semi-solid. The procedure for the liquid coating virus plaque assay is similar to the procedure for using the agarose overlay. The procedure for adding a virus is the same as for the routine virus spotting assay. Compounds of the desired concentration were placed in MEM with 2% FBS. For the HSV-1 and HSV-2 assays, the antibody preparations obtained, for example, from Baxter Health Care Corporation were diluted 1:500 and added to the medium diluted with the compound to limit the extracellular spread of the virus through the medium. For VZV and CMV, there must be no antibodies in the upper coating. For the CMV and VZV assays, additional medium containing no new compounds was added on day 5 and incubated for a total of 8 days and 10 days, respectively. At the end of all assay incubation periods, 2 ml of a 6.0% neutral red solution was added to each well and incubated for 6 hours. The liquid was then aspirated and the virus stain was counted using a stereomicroscope. 5.6.2.2 Screening for Efficacy of EBV Cells: Two lymphoid cell lines, Raji and Daudi from Burkitt's lymphoma, were used. Raji cell lines are non-producers of viral gene products associated with the productive viral cycle. The Daudi cell line is a low level producer, i.e. less than 1°/. The cells spontaneously express EA. These cells are equally susceptible to P3HR-1 viral superinfection as determined by EBV VCA performance. The cells were maintained at 37 ° C with a moisture atmosphere of 5% CO 2 , with 10% heat inactivated FBS, 100 u / ml penicillin, 25 pg / ml gentamicin and 2 mM L-glutamine Acid 156069.doc -209- 201144296 RPMI-1 640 medium was cultured together. Cells were passaged twice weekly and the cell concentration was adjusted to 2 x 106/ml for use. Virus: The following prototypes of infectious EBV can be used: (1) a virus derived from the supernatant fluid of the P3HR-1 cell line, which produces a non-transformed virus that induces VCA production after a primary infection or repeated infection of the B cell line; (2) B95-8 virus, which immortalizes cord blood lymphocytes and induces tumors of the velvet, but does not induce abortive productive infection even in a cell line having a EBV genome replica. For example, to generate virus, P3HR-1 cells at a concentration of 2 x 105/ml were cultured in a medium containing 2% FCS for two weeks at 34 ° C in a moisture atmosphere of 5% CO 2 . The concentrated virus was then prepared from the supernatant of the culture by centrifugation at 12,000 g for 90 minutes in a Sorvall centrifuge. The pellets were resuspended in RPMI-1640 medium in the original volume of 1/1 Torr and stored at -70 °C. Antibody: Murine monoclonal antibody against EBV VCA (Chemicon International, Inc., Temecula, Calif.) was used in immunofluorescence assays and ELISA. For each assay system, the optimal single antibody concentration was determined by antibody titration. For single fluorescent dye analysis, FITC-labeled goat anti-mouse total IgG (Southern Biotechnology Associates, Birmingham, Ala.) was used as the second antibody. EBV repeat infection and compound treatment: Repeated infection was initiated by incubating 0.5 ml of the appropriate concentration of EBV with 106 cells/tube for a total of 1 ml/tube. In most cases, this achieves an infection rate (MOI) of 0.1-0.2 based on VCA induction in Daudi cells. After adsorption at 37 ° C for 1 hour, 3 ml of RPMI-1640 medium was added. The cells were granulated by centrifugation and the supernatant was discarded. 156069.doc • 210· 201144296 solution. Add 4 ml of RPMI-1640 containing a concentration of compound (0.08, 0.4, 2, 10, 50 pg/ml) to a suitable tube. rpmI-1640 was added to the positive and negative control tubes, and each concentration of compound was added to virus-free Daudi cells for toxicity control. After incubation, the cells in each tube were counted using a Coulter counter and washed three times with phosphate buffered saline solution (PBS) (without Ca and Mg). Each cell suspension was adjusted to a concentration of 4.〇χ106 cells/ml in PBS. For EBV IFA and DNA hybridization assays, two sets of slides were prepared for each cell suspension using 4x1 〇 4 cells/spot and air dried overnight. Immunofluorescence assay: The infected and compound-treated cells were counted and washed three times with PBS, and 4 x 104 cells containing PBS were spotted on a multi-well slide and air dried. The cells were then fixed in propanil for 1 minute, washed in PBS, and stained with mouse monoclonal antibody and FITC-labeled goat anti-mouse IgG for immunofluorescence analysis. EBV VCA-specific antibody was used in the immunofluorescence assay. FITC-labeled goat anti-mouse IgG (Southern Biotechnology Associates, Birmingham, Ala.) was used as the second antibody. Slides were stained with 0.1% Evans Blue (Evan, sblue) for 5 minutes and embedded in pBS containing 10 〇/〇 glycerol. The number of FITC positive cells on each smear was determined using a Nik〇n camp light microscope. Five cells in each spot were counted. The number of cells expressing EBV VCA was calculated by multiplying the fraction of antigen-positive cells by the number of cells per ml in the culture at the time of collection. A computer program was used to plot the concentration of the compound versus the number of antigen-positive cells per ml, and the EC5q and EC9q values were calculated. ELISA: Daudi cells infected with P3HR-1 virus and drug-treated 156069.doc -211 - 201144296 were collected by centrifugation and washed three times with PBS. The cells were pelleted and suspended in PBS to a concentration of 4 x 106 cells/ml. 1 〇〇 μ丨 of each suspension was dispensed in triplicate in 96-well plates, air dried and fixed with 95% ethanol and 5% acetic acid. Uninfected cells were prepared in the same manner and used as a control. After washing the tray, primary antibodies and secondary antibodies diluted in 1% bovine serum albumin containing 0.05% Tween-20 were sequentially added to each well and incubated at room temperature. Washing was carried out 3 times with PBS containing 0.005% Tween-20 between antibody additions. 0-phenyldiamine (〇pd) was added and the reaction was stopped with 3N ΗβΟ4 after about 1 min. Optical density was measured at 492 nm and EC50 was estimated using the computer software program described herein » Evaluation of antiviral agents against EBV DNA replication: Enzo simple sensitivity to horseradish peroxidase against EBv (: in situ Detection system (Enz〇

Diagnostics, Farmingdale, N.Y.) to determine the antiviral activity against DNA synthesis. Detection and staining according to the manufacturer's instructions. Three days after repeated infection and compound treatment, slides were prepared for each cell suspension using 4 X 4 cells/spots and air dried overnight. The slides were fixed in acetone for 10 minutes. Biotin-labeled EBV probes were added to each spot of the fixed cells and the slides were covered with a glass cover slip. The slide was then heated on a hot plate at 95 for 5 minutes. After heating, the slides were placed on a slide warmer at 37 t for 30-60 minutes to allow the DNA to adhere. The cover slip is then removed and the post-hybridization reagent is added to each spot. After incubation for 1 minute and washing with washing buffer, the coating was tested. The detection reagent is allowed to remain on the slide for 30-60 minutes on a slide warmer, followed by washing with a wash buffer. The chromogen receptor solution was added and incubated on a slide warmer for 2 Torr. The slides were washed and the counter was stained with a 156069.doc -212· 201144296 blue contrast dye. The slides were then rinsed with deionized water and sealed with water. The slides were examined under an optical microscope at 40 〇 x magnification. Positive cells appear as red spots. Count all cells in several fields. The fraction of red spots in the total number of cells counted multiplied by 100 reflects the percentage of hybridization. Primary infection assay: Umbilical cord blood lymphocytes were initially infected with EBV transformed strain B95-8 to induce the expression of virus-associated nuclear antigen (EBNA) in the cells. It is also known that the B95-8 virus induces DNA synthesis after infection with CBL. The availability of EBNA virus-infected cells in culture allows identification and quantification of EBV-positive cell antigens by indirect IFA staining and FACS. Cord blood lymphocytes isolated by a ficoll-hypaque gradient were cultured in complete RPMI-1640. By 1 厘 1-1640 and 10. 695-8 cell line was grown in the fetal bovine serum for 10-14 days to produce EBV-B95-8. The supernatant was collected and stored at 〇-4 °C. One to six CBLs were infected by incubation with 1 ml of B95-8 supernatant for 1 hour. Remove the virus by centrifugation. After washing once with RPMI-1640, the infected cells were treated with antiviral compounds as previously infected with P3HR-1. The cell culture was incubated for 4-6 days. Cell collection and immunofluorescence staining were the same as described above. 5.6.2.3 Screening for the effects of jjhV-6 and HHV-8 Screening cord blood lymphocytes: Fresh heparinized cord blood can be obtained, for example, from the Birminghain Hospital at the University of Alabama, and Hank is used. The balanced salt solution (Hank's balanced salt s〇luti〇n) was diluted 1:1 and layered on a Histopaque 1077 (Sigma Chemical Co., St. 〇uis, μ〇·) gradient. The tube was centrifuged at 156069.doc -213-201144296 1600 rpm for 30 minutes at room temperature, and the serum was carefully aspirated. Lymphocytes were removed, washed with Hank's balanced salt solution, and centrifuged at 1200 rpm for 10 minutes. The supernatant was aspirated and the cells were resuspended in 10% heat-inactivated FBS, 2 mM L-glutamic acid, 100 U/ml penicillin, 0.25 pg/ml amphotericin B, 25 pg/ml Qingda RPMI 1640 in 0.1 U/ml interleukin-2 (Sigma, St. Louis, Mo.) and 0.5 pg/ml Phaseolus Vulagaris agglutinin protein (PHAP). CBL was used in the HHV-6 and Z-29 (variant B) assays. Human T cell lymphoblastoid cell line HSB-2: HSB-2 cells can be obtained, for example, by the NIH AIDS Research and Reference Reagent Program (Rockville, Md.), and contain 10% heat inactivated FBS, 100 U/ml penicillin Reproduction in RPMI 1640 with 25 pg/ml gentamicin and 2 mM L-glutamic acid. The cells were split 1:5 in a 175 cm2 flask every 3-4 days and used in the HHV-6, GS (variant A) assay. Body cavity-based lymphoma (BCBL-1) cells: used in HHV-8 assays with 10% FBS, 2 mM L-glutamic acid, 10 μΜ β-mercaptoethanol, 100 μl penicillin and 25 gg BCBL-1 cells (NIH AIDS Research and Reference Program, Rockville, Md.) propagated in RPMI 1640 medium of ng gentamicin. Virus: There are two variants of HHV-6, called type A variants or type B variants. An example of a Type A HHV-6 variant is the GS strain, which is propagated in HSB-2 cells and is available, for example, in the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, NIH. These cells (referred to as HSB-2/HHV-6GS) were maintained at 5χ105 cells/ml at 156069.doc •214- 201144296

Under the same conditions and in the same medium as uninfected HSB-2 cells. The cells were divided every 3-4 days by adding 9 uninfected cells to 1 infected cell. The stock price of the lxlO5 of the virus in the cell-associated virus and the cell-free virus can be obtained by growing for 5 days. An example of a Type B HHV-6 variant is Z29 (ATCC, Rockville, Md.) which is grown as a stock solution in CBL by incubation for 10 days, followed by collection, centrifugation and cold to supernatant. By adding 100 ng/ml phorbol 12-myristate 13-acetate, it is potentially expressed in BCBL-1 cell lines derived from primary exudative lymphoma. HHV-8 in the NIH AIDS Research and Reference Program, Rockville, Md. was induced to be lytic HHV-8. BCBL-1 cells were cultured in RPMI 1640 medium containing 10% FBS, 2 mM L-glutamic acid, 10 μM β-mercaptoethanol, 100 U/ml penicillin, and 25 pg/ml gentamicin. Primary antibodies: Primary antibodies for indirect IFA and FACS were selected for antigen specificity, low cross-reactivity with other herpes viruses, and fluorescence intensity as monitored by FACS. Individual antibodies selected for use in the HHV-6 assay system were screened for variant specificity and no cross-reactivity of A or B variants was confirmed in the assay system. Monoclonal antibody 8532 (Chemicon, Temecula, Calif.) targeted HHV-6-induced early nuclear protein and was used as a primary antibody at a concentration of 5 pg/ml in the HHV-6GS assay system. The monoclonal antibody 8535 (Chemi con, Temecula, Cal if.) targeting the B variant 101 kDa viral particle protein was used as a primary antibody at a concentration of 5 pg/ml in the HHV-6Z-29 assay system. HHV-8 monoclonal antibody KS8.1 (Bala Chandran, University of Kansas Department of Microbiology, Molecular Genetics and 156069.doc -215 - 201144296

Immunology) targets HHV-8 viral membrane-associated glycoprotein 8.1 (Zoeteweij et al., 1999) at the late lytic phase of HHV-8 replication and is used at about 5 pg/ml. The monoclonal antibody against EBV VCA glycoprotein 125 (Chemicon, Temecula, Calif.) was used for ELISA at a concentration of 2.5 pg/ml and for IFA at a concentration of 5 pg/ml. Effect against HHV-6: A 5-fold dilution of the drug starting at 50 pg/ml was prepared in the medium. CDV was used as a positive control. A sample for measuring antiviral efficacy was prepared by incubating lxl06 cells with a virus sufficient to infect about 35% of the cells. After infection, appropriate dilutions of the compound are added and the cells are incubated at 37 °C for 4 to 6 days. A virus-free control was prepared by incubating lxl06 cells in a compound-free medium for a specified period of time, and incubation was carried out for 1 hour in a compound-free medium by incubating 6 cells with a virus sufficient to infect 35% of the cells for 1 hour. To prepare a virus control. After incubation, the cells were washed with PBS and permeabilized overnight in methanol at -80 °C for use in FACS. FACS assay: Cells were washed well with PBS and blocking solution containing 5% FBS, 4% normal goat serum (NGS) and 0.5% DMSO. The cells were then incubated with appropriate monoclonal antibodies (HHV-6 early nuclear protein (Chemicon, Temecula, Calif.) against HHV-6, GS variant A, and 101 kDa virions against HHV-6, Z-29 variant B. Egg. White (Chemicon, Temecula, Calif), and KS8.1 (Bala Chandran, University of Kansas, Department of Microbiology, Molecular Genetics and Immunology) for HHV-8. 5.6.2.4 Toxicity against herpesvirus Screening 156069.doc -216- 201144296 Neutral Red Absorption Assay - HFF cells: HFF cells were plated at a concentration of 2.5 X 104 cells/well in 96-well plates 24 hours prior to assay. After 24 hours, the medium was aspirated. And add 125 μΐ of each compound to the first column of wells, then serially dilute 1:5 using an automated Bio-Mek liquid handling system in a manner similar to that used in the CPE assay. The plate is then at 37 ° C. Incubate for 7 days in a C〇2 incubator. At this point, aspirate the medium/compound and add 200 μl/well of DPBS containing 〇·〇ι〇/0 neutral red. Incubate the mixture in a CO 2 incubator 1 hour. Aspirate the compound and wash with Nunc disk Wash the cells. After removing the DPBS wash, add 200 μl/well 50% ETOH/1% glacial acetic acid (in Η quot). Rotate the plate for 15 minutes and read on a disk reader at 550 rim Take the optical density. Calculate the cc50 value using a computer program. Cell proliferation assay - HFF cells: Inoculate HFF cells at a concentration of 2.5\104 cells/well in a 6-well plate containing 1%%?38 24 hours before the assay. In MEM, the test compound was serially diluted in the range of 100 Mg/ml to 〇.〇3 pg/ml in 110/〇FBSiMEM containing 1〇0/〇FBSiMEM. It must be dissolved in DMS0. For the compound, the control wells received MEM containing 1.0% DMSO. The medium was then aspirated from the wells, followed by the addition of 2 ml of each compound to each well. Then at 37«&gt;c under the c〇2 incubator Incubate the cells for 72 hours. At the end of this time, remove the medium_compound solution and wash the cells. Add 1 ml of 〇25% trypsin to each well and incubate until the cells start to detach from the plate, then vigorously pipe up and down (pipette) a cell-medium mixture to disperse the cell suspension, and Add 〇.2 m-1 mixture to 9.8 ml Is〇t〇n m and count using a Coulter counter. Each sample was counted 3 times for each sample using 2 parallel assay wells. 156069.doc • 217· 201144296 MTS tetracystic cytotoxicity assay: A 5-fold dilution of the test compound starting at 50 pg/ml was prepared in medium and added to 1χ1〇6 cells. A control was prepared by incubating 1 χ 1 〇 6 cells in a compound-free medium. After the 3-6 day incubation period, 2 〇〇 μΐ was transferred to a 96-well plate in duplicate. 2 〇 μΐ MTS was added, and the disk was wrapped in a foil and incubated at 37 ° C for 4 hours. The MTS organism is reduced to a water-soluble purine by a dehydrogenase found in metabolically active cells. The amount of formazan product measured by the amount of absorbance of 49 〇 ηπι is directly proportional to the number of viable cells in the culture. A plot of compound concentration versus optical density for each sample was plotted and CC5 was calculated using MacSynergyll. value. Cell proliferation assay - HSB-2 and Daudi cells: A 5-fold dilution of the compound starting at 50 pg/ml was prepared in the medium and added to ιχ1〇6 cells. A control was prepared by incubating ixl 〇6 cells in a compound-free medium. The total number of cells (HSB-2 and Daudi cell lines) of each sample was determined using a Coulter counter after the 3-4 day incubation period depending on the assay system. A plot of compound concentration versus total concentration of cells for each sample was plotted and ic50 values were calculated using MacSynergy II. Bone Marrow Assay: In vitro toxicity can be determined by inhibiting the formation of bone marrow [granulocyte/macellane cell formation unit (CFU-GM)] and red blood cell [erythrocyte outbreak formation unit (BFIJ-E)] communities in a soft agar pure assay. . Using a 21-23 gauge needle attached to a syringe, the striated animal bone marrow was collected from the leg bone of a rat or mouse by rinsing with Isocoves' Modified Dulbecco's medium 'IMDM' cell. A single cell suspension is obtained by repeated aspiration through a needle. The nucleated cells were counted with blood cells and adjusted to the desired cell concentration in 156069.doc •218- 201144296 IMDM. Murine CFU-GM assay was performed with 2.5 nucleated cells/ml, 20% FBS, 10 ng/ml rmGM-CSF and 0.2% agarose. BFU-E culture including 30% FBS, 1% deionized BSAO .1 mM 2-ME'4 U/ml rhEp〇' 10 ng/ml rmIL-3'2.5x 105 nucleated cells/ml and 0.2% agarose (140) ^ containing 0.1 ml of compound (1 〇χ) Triple assay wells (in a 6-well plate) received 1 ml of each culture mixture in each concentration group and mixed slowly. The culture was gelled at 4 ° C, followed by incubation for 7 days (CFU-GM) or 9 days (BFU-E) in a humidified atmosphere of 5% CO 2 in air at 37 °C. The population was counted using a flip-chip microscope. The CFU-GM community was identified as a cell line containing at least 4 cells. BFU_E cultures were stained with dianisidine and more than 6 agglutinated cells containing hemoglobin cells were counted as red blood cell populations. The linear regression analysis of the logarithm of the compound concentration relative to the CFU_GM or BFU_E survival fraction yielded a median inhibitory concentration (IC5〇) and a 9〇% inhibitory concentration (IC9〇). 5.6.3 In Vitro Laboratory Procedure for Influenza Virus, Respiratory Virus and Other Virus Assays 5·6·3·1 Screening for RSV, ριν&amp;ρι “Measles Virus SARS ' VEE - ^MM Virus, West Nile Virus, Pichin The efficacy of the German virus, Puntatoro virus and dengue virus is quickly determined by the selection of the test: when a relatively large number (1 or more) of the test compound can be (IV) 'evaluated in the double concentration test. In this procedure In the test, two concentrations were tested (eg 2 / / „11 and 2 〇 to /1111). Dilute the compound 1:2 when adding the virus to a final concentration of 100 pg/ml and 10 156069.doc •219· 201144296

Mg/ml. Standard cpu try to use the 18-hour monolayer (8〇1〇〇% confluence) of appropriate cells to drain the medium and add test compounds or placebo at each concentration, followed by the addition of virus or virus diluent within 15 minutes. For antiviral and cytotoxicity tests, two wells were used for each concentration of compound. The disc is sealed and incubated to induce a standard period of time required to approach the maximum viral CPE. The disk is then stained with neutral red by the method described below, and the absorbance percentage indicating the living cells is read on the micro-disc automatic reader at two wavelengths of 405 nm and 54 〇 nm, using the difference Eliminate the background. The approximate 5 〇 % endpoint viral inhibitory concentration (ECw) and 50% endpoint cytostatic concentration (IC5G) were determined from which the general selectivity index was calculated: si = (IC5q) / (EC5q). A 3 or greater than 3 is usually indicated to require a confirmatory test. Inhibition of cytopathic effect (CPE): This test was performed in a 96-well flat-bottom microtiter plate for initial antiviral evaluation of all new test compounds. In this CPE inhibition test, four 1 〇 〇 dilutions (eg, 1000, 100, 10, 1 Mg/ml) of each test compound were added to 3 cups containing cell monolayers; within 5 minutes' The virus was then added and the plate was sealed, incubated at 37 deaths and the CPE was read microscopically when the untreated infected control developed 3 to 4+ CPE (about 72 to 120 hours). Known positive control compounds were evaluated in parallel with the test compounds in each test. Positive control compounds are, for example, ribavirin, for dengue virus, influenza virus, measles virus, RSV, Ply, Pichind virus, Punta Toro virus and VEE virus; cidofovir, for adenovirus; pirodavir (pirodovir), for rhinovirus; 6-aza uridine, for West Nile virus and yellow fever virus; and alpha interferon (aIferon) (interferon α-η3)' for 8-step disease #. Use the (4) method in the initial screening test 156069.doc -220- 201144296 to find active compounds for follow-up testing, but for each dilution in 4 cups containing cell monolayers use 8 of the two compounds of each compound A log10 dilution. Data are expressed as 50% effective concentration (EC50). Neutral Red (NR) Dye Absorption Increase: This test was performed to verify the observed CPE inhibition in the initial test and the same 96-well microtiter plate was utilized after the CPE had been read. Neutral red is added to the medium; cells that are not damaged by the virus absorb a larger amount of dye, which is read on a computerized micro-disc automatic reader. For example, a method such as that described by McManus, EwWrowmewi. MicroHo/. 1976, 3 1:35-38 can be used. From this dye absorption test EC5〇. Reduced virus yield: If additional fresh material is available, use CPE inhibition and use the same disc to test the effect of compounds that are considered active by CPE inhibition and absorption by NR dye on the reduction in virus yield. This is achieved by serially diluting into a single layer of susceptible cells and verifying the viral power of the frozen and thawed eluate from each cup. The appearance of CPE in these cells indicates the presence of an infectious virus. As in the initial test, known active compounds were operated in parallel as a positive control. From this data, a 90% effective concentration (EC9Q) was determined which is the concentration of the test compound which inhibits the viral yield by 1 loglO. 5.6.3.2 Screening for toxic visual observations of RSV, PIV and Flu, measles virus, 'SARS ' VEE ^ virus, West Nile virus, Pichind virus, Punta Toro virus and dengue virus: in the CPE inhibition test, The infected and treated wells were operated in parallel with two wells of 156069.doc 221· 201144296 of uninfected cells treated with each concentration of test compound. At this time, CPE was measured by microscopy, and any change in the appearance of the cells of the toxic control cells compared to the normal controls operating in the same dish was also examined microscopically. Such changes can be swelling, granulation, cells with jagged edges, membranous appearance, rounding, detachment from the pore surface, or other changes. These changes are provided by the following symbols: D(丨〇〇% toxicity), PVH (partial toxicity·very severe toxicity -80%), PH (partial toxicity_heavy toxicity·6〇%), p (partial toxicity -40%) ), PS (partial toxicity _ light toxicity 〇 2%) or 〇 (non-toxic _ 〇%), consistent with the degree of cytotoxicity observed. The 50% cytostatic (cytotoxic) concentration (IC50) was determined by regression analysis of this data. Neutral Red Absorption: In the anti-viral test neutral red dye absorption period described above, the two toxic control wells also received neutral red and the degree of color intensity was determined spectrophotometrically. Subsequent determination of neutral red viable cell counts: The effect of compounds considered to have significant antiviral activity on cell growth in the initial CPE &amp; NR test was retested. In this test, cells were seeded with 96-well tissue culture dishes (sufficient to reach about 2% confluence in the wells) and exposed to varying concentrations of test compound while the cells were rapidly split. The plates were then incubated at 37 ° C for 72 hours in a C 2 incubator, at which time a red color was added and the degree of color intensity indicative of the number of viable cells was determined spectrophotometrically; IC50 was determined by regression analysis. Data analysis: The antiviral activity of each test compound is expressed as the selectivity index (SI), which is IC5Q or 1C9 〇 divided by EC5 〇. In general, si is 1 〇 or greater than 1 〇 indicates positive antiviral activity, but other factors are also considered, such as a low SI of the positive control, which can be evaluated for other strains of the original virus that is suppressed, with an SI value of 10 or greater. The compound is used to more fully determine the range of activity of the compound against 156069.doc • 222- 201144296 virus. The general procedure for ort pox virus assays, in order to rapidly screen for compounds that are inactive or too toxic for any herpes virus without evaluation, the initial material is tested as a semi-automated cpE inhibition assay to screen for negative compounds. Typically, all screening assays are performed in low passage human cells, and each assay system contains a positive control (cdv) and a negative control (ACV). Efficacy is demonstrated by at least two different assay systems that detect functional biological activity • and should be confirmed using low passage clinical isolates and drug resistant mutants (if available). In the case of vaccine virus (v = virus (CV), other isolates are used to confirm the efficacy against vv. The use of quiescent and proliferating human fibroblasts and proliferating lymphoblasts to determine toxicity, and for selected compounds, assessment It is toxic in the bone marrow and red blood cell progenitor cells of the tooth. 5·6.4,1 Screening for VV and CV Initially, the CPE assay is used to screen compounds for activity in HFF cells. The force is displayed in other assay systems. Compounds, it is possible to carry out further tests in two other cell lines, Vero and MRC_5, and against other strains of the virus. The screening assay system used is selected to demonstrate biological function, ie cytopathic effect in susceptible human cells. Specific inhibition of (cpE). In the CPE inhibition assay +, add test compound 1 hour before dyeing, so that the assay system will have maximum sensitivity and detect early replication steps (such as adsorption or penetration) and later events Inhibitors. To exclude non-specific inhibition of virus-to-cell binding, use traditional viral plaques to demonstrate reasonable activity in C. All compounds. In this: Dinglai = 156069.doc -223 - 201144296 Add drugs 1 hour after infection. These assay systems can also be manipulated by increasing the pretreatment time to use oligodeoxynucleotides and/or peptides. Demonstrate antiviral activity. By delaying the time of drug addition after infection, information on which step in the viral life cycle (ie, early function versus late function) can be obtained. Direct inactivation assay can be used to determine selected compounds. Virucidal activity. Efficacy: In the assay for primary screening, usually a minimum of six phlegm concentrations are used to cover, for example, 1 〇〇mg/mi to 〇.〇3 mg/ml in 5x increments. The data can be used to generate dose response curves. From this data, computer software programs such as MN Prichard, KR Asaltine and C. Shipman, Jr., University of Michigan, Ann Arbor, Michigan, MacSynergy II are commonly used to calculate viral replication inhibition. 5% by weight (effective concentration 50, EC50). Toxicity: The same compound concentration used to determine efficacy was also applied to uninfected cells in each assay. The toxicity of each test compound was determined. The concentration of the compound cytotoxic to the cells (cytotoxicity concentration 5 〇; CC50) determined by the inability to absorb the neutral dye of the living dye was determined as described above. Neutral red absorption assay can be used. The assay is reproducible and allows for quantification of toxicity based on the number of viable cells rather than cellular metabolic activity. In some cases, the toxicity of new compounds to dividing cells is determined at very early stages of testing. Cell proliferation assay using HFF cells is detectable Sensitive assay for measuring the toxicity of compounds to dividing cells β The concentration of the compound that inhibits cell growth by 50% (IC5〇) was calculated as described above. Compared to four human diploid cell lines and Vero cells, HFF cells are known to be extremely sensitive and predictive of toxicity to bone marrow cells. 156069.doc • 224· 201144296 5.6.4.2 Confirmation of Verification of VV and CV Antiviral activity. A compound showing activity in a cpE inhibition assay was confirmed using a viral plaque reduction assay. The susceptibility of other viral strains of vv, CV and activity in other cell types can also be determined for selected compounds. Toxicity: In addition to the toxic components incorporated into each assay system, a standardized cytotoxicity assay using live dye uptake (neutral red) was performed within 7 days of compound exposure to confluent non-dividing cells. This test quantifies direct cytotoxicity φ (CC5❶). In this regard, the neutral red absorption assay is reproducible and allows for quantification of toxicity based on the number of viable cells rather than cellular metabolic activity. In some cases, the toxicity of new compounds to dividing cells was determined at very early stages of testing. The cell proliferation assay using HFF cells was performed to detect the sensitivity of the compound to the virulence of the dividing cells, and the concentration of the compound which inhibited cell growth by 5% was calculated as described above (IC5〇). S.6, 5 Orthopox virus assay for live hip laboratory procedures 5·6·5,1 for VV and CV effects • Selection of human foreskin fibroblasts (HFF): after circumcision

Fresh human foreskins were obtained as quickly as possible and maintained in minimal essential medium (MEM) containing common concentrations of vancomycin, amphotericin, penicillin and gentamicin for 4 hours. The medium was then removed, the foreskin was cut into small pieces and washed repeatedly with phosphate buffered saline (pBS) lacking calcium and magnesium (PD) until red blood cells were no longer present 8 followed by 3 7 . (: In the C02 incubator, the tissue was trypsinized for 15 minutes with 0.25%/〇 trypsin under continuous stirring. At the end of each 15 minute period, the tissue was allowed to settle to the bottom of the flask. Pour into a flask containing MEM 156069.doc • 225· 201144296 and ιοο/ fetal calf serum via sterile thick cotton cloth. Keep the flask containing the medium on ice throughout the trypsin treatment procedure. Wash a thick cotton cloth with a small amount of serum-containing MEM. Add fresh trypsin to the foreskin each time and repeat the procedure until all tissues are digested. Then centrifuge the cell-containing medium at 1000 RPM for 10 minutes at 4 °. Discard the supernatant. The liquid was resuspended in a small amount of MEMt with 10% FBS. The cells were then placed in an appropriate number of 25 cm2 tissue culture flasks. When the cells became confluent and required trypsin treatment, they were expanded into larger flasks. Keep the cells on vancomycin and amphotericin B for four passages and maintain on penicillin and gentamicin. Usually only used until Cells from the 10th generation. Cytopathic effect inhibition assay: Low-passage hFF cells were seeded at a cell concentration of 2.5×10 5 cells/ml in a 96-well tissue culture plate at a concentration of 2.5×10 5 cells/ml. FBS in MEM. The cells were then incubated in a C〇2 incubator for 24 hours at 37 ° C. After incubation, the medium was removed and 125 ml of the test compound was added to the first column of the triple assay well, all other wells. There is 100 1111 containing 20/0?88 of 1^1^. Then, by using 〇]^, transfer 25 ml at 2000 laboratory automation workstation to serially dilute the compound in the remaining pores of the first column of pores. After the compound, add 1 〇〇 of the appropriate concentration of virus to each well except for the control wells of 1 〇〇 ml MEM. The virus concentration used was 1 〇〇〇 PFU per well, followed by C02 at 37 ° C. The plates were incubated for 7 days in the incubator. After the incubation period, the medium was aspirated and the cells were stained for 4 hours with a 3% hummarine solution of 结晶j % crystal violet. The dye was removed and the tray was rinsed with tap water until all excess was removed Dye so far. Dry the plate for 24 hours' Then, at 620 nm, read 156069.doc -226· 201144296 on the BioTek multi-disc automatic reader. The ec5G value was determined by comparing the compound treated cells with the untreated cells using a computer program. Test: HFF cells were applied to 6-well pans two days before use and incubated at 37 ° C, 5% (: 〇 2 and 90% humidity). On the day of the assay, two concentrations of the desired concentration were prepared in 2 χ MEM. The compound was multiplexed and serially diluted 1:5 in MEM using 6 compound concentrations. The initial starting concentration is usually from 200 mg/ml as low as 〇.〇6 mg/ml. Dilute the virus to be used to the desired concentration in φ MEM containing 1% FBS, which will result in 20-30 viral spots per well. Then aspirate the medium from the well and add 0.2 ml in duplicate. The virus was added to each well to add 〇2...medium to the drug toxic wells. The plates were then incubated for 1 hour under shaking every 15 minutes. After the incubation period, an equal amount of 1% agarose was added to an equal volume of each compound dilution. This addition resulted in a final compound concentration starting at 100 mg/ml and ending at 〇.03 mg/mi and a final agarose coating concentration of 0.5%. The compound/agarose mixture was applied to each well in a volume of 2 ml and the dish was incubated for 3 days, after which the cells were stained with a neutral red solution of 0.01% solution in phosphate buffered saline. After 5-6 hours of incubation, aspirate the dye and use! Viral plaques were counted by a stereomicroscope at a magnification of 。. S.6.5.2 Toxicity Screening for VV and CV Neutral Red Absorption Assay: HFF cells were applied to 96-well plates at a concentration of 2.5 X 1 〇 4 cells/well 24 hours prior to assay. After 24 hours, the medium was aspirated and 125 μM compound was added to the first column of wells and serially diluted 1:5 using a BioMek 2000 laboratory automation workstation in a manner similar to that used in the cpE assay. After the addition of the compound, the plate was at 37. 〇下下c〇2 incubator 156069.doc -227- 201144296 7 days of incubation. At this time, the medium/compound mixture was aspirated, and 200 μl/well of PBS containing 〇·〇 1% neutral red was added. This mixture was incubated in a CO 2 incubator for 1 hour. The dye was aspirated and the cells were washed using a Nunc disk scrubber. After removing the PBS, 200 μl/well of 50% ETOH/1% glacial acetic acid (in H20) was added. The disc was rotated for 15 minutes' and the optical density was read on the disc reader at 540 nm. The EC5G value was determined by comparing the compound treated cells with the untreated cells using a computer program. Cell proliferation assay: HFF cells were seeded at a concentration of 2.5 χ 104 cells/well in MEM containing 1 〇〇/〇 FBS in a 6-well plate 24 hours prior to assay. The compound was serially diluted in the range of 1 〇〇 mg/ml to 0.03 mg/ml in a 1:5 increment in the MEM containing 10% FBS on the day of the assay. For drugs that must be dissolved in DMSO, the control wells received MEM containing p/0 DMSO. The medium was aspirated from the wells, and then 2 ml-concentration of each drug was added to each well. The cells were incubated for 72 hours at 37 ° C in a C 2 incubator. At the end of this time, the medium-compound solution was removed and the cells were washed. Add 1 ml 0.25°/. Trypsin is added to each well and incubated until the cells begin to detach from the disk. The cell-medium mixture was then vigorously pipetted up and down to disperse the cell suspension, and 0.2 ml of the mixture was added to 9.8 ml of Isoton III and counted using a Coulter counter. Each sample was counted 3 times for each sample using 2 parallel assay wells. Bone Marrow Cell Community Assay: Bone marrow sputum can be determined by inhibiting the formation of bone marrow [granulocyte/macrophage colony forming units (CFU_GM)] and red blood cells [red blood cell burst forming units (BFU-E)] in a soft agar pure assay. In vitro toxicity of cells. Rodent bone marrow was collected from rat or mouse leg bones using a 21-23 needle attached to a syringe by flushing with 156069.doc •228- 201144296 Skovic modified Dulbecco medium (IMDM) cell. A single cell suspension was obtained by repeated aspiration through a needle. Counting nucleated cells with blood cells and adjusting to the desired cell concentration in IMDM "Cloning CFU-GM assay with 2.5xlO5 nucleated cells/ml, 20% FBS, 10 ng/ml rmGM-CSF and 0.2% agarose . BFU-E cultures include 30% FBS, 1% deionized BSA, 0.1 mM 2-ME, 4 U/ml rhEpo, 10 ng/ml rmIL-3, 2.5 χ 105 nucleated cells/ml and 0.2% agarose . A triple assay well containing 0.1 ml of compound (1 Torr) (in a 6-well plate) received 1 ml of each culture mixture in each concentration group and mixed slowly. The culture was gelled at 4 ° C, followed by incubation for 7 days (CFU-GM) or 9 days (BFU-E) at 37 ° C in a humidified atmosphere of 5% CO 2 in air. The population was counted using a flip-chip microscope. The CFU-GM community was identified as a pure line of cells containing at least 40 cells. BFU-E cultures were stained with dianisidine and greater than 60 agglutinated cells containing aggregates were counted as red blood cell populations. A linear regression analysis of the logarithm of the compound concentration relative to the CFU-GM or BFU-E survival fraction yielded a median inhibitory concentration (ICso) and a 90% inhibitory concentration (IC90). 5·6·6 Hepatitis virus assay 5·6·6·1 Hepatitis B virus (HBV) A variety of cell culture-based anti-HBV assays are available. Candidate compounds are initially assayed in a primary screening assay. Compounds displaying a rational antiviral and cytotoxicity pattern were subsequently selected as candidates for several other follow-up analyses. For primary screening assays, 2-3 mg of compound having a molecular weight in the range of standard nucleosides (e.g., 300-500) is routinely required. Other compounds may be required for follow-up analysis. 156069.doc -229- 201144296 If available, provide molecular weight and solubility information. If a preferred solvent is not specified, DMSO will be cultured using 100% coarse weave. Compounds are usually dissolved in aqueous solution (normal pH range) at a minimum of 1 〇 final test concentration or dissolved in DMSO at a minimum of 5 〇χ test concentration. Cell lines used in these studies are generally poorly tolerant to EtOH, but a final concentration of EtOH of less than 0.03% is generally acceptable. Compounds that must be tested in other solvents should be accompanied by a small amount of solvent (under a separate access number) to control cytotoxicity. For compounds in solution, a minimum of approximately 0.25 ml of 10 〇χ stock solution is required. Primary assay: Confluent cultures of 2.2.15 cells maintained on 96-well flat-bottom tissue culture plates (confluence in this culture system is equivalent to the activity observed in chronically infected individuals, high levels of HBV replication required) (Sells et al., "/. F/ro/. 1988, 62:2836; Korba and Gerin, Jwiz'Wr. and e.? 1992, 19:55)) Perform HBV antiviral assays (Korba and Gerin, dW) /Wr. Res. 1992, 19:55). HepG2-2_2.15 is a stable cell line containing the genome of the hepatitis B virus (HB V) ay w virus strain. Antiviral compounds that block any advanced steps of viral replication (such as transcription, translation, pregenome encapsidation, reverse transcription, particle assembly, and release) can be identified and characterized using this cell line. The culture was treated with aliquots of test compounds for 9 consecutive days. Usually 4 doses are used in triplicate (10-fold or 3-fold steps). The HBV DNA content in the medium (representing HBV virion production) was assessed by quantitative dot blot hybridization 24 hours after the final treatment. Alternatively, a direct quantitative PCR (TaqMan) assay can be used to directly and accurately measure a copy of the HBV DNA to initially assess whether the compound reduces the production of HBV secreted from the cell. Cytotoxicity was assessed by absorption of neutral red dye 24 hours after the last treatment of 156069.doc -230 · 201144296. Lamivudine (LMV) was used as a standard assay control, but other control compounds were also used to calculate EC5〇 by linear regression analysis (MS EXCEL®, QuattroPr〇8) using data from all combinations of treated cultures. eC9() ACC5() value (Korba and Gerin, JnnWr. Λα. 1992, 19:55; Okuse et al., hiiWr. Λα. 2005, 65:23). The standard deviation φ produced by autoregressive analysis is used to calculate the standard deviation of ECso and EC” values. EC5Q&amp;EC9Q is observed to be twice or 1〇 fold inhibition of HB V DNA, respectively (relative to the average content in untreated cultures) The concentration of the compound. CCw is the concentration of the compound observed to reduce the absorption of the neutral red dye to 1 /2 (relative to the average of the untreated culture). Because of the statistical significance found in this assay system, The HBV DNA content is required to be at least 3-fold inhibited, so the selectivity index (SI) is calculated as cC5〇/EC9〇 (Korba and Gerin, Jwiv/r· Λβ·?. 1992, 19:55). Primary assay The treatment was maintained in a confluent culture of 2.2.15 cells on a 48-well flat-bottomed woven plate. The HBV virion DNA content and cytotoxicity in the culture medium were assessed as described for the primary assay. Intracellular HBV DNA replication was measured by quantitative Southern blot analysis (Korba and Gerin, Λα. 1992, 19:5 5) EC50, EC90 &amp; SI values were calculated for virion DNA and intracellular HBV DNA replication intermediates. In some situations Other assays (level 3 assays) can be performed. Combination studies: Compounds are mixed at approximately equivalent concentrations and maintained at serial dilutions (Korba, Λα·1996, 29:49; Iyer et al. 2004). Compensating for potentially unforeseen interactions (eg, absorption, 156069.doc • 231 · 201144296 metabolism, etc.), changing the concentration of a compound relative to the second compound to about 3 times or 3 times lower, making it an experiment Three different ratios were used. As described for the primary assay, the cultures were treated with serial dilutions of 6-8 mixtures, as in the corresponding monotherapy. In the same experiment, Combostat® (Biosoft, Inc.) was used to analyze the software for the corresponding single. Therapy evaluates the interaction of the compounds in the combination therapy. For combination therapy, the EC50, EC90, CC50, and SI (CC5〇/EC9〇) of the first compound listed are presented. Also refers to the molar ratio of the compound in each combination. After confirming the antiviral activity of the test compound against HBV, quantitative HBV TaqMan PCR assay can be used to determine the efficacy (synergistic, additive, antagonistic) of 2.2.15 cells. And toxicity (combination toxicity) to assess the interaction of compounds with 3TC, IFNa and other compounds. Drug resistance HBV: transient transfection of HBV DNA for analysis of recombinant HBV against clinically relevant mutations conferring resistance to licensed drugs Activity (Tatti# A · Antivi. Res. 2002, 55:27; Iyer# A » AAC 2004, 48:2199). Cultures were transfected with Lipofectamine 2000TM (Gibco, Inc) in a 48-well culture dish following the manufacturer's protocol. The culture was treated with antiviral compounds for 5 days starting 3 days after transfection. Antiviral activity was determined by quantitative Southern blot hybridization of intracellular HBV DNA replication intermediates. The following mutants are currently available: lamivudine (LMV) polM204V, polM204I, polL180M, polM204V/L180M (Allen et al, i/epaio/o illusion ^ 1998, 27:1670); anti-Adefovir two volts Ester (adefovir dipovoxil, ADV) polN236T (Angus et al., Gajiroewiero/ogy 2003, 125:292) » Standardized nomenclature for the designation of HBV polymerase (Stuyver 156069.doc-232-201144296 et al., ugly epaio/og less 2001, 33:751). Other mutants (TNFR, ETVR) are in construction. Additional tests can be performed to assess the ability of the compound to inhibit HBV's known resistance to 3TC and anti-penciclovir mutants. Stable cell lines with control wild-type HBV and the following mutations known to be associated with resistance of HBV to these agents can be used: (1) domain B L526M (rtL180M) and domain C YMDD M550V (rtM204V) ( The most common mutation pattern observed during HBV sudden viremia; (2) L526M alone (the most common mutation associated with penciclovir resistance; also associated with some resistance to 3TC); Control wild type HBV. HBV protein production and RNA transcription: HBV proteins were analyzed by semi-quantitative ELISA using diluted (2 to 10 fold) samples to achieve assayed kinetic reaction ranges (Korba and Gerin, and e·?. 1995, 28:225; Korba et al., 2008, 77:56). Qualitative analysis of HBV proteins was also performed using standard Western blotting techniques (Muller et al., /. / «/eci. £&gt;/? 1992, 165: 929). The HBV surface (HBsAg) and HBVe (HBeAg) antigens from the culture medium samples were analyzed, and the HBV core (HBcAg) derived from the intracellular lysate was analyzed (corrected for total cellular protein content in each culture sample). Intracellular HBV RNA (corrected for the amount of cellular B-actin RNA in each culture sample) was assessed by quantifying northern blot hybridization (Korba and Gerin, ylniivir. 1995, 28: 225). HBV mechanism of action: A variety of assays can be used to ascertain the mechanism of action of antiviral compounds. Examples include the following: Extracellular HBV virions: In addition to quantitative PCR analysis, Southern blotting can be performed on HBV particles secreted from cells treated with 156069.doc -233 - 201144296 compounds; intracellular HBV particles: self-treated HBV particles were isolated from 2.2.15 cells and pre-genomic RNA was examined by Southern blot analysis. This can be helpful in identifying the site of action of late-acting compounds; intracellular HBV replication intermediates: nucleic acids isolated from cells can be examined by Southern blotting to assess cyclic partial double-stranded HBV DNA, linear partial double-stranded DNA And distribution of single-stranded HBV DNA; HBV transcription: effects on HBV genome and sub-genome viral RNA synthesis by northern blotting and primer extension analysis; HBsAg and HBeAg release assay: ELISA for quantification of HBV envelope protein, surface Antigen (HBsAg) and the amount of secreted e antigen (HBeAg) released from culture; Western blot analysis: Western blotting method to study HBV core and envelope protein expression; Novel mechanism of action: specific to HBV transcription and replication The effect may be caused by changes in DNA-protein interactions, which are sometimes affected by cell growth factors at HBV enhancers, promoters or by transcriptional transactivator X-protein; and endogenous polymerase assay: extracellular HBV Virions contain a partially double-stranded circular DNA genome. The purified virions were used to characterize the ability of antiviral drugs to inhibit the endogenous polymerase activity of HBV. Typically, this activity functions to complete (+) strand synthesis after new cells are infected with HBV virions. 5.6.6.2 Hepatitis C virus (HCV) protocol I uses the cell line Huh7 ET (luc-ubi-neo/ET), which contains a new HCV with stable 156069.doc • 234· 201144296 photonic enzyme (LUC) reporter conductor. RNA replicon. It is similar to cell line 5-2 (Krieger et al., // 2001, 75: 4614-4624), but contains other modifications that make the cell line more robust and provide stable LUC performance for antiviral screening. The composition of the replicon is shown as follows: Ε-Ι 5.—| Luc|ubii||Ne〇|—| NS3|HS4A|MS4B|HS5ft|HS5B|—3f ° HCV RNA Replicon ET Contains HCV 5·5 NTR (IRES), which drives the production of the fluorescent luciferase (Luc), ubiquitin (Ubiq) and neomycin phosphotransferase (Neo) fusion proteins. Ubiquitin cleavage releases LUC and Neo genes. The EMCV IRES element (E-Ι) controls the translation of the HCV structural protein NS3-NS5. The NS3 protein cleaves the HCV polymeric protein to release the mature NS3, NS4A, NS4B, NS5A and NS5B proteins required for HCV replication. At the 3' end of the replicon is the trusted 3' NTR of HCV. LUC reporter conductors are used as a measure of HCV replication. The activity of the LUC reporter is directly proportional to the HCV RNA content, and the positive control antiviral compound performs equally well with LUC or RNA endpoints. The use of LUC endpoints is more economical than HCV RNA and can be used in high yield applications to screen libraries of compounds. Primary HCV RNA Replicon Assay: First, the effect of compounds added in triplicate at a single high test concentration of 2 mM mM on LUC activity and cytotoxicity derived from HCV RNA was examined. Human interferon a-2b was included as a positive control compound in each run. Secondary confluent cultures of ET cell lines were applied to 96 well plates dedicated to analysis of cell number (cytotoxicity) or antiviral activity, and test compounds were added to appropriate wells the next day. The cells were treated for 72 hours later when the cells were kept in secondary confluence 156069.doc •235 · 201144296. Compounds that reduce the LUC signal by 50% or more relative to the untreated cell control are moved forward to the subsequent screening step. The cytotoxicity of the compounds was assessed as the percentage of viable cells relative to untreated cell controls. HCV RNA Replicon Confirmation Assay: The HCV RNA Replicon Confirmation Assay is then used to examine the effects of each compound at, for example, five semi-log concentrations. Human interferon a-2b was included as a positive control compound in each operation. Secondary confluent cultures of ET cell lines were applied to 96 well plates dedicated to analysis of cell number (cytotoxicity) or antiviral activity, and test compounds were added to appropriate wells the following day. Cellular treatment for 72 hours later when the cells were maintained in the secondary confluent state. Compound EC50 and EC90 values (antiviral) were obtained from TaqMan RT-PCR using LUC activity derived from HCV RNA replicon or HCV RNA content assessed by HCV RNA. active). Compound IC50 and IC90 values (cytotoxicity) were calculated using CytoTox-l (Promega), and colorimetric assays were used as indicators of cell number and cytotoxicity when using the LUC assay system, while ribosomes (rRNA) were determined by TaqMan RT-PCR. The amount is used as an indicator of the number of cells in an RNA based assay. The compound selectivity index SI5G and SI9 〇 values were also calculated.

5.6.6.3 Hepatitis C Virus (HCV) Protocol II A variety of cell culture-based anti-HCV assays are available. Candidate compounds are initially assayed in a primary screening assay. Compounds that display rational antiviral and cytotoxic patterns are then candidates for several other follow-up analyses. For primary screening assays, it is conventional to require 2-3 mg of a compound having a molecular weight in the range of standard nucleosides (e.g., 300-500). Other compounds may be required for follow-up analysis. Information on molecular weight and solubility is provided, if available. If no preferred solvent is specified, 156069.doc -236- 201144296 uses 100% tissue culture DMSO. Compounds were dissolved in aqueous solution (normal pH range) at a minimum of 10x final test concentration or dissolved in DMSO at a minimum of 5 〇 x test concentration. Cell lines used in these studies are generally poorly resistant to Et〇H, but a final concentration of EtOH of less than 0.03% is generally acceptable. Compounds that must be tested in other solvents should be accompanied by a small amount of solvent (under the 寄存 accession number) to control cytotoxicity. For compounds in solution, a minimum of approximately 0.25 ml of 10 〇χ stock solution is required. ^ Primary test: used in the three-day test (Okuse et al., dwiz'Wr. Λα. 2005, 65:23; Korba et al, JniiWr. and ed. 2008, 77:56) The stable expression on the 96-well plate of the HCV replicon cell line AVA5 (subgenomic (CON1), genotype lb) (Blight et al, 2000, 290: 1972) assessed the antiviral activity against HCV. Antiviral activity was determined by dot blot hybridization analysis of intracellular HCV RNA (corrected for the amount of cellular B-actin RNA in each culture sample). Cytotoxicity was assessed by neutral red dye uptake in cultures maintained in parallel assay plates. The EC50, EC9〇 and CC50 values were calculated by linear regression analysis (MS EXCEL®, QuattroPro®) using data from all combinations of treated cultures (Korba and Gerin, Λα. 1992, 19:55; Okuse et al. 2005, 65:23). The standard error produced by autoregressive analysis is used to calculate the standard deviation of EC5〇 and EC9〇 values. EC5G and EC9〇 were observed for compound concentrations of 2-fold or 10-fold inhibition (relative to the average content in untreated cultures) of intracellular HCV RNA, respectively. CC5〇 was observed to reduce the extent of neutral red dye absorption to 1/2 (relative to the average of untreated cultures) of 156069.doc -237- 201144296 compound concentration. The selectivity index (si) was calculated by CCm/EC^W. Recombinant human interferon 2b (PBL laboratories, Inc.) was used as a control control. Compounds targeting NS3 and NS5B currently in clinical trials can also be used. Secondary Assay: This assay assesses the activity of other genotypes using the pattern described in the primary assay. The activity against genotype lb HCV is included for comparison. An exemplary replicon cell line contains H/FL-Neo (genotype la(H77)' full-length construct) (Blight et al., X Virol. 2003 77:3181). The genotype 2a construct Q6/JFH-1, full length) can be used for evaluation in the future. The ec5(), eC9(), CCw and S.I. values of each replicon cell line were calculated. In some cases, other tests (level 3) may also be included. Combinatorial studies: Compounds were mixed at approximately equivalent concentrations and maintained at serial dilutions (Korba, Jnif Wr. and 1996, 29.49; Iyer et al. 2004). Three different ratios are usually used in one experiment. The cultures were treated with serial dilutions of 6-8 mixtures as described for the primary assay, as in the corresponding monotherapy. The c〇mb〇stat8 (Biosoft, lnc·) analysis software was used in the same experiment to evaluate the interaction of the compounds in the combination therapy against the corresponding monotherapy. For combination therapy, the EC50, ec90, cc5 (^si(cc50/ec90) of the listed first compounds are presented. Also indicates the molar ratio of the compound in each combination. Drug-resistant HCV: due to the fact that resistance mutations have not been identified Authorized against HCV drugs, a group of mutants that confer resistance to compounds in mid- to late-stage clinical trials. Some of the stable stable replicon-containing cell lines (Korba et al., 2〇〇8, 77:56) are compiled. Genotype! B ns5b 156069.doc -238- 201144296 S2 name 2T{Vem k, Nucleosides Nucleotides Nucleic Acids 2005, 24:767) and NS3 A156S and NS3 A156V (Courcambeck et al., 3«&quot; to &gt;_77? To .2006, 11: 847) drug resistant mutants. The genetic background is identical to the genetic background of the BB7 replicon (AVA5 cells) used in the primary assay. The activity against these mutants was assessed as described in the primary assay, but semi-quantitative real-time PCR was used to analyze HCV RNA due to lower levels of replication. Genotype lb mutants can also be evaluated in this manner. For this assay, Huh7.5 cells were transfected with HCV RNA using Liofectamine 2000TM (Gibco, Inc.) in a 6-well plate. Three days after transfection, the cultures were exposed to 125 pg/mL G418 and test compounds. After 10-14 days, the surviving colonies were fixed, stained and counted. The EC5〇 and EC9〇 values of each transfected RNA were calculated. 5.6.7 Papillomavirus assay Human papillomavirus (HPV) 11 and 40 assay: A431 cells were plated at 2x105 cells/well in a 6-well cluster dish. A parallel assay aliquot of HPV-11 (or HPV-40) was added to each well to represent the MOI of 150 particles per cell. The dilution of the compound is added to the triple assay culture. A control well containing no virus is included and it is received as a separate medium. The positive control compound can be, for example, 300 pg/ml HPMPC (cidolfovir). The cell culture was collected, dissolved with Trizol reagent (GIBCO/BRL) and RNA was prepared. QRT-PCR was performed to quantify the ratio of cellular E1-E4 transcripts and TATA-binding protein (TBP) cell reference RNA. The antiviral effect of the compound was evaluated by EC50 value, which represents a 50% reduction in the amount of E1-E4 viral transcript compared to cultures infected with HPV-11 alone (or HPV-40). To recover 50% of total cellular RNA. Compound doses calculate cC5 〇 toxicity. Thus two values, 156069.doc - 239 · 201144296 custom selectivity index (SI) o usually, si & 5 will be significant for the detection of antiviral activity. If necessary, the assay procedure can be modified to test for compounds with microbicidal activity. This modification is indicated by the simultaneous addition of the drug to the A43i cells with the infectious virus. Verification of Bovine Papilloma Virus (BPV): C127 cells were plated at 3χ1〇3 cells/well in wells of a 96-well flat-bottom microplate. An aliquot of the parallel measurement of Bpv-丨 was added to each well, and the lesions were approximately 1 lesion-forming unit. Includes control wells without virus. The drug dilution is added to the triple assay culture of the culture infected with Βρν_丨 and the uninfected culture. Control wells received medium without compound. The positive control compound can be, for example, 5 pg/mi cidofovir. The medium and the compound are fed into the cell culture every 3-4 days. Cell number and viability were assessed using the MTS assay. The antiviral effect of the compound was calculated using the formula below to obtain antiviral activity %: B&amp;A/B&amp;O 100 〇/〇 = antiviral activity % A = 含D. B containing BPV-1 and compound treated culture = od C of cell culture containing BPV-1 = 细胞 cell culture alone. d. EC^ value indicates the virus treated by the compound compared to the culture containing BPV_丨 alone and the culture containing the individual cells. The amount of 〇D (MTS signal) in the culture of the infection was reduced by 50%. From (:(:5()圯(:5()) determines the selectivity index (SI). Usually 'SI>5 will be statistically significant against the activity of the virus. If necessary, the verification procedure can be modified to test killing Microbial active compound. This modification is indicated by the simultaneous addition of the drug to the infectious virus to C 丨 细 069 156 156 156 156 156 156 156 156 156 156 156 156 156 156 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类 人类Preparation of CIN612 Pure Line 9E Cell Cultures. Individual rafts containing multiple layers of 9E cells grown on a collagen matrix impregnated with mitomycin C-treated fibroblasts were delivered to the cell culture medium. And the compound is treated to diffuse into the 9E multilayer. The duration of the culture is continuously processed, which is usually 10 days. After 10 days of culture, 9E筏 is collected and the QRT-PCR assay described for the HPV_11 single layer assay system is used. To test HPV-31b DNA (a measure of viral DNA replication) and E1-E4 virus transcription (viral function). Primers were prepared to quantify HPV-31B DNA and RNA (E1-E4) and quantified compared to TBP. Placebo treatment 9E筏Quantitative measurement of antiviral activity compared to either or both of viral DNA and RNA. Remove one of each sputum for histological analysis (H&E, immunostaining for specific marker keratins [keratin 10, involucrin]) Plot the viral DNA and RNA content versus compound concentration to determine EC5〇 (50% reduction in viral DNA and/or RNA), CC5〇 (50% reduction in total RNA/DNA yield). Select from CC5〇/EC5q Sex index (SI). Typically, SI&gt;5 is significant for detection of antiviral activity. 5.6,8 BK virus (BKV) assay can be followed by, for example, Farasati et al., 2005, 79(1): 116-118. The procedure described is used to perform a prion (BKV) assay. In general, the principle of assay is to measure the effect of a test compound on the viral replication rate of BKV viral capsid protein 1 DNA by quantitative real-time PCR. Simultaneous quantification of housekeeping genes for acid oxidase (ACY) DNA allows for monitoring of host cell replication by 156069.doc -241· 201144296. Regression analysis of dose response curves can determine EC5〇, which is defined as a 50° reduction in BKV DNA yield/ The concentration of the compound The ratio of IC50 to EC5〇 (selectivity index) to compare the antiviral effects of different test compounds related to their safety. For example, BKV Gardner strain (from ATCC) can be used for antiviral testing. . The cells were expanded using DMEM medium supplemented with 1% fetal calf serum and L-glutamic acid, for example, in human embryonic lung fibroblasts (WI-38 cells), incubated at 37 ° C in 5% CO 2 . Each test compound is typically tested using a wide concentration range covering 4-5 orders of magnitude at least three times. Experiments typically involve a negative control consisting of cells exposed only to the diluent. Each compound sensitivity experiment required inoculation of 50,000 log phase WI-38 cells in a 6-well culture dish. After the cells were plated, virus infection was achieved by adding 2χ103 to 2x10 BKV particles to each culture well in a volume of 0.5 mL. After incubation at 37 ° C for 2 hours, the unbound virus was washed away with tissue culture medium. The culture was maintained in DMEM medium supplemented with 10% fetal bovine serum and L-glutamic acid for 7 days at 37 ° C, 5% CO 2 by using 0.25% trypsin-ImM Na at 37 ° C. - EDTA was digested for 10 minutes to collect cells, and viability was assessed by Trypan blue dye exclusion test. DNA lysates were subjected to DNA extraction using a commercial kit (QIAamp DNA Mini kit; Qiagen, Valencia, CA). BKV VP-1 DNA was amplified from total DNA by TaqMan quantitative PCR reaction performed in an ABI Prism 7700 Sequence Detector (ABI, Foster City, CA). To track the variable input of cellular DNA in different cell culture experiments, ACY was performed on each cell lysate. 156069.doc -242- 201144296

TaqMan PCR 〇 5.6.9 Dengue Virus (DENV) assay can be performed in a manner similar to that described in Heaton et al. 'iVoc. iVai/· Jcad 5W., 2010, 107(40): 17345-17350 for DENV External verification. Huh-7.5 cells (sequences derived from hepatocyte Huh7 cell line) were maintained in high glucose DMEM supplemented with 0.1 mM non-essential amino acid, 5% v/v FBS and penicillin-streptomycin. In some cases, DENV-luciferase replicon RNA was introduced into Huh-7.5 cells by electroporation. 24 hours after electroporation, cells were treated with different concentrations of test compound for an additional 24 hours and assayed for luciferase activity. Under other conditions, Huh-7.5 cells were infected with DENV (infection rate = 1) for 4 hours, followed by 4 hours. Treat with different concentrations of test compound. 24 hours after infection, quantification of viral RNA content or released virus and cellular ATP content. Three types of in vitro assays for DENV include Chen et al., Antimicrobial Agents and Chemotherapy, 2010, 54(8): 3255-3261 ή1 By. Type 1: Quantitative measurement of the reduction in viral power in the presence of the test compound.乂61*〇 cells were seeded in a 12-well dish (4 &gt;&lt; 105 cells/well). 24 hours after the inoculation, the cells were infected with DENV at an infection magnification of 0.1, and then treated with the test compound. The medium was collected at the appropriate time, and the viral valence was determined using a virus plaque assay. Type 2: Cell-based flavivirus immunodetection (CFI) is used to measure the amount of viral E protein in infected cells. A549 cells were seeded in 96-well plates (2 x 104 cells/well). The next day, cells were infected with DENV. During infection 156069.doc -243- 201144296, cells were incubated with the test compound/virus mixture for 1 hour under shaking every 10 to 15 minutes. The culture fluid is then supplemented with fresh medium containing the test compound. On the 2nd day after infection, the cells were washed with PBS, fixed with 100% sterol at 4 ° C for 10 minutes, and the intracellular viral E protein was detected by ELISA. The ELISA was performed using mouse monoclonal antibody 4G2 against DENV E protein and goat anti-mouse IgG conjugated with horseradish peroxidase as a primary antibody and a secondary antibody, respectively. Type 3: Assays were used to report replicons using Huh-7 cells and DENV luciferase. The procedure is similar to the procedure described above. 5.7 In vivo assay 5.7.1 Herpes virus in vivo assay 5.7.1.1 HSV-1 and HSV-2 animal sore encephalitis model: Viral species pathway disease endometrial endometrial intra-abdominal abdomen nasal nose nasal skin HSV -l BALB/c mouse HSV-2 BALB/c mouse HSY-1 rat HSV-l SKH-1 mouse encephalitis encephalitis encephalitis newborn animal and encephalitis spread infection encephalitis lip therapy initial New compounds were screened for HSV activity in BALB/c mice (Charles River Laboratories) intraperitoneally inoculated with HSV-1 or HS V-2. After intraperitoneal inoculation with HSV-l or HSV-2, the virus replicates in the intestine, liver and spleen and spreads to the CNS due to viral toxins and may also spread to the peripheral nerves. The virus was first detected in the brain on about day 5, thereby allowing time for the compound to display antiviral effects. This model system is one of the most sensitive models of 156069.doc •244- 201144296 for the efficacy of new antiviral compounds. Although it does not mimic the natural route of infection, it allows screening of new compounds to determine the optimal dosage and treatment regimen. This screening was followed by testing in mice vaccinated intranasally, which is closer to mimicking human infection. If the test compound exhibited activity in mice vaccinated intraperitoneally, it was subsequently evaluated in mice vaccinated by the intranasal route. Three-week-old BALB/c mice were inoculated intranasally with HSV-1 to provide a human herpes encephalitis model using the natural infection pathway. After inoculation with about Hsν·virus strain E-377, the virus replicates k in the nasopharynx and spreads to the CNS via the olfactory nerve and the trigeminal nerve. Untreated animals usually die within 6_1 days. The use of intranasal vaccination is known as the natural route of infection for cancerous encephalitis. Three-week-old baLB/c mice were intranasally inoculated with approximately 4 χ 1 〇 4 pfu of HSV-2 strain MS to provide a disseminated neonatal herpes model involving CNS. After virus inoculation, the virus replicates in the nasopharynx and lung tissue and spreads to the liver, spleen and kidney. In addition, the virus spreads to the CNS via the olfactory nerve and the trigeminal nerve. Parenteral or oral administration of acyclovir ACV is effective in all of the experimental infections mentioned above and is used as a positive control. Immunization was performed on the hairless mouse SKH-1 line to help score skin lesions. Oral vaccination of HSV-1 in these mice provides an appropriate model for testing new antiviral therapies. Mice were anesthetized with a mixture of ketamine/xylazine in this model and injected subcutaneously with an electronic microchip for individual identification. Prior to inoculation, use the # i i 3 tungsten carbide grinding head Drernmel tool to gently sand the nose from the nasal bridge above the nose to the triangular area of the eye. Carefully perform this procedure to prevent bleeding. The area was then wiped with a polyester swab soaked with Hsv_ 1 for 10 seconds. After this procedure, the animals are returned to 156069.doc •245- 201144296 to their cages and observed until recovery. Animals infected with HSV-1 in the oral area showed damage, which began to appear on day 4-6 and usually became apparent on day 丨5. To determine the effect of treatment on dermal viral replication, the severity of the lesion was scored on days 4-21 and the nasal region was wiped on day 3-10. The samples were placed in 2.0 ml medium and frozen at _7 (TC until HSV-1 sputum was applied to rabbit kidney fibroblasts in the CPE microtiter plate assay. All experimental drug efficacy studies were either placebo or vehicle. The control was administered as a control and was also administered locally to the positive control, Schweiz (z〇virax). Mouse model of primary HSV-1/HSV-2 challenge: Primary screening model provides primary infection with HSV using clinical endpoints and virological endpoints A rapid initial assessment of the antiviral efficacy of this model using intrauterine vaccination of female Swiss Webster mice (25 g) to assess potential antiviral therapies and vaccine/adjuvant candidates. Daily tracking of herpes signs and symptoms of the animal, Vaginal to plaque is obtained to assess the effect of therapy on viral replication. Single or combined antiviral therapies can be administered, either orally or systemically, and can be administered at different time intervals before or after the virus challenge. Dosing agent: range study. The dose and route of administration were individualized for each test compound. The size of the treatment group was usually 12_丨6 mice. The primary HSV-2 attack in mice was killed. Screening model: This model was designed to assess protection provided by microbicide candidates for HSV-2 infection. The model utilizes intravaginal vaccination of female Swiss Webster mice for evaluation. Usually by attacking with HSV-2 The compound was administered for the first 5 minutes for the initial test. Further evaluation of the microbicide in this model prolonged the time between the dosing agent administration and the challenge or the range of the test dose. Compound 156069.doc • 246- 201144296 A second species assessment was performed in the guinea pig genital infection model. The assessment included a daily assessment of genital herpes signs and symptoms and a viral examination of vaginal secretions. The treatment group was usually 12-16 mice. Primary genital HSV-2 infected guinea pigs Model: Since the genital and acne treatment diseases of guinea pigs are similar to human diseases, this animal is used as the second species to display the therapeutic effect against HSV in mice. Like humans, the reproduction of guinea pigs; HSV infection is Self-limiting vesicular ulcer disease, which is followed by healing, establishing an incubation period, followed by Spontaneous and induced symptoms and asymptomatic recurrence. An exemplary model utilizes intravaginal vaccination with female Hartley gauinea pigs and provides clinical indices and virological indices to assess treatment for primary disease and subsequent recurrence The effect of the frequency or severity of sexual infections can be administered orally, locally or systemically, and can be administered at different time intervals before or after the virus attack. After vaginal inoculation, use a proven genital herpes The scoring system tracks animal genital herpes development daily. Vaginal smears are also obtained to assess the effect on viral replication. Since this model is a non-fatal model, animals can be sacrificed at the end of the experiment to assess the impact of treatment on latency. This model can be adapted to assess the antiviral activity against available resistant strains of virus (ACV and phosphonic acid). The dose, route of administration, and duration of treatment were individualized for each experimental agent. The size of the treatment group is usually 1 〇 _ 丨 5 animals. The guinea pig model of recurrent genital HSV-2 infection: genital genital herpes The unique feature of the herpes model is that after recovery from primary genital infection, the animal undergoes spontaneous recurrent genital damage and undergoes viral shedding in the absence of injury. This allows assessment of the efficacy of candidate compounds in controlling relapses. Female Hartley guinea pigs that had recovered from symptomatic primary genital infection were randomly assigned to the treatment group of pi antiviral therapy starting on day 21 and continued treatment for 21 days thereafter. Indexes that can be administered orally, locally, or systemically for /alpha therapy include quantification and severity assessment of recurrent episodes over 21 days during and after treatment discontinuation. In addition, collect the vagina to the tablet to estimate any effect on the shedding. The dosage and route of administration were individualized for each experimental agent. The treatment group is usually 1 〇 15 animals in size and the duration of treatment is usually 21 days. Neonatal HSV-2 infection model of guinea pig: an exemplary neonatal HSV infection model mimics the natural infection history of human newborns. This model can be used to evaluate candidate antiviral compounds and combination therapies, including antiviral or antiviral agents in combination with immunomodulators. In addition, this model can be used to assess the efficacy of a candidate vaccine by measuring the protection provided by a placental antibody. In this model, newborn Hartley guinea pigs were inoculated intranasally with HSV-2 within 48 hours of delivery. Newborn animals were then randomized to receive test compound, placebo or acv (control). A positive control ACV (6 mg/kg/day) is used twice daily (BID) to assess daily signs and weight gain of the skin and lungs, CNS symptoms and death. Surviving animals were followed to assess the effectiveness of the treatment for the incidence and frequency of recurrence of skin herpes. The dose and route of administration were individualized for each experimental drug. The duration of treatment is usually 1 day or more than 10 days. 5.7 Λ .2 cell giant virus animal cell giant virus infection model: 156069.doc -248· 201144296 viral species pathway disease MCMV BALB/c mouse intraperitoneal disseminated CMV acute, chronic SCID mouse intraperitoneal disseminated CMV acute HCMV SCID -hu-Ret HCMV replication in intraocular retinal tissue SCID-hu-thy/liv intrathoracic (i.im.) HCMV replication in thymus/liver tissue Human CMV is generally not infected with laboratory animals. For this reason, it is necessary to use an alternative model, which is similar but different in its natural host. Despite the presence of large viral strains of cells in many animal species, both have been studied, including murine and guinea pig CMV. The murine model predicts the efficacy of antiviral drugs such as phosphonic acid (PFA), ganciclovir (GCV) and cidofovir (CDV), which have been evaluated in humans. Three-week-old BALB/c mice were intraperitoneally inoculated with about 2.0 mM 105 pfu of MCMV to cause acute lethal infection with rapid viral replication in lung, liver, spleen, kidney, intestine, salivary gland and other visceral and glandular tissues. The animals died in about 5-7 days. Since this is a fatal infection, this model can be used to quickly identify potential antiviral compounds. Reduction of the virus inoculum to 1 〇 4 pfu of MCMV caused a non-fatal chronic systemic infection, which has many similarities with human CMV infection. The virus can be easily isolated from the company, lung, liver, spleen, kidney, urine, intestine and salivary glands at various times after inoculation. Viral replication persists in these target organs for 45-60 days&apos; and persists in the salivary glands for several months. The nature of chronic infections allows assessment of long-term or maintenance therapy. Severe combined immunodeficiency (SCID) mice lacking functional T and B cells are extremely sensitive to MCMV infection and serve as a cleavage of CMV infection in immunocompromised hosts. SCID mice vaccinated with tMCMV in the Pfu range and maintained untreated -249-156069.doc 201144296 eventually died in a dose-dependent manner. The average number of days of death for animals receiving ΐ()5_ was approximately 14 days, while animals vaccinated with 1〇pfu survived for an average of 25 days. For every 1 〇 gl 增加 increase in virus inoculum, the survival time was reduced by about 3 days. In order to determine the pathogenic mechanism of MCMV in SCID mice, the mice were vaccinated with 1〇pfu for three days after the induction of wood, and three mice were given painless lethality, and their tissues were removed and homogenized. The sMCMV was first detected in the salivary glands on day 6, and then detected in the lungs, spleen, kidney, adrenal glands and sputum on days 9-12. The liver, which is one of the widest container organs in normal mice, does not exhibit a detectable virus before the first day. In addition, the brain is infected on the 18th day. These data indicate that SCID mice vaccinated with low concentrations of MCMV caused disseminated infection with viral replication in the same target organs as those observed in immunodeficient humans. These animals exhibited high viral content in their tissues over a period of 2 to 3 weeks, thereby preserving sufficient time to confirm the antiviral response in treated animals compared to placebo animals. Human CMV infection can cause a wide range of clinical manifestations, especially in immunocompromised hosts. Since the virus is host specific, there are a few models to study HCMV infection, and infection and replication are limited to human cells. In this regard, a model involving HCMV infection of fetal retinal tissue implanted in the eyes of a severely combined immunodeficiency (SCID) mouse can be utilized. A small fragment of the fetal retina is implanted into the anterior chamber and vaccinated with 2,000 to 10,000 pfu of HCMV 4 to 6 weeks after transplantation. The animals were given painless lethality and the eyes were removed at various time points after infection. The eye is prepared for microscopic analysis by sectioning the fixed tissue, or the eye is homogenized to detect infectious HCMV by viral plaque assay. This model has been validated using GCV, CDV and other antiviral therapy 156069.doc 201144296. In addition, this model can also be used to study and identify the toxic characteristics of HCMV by examining the growth of various HCMV mutants. The SCID-hu thy/liv implant model can also be used in compound efficacy studies. In this model, human fetal thymus gland and small fragments of the liver were implanted in the kidney capsule under SCID mice. After approximately 12-16 weeks, 10 0 - 04 pfu HCMV was used to inoculate implants that fully formed blood vessels and were quite large (10-50% of kidney size). At various time points post-infection, the implants were biopsied and homogenized, and HCMV replication was quantified by viral plaque assay. As with the SCID-hu mouse eye model, this model can be adapted to determine the efficacy of various antiviral therapies. Immunocompromised GPCMV model: This day's murine model mimics the immune function of CMV infection in incomplete hosts, a common target group for large viral infections. Young Hartley guinea pigs were immunosuppressed by administration of cyclophosphamide 1 day and 7 days prior to virus inoculation with approximately 105 pfu of salivary gland passaged guinea pig cell giant virus (GPCMV). In a typical experiment, the 12-week animals began receiving the test compound or placebo 24 hours after infection. Animal signs and deaths are tracked daily, and death usually occurs on day 14, as described by Bourne et al., Jw/Wra/ and esearc/z 2000, 47: 103-09. The effect on viral replication was measured by killing the animals and quantifying the virus in specific organs and blood by real-time PCR and/or culture. The amount of the compound is usually based on the average guinea pig weight of 350-500 g. New GPCMV model: CMV infections in premature newborn animals can be life-threatening diseases if left untreated. The neonatal guinea pig model is similar to perinatal CMV infection and allows for the systematic evaluation of antiviral compounds in relatively immature hosts. In this model, fresh Hartley guinea pigs were infected with about 106 pfu of GPCMV from the 176069.doc •25b 201144296 salivary gland at 24-48 hours after birth. Treatment with an antiviral or placebo administered orally or by intraperitoneal injection begins at 0-24 hours after infection. Infection causes a decrease in weight gain and is spread to up to 70% of the 10th angel after infection due to dissemination to target organs such as liver, spleen and brain (Bravo et al., dwiz.Wra/ 2003, 60:41-49) 0 per曰 Track disease signs and deaths in animals. The effect on viral replication was assessed by killing the animals and comparing the viral power prices in various target organs and blood by real-time PCR and/or culture. Administration is usually based on an average of 100 g of the weight of the newborn guinea pig. Congenital GPCMV model: CMV is the most common congenital infection. Scorpio is a small mammal that causes fetal infection and disease through the placenta, thereby allowing the study of new antiviral agents and unique therapies that target placenta and congenital infections. In this model, Hartley's pregnant guinea pigs were infected with about 105 pfu of GPCMV during about 70 to 55 days of the 70-day gestation period. Animals can be treated systemically or orally. Endpoints include prevention of premature delivery, progeny survival, and placental PCR analysis, and collection of other maternal tissues (blood, liver, and spleen) and young animal organs (liver and spleen) 3, 5, or 10 days after infection (Bravo et al. , JowrAia / 〇 / / «/echoM·? ΖΗπαΜί 2006, 193: 591-7). The dose is usually based on the weight of the pregnant guinea pig of about 1200 g. CMV model of hearing loss: Hearing loss is the most common manifestation of congenital CMV infection. Direct inoculation into the cochlea via a round window using GPCMV (approximately 105 pfu) induces hearing loss in guinea pigs, as measured by ABR. The animals can then be treated to prevent hearing loss. The test compound can be administered systemically, orally, and possibly by direct intratympanic administration. The dose is usually based on the animal weight of about 350 g. 156069.doc • 252- 201144296 Murine CMV Model: The murine CMV model was used to study the pathogenesis of CMV and to evaluate new anti-CMV compounds. In this model, 5-week-old female mice were infected with lxl〇6 pfu of MCMV by intraperitoneal injection. Treatment can be initiated before infection or after infection for 3-5 days. Animals are sacrificed 3 to 5 days after infection, and viral valence of the spleen and liver is determined by viral plaque assay. Other tissues, such as salivary glands and lungs, can also be analyzed. Ganciclovir (5 〇 mg/kg ' twice daily) was used as a control drug and inhibited MCMV replication in this model. Administration depends on the weight of the animal (usually about 25 g). In vivo assay of H2 influenza virus Efficacy: The influenza animal model consists of infecting laboratory mice with various strains of influenza A (H1N1, H3N2, H5N1) and B virus, and using several parameters to measure disease severity. The parameters that can be used include the following: (a) Monitoring the oxygen saturation (Sa〇2) content in the living activity at frequent intervals using pulse oximetry; (b) using the lungs acquired at specified intervals during infection. An in vitro end-dilution assay for homogenization to measure the price of infectious pneumovirus; (c) using the lungs obtained to determine the degree of lung consolidation, as determined by lung fading scores and lung weight; (d) due to virus Animal death caused by pneumonia; (e) average survival time of animals; and (f) selected histopathological analysis of lung sections. Where appropriate, studies are conducted to determine the development of viruses that are resistant to important antiviral drugs. Toxicity: One or more toxicity tests are performed on the test compound under evaluation. Such measurements include: (4) fatality; and (b) loss of host weight or failure to increase body weight. When necessary and applicable, the following additional parameters can also be studied: (4) Face acid oxalate transaminase (SG〇T) as a marker of possible liver damage in serum 156069.doc •253 · 201144296 and pyruvate transaminase Increased circulating serum levels (SGPT); (b) increased circulating creatinine (CT) levels as an indicator of likelihood of renal weakness; and (c) increased circulating creatinine phosphokinase (CK) levels as an indicator of general tissue damage . 5.7.3 In vivo assay of respiratory virus

5.7.3.1 RSV, PIV-3, MV and hMPV respiratory fusion virus (RSV), parainfluenza virus type 3 (ριν_3), measles virus (MV) and human metapneumovirus (hMPV) are human pathogens, which are lacking A licensed vaccine to prevent diseases caused by RSV, PIV-3 or hMPV, but effective MV vaccines are available. Verbazole, immune serum globulin and humanized monoclonal antibodies have been approved for use against some of these paramyxoviruses. virus. However, all such agents are limited and may be relatively expensive. Therefore, it is necessary to clarify and develop new compounds, reagents or vaccines that are active against such viruses. Potential antiviral agents and vaccines that are effective against scale 3, PIV-3, MV or hMPV are evaluated in cotton rats. In addition, studies were conducted to characterize, enhance or further develop different paramyxovirus-cotton rat models. Evidence from numerous studies supports the applicability of different paramyxovirus-cotton rat models to preclinical evaluation of potential paramyxovirus antiviral agents and vaccines. 3. /.5.2 SARS^ # Efficacy: SARS virus animal model utilization A lactating mouse infected with a virus and a vortex. Moderate pulmonary infection is caused by sporadic pulmonary hemorrhage 1 - mainly from the lungs

Recycling of infectious virus performance. The parameters of the test agent for the development of the disease in the mouse lung. K Toxicity: One or more toxicity tests were performed on the test compound under evaluation. 156069.doc -254· 201144296 These measurements are: (4) fatal, and (b) loss of host weight or failure to increase weight. When necessary and applicable, the following additional parameters can also be studied: (4) The glutamic acid transaminase (sg〇t) and the propionate transaminase (SGPT) as a marker of possible liver damage in Qiqing Increased circulating serum levels; (8) increased circulating creatinine (CT) levels as an indicator of likelihood of renal weakness; and (c) increased circulating creatinine phosphokinase (CK) levels as an indicator of general tissue damage. Live pox virus test in the live pox • 7 乂J 苈凄 苈凄 苈凄 羊 羊 羊 O O O O O O O O O O O O O O O O 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室 实验室Lung infection, which causes death associated with tonsillemia-like toxemia. The parameters used to evaluate test compounds in this model include: (4) animal death; (b) average survival time of the animals; (4) lung and # viral power prices; and (4) host weight loss. Other parameters may include: (4) monitoring Sa02 content; (8) checking lung consolidation by lung scores and lung weight gain; and (4) histopathological analysis of lungs and other organs. _ It also utilizes skin infections induced by H virus in mice with reduced function in hairless mice. This infection is progressive and causes death in mice. It is now also used in selected antiviral experiments. The parameters used to evaluate the test agent in this skin infection model include: (4) animal death; (8) severity score of the initial induced lesion; (4) the size of the initial induced lesion; (4) the number of spontaneous "satellite" lesions; e) Viral price in various organs of animals. Animal vaccinia virus and vaccinia virus infection model: 156069.doc -255 - 201144296 Viral species pathway disease vaccinia virus (BR) BALB/c mouse intraperitoneal death - rapid involvement of intrahepatic death in liver-visceral BALB/c mice Slowly involved lung-respiratory vaccinia virus (WR) SKH-1 mice intradermal skin lesions SCID mice intraperitoneal disseminated disease BALB/c mice intranasal death spread disease vaccinia virus (IHD) BALB/c mice intranasal Death spread disease vaccinia virus (WR) SCID mouse intraperitoneal death spread disease vaccinia virus (NYC) SCID mouse intraperitoneal death acne pathogen variola virus can not be used outside the BSL-4 closed region and not in adult mice Can cause disease. A variety of orthopoxviruses can be used as alternative viruses for acne, including VV and CV. It can be inoculated intraperitoneally or intranasally into SCID mice with death as the end point. In normal mice, CV, VV-WR or VV-IHD, but not VV-Copenhagen Strain, will produce mortality when inoculated by multiple routes. Intranasal inoculation of mice with CV caused infections similar to systemic or disseminated acne. Other routes of vaccination (such as intraperitoneal or intravenous inoculation with VV or CV) will involve less of the bronchi and cause more skin damage. The VHD IHD strain is more toxic in BALB/c mice than the WR strain. VV WR strains produced mortality in intranasally inoculated BALB/c mice and intraperitoneally inoculated SCID mice. SKH-1 hairless mice can also be inoculated with VV and CV by inoculation of the polished oral area, similar to HSV technology. Mice can be treated systemically or locally with antiviral compounds to assess the efficacy against disease (damage score) or viral replication (viral cost). 156069.doc •256· 201144296 5.7·4.2 Mousepox virus (ratpox assay) Ratpox virus is the pathogen of mousepox, which is an acute rash disease in mouse communities in Europe, Japan, China and the United States. Laboratory studies have shown that ECTV has a very narrow perimeter, which only infects certain mouse species. It has been isolated. Many ECTV strains have been shown to have different toxicity to mice. Moscow, Hampstead and NIH79 strains have been studied, and the Moscow strain is one of the most infectious and toxic diseases in mice. Studies in the last 50 years have described in detail the genetic susceptibility (A, BALB/c, DBA/2 and C3H/He; about 7 days after infection) and inbreeding (C57BL/6 and AKR) inbreeding And distant and distant mating mice in the process of viral and pathological diseases; identification and characterization of important cell-mediated responses and innate responses to recover from infection; and the discovery of control of rpm-1, rmp-2 against severe vaccinia , rmp-3 and rmp_4 loci. Different mouse genotypes, strains, and viral doses produce different disease patterns for a given route of infection. After respiratory infections, mousepox and acne have at least two different characteristics. φ First, the disease process in mousepox is shorter than that of acne. The concealed period of varicella and acne is 6 days and 1 day. The fatal condition of varicella usually occurs 7 to 14 days after infection (ρ.ι.), while the death of common acne occurs approximately 18 to 22 days after infection. The second major damage was observed in the liver and spleen, and relatively few such organs were involved in acne. A characteristic of acne similar to acne is that the dose of virus required to cause disease in the upper and lower respiratory tract is relatively small. Another similarity is the detection of a virus in the breathing gas during the pre-rash phase. In addition, both diseases are characterized by characteristic rash skin treatment. The development of rash in the presence of vaccinia depends on a number of parameters, including mouse strain, 156069.doc-257-201144296 virus strain, vaccination route and viral dose. Efficacy: An important use of the mousepox model is to evaluate orthopoxvirus compounds and vaccines. The ECTV aerosol model is provided to assess the broader dynamic range of compounds. An aerosol lethal dose of 100 PFU can be used, which is about 3 times the LD50 value of 32 PFU' and may be within the range of infectious doses of aerosolized sores. Alternatively, a dose of 1000 to 10,000 times the LDm can be used to thoroughly check the stability of the test compound. 5·7·4.3 Monkeypox Virus (MPXV) Monkeypox virus can be carried out by following the procedure described in, for example, Americo et al., /οΜπα/ 〇/ Wro/ogy, 2010, 84(16): 8172-8180 ( Animal test for MPXV). In general, the assay is based on intranasal or intraperitoneal infection of CAST/EiJ mice with MPXV, such as MPXV's Congo Basin clade or MPXV West African clade. At the time of infection, the animals exhibited weight loss, morbidity and death in a dose-dependent manner. In addition, MPX replication was observed in the lungs, spleen and liver of the test animals. Thus, the antiviral efficacy of a test compound can be assessed by following the following criteria: such as weight loss, morbidity and mortality in the presence and absence of a test compound when infected with MPXV. In addition, replication in animal organs, such as the lungs, spleen and liver, in the presence and absence of test compounds at the time of infection can also be examined to assess antiviral efficacy. 5.7.4.4 Ghostpox virus (RPV) can be followed by following the procedure described in, for example, Rice et al, Wrww, 2011, 3: 63-82 and Adams et al., 乂 Wro/., 2007, 81: 11084-11095. .doc -258- 201144296 For animal testing of rabbit pox virus (RPV). In general, the model is based on the bilateral, intradermal infection of New Zealand White rabbit with 100-1000 pfu of RPV. At the time of infection, the animals exhibited weight loss, elevated body temperature (fever), severe respiratory distress, swelling of primary and secondary lesions, eye and nasal discharge, and necrosis at the site of inoculation. In addition, viral replication was observed in the respiratory tract. If left untreated, the animal will eventually experience death (painless death) according to the Painless Death Guide. Thus, the antiviral efficacy of a test compound can be assessed by following the criteria described above, including the length of time of infection and viral replication. Additionally, the overall clinical score can be examined to assess antiviral efficacy. Alternatively, the animal assay can be based on, for example, the procedure described in Roy et al, Wrwse®, 2010, 2: 2096-2107, where similar clinical criteria are examined following infection with an aerosol containing RPV. In this model, an experimental infection of RPV is initiated by exposure to an aerosol having a particle size distribution that preferentially penetrates the tracheobronchial region of the lungs and the lung region (focusing on the lower respiratory tract). 5.7.5 In vivo assay of papillomavirus 5.7.5.1 The cotton-tailed rabbit papilloma virus (CRPV) model is combined with the cotton-tailed rabbit papillomavirus (CRPV) model and follows substantially similar to, for example, Christensen, C/ The procedure described in jew/siry c& 2005, 16: 283-294. Briefly, a local formulation of the test compound was tested in three doses at 4 sites per rabbit in a group of 5 rabbits. Another rabbit group included placebo treatment. Alternative delivery includes intralesional and systemic treatment depending on the nature of the compound to be tested (e.g., antiviral, immunomodulatory). 156069.doc -259- c: 201144296 Adult New Zealand white rabbits are commercially available, for example, from CoVance, Inc. Rabbits have both sexes. Quarantine and clean up the rabbit (14 days). Each rabbit was inoculated with 10 2 wt CRPV (CRPV stock solution) (4 sites: 2 on the left side of the back (L1 and L2) and 2 on the right side of the back (R1 and R2)). The combination of LI, R1, L2 and R2 sites is treated. An exemplary processing scheme is provided below. Group A: All 4 sites = placebo ointment; Group B: L1 and L2 = GS327422 (0.1%); R1 and R2 = GS327422 (0.03%) Once a week (Monday) for 8 weeks; Group C : L1 and L2 = GS327422 (0.1%); R1 and R2 = GS327422 (0.03o/〇) are processed three times a week (MWF) for 8 weeks; and Group D: L1 and L2 = GS327422 (0.1%); R1 And R2=GS327422 (0.03°/〇) is processed every Friday (MTWTF) for 8 weeks. The experiment contained 20 rabbits. Most experiments included 4-5 rabbit groups (group A-E). The placebo group was used as a control to assess the local effects of treatment in treatment groups B to D. The vehicle is made up of placebo and sputum. The B-D group represents a comparison of test compounds versus placebo negative controls. The dosage of the compound is selected based on various criteria including past experience. Treatment (partial) begins when the papilloma is visible but not greater than 5.0 mm GMD. This time point allows assessment of the impact on visible papilloma and is clinically relevant. The treatment was once a week (Group B), 3 times a week (Group C-MWF) and 5 times a week (MTWTF) for 8 weeks, and the dose at each site was 〇·1 ml. Alternatively, treatment can be initiated 14 days after infection when there is no visible papilloma to maximize treatment effectiveness. Body weight was obtained weekly and, if necessary, serum was collected at the end of the treatment period for blood chemistry analysis. Papilloma was measured weekly in the 3-axis direction (length X width X height) in units of 156069.doc • 260. 201144296 mm. Data were entered into the total analysis table and the geometric mean diameter of each papilloma was calculated, the mean ± SEM of each group, a t-test was performed between each paired group and a plot of the size of the papilloma versus time was plotted. A weight change curve is also drawn. At the end, kidney and liver samples were taken for histology and toxicity assessment. The skin/papilloma site was monitored photographicly and the histology of the biopsy was assessed at the end of the experiment/treatment. Serum samples can be collected for blood chemical analysis to assess any toxicity of the compound being treated. 5.7. S.2 Mouse Xenograft Model The mouse subcutaneous and skin xenograft models are schematically depicted in Figures 1 and 2. 576 In vivo assay of other viruses 5·7, 6Λ Puntatoro virus efficacy: Infection of Lanta Tatrovirus in C57BL/6 mice and Syrian golden hamsters (Syrian g〇lden hamster), systemic diseases Similar to the disease induced by Ligu fever. The parameters used in the anti-virus test include: (a) animal death; (b) hepatic jaundice, as seen in yellow liver; (c) ALT in serum, and (d) viral power in liver and serum; And (e) loss of host weight. Toxicity: One or more toxicity tests are performed on the test compound under evaluation. These measurements are: (4) fatal; and (8) loss of host weight or failure to increase weight. The following additional parameters may also be studied when needed and applicable: (4) Circulating serum levels of succinate oxalate transaminase (SGOT) and acetone I transaminase (SGPT) in serum for markers of liver damage (8) Increased circulating (IV) (CT) content as an indicator of likelihood of renal weakness; and (4) Increased circulating creatinine phosphokinase (CK) content as an indicator of general tissue mussel injury. 156069.doc -261 - 201144296 5.7.6.2 Pichind virus Efficacy: The Pichind virus model utilizes Syrian golden hamsters. Antiviral tests used parameters including: (a) animal death; (b) viral power in the brain, liver, spleen, and win; and (c) elevated levels of ALT in serum. Toxicity: One or more toxicity tests are performed on the test substance under evaluation. These measurements are: (a) fatal; and (b) loss of host weight or failure to increase weight. Other parameters may be studied when needed and where applicable: (a) circulating serum levels of glutamate oxalate transaminase (SGOT) and pyruvate transaminase (SGPT) as markers of possible liver damage in serum (b) an increase in circulating creatinine (CT) content as an indicator of a likelihood of renal weakness; and (c) an increase in circulating creatinine phosphokinase (CK) content as an indicator of general tissue damage. S.7.6.3 VEE virus efficacy: VEE virus animal model uses intranasal administration of C3H/Hen mouse TC-83 vaccine virus strain; virus travels to the central nervous system, resulting in higher viral power and animal death in the brain . The SemHki Forest virus model is very similar to the model of Banzi virus and has the same disease parameters. The Semliki Forest Virus is a BSL-3 pathogen that requires special treatment. Parameters for evaluation include: (a) animal death; (b) an average number of days of death; (c) viral power in the brain; and host weight loss. ★ Toxicity··Test one or more toxicity tests on the test substance in the evaluation. These measurements are: (4) fatal; and (8) host weight loss or inability to increase body weight 1 and the appropriate 'other parameters' can also be studied: (4) serum as a marker of this liver damage glutamate conversion Aminase (SG〇T) and 156069.doc •262- 201144296 Increased circulating A content of alanine-transaminase (SGPT); (b) Increased circulating creatinine (CT) content as an indicator of probable renal weakness And (〇) an increase in circulating creatinine phosphokinase (CK) content as an indicator of general tissue damage. 5,7 ·6·4 West Nile Virus Efficacy: West Nile virus animal model currently uses mice and hamsters. In each model, neurological signs are produced, leading to the eventual death of the animal. This virus is a BSL_3 pathogen recovered from various tissues. Other parameters are also examined, such as functional capabilities. Disease parameters used in antiviral assessment include: animal death; (b) prolonged mean days of death; (c) viral power in brain and other tissues; and (d) loss of host weight. Toxicity: One or more toxicity tests are performed on the test substance under evaluation. These measurements are: (a) fatal; and (b) loss of host weight or failure to increase weight. When necessary and applicable, the following additional parameters can also be studied: circulating serum levels of the face acid oxalate transaminase (sg〇t) and pyruvate transaminase (SGPT) in serum as markers of this liver injury. (b) Increased circulating creatinine (CT) levels as an indicator of likelihood of renal weakness; and (4) increased circulating creatinine phosphokinase (CK) levels as an indicator of general tissue damage. 5.7.5.5 Dengue sterilization can be used substantially similar to, for example, Guabiraba et al., ρζΜ ο see g 2010, 5(12): el 5680 and Souza et al. 'TWz&quot;. 2009, 106(33): 14138-14143 The procedure described is performed in vivo assay of deNV. The DENV virus stock solution was diluted in endotoxin free PBS or DPBS to the appropriate concentration. The virus was injected intraperitoneally into mice. The test compound 156069.doc-263·201144296 is administered via an appropriate route at an appropriate dosing frequency (e.g., oral administration twice a day). The fatality rate is assessed every 12 hours and other parameters (weight loss, inflammation, etc.) are checked as appropriate. For tests using genetically knockout mice, controls typically include the same tests performed on wild type mice. Negative controls typically involve the replacement of test compound administration vehicles. In the case of evaluating the vaccine of the DENV virus, it can be assayed using a procedure similar to that described, for example, by Johnson et al., IX, 仏〇/仏〇/〇幻^ 1999, 73(1)·783 786. This assay uses IFN-deficient mice (e.g., Αΐ29 mice lacking the α/β IFN and γ IFN receptor genes) and is involved in intraperitoneal administration of DENV to such mice. Usually, when the vote is £^&gt;1¥, the mice lacking are generally fatal, regardless of age. Based on this, the criteria such as survival time and survival rate can be monitored in IFN-deficient mice immunized with the test vaccine to assess the in vivo efficacy of the test vaccine. 7. 7 In vivo assay of prion diseases Efficacy. The prion transgenic mouse model uses the endogenous mouse prp_sen gene knockout mice. These mice exhibited hamster PrP-sen to a high degree in a wide range of tissues including the brain. Animals infected with hamster pruritus replaced the Syrian hamster model. The latter animals required about 120 days to reach death due to itching infection, while the prion transgenic mice died within about 82 days when infected with the same agent. Death is used as a parameter for anti-prion assessment. Toxicity: One or more toxicity tests are performed on the test substance under evaluation. These measurements are: (a) fatal; and (b) loss of host weight or failure to increase weight. When necessary and applicable, the following additional parameters can also be studied: (4) glutamate oxalate transaminase (S(J〇T) and pyruvate transaminase (SGPT) in serum as a marker for Cox&gt; Increased circulating serum levels; (b) increased circulating creatinine (CT) levels as an indicator of renal weakness in 156069.doc 201144296; and (C) circulating creatinine phosphokinase (CK) as an indicator of general tissue damage Increase in content 5. 7.8 Other tracking tests

Tracking assays for promising antiviral agents seen in original animal studies may include the effect of the test compound administered on key immune components in infected and uninfected mice (toxic controls). The immune effects studied included: (a) cytotoxic T lymphocyte activity; (b) natural killer cell activity; (c) total T cells, T helper cells, T inhibitory/cytotoxic cells, and B cell counts; Reaction to T cell mitogen phytohemagglutinin (PHA); (e) production of interferon; and (f) production of neutralizing antibodies. Where appropriate, conduct studies to determine the development of viruses that are resistant to important antiviral drugs. 6. ELOVL assays ELOVL assays can be performed in vitro using procedures substantially similar to, for example, Shimamura et al., Jowrwa/o/P/iarwaco/og;y, 2010, 630: 34-41. 6Λ In vitro assay 6.1.1 Prolonged enzyme assay using 30 μΐ containing 100 mM potassium phosphate buffer (pH 6.5) ' 200 μΜ BSA (no fatty acid), 500 μΜ NADPH, 1 μΜ rotenone, 20 μΜ propylene dimercapto -CoA, 833 kBq/ml [14C] propylene dithiol-CoA (GH Healthcare Science, Little Chalfont, UK) and a thiol-CoA substrate reaction mixture were extended. The following long-chain thiol-CoA was used as the preferred substrate for each ELOVL: ELOVL1, 10 μΜ stearin-CoA; ELOVL2, 10 μΜ arachidene-CoA; ELOVL3, 10 μΜ stearin 156069.doc -265 - 201144296 Streptomyces-CoA; ELOVL5, 40 μΜ peanut tetrasyl-based-CoA; and ELOVL 6, 40 μΜ hexadecanol-CoA. To start the reaction, 20 μL of ELOVL microsome fraction was added to the substrate mixture, followed by incubation at 37 ° C for 1 hour in a 96-well plate under gentle shaking. After 1 hour of incubation, 1 μμΐ 5 ]\4 11 (:1 was added to allow the thiol-(:0 eight hydrolysis, followed by the use of the mountain 61]^&amp;16 cell harvester (PerkinElmer, Waltham, ΜΑ) Unifilter-96, GF/C disk (PerkinElmer, Waltham, MA) was filtered. The reaction mixture e was then washed with steamed water to a 96-well GF/C filter disk to remove excess [MC] propylenediyl-CoA and dried. 25 μΐ MICROSCINT 0 was added to each well and the radioactivity was determined. 6Λ.2 Fatty acid elongation assay in mouse hepatocytes Mouse liver cancer Η 2.35 cells were cultured in a moisture-containing incubator at 33 ° C, 5% CO 2 Dulbecco's modified Eagle's medium &gt; DMEM supplemented with 200 nM dexamethasone and 4% heat-inactivated fetal bovine serum (FBS) on a 24-well plate (Invitrogen, Carlsbad, CA) The test compound was dissolved in the medium and incubated with the secondary confluent H2.35 cells for 1 hour at 33 ° C. [1-14C] palmitic acid (PerkinElmer Japan, Kanagawa, Japan) was added to each well to reach Final concentration of 0.8 pCi/ml to detect elongase activity. After incubation at 33 ° C for 4 hours, the medium was removed and used The labeled cells were washed with PBS (3 x 〇. 5 ml) and dissolved in 250 μΐ 2 Μ sodium hydroxide. The cell lysate was incubated at 70 ° C for 1 hour to hydrolyze the radiolabeled cell lipids. After acidification with 100 μΐ 5 M HCl, the fatty acid was extracted with 300 μM acetonitrile. The radiolabeled palmitic acid was quantified by reverse phase radioactive HPLC (RI-HPLC) 156069.doc -266- 201144296 (16:〇), standard oil Acid (16:1), stearic acid (18:0) and isooleic acid: oleic acid () are determined by comparing the residence time with known fatty acid standards, and the identity of the heart-to-day fatty acid. The ratio of the radiolabeled C18 (C18: 〇 + C18: 1) to C16 (C16: 0 + Cl6: i) estimated from the peak areas measured in the RI HPLC was estimated by extending the index (to monitor the prolonged activity). In vivo assays for palmitate determination in the liver of 6·1·1 mice by following the conversion of radiolabeled 丨6:〇 to 16::丨, 丨8:〇 and 丨8: i in mice; In vivo efficacy of 疋ELOVL6 inhibitor. EL〇VL6 inhibitor was orally administered to male C57BL/6J mice, and after 丨 hours, it was administered intraperitoneally at i〇pCi/ With a radioactive tracer - palmitic acid. For the time course study of pharmacodynamic effects, [1-14C] palmitic acid was administered at 8 or 12 hours after administration of the test compound. "Isoflurane was used for i hours after administration of the radioactive precursor ( 4%) Animals were anesthetized and sacrificed to collect blood from the vena cava. Liver (50 mg) was collected and incubated for 1 hour at 7 (rc in potassium hydroxide/ethanol (2 ml/14 ml). Non-acid lipids were extracted with 4 ml petroleum ether and discarded. 2 ml 6 M HC1 was used After saponification, the fatty acid was extracted with 2 ml of petroleum enrichment. The ether phase containing the fatty acid moiety was evaporated under nitrogen and reconstituted in decyl alcohol to measure radioactivity by RI-HPLC. The radioactivity corresponding to each fatty acid was quantified to calculate EI. 6.2.2 In vivo efficacy in diet-induced obesity (DIO) mice Male C57BL/6J mice were maintained on a high-fat diet (D12492, Research Diets, Inc., NJ) for 7 months at random. Two doses (〇9··30 and 18:30) were orally administered to mice with ELOVL6 at a dose of 30 mg/kg to inhibit 156069.doc -267- 201144296 (dissolved in 0.5% thioglycol) for 14 days. On the 13th day, the body and Weicheng were tested and the intraperitoneal glucose tolerance test (0.5 kg/g glucose) was performed. On day 14, the mice were sacrificed. The mice were given 4 hours after the final administration of the EL〇VL6 inhibitor. The liver tissue was anesthetized and immediately separated, weighed, frozen in liquid nitrogen and stored at -80. (: down until use. Prepare plasma and Glucose, insulin and leptin were measured using commercially available assay kits (glucose, KyowaMedex, Tokyo, Japan; leptin and insulin, Morinaga, Tokyo, Japan). Liver tissue was isolated to measure triglyceride content and Fatty acid composition. For the liver diglyceride content, homogenize the separated tissue in 2 ml of distilled water, and then add 6 ml of air/methanol (2:ι) β centrifugation, then transfer the gas phase to 1 ml of steam. In the new glass tube of water, '3 m helium was added. After centrifugation, the lower phase was collected and evaporated to dryness. The extract was dissolved in 2-propanol and the concentration of diglyceride was measured by enzymatic method (Determiner TGII, Kyowa Medex,

Tokyo japan). For liver fatty acid composition, liver samples were incubated at 6 NaOHt: in 1 〇〇 volume (w/v) of 5 M NaOH/ethanol (1:1). After 2 hours of incubation, 500 μΐ 5 MCI 7:0 (internal standard) was added to all hydrolyzed products. The fatty acid composition was analyzed by derivatizing fatty acids in the tissue hydrolysate with 2-nitrophenylhydrazine (2-NPH) and purifying these derivatives using a 0asisHLB column. An aliquot of the eluate (1 μ μl) was injected into the HPLC equipment for analysis. Using the Shimazu ΙΟΑνρ system (Kyoto, Japan) equipped with a UV detector (SPD-lOAvp), two poly (LC-10ADvp), an autosampler (siL-10ADvp) and a column oven (CTO-lOACvp) HPLC analysis. The mobile phase consisted of CH3CN-water (80:20, flow rate: 0.6 ml/min). The separation was carried out at 35 ° C using CAPCELL PAK C18 MGII (2.0 156069.doc -268 - 201144296 mm inner diameter xl50 mm '5 μιη), and then the UV absorbance was measured at 400 nm. The elongation index represents the ratio of (from 18 (0:18:0+€:18:1) to 〇:16 ((:16:0+(:16:1)). 6.2.3 KKAy mice In vivo efficacy in vivo (09:30, 18:30) The ELOVL6 inhibitor (dissolved in 0.5% methylcellulose) was orally administered at a dose of 30 mg/kg to provide a regular diet (CE2, Male KKAy mice of CLEA Japan) lasted for 28 days. On day 21, • intraperitoneal glucose tolerance test (0.5 kg/g glucose) was performed. On day 28, body composition was determined and mice were sacrificed. Blood test parameters, liver triglyceride content and fatty acid composition were measured. 6.2.4 Pharmacokinetics study in mice by gavage method will be single in 0.5% methylcellulose aqueous suspension vehicle The test compound was orally administered to C57BL/6J mice at a dose of 1 mg/kg body weight. Blood samples were obtained from the abdominal vein 2 hours after administration and liver samples were obtained. Under the condition of diet, 'at 17: 〇〇 〇〇mg/kg was administered to mice φ and fed a diet containing 〇13% test compound overnight. The mice were then sacrificed the next morning. The liquid sample was centrifuged to separate the plasma. The liver sample was homogenized with phosphate buffered physiological saline (pH 7.4). The protein of each sample was removed with ethanol containing the internal standard by liquid chromatography mass spectrometry/mass spectrometry (Quattro) Ultima mass spectrometer; Waters, Milford, MA) uses electrospray ionization probes to detect test compounds and internal standards in positive ionization mode, and uses multiple reaction monitoring modes to monitor production of combined precursors. Examples can be based on familiar organic synthesis techniques A number of ways are known to prepare the compounds disclosed in 156,069.doc 201144296. Further, the reactions and techniques described herein can be used to prepare the unexamined compounds. In the description of the synthetic methods described below It should be understood that 9 is not otherwise indicated, otherwise all proposed reaction conditions, including the atmosphere of the refrigerant reaction, the reaction temperature, the duration of the experiment and the choice of treatment procedures, may be selected as the standard conditions for the reaction. Those who are familiar with organic synthesis technology should Understand that the functional groups present on the various parts of '5' should be compatible with the proposed reagents and reactions. Substitutes will be readily apparent to those skilled in the art' and thus indicate alternative methods. The starting materials of the examples are commercially available or can be readily prepared from known materials by standard methods. Synthetic methods are generally synthesized (i) Synthetic four flavors _Intermediate

Step S-ι: treatment of aniline (A) (1 〇 equivalent) and diethylamine (1.0 eq.) in anhydrous dichloroethane (DCE) (〇2 M) with phosgene (〇4 equivalent) under argon The solution was heated to reflux for 2 hours or until the reaction was completed by LCMS or TLC. The reaction was then cooled to room temperature, diluted with EtOAc EtOAc EtOAc. The desired isocyanate (B) was used in the next step without purification. Step S-2: heating the mixture of isocyanate (B) (1 〇 equivalent) and trimethyl sulfonium azide 156069.doc • 270- 201144296 (2.0 equivalents) to reflux for 24 hours or until the reaction is completed by TLC . Excess azide is removed in vacuo and the residue is crystallized from toluene or methanol to afford the desired tetrazolone intermediate (c) as a white solid. (ii) synthetic amine intermediates

Step S-3: Copper iodide (1 equivalent) and carbonic acid planer (2 equivalents) were added to a microwave vial, and the vial was evacuated and filled three times with argon. Next, an aryl iodide (D-1)-containing anhydrous dimethyl decylamine (〇6 M), an alkylamine (R ΝΗ2) (2.0 equivalent), and 2-isobutyl decylcyclohexanone (〇2) Equivalent) was added to the vial, the vial was sealed, and the resulting mixture was heated to 1 Torr under microwave irradiation for 2 hours or until the reaction was completed by LCMS or TLC. At this time, the vial was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate and filtered over EtOAc. The mash was washed with brine (3 x), dried over MgSO.sub., filtered and concentrated in vacuo. The residue was purified by EtOAc (EtOAc/EtOAc) elute Step S-4: To a nitro compound (D-2) (l. 〇 equivalent) and iron (ι 5 · 〇 equivalent) in a 1:1 absolute ethanol / anhydrous tetrahydrofuran solution (0.. 8 mL / mmol g Water (10 gL/ml solvent) was added to the mixed person in the purpose. The mixture was then cooled to 〇°c, and a solution of concentrated sulfuric acid (4.0 eq.) in water (1·2 ml/mmol ester) was added dropwise to a mixture of 156069.doc-271 - 201144296. The reaction was allowed to warm to room temperature and stirred for an hour or until the reaction was completed by LCMS or TLC. The reaction was then filtered through Celite® pad with ethyl acetate. The filtrate was diluted with brine, aq. EtOAc EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography (ethyl acetate /hexane) eluting Step S-5: Add a carbonyl compound (10.0 equivalents of ketone or aldehyde) and sodium borohydride (1 〇〇 equivalent) to D-3 (1.0 eq.) in acetic acid (a stirred solution of 〇2), and mix it under the dish. The mixture was known to be 1 hour or until the reaction was completed by [CMS or TLC. The reaction was then diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (5 EtOAc) and brine (2x) and dried organic The layers were filtered and concentrated in vacuo. EtOAcqqqqqqqqqq

R9 R8 E NHRC R10 Step S-6 · Add triethylamine (13#) to the amine intermediate (8) (13 equivalents) in anhydrous tetrahydrofuran (0.5 M) under argon. ), three phosgene (〇.7 equivalent). The resulting heterogeneous mixture was stirred at room temperature for 15 minutes, treated with dimercaptoamine oxime (DMAPXl.o equivalent) and tetrazolone intermediate (c) g 〇 equivalent) diluted with anhydrous tetrazole (to 〇 25 call the final concentration, regarding 156069.doc *272- 201144296 amine)' and heat to reflux for i hours or until the reaction is completed by LCMS4TLC. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and brine, and the aqueous layer and organic layer were separated. The organic layer was washed with brine, EtOAc EtOAc EtOAc. The residue was purified by EtOAc (EtOAc/EtOAc) (iv) the general method of synthesis

The general synthetic methods are not intended to be limited to the coupling of an amine intermediate (such as (E)) with a phenyltetrazolone intermediate (such as (c)) in forming the compounds provided herein. For example, Lu' has used the general method described above to couple other amines with four salivas to give a variety of four. (d) Compounds such as the tetrasporine compounds provided in the formula. Exemplary synthesis of compounds

(0 Synthesis of tetrazolone compound 7 &amp;

Compound 3. A mixture of municipal f isocyanate 2,6•trifluorobenzene vinegar (2) (1 () equivalent) and gastrimethane (2.0 eq.) was heated to reflux for 12 hours. 156069.doc -273 - 201144296 Excess azide was removed in vacuo and the residue was crystallized from toluene to give a white needle. Compound 5: in argon, in a solution of commercially available 5-iodo-2-indoxybenzoic acid in a solution of anhydrous dimethylformamide (DMF) (〇.5 M) Solid potassium carbonate (1.5 eq.), benzyl bromide (1 eq.) was added, and the mixture was stirred at room temperature for 4 hrs, acidified with 10% HCl, and diluted with brine and ethyl acetate. The aqueous layer and the organic layer were separated, and then evaporated, evaporated, evaporated, evaporated Compound 6: Copper iodide (1 equivalent) and carbonic acid planer (2 〇 equivalent) were added to the microwave vial, and the vial was evacuated and filled three times with argon. Next, anhydrous dimethyl decylamine (0.6 M), isopropylamine (2. oxime equivalent) and 2-isobutyl decylcyclohexanone (0.2 eq.) containing compound (5) were added to the vial, and the vial was sealed and The resulting mixture was heated to 1 Torr under microwave irradiation for 2 hours. At this time, the vial was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate and filtered over Celite® pad with ethyl acetate. The filtrate was washed with brine (3 mL), dried over EtOAc EtOAcjjjjjjjjjjjjjj To a solution of the compound (6) (1.5 eq.) in anhydrous dichloromethane (0.5 M) was added triethylamine (3 〇 equivalent) and triphosgene (1.5 vol.) at room temperature under argon. The resulting heterogeneous mixture was stirred for 15 minutes, concentrated in vacuo, and the residue was taken crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3) (1 〇 equivalent) treatment The mixture was heated to reflux for 1 hour, cooled to room temperature 156069.doc • 274- 201144296 and diluted with ethyl acetate and brine, and the aqueous and organic layers were separated. The organic layer was washed with aq. EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Compound 8: Under argon, to compound 7 (1.0) Add 5% Pd/C (0.1 eq.) to a solution of 2:1 methanol / THF (0.1 M), and replace the inert atmosphere with hydrogen. The mixture was stirred at room temperature for 30 minutes and passed through methanol. The celite pad was filtered, and the obtained filtrate was concentrated in vacuo. EtOAc EtOAc (EtOAc) Tetrazolone compounds 15 and 16

Compound 10: To a stirred solution of 1:1 THF:H 2 〇 (0.6 M) was added in an amount of 1:1 at room temperature under nitrogen. The reaction was heated to 80 t for 2 hours. The resulting solution was cooled to: temperature and reduced in volume by rotary evaporation. The resulting solution was acidified to 156069.doc-275·201144296 to ρ=ι, extracted with ethyl acetate, dried over sodium sulfate and concentrated by rotary evaporation to give compound (10) which was used without further purification. . Compound u: To a stirred solution of (1 〇) (1 〇 equivalent) in 2〇:1 acetone:DMF (0.2M) at room temperature under nitrogen, potassium carbonate (15 equivalents), p-methoxy The benzyl group (1.0 eq.) and sodium iodide (catalytic amount) were heated to 7 ° C for 6 hours. The resulting solution was cooled to room temperature and the volume was reduced by rotary evaporation. The resulting solution was diluted with EtOAc and EtOAc (EtOAc)EtOAc. The oil obtained was purified by chromatography (hexane to 25% ethyl acetate /hexane) to afford Compound (11). Compound 12: Add carbonated (2 〇〇 equivalent), copper iodide (〇·1 equivalent) to a stirred solution of compound (n) (1 〇 equivalent) in DMF (0.12 M) in a microwave vial at room temperature. ), 2-isobutyl nonylcyclohexanone (0.2 eq.) and cyclohexylamine (3 〇 equivalent). The resulting suspension was heated in a microwave at 100 ° C for 1 hour. The resulting suspension was cooled to room temperature, diluted with ethyl acetate, washed with a diluted aqueous solution of lithium and washed with water. The organic layer was dried with sodium sulfate and EtOAc (EtOAc)EtOAc. Compound (12). Compound 14: To a stirred solution of the commercially available compound (13) (1.00 eq.) was added azidotrimethyl decane (4.00 equivalents ρ. The resulting suspension was heated at 90 s for 6 hours. The hot reaction solution was poured directly onto toluene containing: In a beaker of ice (1:1), the obtained yellow precipitate was collected by vacuum filtration and washed with cold toluene to give compound (14) as a yellow solid. Compound 15: Compound (12) (1.2 eq.) Add triethylamine (3 〇 equivalent) and triphosgene (1 〇 equivalent) to a stirred solution of 2-3069.doc •276- 201144296 (0.5 Μ). Remove the ice bath and The solution was stirred at room temperature for 15 minutes, followed by concentration by rotary evaporation. The obtained foam was dissolved in toluene (1·4 Μ), followed by the compound (14) (1.0 eq.) and the decylamino group. The resulting suspension was heated at 70 c for 6 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed with water. Chromatography by column chromatography (ethyl acetate / hexane) • Purification of the obtained oil to give the compound (15) as a white solid. Compound 16: mp EtOAc (1 EtOAc) The hydrazine trifluoroacetate equivalent) and the methyl ether (1.0 eq.) were added. The reaction was allowed to proceed for 1 minute at room temperature. The reaction was diluted with di-methane and neutralized with aqueous sodium bicarbonate. The organic layer was dried with EtOAc (EtOAc m. φ (Mi) synthesis of tetrazolone compounds 17 and 18

Compound 17: Palladium hydroxide/carbon (〇2 equivalent) was added to a stirred solution of the compound (16) (1 〇 equivalent) in Me〇H (0.02 M) under nitrogen, followed by vacuuming and exposure to helium. (1 atm, balloon). The reaction was allowed to proceed overnight at room temperature. The resulting solution was filtered through celite, washed with dichloromethane, 156 069. doc. 277 - 201144296 and concentrated by rotary evaporation. The oil was purified by preparative HPLC ( EtOAc EtOAc (EtOAc) elute Niobic acid (5 〇〇 equivalent). The reaction was heated at 100 C for 1 hour. After cooling to room temperature, the reaction was diluted with EtOAc EtOAc (EtOAc)EtOAc. The oil was purified by preparative EtOAc (EtOAc) elute The compound (18) is described above as a compound, but it is in an equilibrium state in the form of a mixture of tautomers as shown below.

Synthesis of tetrazolone compounds 24 and 25

Compound 20: Sodium carbonate was added sequentially to a solution of the municipal "· oxycyclohexanecarboxylic acid 156069.doc -278- 201144296 (19) (1.0 eq.) in anhydrous DMF (0.5 Torr) under argon. (1.5 eq.), benzyl bromide (1.1 eq.). The mixture was stirred at room temperature for 4 hrs. </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The organic layer was dried (MgSO4), filtered,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjj a solution of benzyloxycyclohexanecarboxylate (20) (0 〇) and a solution of 2 M ethylamine in THF (2.0 eq.) in anhydrous DCE (1.4 M), and the mixture was stirred at room temperature for 1 hour. The layers were separated with aq. EtOAc EtOAc (EtOAc m. The residue was purified (ethyl acetate / hexane) to afford compound (21) Compound 23 - A mixture of commercially available 2,6-dichlorophenyl isocyanate (22) (1.0 eq.) and dimethyl decane azide (2 〇 equivalent) was heated to reflux for 12 hours. Excess azide was removed in vacuo, and the residue was crystallized from decyl alcohol to give compound (23) as white needles. Chemicals 24. Under argon, 3 equivalents to the compound in anhydrous hydrogenhydrofuran Triethylamine (i. 3 equivalents) and triphosgene (1.3 * amount) were added sequentially to the solution in (〇·5 M). The resulting heterogeneous mixture was stirred at room temperature for η min and diluted with anhydrous tetrahydrofuran ( 0.25 μ, with respect to amine), and treated with DMAp (1 〇 equivalent) and hydride (23) (1. 〇 equivalent). The resulting mixture is heated to reflux for 1 hour to recover from 'cold to temperature and with acetic acid B. G is diluted with brine, and the aqueous layer and the organic layer are separated. The organic layer is washed with brine, 1% HCI aqueous solution, brine, 156069.doc • 279· 201144296, dried by MgS〇4, filtered and vacuumed The residue was purified by EtOAc (EtOAc/EtOAc) (24) Compound 25: Add 〇% Pd(〇H)2/carbon (〇) equivalent to a solution of the compound (24) (1 〇 equivalent) in methanol (〇j Μ) under argon. And replace the inert atmosphere with hydrogen. The resulting mixture was stirred at room temperature for 2 hours, filtered through a pad of celite, and filtered, and evaporated. The residue was purified by preparative EtOAc (EtOAc:EtOAc) (y&gt;) Synthesis of tetrazolone compounds 27 and 28

Compound 27: Under gas, the product was sold to the market. Triethylamine (1.3 eq.) and triphosgene (1.3 eq.) were added sequentially to anhydrous tetrahydrofuran (〇.5 M) in hexanes (3). The resulting heterogeneous mixture was stirred at room temperature for 15 minutes&apos; diluted with anhydrous tetrahydrofuran (0.25 Torr, with respect to amine) and treated with DMAP (1.0 eq.) and compound (23) (1 eq. The resulting mixture was heated to reflux for 1 hour, cooled to room temperature and diluted with ethyl acetate and brine, and the aqueous and organic layers were separated. The machine layer, the domain MgS〇4, was washed with brine, 10% aqueous HCl solution, 156069.doc • 280·201144296^, and concentrated in vacuo. It is used without further purification. An analytical sample was obtained by preparative hpLC (acetonitrile/water containing hydrazine·1% formic acid) to give a white solid (27). &quot; Compound 28 · Compound (27) (1 〇 equivalent) was dissolved in anhydrous dichloromethane (0.2 M) under EtOAc, and was applied dropwise with TFA (3:1 DCM/TFA). The resulting solution was stirred at room temperature for 1 hour and concentrated in vacuo. The amine salt is then dissolved in anhydrous di-methane, cooled to 0 ° C and treated with excess ethyl chlorohydrin (equivalent) and triethylamine (1.0 eq.). The mixture was stirred for 15 min at EtOAc (EtOAc) EtOAc (EtOAc) The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by preparative EtOAc (EtOAc:EtOAc) (vi) Synthesis of tetrazolone compounds 32 and 33 NH2 F, captain

NCO

Ο INI person "H \ · N=N

O JO

OH OBn 30 31

F ό 33

Compound 30: 5-Amino-2-pyridinecarboxylic acid (29) G 156069.doc 281 - 201144296 ketone (1.1 equivalents) at room temperature under nitrogen

To a stirred solution of AcOH (0.9 Torr) was added cyclohexane and sodium triethyloxyborohydride (1.1 eq.). The material was allowed to boil for 72 hours at room temperature. Methanol was added, and the compound (30) was obtained by the hydrazine hydrazine water: the hydrazine condensed organic layer, which was used without further purification. Compound 31: To a stirred solution of the compound (30) (1. 〇 equivalent) in 2:1 CH2C12: DMSO (0.13 M), Ag 〇 (3 〇 equivalent), benzyl bromide (1.1 eq. at room temperature) The reaction was allowed to proceed overnight. The resulting solution was filtered through a pad of Celite, washed with water, washed with water, dried over sodium sulfate, and concentrated by rotary evaporation. hexane to 5 〇 Purification of the obtained oil to give the title compound (31): Compound 32: Compound (31) (9 eq) in di-methane (0.5 M) Triethylamine (3 eq. equivalent) and triphosgene "force equivalent" were added to the stirred solution. The ice bath was removed, and the solution was stirred at room temperature for 15 minutes, followed by concentration by rotary evaporation. The obtained foam was dissolved. Intoluene (〇4 M), compound (3) (1. 〇 equivalent) and dimethylaminopyridine (1 〇) were added. The resulting suspension was heated at 90 C for two hours. Warm, dilute with ethyl acetate and wash with water. Dry the organic layer with sodium sulfate and steam Concentration was carried out. The obtained oil was purified by column chromatography (hexane to 5% ethyl acetate /hexane) to afford compound (32). Compound 33: at room temperature to (32) 1 〇〇 equivalent) Add 2 〇 of palladium hydroxide/carbon (about 〇·2 equivalents) to a stirred solution of decyl alcohol (〇丨M). The reaction is evacuated and purged with nitrogen, then fed Hydrogen gas. After stirring for 1 hour, the reaction was filtered through celite, 156069.doc 201144296, washed with dichlorohydrazine, and concentrated by rotary evaporation. Chromatography by chromatography (dichloromethane to 9) :1 dichloromethane:methanol). The obtained oil was purified to afford crystals as a clear oil. (yii) Synthetic four scented compounds 4Q and 41

Ό - 〇Compound 36: Add to commercially available compound (34) (1 〇 equivalent) and analytic acid (1.5 liter) in anhydrous DMF (0.3 M) in a stirred suspension at room temperature under nitrogen. Benzyl/odor (1.2 when; £). The reaction was spoiled for 19 hours, then additional potassium carbonate (1 eq.) was then added and then phenol (1.2 eq.) was added and stirring was continued for 24 hours. With the help of

The resulting suspension was filtered through a pad of celite, and the filtrate was diluted with EtOAc and washed with brine and &lt;RTIgt; The aqueous layer was back-extracted with EtOAc (EtOAc) (EtOAc). Obtained as an orange oil, which was purified by flash chromatography (hexane/EtOAc EtOAc:EtOAc) To the end. (: (36) (1.0 eq.) and iron powder (15.3 eq.) Add 156069.doc • 283 · 201144296 H2SO4 (0.6 ml/mmol) in a stirred solution of 1:6 absolute ethanol/THF (0.3 M) a solution in H2 〇 (1.8 ml/mmol). The resulting mixture was stirred at room temperature for 1 hour, filtered through a pad of celite with AcOEt and diluted with brine and additional AcOEt. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, brine, dried (MgSO.sub. Acetone (5 eq.) and sodium borohydride (2 eq.) were added sequentially to a stirred suspension of glacial acetic acid (0.3 M). The resulting mixture was taken at room temperature for 1 hour, diluted with AcOEt, and brine ( 3 x), saturated sodium bicarbonate solution (6 χ ' until pH is basic) and brine (2x) washed, dried (MgSOO organic layer filtered and concentrated in vacuo) by flash chromatography (hexane/AcOEt 91 To 3:1) to obtain the compound (38) as an oil after purification (yield 80 ° /., in 2 steps) Compound 40: In a stirred solution of the compound (38) (1 〇 equivalent) in di-methane (0.3 M), triethylamine (2 〇 equivalent) and triphosgene (〇7 eq.) The ice bath was removed and the solution was stirred in vacuo for 15 min and concentrated in vacuo. The obtained foam was dissolved in toluene (3M), followed by compound (39K!) equivalents and dimethylamine. Base. Adjacent (four) amount. Heat the resulting suspension to reflux for 3 hours, then cool to room temperature, dilute with ethyl acetate vinegar and wash with water, 1G% hydrochloric acid solution and brine. Dry (10) called organic

The layers were dried and concentrated in vacuo. The obtained crude product f' was purified by flash chromatography (hexanes / EtOAc / EtOAc) to yield (yield: 66%). Compound 41: 10% Pd/C (0.15 equivalent) was added to a solution of compound (4 〇) (1 〇 equivalent) in w methanol 156069.doc •284· 201144296 /AcOEt (0.3 Μ) under argon, And replace the inert atmosphere with hydrogen. The resulting mixture was stirred at room temperature for 30 minutes, filtered through a pad of Celite, and concentrated in vacuo. The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc) + = 495.1. (viii) Synthesis of tetraketone compounds 51 and 52 Ά . —j OPh side - OPh 'force N. 2 — OPh ώΝ〇2 ΜβΟ^γ C00H 42 C00M( 43 a COOMe 44 COOMe 45 COOH 46 0 0Xi Ί A again” CN:N ό 62 COOH °Ό · F n COOBn — PN:N _ 60 ?PhH Μβ〇 ψΝΌ 1°: °^Ό OPh -MeO people's wide. Shi. X)

Compound 44: as described in the literature (Del Corona, L.; Signorelli, G.; Pinzetta, A.; Coppi, G. Eur. J. Med. Chem. 1993, 28: 419-425), via commercial availability 4-Fluorosalicylic acid (42) is thiolated, followed by nitration to prepare compound (44) in a yield of 64%. Compound 45: To a solution of the compound (44) (1.0 eq.) in anhydrous DMF (0.9 M), EtOAc (1.sub.1) and potassium carbonate (1.5 eq.), and the mixture was stirred at room temperature for 1 hour. Wash with AcOEt, dilute the filtrate with AcOEt and wash with 10% HCl and brine (5 EtOAc). The aqueous layer was back extracted with AcOEt and the aqueous layer was washed with brine. The combined organic layers were dried (MgSO4) filtered and concentrated in vacuo. The oily compound (45) was obtained, which was used directly. 156069.doc -285 ' 201144296 Compound 46: Add LiOH (1.5 equivalents) to a solution of methyl ester (45) (1.0 eq.) in 2:2:5 Me0H/THF/H20 (0.3 Μ) at 60 ° C The suspension was stirred for 1.5 hours. The reaction mixture was cooled to rt. The aqueous layer was acidified with 10% HCl and extracted with AcOEt (3x). The combined AcOEt layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Compound 46 was obtained as a pale yellow foam which was used directly. Compound 47: To a stirred solution of the acid (46) (1.0 eq.) The reaction was stirred for 19 h, filtered thru a pad of EtOAc (EtOAc) eluting with EtOAc (EtOAc). The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. Compound 48: Cooled to hydrazine. (: (47) (1.0 eq.) In a stirred solution of 2:1 THF/AcOH (0.6 Μ), zinc powder (lo.o equivalent) was added portionwise. The resulting mixture was stirred under hydrazine for 1 hour. The mixture was filtered over a pad of EtOAc (EtOAc) eluting with EtOAc (EtOAc). Compound (48) as a pale yellow oil, which crystallised upon standing. Compound 49: Cyclohexanone (4.0 eq.) was added to a stirred suspension of aniline (48) in glacial acetic acid (0.3 M). Sodium (2.5 eq.). The resulting mixture was stirred at room temperature for 1 hour, diluted with AcOEt, and washed with brine (3×), sat. sodium bicarbonate (6×, until pH is basic) and brine (2×). (MgS 〇 4) The organic layer was filtered <RTI ID=0.0>(</RTI> to <RTI ID=0.0></RTI> to <RTIgt; Yield 46%, in 5 steps) Compound 51: at 0 ° C, to compound (49) (1.0 when Triethylamine (2.0 eq.) and triphosgene (0.7 eq.) were added to a stirred solution of methylene chloride (0.2 M). The ice bath was removed and the mixture was stirred at room temperature for 15 min and concentrated in vacuo. The obtained foam was dissolved in toluene (0.2 M), followed by the addition of compound (50) (1.1 eq.) and dimethylaminopyridine (1.0 eq.). The resulting suspension was heated to reflux for 2 hours, then cooled to room. The mixture was diluted with EtOAc, EtOAc (EtOAc)EtOAc. The resulting product was purified to give the compound as a crystalline solid (51 (yield: 22%). Compound 52: Compound (51) (1.0 eq) in 1:1 methanol / THF (0.1 M) 10% Pd/C (0.15 equivalent) was added to the solution, and the inert atmosphere was replaced with hydrogen. The resulting mixture was stirred at room temperature for 1 hour, filtered through a pad of Celite, and concentrated in vacuo. The compound (52) was obtained as a crystalline solid (yield: 99%). Human FASN protein The human FASN protein (SEQ ID NO. 1) was purified from SKBR3 cells using the program modified from the procedure of Jayakumar et al., PAMS 1995, 92:8695-8699. SKBR3 cells were obtained from ATCC and supplemented with Growth was carried out in DMEM high glucose medium with 10% FBS, 1 pg/mL bovine pancreatic insulin, 100 U/mL penicillin and 100 pg/mL streptomycin. Confluent cells were trypsinized with 156069.doc -287 - 201144296 and washed three times with PBS buffer, then frozen in liquid nitrogen and stored at -80 °C. The frozen cells were thawed on ice and resuspended in a lysis buffer (25 mM Tris-HCl, pH 7.0, 15 mM NaCl, 1 mM EDTA and 1 mM DTT) with protease inhibitor. The cells were lysed by sonication and cell debris was removed by centrifugation at 20,000 rpm for 30 minutes. A neutralized saturated ammonium sulfate solution was added to the supernatant to a final concentration of 35%. The solution was allowed to stand on ice for 1 hour, and the precipitated protein was collected by centrifugation at 20,000 rpm for 30 minutes. The protein was redissolved in NaCl-free lysis buffer and loaded onto a mono Q column. The bound protein is dissolved in a linear gradient containing a solution buffer of NaCl. Each fraction was analyzed by SDS-PAGE and FASNNADPH consumption assay. The fractions containing FASN were pooled and concentrated to 2-3 mg/mL. Glycerol was added to 20% ' and the protein was frozen in liquid nitrogen and stored at -8 °C. FASN NADPH Consumption Verification All chemicals were purchased from Sigma (St. Louis, MO). The procedure for NADPH consumption testing is similar to that described in Cox et al., 1983, 80: 4233-4237. A dilution series of test compounds (typically 60 nM-1.0 mM) was prepared in DMSO on a 96-well polypropylene microassay plate, and each of the 4.0 pL was transferred to a black polystyrene assay micro-distribution disk with 36 Μί FASN assay buffer (50 mM potassium acetate, pH 7.0, 1.0 mM EDTA '0·01ο/〇ΝΡ-40) and 5.0 mM fresh DTT were mixed. FASN protein (40 μί 150 nM FASN) was added to each well and the microtiter plate was incubated for 30 minutes at 37 °C. By adding 20 μί 5x substrate mixture to a final concentration of 60 nM FASN, 2·4 ηΜ-40 μΜ compound, 0.2 mM NADPH, 50 μΜ 醯 醯-CoA, 156069.doc -288- 201144296

Initial enzyme activity measurements were performed in 0.5 mM propanediyl-CoA 100 pL assay buffer and 5.0 mM DTT and 4.0% DMSO. FASN enzyme activity in the presence of 4% DMSO in a kinetic manner by glory (λΕΧ = 340 nm, λΕπι = 460 nm) on the EnVision 2100 multi-label reader (Perkin Elmer, Waltham, ΜΑ) As the largest control, the background (minimum control) was measured by eliminating the propylenediyl-CoA in the substrate mixture. The inhibition curve was fitted by a logistic function to obtain an IC50 value: inhibition °/. = 1 Suppression °/〇 100 ι+Mkr coefficient Using this assay, it was found that the compounds provided herein inhibit FASN activity. The activity obtained by the above FASN NADPH consumption test is indicated by an asterisk (*) in Table 1, Table 2, Table 3 and Table 4, where "A*" refers to a compound having an IC50 of 60 nM or less; "B*" means IC5〇 includes compounds ranging from 60 nM to 250 nM; “C*” means IC5〇 includes compounds ranging from 250 nM to 1000 nM; “D*” means IC5G includes from 1000 nM or more to 10,000 nM. A compound; and "E*" means a compound having an IC5〇 of 10,000 nM or more. FASN scintillation proximity Flashplate assay Ethyl-CoA, propylene di-coa-A, NADPH, bovine gamma globulin and ORLISTAT were purchased from Sigma (St. Louis, ΜΟ). Ginseng (2-carboxyethyl)phosphine hydrochloride (TCEP) was purchased from Pierce Biotechnologies (Rockford, IL). [3H]-Ethyl-coenzyme A was purchased from Moravek Biochemicals (Brea, CA). 156069.doc • 289 · 201144296

A FlashPlate® PLUS fat-filled 96-well scintillator coated micro-quantitative disk was purchased from Perkin Elmer Life and Analytical Sciences (Shelton, CT). The FASN flashing proximity FlashPlate assay is similar to the method described in Weiss and Glickman (41515〇/), 1^1£)~7^/2/7〇/ 2003, 1:161-6. A dilution series of test compounds (typically 60 ηΜ-1·0 mM) was prepared in DMSO in a 96-well polypropylene microassay plate. Then 20-fold dilutions in FASN assay buffer (50 mM potassium sulphate pH) In 7.0, 1.0 mM EDTA, 0.01°/〇NP-40), transfer 5.0 μM each to a FlashPlate® PLUS 96-well plate with 35 pL FASN assay buffer and 0.5 mg/mL bovine gamma globulin and 1 mM TCEP is mixed. FASN protein (10 μί, 10 ηΜ) was added to each well, and the microtiter plate was incubated at 37 ° C for 30 minutes. Add 10 gL of 20 mM NADPH and add 10 pL·substance mixture to a final concentration of 1 nM FASN, 100 μΜ Ethyl-CoA, 6 μ (:ί [3Η]-B in a volume of 100 μί per well Sulfhydryl-CoA, 300 μM malonyl-coenzyme A, 2 mM

The initial reaction was initiated with NADPH, 0.5 mg/mL bovine gamma globulin and 1 mM TCEP. The assay plate was incubated at 37 °C for 2 hours and the reaction was stopped with ORLISTAT in 2 pL of 2.5 mM stock solution in DMSO to approximately 50 μM. Disk data was read in a Wallac 1450 Microbeta Plus liquid scintillation counter (Perkin Elmer, Waltham, ΜΑ) and a count per minute (CPM) was collected over 2 minutes. The inhibitor CPM and maximum FASN enzymatic activity (Max) CPM were compared and the background (Min) CPM measured by the FASN enzyme was omitted in the background well. Calculate the % inhibition value and fit the curve by a four-parameter Logis function to get the IC5 threshold: % inhibition = ^_ί^ΜζΜ^χ100% (Max-Min) 156069.doc •290· 201144296 Use this check to find this article The compounds provided inhibit FASN activity. The activity obtained by the above FASN scintillation proximity Flashplate assay is provided in Table 1, Table 2, Table 3 and Table 4, wherein "A" refers to a compound having an IC50 of 15 nM or less; "B" means that IC5 is comprised of 15 nM. To include 100 nM of compound; "C" means that IC5 is a compound including 100 nM or more to 200 nM; "D" means IC5 is a compound including 200 nM or more to 5000 nM; and "E" Refers to compounds with IC5〇 above 5000 nM.

FASN cells Flashplate assay Compounds were added to HCT116 cells (1 X 106 cells per well, 6 well plates) 24 hours after plating and incubated for 24 hours (37 ° C, 5% CO 2 ). The cells were collected and pelleted and washed with PBS. Add 30 pL of FAS buffer (50 mM KPB, pH 7.0, 1.0 mM EDTA, 0.01% NP-40, 1 mM TCEP) deducting BGG to the cell aggregates and freeze/thaw (3 x, liquid nitrogen / The cells were lysed in a 42 ° C water bath, and the fragments were then aggregated into granules (20,000 ref, 15 minutes, 4 ° C). The total protein concentration of the lysate was determined (Pierce BCA Total Protein Assay, BSA Standard) and the sample was calibrated to 1 mg/mL total protein in assay buffer. Assay configuration: Add 50 pL of assay buffer to each well of a FlashPlate (PerkinElmer, FlashPlate Plus fat-filled 96-well scintillator-coated microassay plate). Add 10 gL or less to the well: 1 mM acetamino-CoA, 3 mM propylenediamine-CoA, 0.05 mCi/mL [3H] acetyl-CoA and 20. mM NADPH, final concentration 100 μΜ Ethyl-CoA, 300 μM propionate-&lt;:〇人,〇.5#(^/孔[311]乙醯基-(:〇八和二〇〇〇01^ NADPH. Finally, Add 10 pL of FAS enzyme to the well as HCT116 cell lysate or 156069.doc -291- 201144296 purified FAS (for standard curve). Raise the FlashPlate at 37 °C for 120 minutes, then read on the MicroBeta instrument Using this assay, the compounds provided herein were found to inhibit FASN activity. HCV_replicon luciferase assay Directed DMEM complete medium (Life Technologies) supplemented with 10% FCS, 2 mM glutamic acid, penicillin and streptomycin Lx non-essential amino acid was pre-warmed in a constant temperature water bath at 37 ° C for use as a growth medium. Discs containing HCV-replicon reporter cells maintained in a C02 incubator at 37 ° C were removed from the incubator. The medium was aspirated and the cells were washed with 1 ml of PBS. The solution was discarded and 1 ml of 1.25% trypsin / 0.02 ° / EDTA was added to rinse again. The trypsin/EDTA solution was removed with a vacuum pump and the cells were incubated for 3 to 5 minutes at 37 ° C. The cell morphology was examined under a flip-chip microscope until the single cell suspension was transparent, followed by slow pipetting. 3 ml of complete medium was used to suspend the cells. When suspended, the number of cells was counted using a hemocytometer, and the cell density was adjusted to l〇〇K/ml by adding an appropriate volume of complete medium. Add 100 μl (100 μΐ) of cells. The suspension was placed in each well of a 96-well white plate so that the cell density of each well was 10 Κ/well. The 96-well assay plate was placed in a 37 ° C 5% CO 2 incubator for 24 hours. At the end of the incubation, the disk was removed and Add a variety of test compounds at the desired concentration using serial dilutions. Place the plate back in a C02 incubator at 37 ° C for 48 hours. After incubation, add 30 μΐ of Stead-Glo Luciferase System® (Promega) reagent to each well. Gently mix for 5 minutes to allow the cells to fully dissolve. Measure the luminescence with Envision® (Perkin-Elmer) with a 2 second integration time. 156069.doc • 292- 201144296 Test with the following compounds:

156069.doc ,293 · 201144296

Since this test, the IC5G value of the HCV-replicon of the test compound has ranged from about 4 π Torr to about 7.3 μί. These results indicate that the compounds provided herein are potent inhibitors of HCV. The DMEM complete medium (Life Technologies) was supplemented with 10% FCS, 2 mM glutamic acid, penicillin and streptomycin, and 1% &lt;non-essential amino acid, and pre-warmed in a constant temperature water bath at 37 °C. Used as a growth medium. Discs containing HCV-replicated daughter cells maintained in a C02 incubator at 37 ° C were removed from the incubator. The medium was aspirated and the cells were washed with 1 ml of PBS. The solution was discarded and 1 ml of 1.25% trypsin/0.023⁄4 EDTA was added to re-wash the cells. The chymotrypsin/EDTA solution was removed with a vacuum pump and the cells were incubated at 37 °C for 3 to 5 minutes. The morphology of the cells was examined under a flip-chip microscope until the single cell suspension was transparent, and then the cells were suspended by slowly pipetting with 3 ml of complete medium. When suspended, the number of cells was counted using a hemocytometer, and the cell density was adjusted to 1 〇〇K/mb by adding an appropriate volume of complete medium to add 1 〇〇 microliter (100 μΐ) of the cell suspension to a 96-well white plate. The cells were each so that the cell density of each well was 10 Å/well. Place the 96-well assay plate at 37. 〇 5% C02 incubator in the box for 24 hours. At the end of the incubation, the plates were removed and a variety of test compounds were added using serial dilutions to obtain the desired concentration of 156069.doc •294· 201144296 degrees. The tray was returned to the C02 incubator at 37 ° C for 48 hours. After incubation, add 10 μΐ 5 mg/ml 3-(4,5-dimercaptothiazol-2-yl)-2,5-diphenyltetrazole rust (MTT) to each well, and at 37 The mixture was incubated for 4 hours in a °C C02 incubator. A 100 microliter (100 μΐ) test solution (10% SDS + 5% isobutanol + 10 mmol/1 HC1) was added directly to each well and the mixture was incubated overnight in a 37 ° C 53⁄4 C〇2 incubator. The absorbance at 580/680 nm was measured on a SpectraMax Plus 384® (MDC). φ Cu palm citrate assay in Dulbecco's Minimum Eagle's medium supplemented with 0.5 g/1 [U-13C] glucose (Cambridge Isotope Laboratories) and 2.08 unlabeled glucose (sigma) (Dulbecco's HCT-116 tumor cells (ATCC) were labeled for 24 hours in minimum Eagle's medium. Cells were treated in parallel with test compounds in 0.2% DMSO. After 24 hours, the cells were collected with trypsin/EDTA, counted by a hemocytometer, washed with pBS, and centrifuged at 2 rpm for 5 minutes. The agglomerates of 5 M cells were stored at -80 °C. • Saponification of cells in a strong base at 70 C overnight. The medium was acidified and palmitic acid was extracted with hexane. After drying the hexane layer, palmitic acid was reconstituted in slightly acidic methanol. The incorporation of palmitic acid was then monitored via GCMS. If no C丨3 is incorporated into the palmitate, palmitic acid synthesis is considered to have ceased. The unhindered palmitate synthesis was determined by the amount of human cl3 in the absence of the test compound. Using this test, it was found that the compound of this product was shaken + y human juice k to inhibit the synthesis of palmitate. Pharmacokinetic Studies 156069.doc -295. 201144296 Distribution by Oral Administration 曰Before the start of the test's study to determine liver perfusion is necessary to accurately determine the amount of test compound in the liver. Animals were perfused prior to liver collection, if necessary. In addition, a small number of animals were subjected to a single dose of 24 small (four) sex studies to verify their tolerated test compound levels. Animals were administered a single oral (p) dose based on the nearest body weight in a volume of 10 ml/kg. A 5% carboxymethylcellulose/5% DMSO/0.5% Tween containing 20 mg/ml (20 mg/ml) of the test compound was used. A vehicle control is also included. At 0, 15, 30, 60, 120, 240, 360, 480 and 1440 minutes after the dose was administered, 3 animals of each group were anesthetized by inhalation of carbon dioxide and euthanized by cardiac puncture. Blood was collected in a heparin clock vacuum ventilator&apos; on wet ice and at 4. (: Centrifuge at 10,200 rpm for 5 minutes in a 15 minute collection) The plasma was collected in a new eppendorf tube, frozen on dry ice and stored at _8 °c until ρκ analysis. And cut in half. One and a half of each tumor was placed in liquid nitrogen in a pre-weighed Genogrinder tube, placed on dry ice and stored at -80 ° C until pharmacokinetic analysis; The other half was cooled in liquid nitrogen in a pre-weighed Gino Reid tube, placed on dry ice and stored at _8 Torr.

Inhibition of Human FASN Scintillation Proximity Flashplate Assay and NADPH Consumption Assay Compounds prepared following the above synthetic methods are provided in Tables 1-4 below. The substituent abbreviations used in Tables 1-4 are provided in Table 5. Use the above FASN scintillation Proximity Flashplate assay (IC5〇; nM) or FASN NADPH depletion assay 156069.doc • 296· 201144296 (*) (IC5〇; nM) to identify compounds that act as inhibitors of human FASN. The corresponding activity of the isolated compound and the measured mass (ES + ) are also provided.

156069.doc -297- 201144296 Table 1 Structural activity (M+H)+ \CN N=N c〇2h c 463.2 L· N=N e/ / FB* 420.1 \ N=N / OPh Et A 446.1 m ό B * 450.2 Ph E, / B* 404.1 &lt;^MrCC Le N==NJ c* 414.1 〇MeO Le N=NL ,.洳 D* 560.2 156069.doc -298· 201144296

Table 1 Structural activity (M+H)+ &gt;Mr〇r- OMe Et B* 384.1 &lt;^Mr〇C Le N==N /ργ — A 518.2 LN=NE/ Xco2h B* 414.1 0 . OMe ^MfXX Le N=N / XC02Bn V〇D* 608.2 OMe N_N / C〇2H V〇c* 518.2 Q^Vvcr. &quot; \ N=N / OMe Et B 474.2 Le N=N e/ , Me B* 504.2 156069.doc -299- 201144296

156069.doc •300- 201144296

156069.doc -301 · 201144296 Table 1 Structural activity (M+H)+ 0 Λ OiPr Le N=NE/ , h D* 442.2 yC-, -, 0 Λ On-Bu Le N=N e/ , noisy A 456.2 Also 〆 \ N=N / Cl Me c* '330.1 Cl iPr c* 358.1 Cl Me B* 408.0 C^AA-〇Cl B* 356.1 ^ΑΛΧΧ Cl Me c* 348.1 Me Cl Me c* 384.1 156069.doc -302 · 201144296

156069.doc - 303 · 201144296 Table 1 Structural activity (M+H)+ &lt;^Mr〇F _e)2 B* 360.1 \ρ N=N e/ Factory FA 382.1 Private \&lt;x \ N=NJ ., B* 362.1 0 Λ OiPr &lt;^MfXX FN==NE/ XC02H B 448.1 \ N=NL co Royal A 524.2 CfMjO F ό B* 394.1 0Mxr F Et B* 380.1 156069.doc -304 · 201144296

156069.doc -305 - 201144296 Table 1 Structural activity (M+H)+ \f N=N Et/ Plant FA 421.1 F ό A 474.2 β'ΜΧΤ F Et B* 360.1 \ N=N / FA* 358.1 Also?χχ F Et r A* 382.1 F Et B* 360.1 F CH2CN c* 357.1 156069.doc -306- 201144296

Table 1 Structure Activity (M+H)+

MX)

Et

B* 480.1 A 513.2 B* 368.1 A 510.2 B* 360.1 A* 346.1 B* 396.1 156069.doc -307- 201144296

156069.doc -308- 201144296 ~^Λ

Structure activity (Μ+Η)+

Β* 524.2

A* 449.2

Β* 464.1

Β* 510.2

A* 535.1

Β* 410.0 156069.doc -309- 201144296 Table 1 Structural activity (M+H)+ MMr〇F iPr B* 360.1 \ Ν=Ν / XF F Me B* 350.1 Phytochemical HA 718.3 ί?ΑΛΧ) \ N= N / Factory F Me k B* 400.1 \ N==N e/ r FB* 444.2 Private N=NJ Factory Cl B* 414.0

156069.doc -310- 201144296

156069.doc •311 · 201144296

156069.doc • 312· 201144296

Table 1 Structural activity (M+H)+ F Et JA 482.1 ^MfO \ N=N e/ Plant PhO A 438.1 FB* 484.2 Private 乂rCT \FN==NE/ X〇〇2h B 420.1 C^AaX) n= Ne/ Plant N〇2 A* 391.1 FB 1 B* 442.0 ^fMr〇C \ N==N e/ , A 420.1 156069.doc •313 - 201144296 Table 1 Structural activity (M+H)+ F Me A* 366.0 CfMjO F ό A 400.2 F /C(0)NHEt a'Mxr0 F 0 A 599.2 /F n ^C02Et &lt;^m』xxg ό A 600.2 Me \ N=N / Ό02Η 0 A 596.2

156069.doc •314· 201144296

Table 1 Structural activity (M+H)+ Me 乂\ Ν=Ν / XC02Bn 0 A 686.2 F 〇V-N0) &lt;^Mfxxa F ό A 573.2 / ^ 广\ /S02Me F ό A 606.2 &lt;^Mr〇 C r Γ^\ co2h A 559.2 私乂,χγ 0 A 487.2 156069.doc •315· 201144296 Table 1 Structural activity (M+H)+ r ^ac F 0 A 570.2 Me. MxxR \ N=NJ , C02H f 0 A 537.2 ^Λλχτ〇ε, 'FN=N \〇2H B 556.2 β'ν,ΧΓ \ N_NJ , C02Me ύ A 488.2 0 A 518.2 156069.doc •316- 201144296

Table 1 Structural activity (M+H)+ 乂/乂 F 0 A 501.2 AMrCC 0 A 473.2 0 A 628.3 0 n / NBoc \ N=N / \〇2Bn 0 A 718.3 156069.doc •317- 201144296 Table 1 Structure Activity (M+H)+ 'FN==N Xc〇2H B 529.2 .F 'FN=N Xco2h A 504.2 9VrVCT VN=N / \c〇2H 0 A 487.2 0 MeO &lt;^MrXX0Me F ό A 490.1 Private . 0 A 486.2 156069.doc -318- 201144296

Table 1 Structural activity (M+H)+ F ό ! A 639.2 F Ν=Ν 7 / C〇2H MeO B 504.2 F ό ! A 548.2 FN==N / [ C〇2Bn MeO A 594.2 and rVCX \ N=N /pr 'c(o)nh2 A 360.1 156069.doc -319- 201144296 ~^ϊ Structural activity (M+H)+

638.2

F

A 459.2

F

A 559.2

A 391.1

454.0 156069.doc -320- 201144296

Table 1 Structural activity (M+H)+ \ N= F ) MeO. ^jXx =N / \〇2H 0 A 474.2 \ N=N /pr ^^C02H A 532.0 Private {XT o A 474.2 Q^'VXT, \ N=NL ^^C02Bn A 622.1 \ N=N / \〇H 0 A 460.1 \ N= F Vvcr =N /Pr Xc〇2h A 376.1 156069.doc -321 - 201144296 Table 1 Structural activity (M+H) +

N N 〇

N=N I F iPr

Co2h

B 361.1

N N 0

N=N / F iPr

NH2 C02Bn

A 466.1

o Λ N=N / F iPr

NHBoc co2h

A 476.1 460.1

Λλ N=N / F iPr

NHBoc CO^Bn 566.2

N=N o Λ iPr

C02H PhO

A 467.1 156069.doc •322· 201144296 Table 1 Structural activity (M+H)+ \ N=N / / F iPr IA 379.0 \ N= F =NL , 〇 2h A 391.1 \ N= FN i,Pr pj A 543.1 〇; / \ N: F ιλχχ = NJ , C02H B 432.1 \ N= F , and xy- -j /Λ^ iPr / FA 469.1 9^'Mxr l N==NLC〇2H A 395.0 - 323 - 156069.doc 201144296 Table 1 Structural activity (M+H)+ F ιλΧΧ =NJ, C02Bn A 522.2 MMr〇C 0 A 443.1 \ N= F Vvcr 0 A 474.2 F rV〇TiH =NL 〇Me A 391.1 MMr〇C \ N =NL c〇2Bn A 485.1 VWVCr \ N=N / F iPr B 376.1 156069.doc - 324 - 201144296

Table 1 Structural activity (M+H)+ and \N-N / Ό(0)ΝΗΒη 0 A 533.2 0 MeO \ Ν=Ν /Pr Xco2h B 421.1 9^'VrCT8 'α N=NE/ B 408.1 \C1 n =N e/厂\c〇2h MeO D* 452.0 f'Mxr 'a N=N e/ , A 456 \ N=N e/ B 436.1 夺 Mr〇C \C| N==NE/ \o2pmb A 576.1 156069.doc - 325 - 201144296 Table 1 Structural activity (M+H)+ &lt;^Mfxxa \c| N=N e/ \〇2H B* 456.0 Cl 〇\ N=N / Cl Et B* 525.0 'C 丨N=N e/ 'C〇2Bn B* 546.0 'd N=N e/ , CI B* 576.1 〆N^) \C, N==NE/ Factory B* 396.0 \α N=NJ \02H A* 456.0 Cl iPr c* 349.0 -326 · 156069.doc 201144296

Table 1 Structural activity (M+H)+ \α N=N Et/ , CN B* 403.0 Private \cc Ϊ N=N e/ (4) B* 452.0 0^MrXX^ h N=N e/ , 丨B* 546.0 /Cl { \ I //. /^\^C(=0)NHS02Ph \ N=N / Cl Et B* 561.0 \ N=N / Cl Et 〇! A 456.0 h N=N e/ Call B* 393.1 Private乂rCT Cl Et B* 423.0 156069.doc •327- 201144296 Table 1 Structural activity (M+H)+ h N=N b! N〇2 B* 423.0 Cl Et C02H B 422.0 Cl (ch2)3nhso2ch3 D* 529.0 0 ^Mrxx^n \C 丨N=N e/ B* 542.1 Li n-NE/ ch2otbdms B* 522.1 \ N=N / c* 589.1

156069.doc -328- 201144296

Table 1 Structural activity (M+H)+ βλ and jy- D* 499.1 C^Aaxtcoih \CI N=NE/ Γ MeO B* 452.0 Cl Et J c* 441.0 a N-NE/ C(=0)NHS02Ph A* 561.0 \c| n=ne/ Xch2oh c* 408.1 Cl Et B* 393.1 ^ΑΛΧ) Cl Et c* 378.0 156069.doc -329- 201144296

156069.doc -330- 201144296

Table 1 Structural activity (M+H)+ OMe Le N=N e/ 0Me c* 534.2 Private cut OMe Et JB 450.2 LN==N / second butyl, HA 430.1 "MrCC 〇Me 0 A 472.2 cfMrxr Le N= =N Et; C〇2H B 432.1 丨 lean LN=N 1 Χ〇02Βη A 562.2 156069.doc -331 - 201144296 Table 1 Structural activity (M+H)+ OMe B 412.2 〇Me B OCH2CH2Ph A 478.2 9^' VrCr Le N==NJB 432.1 F ζ \ II II l^\^OCH2CH2Ph Le N=NLC〇2TMBA 656.2 \ N=N / XF OMe tBu D 404.2 Le N=NC〇2H A 486.2 Le N=NL C02H B 416.1

156069.doc •332- 201144296

156069.doc 333 - 201144296 Table 1 Structural activity (M+H)+ .F WN Γγ^ OMe Et °&quot;^^\;5==^ D 598.2 4όΛΜχι co2h A 494.1 LN=N 1 ,h B* 414.1 cfMfxx \ N=N / C02H OMe tBu D 430.1 ^N6A^〇xrc〇2H OMe Et B 508.2 93⁄4 lean OMe N iW C02Bn A 536.2 &lt;^Mr〇T Le N==NLC〇2h B 446.1 156069.doc •334 - 201144296

156069.doc - 335 · 201144296 Table 1 Structural activity (M+H)+ Le N=NL Vsn D 520.2 乂r乂OMe Et A 358.1 广, /F 〇tBu OMe Et D* 414.2 CfMra Le N==N / Second butyl - A 520.2 OMe N_N C(0)NH(0H) A 487.2 0 MeO Le N=N Ji C〇2H A 486.2 •336· 156069.doc 201144296

Table 1 Structure Activity (M+H)+ Private. ~ '〇 N=N 1 Xco2h ,. A 0 B 574.2. A 0 A 530.2 fM/XT L ό MeO A 560.2 AMrOC OiPr N~NC〇2H A 514.2 0 MeO ^^r^jXX Lr N==N J. _ B 514.2 156069.doc - 337 - 201144296 Table 1 Structural activity ( M+H)+ 0 MeO &lt;^ΜΧχ Lr N=N J. C〇^Bn B 604.3 AMrCT UN=NL , _ B 550.2 Private cut C〇2h b ph〇/ D* 464.1 Private\〇C02Me Et B* 386.1 〇乂. ~, r D 533.2 f'Mxr Λ〇 Λ〇 , pr 〇 A 619.2

156069.doc -338· 201144296

Table 1 Structural activity (M+H)+ Q; J \ N= Ο lr and rCC =N “ Vh D 529.2 φ \ Ν= Ο VVcr =NLC〇2Bn A 617.2 \ Ν= 广^入〇Ο,又r〇 T = N /Pr 'c〇2H B 527.2 into Et J Ο c 531.2 ΒηΗ Production. Β A 461.2 156069.doc • 339· 201144296 Table 1 Structural activity (M+H)+

0

B 553.2

A 563.2

Ο

A 653.2

BnMeN

o N=N Λ

OMe C〇2Bn

Me2N 0

A

B

D 539.2 549.2 487.2

156069.doc -340 - 201144296

Table 1 Structure Activity (M+H)+ &lt;^Mr〇C In. , Pr Me2N A 577.2 Privacy r〇 V B* 428.1 ! ^ σ B* 442.2 CfMrO B* 432.2 156069.doc -341 · 201144296 Table 1 Structure

F

B* 446.2

F

B 541.2

B* 406.0

F

B* 424.0

A 616.2 156069.doc -342 - 201144296

Table 1 Structure Activity (M+H)+ VN ό B 496.1 Minutes Mr 2C2 l2 n=n λ B 468.2 Minutes Mxr Vl n=n 八. 2h C 478.2 HiVO Cl Me D* 331.1 fdrVO F Me c* 333.1 $VrCTH F ό A 445.1 156069.doc -343 - 201144296

156069.doc -344- 201144296

Table 1 Structural activity (M+H)+ FN=Nr\XL A 536.2 CfM^C00H f ν=νλΧ1 0 Ό A 522.2 F COOH c^/νλ Λ〇μθ F Ν=ΝΛΪ1 ° Ό A 566.2 F COOH , (4) 03⁄4 A 552.2 F COOH ς^ΑΛ^ό ό Γ A 448.12 156069.doc 345 - 201144296 Table 2 Structural activity (M+H)+ N—N l /&quot;&quot;i'NHBoc D* 443.1 Ύ w Q— E* 443.1 Wi^y E* 328.0 人乂1 wN/ 〇^NHAC E* 385.1 Ο^Λλ ^ \_/ ΓΛ LN—N / ).....'ilNHAc E* 385.1 .Cl ί^ΑΛ^TM \ N—N 1 \ a E* 399.1 Cl 〇(\ \ 11 II $(=0)_e Cl N==N / ) E* 385.1

156069.doc -346- 201144296

Table 2 Structural activity (M+H)+ QC〇2tBu D* 442.1 \ N=N / factory\N^ c, QE* 439.1 Ο^ΛΛ^ W ^NHBoc C, D* 457.1 ζίΧ(~ \ / N*^ \^C(0)NEt2 \ N=N / Plant Cl D* 441.1 〇X(' Cl D* 385.1 〇X(' c, E* 399.1 156069.doc - 347- 201144296 Table 2 Structural Activity (M+H) + Private V. D* 453.1 &lt;^Mn α νΛ co2h E* 386.0 \ N= Cl D* 342.0 CiX(~ \ j N*^ X^NHSOzMe Cl E* 435.0 〇X(~ \ / \^NHC(= 0) NHEt Cl E* 428.1 a; \ N= Cl E* 310.1 156069.doc • 348 · 201144296

156069.doc 349- 201144296 Table 2 Structural activity (M+H)+ D* 456.2 (^ΑΛη&gt;〇丫Η〇丫Η D* 392.2 You C〇c* 358.1 B 394.1 Η—Η 1 Factory B* 366.1 ^λΛΌ 〇 Ph B* 414.2

156069.doc -350- 201144296

Table 2 Structural activity (M+H)+ 0Ph c* 472.2 ^λΧΧ) FB* 372.1 FD* 403.1 F KJ B* 388.1 F vJ B* 372.1 \ N=N / factory FB* 358.1 \ N=N / 7&quot;&quot ;^ F \j B* 473.2 156069.doc •351 - 201144296

156069.doc •352 · 201144296

Table 2 Structural activity (M+H)+ and \N-N / / NHBoc F \j B* 473.2 N(Me)2 Private and eft is B 604.2 F c* 426.1 ^αλ^ο , FN=N / Factory XNH2 B* 373.1 \ N=N / 7^^ Cl D* 524.1 〆A* 424.1 156069.doc -353 - 201144296

156069.doc -354- 201144296

Table 3 Structural activity (M+H)+ OPh D* 521.2 \ N= Cl II /C(=0)CH2Ph vV〇=Ν / Et c* 503.1 Λ \ Ν= CI /? r^X ^C(=0 NHEt Et D* 456.1 CI yHE, =N / Et D* 457.1 156069.doc - 355 - 201144296 &quot;^3~ Structural activity (M+H)+

D* D* 485.1 485.1

E* 399.1

D* 463.1

0

-Ac D* 427.1

E* 501.2 156069.doc 356· 201144296

156069.doc •357· 201144296 Table 3 Structural activity (M+H)+ Cl Et Me D* 414.1 Cl vv〇Et D 336.1 Cl nPr D 350.1 ί^ΛΛ^ο \C| N=N nU D 351.1 〇VN= , r〇HE* 288.1 O^'VrO Et E* 316.2 SMe Et D* 362.2 156069.doc •358 · 201144296

Table 3 Structure Activity (M+H)+

〇

Et

Ο

D* D* D* D* D* E* D* 408.2 344.2 442.1 372.2 334.2 315.2 350.1

Ν=Ν Br and ΛΟ

Et D* 394.1 156069.doc -359- 201144296 Table 3 Structure Activity (M+H).

0

E* 364.2

Ocf3 〇

D* 400.2

ο

D* 341.2

OMe ο

Et D* 346.2

D* 336.1

D* 358.2

D* 330.2 156069.doc •360· 201144296

Table 3 Structural activity (M+H)+ Cl nPr D* 364.2 N= 3 VyO Et D* 361.2 N= \\o Et E* 346.2 N=N / Et E* 384.2 N= VV〇Et E* 350.1 N= N / Et D* 359.2 N= vV〇Et E* 334.2 156069.doc •361 · 201144296

156069.doc 362- 201144296

Table 3 Structural activity (M+H)+ f'Wo Cl ch2ch2cn D* 409.1 Cl Et D* 384.1 Cl (ch2&gt;3nhso2ch3 D* 491.1 乂r〇Cl CH2CH2NHBoc E* 499.2 0 D* 497.1 /Cl ^Aa^C&gt ;c〇!PMB \ N=N / Cl Et E* 548.1 'ci N==N e/ c, D* 518.1 156069.doc •363 · 201144296 &quot;^3~~ Structural activity (M+H)+

Me D* 510.2

NHBoc E* 499.2

D* 518.1

156069.doc •364- 201144296

Table 3 Structure Activity ίΜ+Η)+ ,ci

Cl ο

D* 513.2

D* 484.1

D* 455.1 E* 554.2

D* 428.1

D* 427.1 156069.doc •365 · 201144296 Table 3 Structural activity (M+H)+ \ N= Cl vv〇CH2CH2NHAc E* 441.1 0 D* 497.1 D* 560.2 .Cl 〇ζ \ II II r^X^C( =0) NHMe VWyO^ Cl Et D* 441.1 CHO D* 498.1 .Cl Cl vv〇〇E* 436.1 156069.doc -366- 201144296

Table 3 Structural activity (M+H)+ Cl CH Me E* 495.1 Cl Et Me E* 510.2 C, Vx NH 乂NHEt D* 484.2 .ci \ N=N / Cl Et E* 427.1 Me Private 乂r〇Me Et E* 344.2 156069.doc -367- 201144296 Table 3 Structural activity (M+H)+ 严 r \ N= Cl w〇Et E* 418.1 Me Cl ' 0 vv〇Et D* 364.2 OMe D* 418.2 Ο^Λα^ 〇!Ρμβ \ Ν=Ν / Η OMe 0 B 576.2 OMe 0 C 456.2 156069.doc -368- 201144296

Table 3 Structure Activity (M+H)+

E* E* D* 386.3 386.3 384.1

E* 395.1

D* 352.2

E* 418.1

D* 472.0 156069.doc -369 - 201144296 Table 3 Structural activity (M+H)+ Et D* 384.1 Ν=Ν / Et D* 352.2 Cl Vv^ Et D* 384.1 VN y\Q Et D* 374.1 Me \ N = Me 〇〇vv〇Et E* 358.2 W'VV〇'c 丨N=NE/ D* 418.1 \ N~N e/ E* 370.1 156069.doc •370· 201144296

156069.doc •371 - 201144296 Table 3 Structural activity (M+H)+ \ N: CI w〇_e)2 D* 363.1 again / again ^〇c, wu D* 363.1 QV \ N= Cl vv〇_e ) 2 c 377.1 QV \ N= Cl vVO _e) 2 D 391.2 person / N * ^, Et N = N / HE * 234.1 0 - human 乂 ~ \ W / Cl nPr c * 404.2 \C| N=NJ c* 422.2 156069.doc -372 - 201144296

156069.doc •373 · 201144296 Table 3 Structure Activity (M+H)+ Cl nPr \/ D 336.1 .Cl 0 0 broad i n=n J r\^cH〇 i h D* 487.1 Table 4 Structure Activity Μ+Η)+

D* 322.1 〇

Ε* 322.1

Ε* 348.2

Me

156069.doc •374- 201144296

Table 5 Name abbreviated structure methyl Me -ch3 Ethyl Et -CH2CH3 n-propyl nPr -CH2CH2CH3 isopropyl iPr -ch(ch3)2 n-butyl nBu -CH2CH2CH2CH3 third butyl tBu -c(ch3)3 second Butyl-CH(CH2)(CH2CH3) isobutyl iBu-CH2CH(CH3)2 n-pentyl nPent -CH2CH2CH2CH2CH3 3_mercapto or ind-3-yl-CH(CH2CH3)2 pentyl-ch2ch(ch3)ch2ch3 Neopentyl-ch2c(ch3)3 3-mercapto-2-butyl-ch(ch3)ch(ch3)2 Third pentyl•c(ch3)2ch2ch3 n-hexyl nHex-CH2CH2CH2CH2CH2CH3 phenyl Ph-c6H5 benzyl Bn -ch2c6h5 Acetyl Ac-C(=0)CH3 156069.doc -375 · 201144296 Table 5 Name abbreviated structure Third butoxycarbonyl Boc -c(=o)oc(ch3)3 Tert-butyl dimethyl Alkyl-based TBDMS _Si(Me)2tBu p-methoxybenzyl PMB-CH2C6H5(4-OMe) Biotin f Equivalents All references and patents mentioned herein are hereby incorporated by reference in their entirety In general, the individual publications or patents are specifically and individually incorporated by reference. In the event of a conflict, the application (including any definitions herein) shall prevail. Equivalents While the specific embodiments of the invention have been described, the foregoing description is illustrative and not restrictive. Many variations of the present invention will become apparent to those skilled in the art in view of this disclosure. The full scope of the invention should be determined by reference to the scope of the claims and the full scope of the invention, and the description and the variations. All numerical values indicating the amounts of ingredients, reaction conditions and the like used in the specification and claims are to be understood as modified in all respects by the term "about" unless otherwise indicated. Therefore, unless otherwise indicated, the numerical parameters set forth in the specification and the appended claims are to be construed as an BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic view showing a subcutaneous xenograft model of a mouse for detecting papilloma virus; and Fig. 2 is a view showing a mouse skin xenograft model for identifying a papilloma virus.

156069.doc • 377· 201144296 Sequence Listing &lt;11〇&gt; American Infiniti Discovery Company &lt;120&gt; as a fatty acid synthase inhibitor tetrazolone &lt;130&gt; 12928-033-999 &lt;140&gt; 100115819 &lt;141&gt; 2011-05-05 &lt;150&gt;61/331,575;61/331,644;61/419,174;61/437,564; 61/472,566 &lt;151&gt;2010-05-05;2010-05-05;-12-02;2011-01-28; 2011-04-06 &lt;160&gt; 1 &lt;170&gt; FastSEQ for Windows Version 4.0

&lt;210&gt; 1 &lt;211&gt; 2511 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt; 1 Met Glu Glu Val Val lie Ala Gly Met Ser Gly Lys Leu Pro GIu Ser 15 10 15

Glu Asn Leu Gin Glu Phe Trp Asp Asn Leu lie Gly Gly Val Asp Met 2CT~ One Two 25 30

Val Thr Asp Asp Asp Arg Arg Trp Lys Ala Gly Leu Tyr Gly Leu Pro 35 40 45

Arg Arg Ser Gly Lys Leu Lys Asp Leu Ser Arg Phe Asp Ala Ser Phe 50 55 60

Phe Gly Val His Pro Lys Gin Ala His Thr Met Asp Pro Gin Leu Arg 65 70 75 80

Leu Leu Leu Glu Val Thr Tyr Glu Ala lie Val Asp Gly Gly lie Asn 85 90 95

Pro Asp Ser Leu Arg Gly Thr His Thr Gly Val Trp Val Gly Val Ser 100 105 110

Gly Ser Glu Thr Ser Glu Ala Leu Ser Arg Asp Pro Glu Thr Leu Val 115 120 125

Gly Tyr Ser Met Val Gly Cys Gin Arg Ala Met Met Ala Asn Arg Leu 130 135 140

Ser Phe Phe Phe Asp Phe Arg Gly Pro Ser lie Ala Leu Asp Thr Ala 145 150 155 160

Cys Ser Ser Ser Leu Met Ala Leu Gin Asn Ala Tyr Gin Ala He His 165 170 175

Ser Gly Gin Cys Pro Ala Ala lie Val Gly Gly lie Asn Val Leu Leu 180 185 190

Lys Pro Asn Thr Ser Val Gin Phe Leu Arg Leu Gly Met Leu Ser Pro 195 200 205

Glu Gly Thr Cys Lys Ala Phe Asp Thr Ala Gly Asn Gly Tyr Cys Arg 210 215 220

Ser Glu Gly Val Val Ala Val Leu Leu Thr Lys Lys Ser Leu Ala Arg 225 230 235 240

Arg Val Tyr Ala Thr lie Leu Asn Ala Gly Thr Asn Thr Asp Gly Phe 245 250 255

Lys Glu Gin Gly Val Thr Phe Pro Ser Gly Asp lie Gin Glu Gin Leu 260 265 270 lie Arg Ser Leu Tyr Gin Ser Ala Gly Val Ala Pro Glu Ser Phe Glu 156069 - Sequence Listing.doc 201144296 275 280 285

Tyr I)e Glu AJa His Gly Thr Gly Thr Lys Val Gly Asp Pro Gin Glu 290 295 300

Leu Asn Gly lie Thr Arg Ala Leu Cys Ala Thr Arg Gin Glu Pro Leu 305 310 315 320

Leu lie Gly Ser Thr Lys Scr Asn Met Gly His Pro Glu Pro Ala Ser 325 330 335

Gly Leu Ala Ala Leu Ala Lys Val Leu Leu Ser Leu Glu His Gly Leu 340 345 350

Trp Ala Pro Asn Leu His Phe His Ser Pro Asn Pro Glu He Pro Ala 355 360 365

Leu Leu Asp Gly Arg Leu Gin Val Val Asp Gin Pro Leu Pro Val Are 370 375 380

Gly Gly Asn Val Gly He Asn Ser Phe Gly Phe Gly Gly Ser Asn Val 385 390 395 400

His lie lie Leu Arg Pro Asn Thr Gin Pro Pro Pro Ala Pro Ala Pro 405 410 415

His Ala Thr Leu Pro Arg Leu Leu Arg Ala Ser Gly Arg Thr Pro Glu 420 425 430

Ala Val Gin Lys Leu Leu Glu Gin Gly Leu Arg His Ser Gin Asp Leu 435 440 445

Ala Phe Leu Ser Met Leu Asn Asp lie Ala Ala Val Pro Ala Thr Ala 450 455 460

Met Pro Phe Arg Gly Tyr Ala Val Leu Gly Gly Glu Arg Gly Gly Pro 465 470 475 480

Glu Val Gin Gin Val Pro Ala Gly Glu Arg Pro Leu Trp Phe lie Cys 485 490 495

Ser Gly Met Gly Thr Gin Trp Arg Gly Met Gly Leu Ser Leu Met Arg 500 505 510

Leu Asp Arg Phe Arg Asp Ser lie Leu Arg Ser Asp Glu Aia Va] Lys 515 520 525

Pro Phe Gly Leu Lys Val Ser Gin Leu Leu Leu Ser Thr Asp Glu Ser 530 535 540

Thr Phe Asp Asp lie Val His Ser Phe Val Ser Leu Thr Ala lie Gin · 545 550 555 560 lie Gly Leu He Asp Leu Leu Ser Cys Met Gly Leu Arg Pro Asp Gly 565 570 575 lie Val Gly His Ser Leu Gly Glu Val Ala Cys Gly Tyr Ala Asp Gly 580 585 590

Cys Leu Ser Gin Glu Glu Ala Val Leu Ala Ala Tyr Trp Arg Gly Gin 595 600 605

Cys lie Lys Glu Ala His Leu Pro Pro Gly Ala Met Ala Ala Val Gly 610 615 620

Leu Ser Ding rp Glu Glu Cys Lys G】n Arg Cys Pro Pro G]y Val Val Pro 625 630 635 640

Ala Cys His Asn Ser Lys Asp Thr Val Thr lie Ser Gly Pro Gin Ala 645 650 655

Pro Val Phe Glu Phe Val Glu Gin Leu Arg Lys Glu Gly Val Phe Ala 660 665 670

Lys Glu Val Arg Thr Gly Gly Met Ala Phe His Ser Tyr Phe Met Glu 675 680 685

Ala He Ala Pro Pro Leu Leu Gin Glu Leu Lys Lys Val lie Arg Glu 690 695 700

Pro Lys Pro Arg Ser Ala Arg Trp Leu Ser Thr Ser lie Pro Glu Ala 705 710 715 720

Gin Trp His Ser Ser Leu Ala Arg Thr Ser Ser Ala Glu Tyr Asn Val 725 730 735

Asn Asn Leu Val Ser Pro Val Leu Phe Gin Glu Ala Leu Trp His Val 740 745 750

Pro Glu His Ala Va] Val Leu Glu lie Ala Pro His Ala Leu Leu Gin 755 760 765

Ala Val Leu Lys Arg Gly Leu Lys Pro Ser Cys Thr lie lie Pro Leu 770 775 780

Met Lys Lys Asp His Arg Asp Asn Leu Glu Phe Phe Leu Ala Gly lie 785 790 795 800

Gly Arg Leu His Leu Ser Gly lie Asp Ala Asn Pro Asn Ala Leu Phe 805 810 815

Pro Pro Val Glu Phe Pro Ala Pro Arg Gly Thr Pro Leu lie Ser Pro 820 825 830

Leu lie Lys Trp Asp His Ser Leu Ala Trp Asp Val Pro Ala Ala GJu 835 840 845

Asp Phe Pro Asn Gly Ser Gly Ser Pro Ser Ala Ala lie Tyr Asn lie 850 855 860

Asp Tlir Ser Ser Glu Ser Pro Asp His Tyr Leu Vai Asp His Thr Leu 865 870 875 880

Asp Gly Arg Val Leu Phe Pro AJa Thr Gly Tyr Leu Ser He Val Trp 885 890 895

Lys Thr Leu Ala Arg Ala Leu Gly Leu Gly Val Glu Gin Leu Pro Val 156069. Sequence Listing.doc 201144296 900 905 910

Val Phe Glu Asp Val Val Leu His Gin Ala Thr lie Leu Pro Lys Thr 915 920 925

Gly Thr Val Ser Leu Glu Val Arg Leu Leu Glu Ala Ser Arg Ala Phe 930 935 940

Glu Val Ser Glu Asn Gly Asn Leu Val Val Ser Gly Lys Val Tyr Gin 945 950 955 960

Trp Asp Asp Pro Asp Pro Arg Leu Phe Asp His Pro Glu Ser Pro Thr 965 970 975

Pro Asn Pro Thr Glu Pro Leu Phe Leu Ala Gin Ala Glu Val Tyr Lys 980 985 990

Glu Leu Arg Leu Arg Gly Tyr Asp Tyr Gly Pro His Phe Gin Gly lie 995 1000 1005

Leu Glu Ala Ser Leu Glu Gly Asp Ser Gly Arg Leu Leu Trp Lys Asp 1010 1015 1020

Asn Trp Val Ser Phe Met Asp Thr Met Leu Gin Met Ser lie Leu Gly 1025 1030 1035 1040

Ser Ala ys His Gly Leu Tyr Leu Pro Thr Arg Val Thr Ala He His 1045 1050 1055 lie Asp Pro Ala Thr His Arg Gin Lys Leu Tyr Thr Leu Gin Asp Lys 1060 1065 1070

Ala Gin Val Ala Asp Val Val Val Ser Arg Trp Leu Arg Val Thr Val 1075 1080 1085

Ala Gly Gly Val His lie Ser Gly Leu His Thr Glu Ser Ala Pro Arg 1090 1095 1100

Arg Gin Gin Glu Gin Gin Val Pro lie Leu Glu Lys Phe Cys Phe Thr 1105 1110 1115 1120

Pro His Thr Glu Glu Gly Cys Leu Ser Glu Arg Ala Ala Leu Gin Glu 1125 1130 1135

Glu Leu Gin Leu Cys Lys Gly Leu Val Gin Ala Leu Gin Thr Lys Val 1140 1145 1150

Thr Gin Gin Gly Leu Lys Met Val Val Pro Gly Leu Asp Gly Ala Gin 1155 1160 1165 lie Pro Arg Asp Pro Ser Gin Gin Glu Leu Pro Arg Leu Leu Ser Ala 1170 1175 1180

Ala Cys Arg Leu Gin Leu Asn Gly Asn Leu Gin Leu Glu Leu Ala Gin 1185 1190 1195 1200

Val Leu Ala Gin Glu Arg Pro Lys Leu Pro Glu Asp Pro Leu Leu Ser 1205 1210 1215

Gly Leu Leu Asp Ser Pro Ala Leu Lys Ala Cys Leu Asp Thr Ala Val 1220 1225 1230

Glu Asn Met Pro Ser Leu Lys Met Lys Val Val Glu Val L^u Ala Gly 1235 1240 1245

His Gly His Leu Tyr Ser Arg lie Pro Gly Leu Leu Ser Pro His Pro 1250 1255 1260

Leu Leu Gin Leu Ser Tyr Thr Ala Thr Asp Arg His Pro Gin Ala Leu 1265 1270 1275 1280

Glu Ala Ala Gin Ala Glu Leu Gin Gin His Asp Val Ala Gin Gly Gin 1285 1290 1295

Trp Asp Pro Ala Asp Pro Ala Pro Ser Ala Leu Gly Ser Ala Asp Leu 1300 1305 1310

Leu Val Cys Asn Cys Ala Val Ala Ala Leu Gly Asp Pro Ala Ser Ala 1315 1320 1325

Leu Ser Asn Met Val Ala Ala Leu Arg Glu Gly Gly Phe Leu Leu Leu 1330 1335 1340

His Thr Leu Leu Arg Gly His Pro Leu Gly Asp lie Val Ala Phe Leu 1345 1350 1355 1360

Thr Ser Thr Glu Pro Gin Tyr Gly Gin Gly lie Leu Ser Gin Asp Ala 1365 1370 1375

Trp Glu Ser Leu Phe Ser Arg Val Ser Leu Arg Leu Val Gly Leu Lys 1380 1385 1390

Lys Ser Phe Tyr Gly Ser Thr Leu Phe Leu Cys Arg Arg Pro Thr Pro 1395 1400 1405

Gin Asp Ser Pro lie Phe Leu Pro Val Asp Asp Thr Ser Phe Arg Trp 1410 1415 1420

Val Glu Ser Leu Lys Gly lie Leu Ala Asp Glu Asp Scr Scr Arg Pro 1425 1430 1435 1440

Val Trp Leu Lys Ala lie Asn Cys Ala Thr Ser Gly Val Val Gly Leu 1445 1450 1455

Val Asn Cys Leu Arg Arg Glu Pro Gly Gly Asn Arg Leu Arg Cys Val 1460 1465 1470

Leu Leu Ser Asn Leu Ser Ser Thr Ser His Val Pro Glu Val Asp Pro 1475 1480 1485

Gly Ser Ala Glu Leu Gin Lys Val Leu Gin Gly Asp Leu Val Met Asn 1490 1495 1500

Val Tyr Arg Asp Gly Ala Trp Gly Ala Phe Arg His Phe Leu Leu Glu 1505 1510 1515 1520

Glu Asp Lys Pro Glu Glu Pro Thr Ala His Ala Phe Val Ser Thr Leu 156069 - Sequence Listing.doc 201144296 1525 1530 1535

Thr Arg Gly Asp Leu Ser Ser lie Arg Trp Val Cys Ser Ser Leu Arg 1540 1545 1550

His Ala Gin Pro Thr Cys Pro Gly Ala Gin Leu Cys Thr Val Tyr Tyr 1555 1560 1565

Ala Ser Leu Asn Phe Arg Asp lie Met Leu Ala Thr Gly Lys Leu Ser 1570 1575 1580

Pro Asp A]a lie Pro Gly Lys Trp Thr Ser Gin Asp Ser Leu Leu Gly 1585 1590 1595 1600

Met Glu Phe Ser Gly Arg Asp Ala Ser Gly Lys Arg Val Met Gly Leu 1605 1610 1615

Val Pro Ala Lys Gly Leu Ala Thr Ser Val Leu Leu Ser Pro Asp Phe 1620 1625 1630

Leu Trp Asp Val Pro Ser Asn Trp Thr Leu Glu Glu Ala Ala Ser Val 1635 1640 1645

Pro Val Val Tyr Ser Thr Ala Tyr Tyr Ala Leu Val Val Arg Gly Arg 1650 1655 1660

Val Arg Pro Gly Glu Thr Leu Leu lie His Ser Gly Ser Gly Gly Val 1665 1670 1675 1680

Gly Gin Ala Ala lie Ala lie Ala Leu Ser Leu Gly Cys Arg Val Phe 1685 690 1695

Thr Thr Val Gly Ser Ala Glu Lys Arg Ala Tyr Leu Gin Ala Arg Phe 1700 1705 1710

Pro Gin Leu Asp Ser Thr Ser Phe Ala Asn Ser Arg Asp Thr Ser Phe 1715 1720 1725

Glu Gin His Val Leu Trp His Thr Gly Gly Lys Gly Val Asp Leu Val 1730 1735 1740

Leu Asn Ser Leu Ala Glu Glu Lys Leu Gin Ala Ser Val Arg Cys Leu 1745 1750 1755 1760

Ala Thr His Gly Arg Phe Leu Glu lie Gly Lys Phe Asp Leu Ser Gin 1765 1770 1775

Asn His Fro Leu Gly Met Ala lie Phe Leu Lys Asn Val Thr Phe His 1780 1785 1790

Gly Val Leu Leu Asp Ala Phe Phe Asn Glu Ser Ser Ala Asp Trp Arg 1795 1800 1805

Glu Val Trp Ala Leu Val Gin Ala Gly lie Arg Asp Gly Val Val Arg 1810 1815 1820

Pro Leu Lys Cys Thr Val Phe His Giy Ala Gin Vai Glu Asp Ala.Phe 1825 1830 1835 1840

Arg Tyr Met Ala Gin Gly Lys His lie Gly Lys Val Val Val Gin Val 1845 1850 1855

Leu Ala Glu Glu Pro Glu Ala Val Leu Lys Gly Ala Lys Pro Lys Leu 1860 1865 1870

Met Ser Ala lie Ser Lys Thr Phe Cys Pro Ala His Lys Ser Tyr lie 1875 1880 1885 lie Ala Gly Gly Leu Gly Gly Phe Gly Leu Glu Leu Ala Gin Trp Leu 1890 1895 1900 lie Gin Arg Gly Val Gin Lys Leu Val Leu Thr Ser Arg Ser Gly lie 1905 1910 1915 1920

Arg Thr Gly Tyr Gin Ala Lys Gin Val Arg Arg Trp Arg Arg Gin Gly 1925 1930 1935

Val Gin Val Gin Val Ser Thr Ser Asn lie Ser Ser Leu Glu Gly Ala 1940 1945 1950

Arg Gly Leu He Ala Glu Ala Ala Gin Leu Gly Pro Val Gly Gly Val 1955 1960 1965

Phe Asn Leu Ala Val Val Leu Arg Asp Gly Leu Leu Glu Asn Gin Thr 1970 1975 1980

Pro Glu Phe Phe Gin Asp Val Cys Lys Pro Lys Tyr Ser Gly Thr Leu 1985 1990 1995 2000

Asn Leu Asp Arg Val Thr Arg Glu Ala Cys Pro Glu Leu Asp Tyr Phe 2005 2010 2015

Val Val Phe Ser Ser Val Ser Cys Gly Arg Gly Asn Ala Gly Gin Ser 2020 2025 2030

Asn Tyr Gly Phe Ala Asn Ser Ala Met Glu Arg He Cys Glu Lys Arg 2035 2040 2045

Arg His Glu Gly Leu Pro Gly Leu Ala Val Gin Trp Gly Ala lie Gly 2050 2055 2060

Asp Val Gly lie Leu Val Glu Thr Met Ser Thr Asn Asp Thr lie Val 2065 2070 2075 2080

Ser Gly Thr Leu Pro Gin Arg Met Ala Ser Cys Leu Glu Val Leu Asp 2085 2090 2095

Leu Phe Leu Asn Gin Pro His Met Val Leu Ser Ser Phe Val Leu Ala 2100 2105 2]10

Glu Lys Ala AJa Ala Tyr Arg Asp Arg Asp Ser Gin Arg Asp Leu Val 2115 2120 2125

Glu Ala Val Ala His lie Leu Gly lie Arg Asp Leu Ala Ala Val Asn 2130 2135 2140

Leu Asp Ser Ser Leu Ala Asp Leu Gly Leu Asp Ser Leu Met Ser Val 4- 156069 - Sequence Listing.doc 201144296 2145 2150 2155 2160

Glu Val Arg Gin Thr Leu Glu Arg Glu Leu Asn Leu Val Leu Ser Val 2165 2170 2175

Arg Glu Val Arg Gin Leu Thr Leu Arg Lys Leu Gin Glu Leu Scr Ser 2180 2185 2190

Lys Ala Asp Glu Ala Ser Glu Leu Ala Cys Pro Thr Pro Lys Glu Asp 2195 2200 2205

Gly Leu Ala Gin Gin Gin Thr Gin Leu Asn Leu Arg Ser Leu Leu Val 2210 2215 2220

Asn Pro Glu Gly Pro Thr Leu Met Arg Leu Asn Scr Val Gin Ser Ser 2225 2230 2235 2240

Glu Arg Pro Leu Phe Leu Val His Pro lie Glu Gly Scr Thr Thr Val 2245 2250 2255

Phe His Ser Leu Ala Ser Arg Leu Ser lie Pro Thr Tyr Gly Leu Gin 2260 2265 2270

Cys Thr Arg Ala Ala Pro Leu Asp Scr lie His Ser Leu Ala Ala Tyr 2275 2280 2285

Tyr lie Asp Cys lie Arg Gin Val Gin Pro Glu Gly Pro Tyr Arg Val 2290 2295 2300

Ala Gly Tyr Ser Tyr Gly Ala Cys Val Ala Phe Glu Met Cys Scr Gin 2305 2310 2315 2320

Leu Gin Ala Gin Gin Ser Pro Ala Pro Thr His Asn Scr Leu Phe Leu

2325 2330 2335

Phe Asp Gly Ser Pro Thr Tyr Val Leu Ala Tyr Thr Gin Ser Tyr Arg 2340 2345 2350

Ala Lys Leu Thr Pro Gly Cys Glu Ala Glu Ala Glu Thr Glu Ala lie 2355 2360 2365

Cys Phe Phe Val Gin Gin Phe Thr Asp Met Glu His Asn Arg Val Leu 2370 2375 2380

Glu Ala Leu Leu Pro Leu Lys Gly Leu Glu Glu Arg Val Ala Ala Ala 2385 2390 2395 2400

Val Asp Lea lie lie Lys Scr His Gin Gly Leu Asp Arg Gin Glu Leu 2405 2410 2415

Ser Phe Ala Ala Arg Ser Phe Tyr Tyr Lys Leu Arg Ala Ala Glu Gin 2420 2425 2430

Tyr Thr Pro Lys Ala Lys Tyr His Gly Asn Val Met Leu Leu Arg Ala 2435 2440 2445

Lys Thr Gly Gly Ala Tyr Gly Glu Asp Leu Gly Ala Asp Tyr Asa Leu 2450 2455 2460

Ser Gin Val Cys Asp Gly Lys Val Ser Val His Val lie Glu Gly Asp 2465 2470 2475 2480

His Arg Thr Leu Leu Glu Gly Ser Gly Leu Glu Ser lie lie Ser lie 2485 2490 2495 lie His Ser Ser Leu Ala Glu Pro Arg Val Ser Val Arg Glu Gly 2500 2505 2510

156069 - Sequence Listing. doc

Claims (1)

201144296 VII. Patent application scope: 1. A compound of formula (I), RB (I) Or a pharmaceutically acceptable form thereof; wherein: the RA is selected from the group consisting of C6-丨4 aryl and 5-14 membered heteroaryl; the R is selected from the group consisting of 〇6·Ηaryl and 5_i4 membered heteroaryl; RC2)2, -N(RC2)2, R is selected from -OH, -c(4))W, -CH〇, _c〇2RC1, _c(4))n(rC2)2, Cl C(=NR-)〇RC1. C(=NRC2)N(rc2)2 , _s〇2RCl ^ s(=〇)R( •Sl(R )3, Cl”0, 0,Cl·10, fully functional alkyl, C2.10 alkenyl, c2_10 Alkynyl, 3-14 membered heteroaliphatic, 〇31〇 carbocyclyl, 3-14 membered heterocyclyl, cardinyl 4 aryl and 5-14 membered heteroaryl, with the limitation that ... is not; in each case RC1 is independently selected from the group consisting of Ci-1G alkyl, Cmg total alkenyl, 〇2-1()alkenyl, (:2-1()alkynyl, 3-14 membered heteroaliphatic, (^31( Carbocyclyl, 3-14 membered heterocyclyl, C6_M aryl and 5-14 membered heteroaryl; in each case the RC2 is independently selected from the group consisting of hydrogen, hydrazine, -hydrazine Rcl, -N (RC3) 2. -CN, -C(=0)RC1, -C(=〇)N(RC3)2, -C02RC1, -S02Rci, _C(=NRC3)〇Rcl, -C(=NRC3)N(RC3)2 , S02N(RC3)2, _s〇2RC3, -S〇2〇RC3, -SORcl, 156069.doc 201144296 -C(=0)SRC3, •C(=S)SRC3,-P(=〇)2 Rcl, -C(=S)N(RC3)2 -P(-0)(R)2, -P(=0)2N(Rc3)2, _p(=〇乂NR.", ^1. , all (tetra)yl, % dilute, alkynyl, 3-14 membered heteroaliphatic, C3_i. Carbocyclyl '3·14 membered heterocyclic, % aryl and 5.14 membered heteroaryl, or both The RC2 group is bonded to form a 3-14 membered heterocyclic or anthracene heteroaryl ring; or R and Rc are joined together with the nitrogen atom to which each is attached to form a 5-14 membered ring; wherein: RB is substituted with the following group: -L -R0 wherein: L is a covalent bond or a divalent Cuo hydrocarbon bond, wherein one, two or three methylene units of L are optionally passed one or more of _〇_, -S-, -NRB8 - ' -(C=NRB8)- ' -C(=0)- ' -C(=S)- ' -S(=0)- ' -S(=0)2-, Divalent Carbocyclyl, II a valent heterocyclyl, a divalent aryl or a divalent heteroaryl; the RD is selected from the group consisting of -CN, -no2, -N3, -S02H, -S03H, -C(=0)RB7, -C02H, -CHO, -C(ORB9)2, -C02RB7, -0C(=0)RB7, -0C02RB7, -C(=0)N(Rb8)2, -oc(=o)n(rB8)2, -NRB8C(=0 ) RB7, -NRB8C02RB7, -NRB8C(=0)N(RB8)2, -C(=NRB8)ORB7 ' -〇C(=NRB8)RB7 &gt; -OC(=NRB8)ORB7 ' -C(=NRB8) N(RB8)2, -OC(=NRB8)N(RB8)2 -NRB8C(=NRB8)N(RB8)2, -C(=0)NRB8S02RB7, -NRB8S02RB7, -S02N(RB8)2, 156069.doc -2 · 201144296 -S02RB7, _S〇2〇RB7,-0S02RB7, -S(=0)RB7, _〇s(=o)rB7, -C(=S)N(RB8)2, -c(=o)srB7, -C(=S)SRB7, -SC(=S ) SRB7, -P(=0)2Rb7' -0P(=0)2RB7' -P(=0)(RB7)2. -0P(=0)(RB7)2 &gt; -0P(=0)(0Rb9 ) 2 ' -P(=〇)2N(RB8)2 . -0P(=0)2N(RB8)2 ' -P(=0)(NRb8)2 ' -〇P(=〇)(NRB8)2 . -NRB8P(=0)(0RB9)2. -NRB8P(=〇)(NRB8)2, -B(ORb9)2, ?βκβ7(〇κΒ9) and tetrazolyl; RB7 lines in each case are independently selected from Cl l0 alkyl, C11Q perhaloalkyl, C2_1G alkenyl, C2_1G block, 3-14 membered heteroaliphatic, c31() carbocyclyl, 3-14 membered heterocyclyl, C6.14 aryl and 5 -14 member heteroaryl; in each case, RB8 is independently selected from the group consisting of hydrogen, 〇H, -ORB7, _N(RB9)2, -CN, -C(=0)RB7, _C(=〇)N( RB9)2, _c〇2rB7, -S02RB7 ' -C(=NRB9)〇rB7, _c(=nrB9)n(rB9)2, -S02N(RB9)2, -S02RB9, -S〇2〇RB9, s〇 rB7, C(=S)N(RB9)2, -C(=0)SRB9, -C(=S)SRB9, -P(=〇)2RB7, -p(=〇)(rB7)2, -p (=o)2N(RB9)2,·ρ(=0)(νιιβ9)2 Ci 1Q alkyl, Ci-^ all-alkyl, C2_1Q alkenyl, c2_1Q alkynyl, 3-14 heteroaliphatic, (3.10 carbocyclyl, 3-14 membered heterocyclyl, C014 aryl and 5-14 A heteroaryl group, or two RB8 groups, are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; and in each case the rB9 is independently selected from the group consisting of hydrogen, Ci iQ alkyl, Ci. Perhaloalkyl, C2_10 alkenyl, C2-10 alkynyl, 3-14 membered heteroaliphatic, C3 i〇 carbonyl, 3-14 membered heterocyclyl, Cw4 aryl and 5-14 membered heteroaryl, or both The RB9 group is joined to form a 3-14 membered heterocyclic group or a 5.14 membered heteroaryl ring. 2. The compound of claim 1, wherein l is a covalent bond. 156069.doc 201144296 3. The compound of claim 1, wherein L is a divalent C丨-10 hydrocarbon chain, wherein one of the methylene units of L. is optionally and optionally via a divalent carbocyclic group, a divalent Substitution of a cyclic group, a divalent aryl group or a divalent heteroaryl group. 4. For example. The compound of the first item 1 wherein RD is selected from -CN, -N〇2, -S02H, S03H &gt; -C(=〇)RB7 &gt; -C02H ' -CHO ' -C02Rb7 ' -C(~〇) N(RB8)2, -C(=NRB8)〇RB7, _c(=NRB8)N(RB8)2, -c(-〇)NRB8S02RB7 ' -S02N(RB8)2 &gt; -S02RB7 ' -S〇2〇 RB7 ' _s (one 〇) RB7, -C(=S)N(RB8)2, -C(=〇)SRB7, -C(=S)SRB7, -p(=〇)2RB7 ' -P(=〇 (RB7)2 n -P(=0)2N(RB8)2 &gt; -P(=〇)(NRB8)2, -B(ORB9)2, -BRB7(〇RB9), and tetrazolyl. 5. A compound according to item 4, wherein rd is selected from the group consisting of _c(=〇)rB7, _c〇2H, CHO, _c〇2Rb7, _c(=〇)n(rB8)2, -C(=nrB8) 〇rB7, -C(=NRB8)n(RB8)2, -C(=0)NRB8S02RB7, -C(=S)N(RB8)2, -C(=0)SRB7 and -C(=S)SRB7 . 6. The compound of claim 5 wherein rD is selected from the group consisting of _c(=〇)rB7, _c〇2h, -CHO and _c〇2RB7. 7. The compound of claim 6, wherein RD is -C02H. A compound according to claim 1, wherein rb is further substituted by the following group: -Re wherein: RE is selected from the group consisting of halogen, -OH, -ORB10, -〇N(RB11)2, -N(Rbu)2, - N(ORB12)RB12, _SH, _SRB1〇, -SSRB12, _〇C(=0)RB1〇, -oco2rB10, -oc(=o)n(rb11)2, -nrb11c(=o)rB10, -NRB11C02RB1〇 -NRB11C(=0)N(RB11)2, _OC(=NRB11)RB1〇, 156069.doc -4- 201144296 -OC(=NRBll)ORB1° , -oc(=nrb11)n(rb&quot;)2 , -NRBnC(=NRB11)N(RB1 丨)2, _NRB11S02RB1〇, _〇S02RB1〇, -〇S(=0)RB1〇, _Si(RB10)3 ' _〇Si(RB10)3, _SC(8)SRbi〇, -0P (=0)2Rb1°, -OP(=O)(RB10)2, -OP(=〇)(〇RB12)2 ' -0P(=0)2N(Rb,1)2, -0P(=0) (NRB11)2, -NRB1 丨P(=〇)(〇RB12)2, _NRB11P(=〇)(NRB11)2, -p(RB12)2, -P(RB12)3, -OP(RB12)2 -OP(RB12)3, 3-14 membered heterocyclic group and 5-14 membered heteroaryl group wherein the 3-14 membered heterocyclic group or the 5-14 membered heteroaryl group is bonded to a nitrogen atom; The lower RB1G is independently selected from (: **·! decyl, perhaloalkyl, C2-1Q alkenyl, C2.1G alkynyl, 3-14 membered heteroaliphatic, c3_1Q carbocyclyl, 3- 14 membered heterocyclic group, C6_i4 aryl group and 5-14 membered heteroaryl group; RBU in each case is independently selected from hydrogen, 〇H, _〇rB10, -N(RB12)2, -CN, -C (=0) RB1°, -C(=〇)N(RB12)2, -C02RB10, -S02RB1° &gt; -C(=NRB12)〇RB10 . -C(=NRB12)N(RB,2)2 ' -S02N(RB12)2 ' -S02RB12 ' -S〇2〇RB12 ' -SOR810 ' -C(=S)N(RB12)2, -C(=0)SRB12, -C(=S)SRB12, -P (=〇) 2RB10, -P(=〇)(RB1°)2, _p(=o)2N(RB12)2, _p(=〇)(nrB12)2, Ci i〇alkyl, C^o perhalogen Alkyl, c2.10 alkenyl, c210 alkynyl, 3-14 membered heteroaliphatic, Cm carbocyclyl, 3-14 membered heterocyclyl, C614 aryl and 5-14 membered heteroaryl, or two RB11 groups attached Forming a 3-14 membered heterocyclic group or a 514 membered heteroaryl ring; and in each case, rb 2 is independently selected from the group consisting of hydrogen, Ci•alkyl, Ci_i〇 allialkyl, C2-10 alkenyl, Cm Alkynyl, 3-14 member heteroaliphatic, c3i〇156069.doc 201144296 anthracyl 3 14 member, C6 &quot; aryl and 514 member heteroaryl or two RB12 groups joined to form a 3-14 member heterocyclic group Or 514 members of heteroaryl rings. 9. For the compound of claim 8, the tRE is selected from the group consisting of a lignin, _〇h, _〇rBi〇, -ON(RBll)2, -N(Rb,,)2 . -N(〇RB12)RB12 _SH Λ srbio % _SSRBI2, _Si (RB1 V, -〇Si(RB1°)3, ARB 丨2)2, _p(RB12)3, -OP(R)2, -〇P(RB12)3,3 a 14-membered heterocyclic group and a 5-14 membered heteroaryl group, wherein the 3-14 membered heterocyclic group or the 5-14 membered heteroaryl group is bonded to a nitrogen atom. 10. The compound of claim 9 wherein RE is selected From halogen, _〇rB10 and -N(RBn)2 〇11. The compound of claim ,, wherein Rc is selected from C alkyl, q^perhaloalkyl 'C2.1Q alkenyl, C2_丨G Alkynyl, 3-14 membered heteroaliphatic, c3.1Q carbocyclyl, 3-14 membered heterocyclyl, (6. fluorenyl and 5-14 membered heteroaryl. 12. As claimed in claim 11 A compound wherein Rc is C3-10 alkyl. 13. The compound of claim 11, wherein Rc is (: 3.10 carbocyclyl. 14. A compound of the claim!, wherein ... is a 4 aryl or 514 member And a compound of claim 14, wherein RactM aryl, and rB 1 4 aryl. 16. The compound of claim 14, wherein ra* 514 is heterozygous Aryl and Han 8 is C6-14 aryl. 17. The compound of claim 1 wherein the compound is a compound of formula (II): 156069.doc 201144296 R2 (II) or a pharmaceutically acceptable form thereof; wherein each of the groups W-R1, W-R2, W-R3, W-R4 and W-R5 independently represents a nitrogen atom (N) or represents C-R1, respectively , C-R2, C-R3, C-R4 or C-R5; and wherein R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, -CN, -N〇2 -N3, -S02H, -S03H, -OH, -ORA1, -ON(RA2)2, -N(RA2)2, -N(ORA3)RA3, -SH, -SRA1, -SSRA3, -C(=0 ) RA1, -co2h, -CHO, -C(ORA3)2, -co2ra1, -0C(=0)RA1, -oco2rai, -c(=o)n(rA2)2, -OC(=0)N( RA2)2, -NRA2C(=0)RA1, -nrA2co2ra1, -nrA2c(=o)n(rA2)2, -C(=NRA2)ORA1, -OC(=NRA2)RA1, -OC(=NRA2)ORA1 , -C(=NRA2)N(RA2)2, -OC(=NRA2)N(RA2)2, -NRA2C(=NRA2)N(RA2)2, -C(=0)NRA2S02RA1, -nrA2so2rA1, -so2n (rA2)2, -S02RA1, -S020RA1, -0S02RA1, -S(=0)RA1, -0S(=0)RA1, _Si(RA1)3, -OSi(RA1)3, -C(=S)N (RA2)2, -C(=0)SRA1, -C(=S)SRA1, -SC(=S)SRA1 ' -P(=0)2Ra1 ' -0P(=0)2RA1 ' -P(=0 )(RA1)2 ' -0P(=0)(Ra,)2, -OP(=0)(ORA3)2, -P(=0)2N(RA2)2, -op(=o)2n(rA2 ) 2, -p(=〇)(nrA2)2, -〇p(=〇)(NRA2)2, NR A2P(=〇)(〇RA3)2, -NRA2P(=0)(NRA2)2, _p(rA3)2, 156069.doc 201144296 -P(RA3)3, -OP(RA3)2, -〇p( RA3)3, _b(〇rA3)2 or -BR(ORA3), (:!.) 〇alkyl '^^. All _ alkyl, C2.1q alkenyl, c2 fast radical, 3-14 member lipid Family group, c3-1G carbocyclic group, 3-14 membered heterocyclic group, c6 aryl group and 5-14 membered heteroaryl group; or ruler 1 and 112, 112 and 113, 113 and Han 4 or Han 4 and R5 One or more of them are joined to form (a carbocyclic group, a 3-14 membered heterocyclic group, a C6·!4 aryl group or a 5-14 membered heteroaryl ring; in each case, the RA1 is independently selected from the group consisting of Cl_1G alkyl groups, c!•丨. Perhaloalkyl, C2-1G alkenyl, C2·. Alkynyl, 3-14 membered heteroaliphatic, CVh) carbocyclyl, 3-14 membered heterocyclyl, C6.14 aryl and 5-14 membered heteroaryl; in each case the RA2 is independently selected from Hydrogen, 〇Η, 〇και, -N(RA3)2, -CN, -C(=0)RA丨, -C(=0)N(RA3)2, _c〇2RA丨, -S02Rai, - C(=NRA3)〇RA1, -C(=NRA3)N(RA3)2, -S02N(RA3)2, -S02RA3 ' -S〇2〇RA3, _S0RA1, -C(=S)N(RA3)2 , -C(=0)SRA3, -C(=S)SRA3, -P(=〇)2RAi, P(=o)(RA1)2, -p(=〇)2N(RA3)2, -p( =〇)(NRA3)2, Ci". Alkyl, C _ 10 perhaloalkyl, C 2 -i decenyl, c 2-10 alkynyl, 3-14 membered heteroaliphatic, C 3 ·fluorenyl, 3-14 membered heterocyclyl, a CV丨4 aryl group and a 5-14 membered heteroaryl group or two RA2 groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; and in each case, the RA3 group is independently selected from Hydrogen, Cl. decyl, Ci i〇4, C2-10 alkenyl, C2-i decynyl, 3-14 membered heteroaliphatic, c3_10 carbocyclyl, 3-14 membered heterocyclic ring a group, a C^m aryl group and a 5.14 membered heteroaryl group, or two RA3 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; wherein each group is W-R6, W-R7 , W-R8, W-R9 and W-R10 independently 156069.doc 201144296 represents a nitrogen atom (N) or represents C-R6, C-R7, C-R8, C-R9 or C-R10; R6, R7 , R8, R9 and are independently selected from the group consisting of hydrogen, halogen, _CN, -N〇2, -N3, -S02H, -S03H, -OH, -ORB1, -ON(RB2)2, -N (RB2)2, -N(〇RB3)RB3, -SH, -SRB1, -SSRB3, -C(=0)RB1, -C02H, -CHO, -C(ORB3)2, -C02RB1, -0C(= 0) RB1, -002, RB1, _C (=0) N (RB2) 2, - 〇 c (= o) n (rB2) 2, -NRB2C (=0) RB1, _NRB 2C02RB1, -NRB2C(=0)N(RB2)2, -C(=NRB2)〇RB1 s -OC(=NRB2)Rb1 ' -OC(=NRB2)ORB1 λ -C(=NRB2)N(RB2)2 ^ -OC(=NRB2)N(RB2)2 ' -NRB2C(=NRB2)N(RB2)2 &gt; -C(=0)NRB2S02RB1, -NRB2S02RB1, -S02N(RB2)2, -S02RB1, -S02〇 RB1, _〇s〇2RB1, _s(=〇) RB1, -〇S(=0)RB1, -Si(RB1)3, -0Si(RB1)3, _c(=S)N(RB2)2, - C(=0)SRB1, -C(=S)SRB1, -SC(S)SRB1, -P(=0)2RB1, _〇p(=〇)2RB1, -P(=0)(RB1)2 -OP(=〇)(RB1)2, -〇P(=〇)(〇RB3)2, -P(=0)2N(RB2)2 &gt; -〇P(=0)2N(RB2)2 &gt ; -P(=0)(NRB2)2 ' -0P(=0)(NRB2)2 ' -NRB2P(=〇)(〇rB3)2 . -NRB2P(=0)(NRB2)2 ' -P(RB3 2, -p(RB3)3, _OP(RB3)2, 〇p(rB3)3, _b(〇rB3)2, -BR(OR), (:].10 alkyl, Cmo perhaloalkyl, C2.10 alkenyl, C2-10 alkynyl, 3-14 membered heteroaliphatic, c3.lQ carbocyclyl, 3-14 membered heterocyclyl, C614 aryl, 5-14 membered heteroaryl, _L-RD and -RE; or R6 and R7, r7 and r8, R and R9 or one or more of R9 and R10 are bonded to form a ^(9) carbocyclic group, a 3-14 membered heterocyclic group, (:6_14 aryl or 5-14 a heteroaryl ring; or 11丨〇 and 1^ are bonded to form a 3-14 membered heterocyclic group or 5 a 14-membered heteroaryl ring; 156069.doc -9- 201144296 wherein at least one of R6, R7, R8, R9&R 〇 is the group _l rD; in each case the rb1 is independently selected from Ci ig alkyl, Ci iq perhaloalkyl, C2.1G dilute, Cm alkynyl, 3-14 membered heteroaliphatic, C3 | G carbocyclyl, 3-14 membered heterocyclyl, c6-14 And 5-14 membered heteroaryl; in each case, the RB2 is independently selected from the group consisting of argon, 〇H, _〇rBi, -N(RB3)2, -CN, -C(=〇)Rbi, _C( =〇)n(rb3)2, -C〇2RB1, -S02RB1 &gt; .C(=NRB3)〇rBi , -C(=NRB3)N(RB3)2 &gt; -S02N(RB3)2, _S〇2rB3 , -S〇2〇rB3, s〇rB1, -c(=s)n(rB3)2, -C(=〇)srB3, _c(=s)srB3, _p(=〇)2RB1, -P(= 〇) (RB1)2, -P(=〇)2N(RB3)2, _p(=〇)(nrB3)2, CH. Alkyl, Cm〇, a functional alkyl group, a Cm alkenyl group, a Cm alkynyl group, a triterpenoid heteroaliphatic group, (: 3-1 anthracenylcarbocyclyl, a 3-14 membered heterocyclic group, (6-6 aryl group) And a 5-14 membered heteroaryl group, or two RB2 groups are bonded to form a 3-14 membered heterocyclic group or a 514 membered heteroaryl ring; in each case, the RB3 is independently selected from the group consisting of hydrogen, c丨丨q alkyl, and Cm〇 Haloalkyl, C2_10 alkenyl, c2. 0 alkynyl, 3-14 membered heteroaliphatic, c3 i〇 carbocyclyl, 3-14 membered heterocyclyl, c0i4 aryl and 5-14 heteroaryl, or Two RB3 groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; L is a covalent bond or a divalent (:!·) hydrocarbon chain, one of which is one, two or three The methylene units are optionally and independently passed through one or more of _〇_, _s_, -NRB8-, -(C=NRB8)-, _C(=〇)_, .cps)·, s(=〇) , -S(=0)2-, a divalent carbocyclic group, a divalent heterocyclic group, a divalent aryl group or a divalent heteroaryl group; and wherein the RD is selected from the group consisting of -CN, -N02, _n3, _s〇 2h, _s〇3h, 156069.doc •10- 201144296 -C(=0)RB7, -C02H, -CHO, -C(ORB9)2, -co2rB7, -0C(=0)RB7, -0C02RB7, -C (=0)N(RB8)2, -oc(=o)n( rB8)2, -nrB8c(=o)rB7, -nrB8co2rB7, -NRB8C(=0)N(RB8)2, -C(=NRB8)ORB7, -〇C(=NRB8)RB7, -OC(=NRB8) ORB7, -C(=NRB8)N(RB8)2, -〇C(=NRB8)N(RB8)2, -NRB8C(=NRB8)N(RB8)2, -c(=o)NRB8so2RB7, -NRB8S02RB7, -so2n(rB8)2, -so2RB7, -so2〇RB7, -oso2RB7, -s(=o)rB7, -os(=o)rB7, -C(=S)N(RB8)2, -C(= 0) SRB7, -C(=S)SRB7, -SC(=S)SRB7, _P(=0)2RB7, -0P(=0)2rB7, -P(=〇)(rB7)2, 〇p(= 〇)(RB7)2, -〇P(=〇)(〇RB9)2, -P(=0)2N(RB8)2, -0P(=0)2N(RB8)2, -P(=〇) (NRB8)2, -OP(=0)(NRB8)2, -NRB8P(=〇)(ORB9)2 - -NRB8P(=〇)(NRB8)2 ' -B(ORB9)2 ' -brB7(〇rB9 And tetrazolyl; in each case, RB7 is independently selected from the group consisting of C11Q alkyl, C11G perhaloalkyl, Cn. Dilute, Cm alkynyl, 3-14 membered heteroaliphatic, C31 (cyclo), 3-14 membered heterocyclic, C6-14 aryl and 5-14 membered heteroaryl; RB8 in each case independently Selected from hydrogen, 〇H, -〇rB7, -N(RB9)2, -CN '-C(=〇)rB7, _c(=〇)n(rb9)2, _c〇2rB7, -S02RB7, -C (=NRB9) 〇rB7, _c(=NRB9)N(RB9)2, -S02N(RB9)2, -S02RB9, -S〇2〇RB9, s〇rB7, _C(=S)N(RB9)2 -C(=〇)SRB9, c(=s)srB9, _p(=〇^rB7, -p(=o)(RBV -p(=o)2n(rB9)2, _p(=〇)(nrB9) 2, Ci alkyl, c^o functional alkyl, c2.1G alkenyl, C21G alkynyl '314-membered heteroaliphatic, Cm carbocyclyl, 3-14 membered heterocyclyl, C6·丨4 aryl And 514 members of heteroaryl, 156069.doc -11 - 201144296 or two RB8 groups are joined to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring; and in each case the RB9 is independently selected from Hydrogen, Ci 1()alkyl, Ci i〇* haloalkyl, C 2-10 alkenyl, C 2 . decynyl, 3-14 membered heteroaliphatic, C 3 —10 carbocyclyl, 3-14 membered heterocyclyl, a Clη aryl group and a 5-14 membered heteroaryl group, or two RB9 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; the RE system is selected from the group consisting of dentate and -OH. -ORB10, -〇N(RB11)2, -N(RB11)2, -N(ORB12)RB12, _SH, _srbio, _ssrB12, _〇c(=〇)rB10, -0C02RB]°, -〇C(= 〇) N(RB11)2, -NRBUC(=0)RB10, -NRB11C02RB10' -NRB11C(=0)N(RB1,)2&gt; -0C(=NRB11)RB1° ' -〇C(=NRB11)〇RB , ° , -OC(=NRB11)N(RBn)2 , -NRB11C(=NRB1,)N(RB1,)2 ^ -NRB11so2RB1° &gt; -oso2rB10 ' -〇S(=0)RB1., -Si( RB10)3, -0Si(RB,°)3, -SC(S)SR810, -OP(=〇)2RB10, _〇p( = 〇)(RB10)2, _〇P(=〇)(〇RB12 2, -OP(=〇)2N(RB11)2, -〇p(=〇)(NRB11)2, -NRB11P(=〇X〇RB12)2, -NRB&quot;p(=〇)(NRB11)2 , -P(RB12)2, -P(RB丨2)3, -〇P(RB12)2, -0卩(!^12)3, 3-14 membered heterocyclic group and 5-14 membered heteroaryl group Wherein the attachment point of the 3-14 membered heterocyclic group or the 5-14 membered heteroaryl group is on the nitrogen atom; in each case, the RB1G system is independently selected from the group consisting of alkyl, C丨.丨〇perhaloalkyl, C2 .1G alkenyl, C2_1G alkynyl, 3-14 membered heteroaliphatic, C3.1G carbocyclyl, 3-14 membered heterocyclyl, C6_14 aryl and 5-14 membered heteroaryl; RBn is independent in each case The ground is selected from the group consisting of hydrogen, -OH, -ORB, 0, -N(RB12)2, _CN, _c(=〇)rbio, _c(=〇)n(rbi2)2, _c〇2Rbio, -S02RB10, -C(=NRB12)〇RB10, -C(=NRB12)N(RB12)2, 156069.doc • 12- 201144296 -S02N(RB12)2, -so2rB12, -so2orB12, -SORB10, -c(=s)n(rb12)2, -c(=o)srB12, _C(=S)SRB12, -P(= 〇) 2RB10, -P(=O)(RB10)2, -P(=0)2N(RB12)2, _P(=0)(NRb丨2)2, Cmo alkyl group, Ci-io perhalogenated group , C2-10 dilute group, C2-10 fast group, 3-14 member heteroaliphatic group, (: 3_1 () carbocyclic group, 3-14 membered heterocyclic group, &lt;: 6-14 aryl group and 5- A 14-membered heteroaryl group or two RB11 groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; in each case, the RB12 is independently selected from the group consisting of hydrogen, Ci-1G alkyl, Ci .io perhaloalkyl, (: 2-10 alkenyl, (: 2-10 alkynyl, 3-14 membered heteroaliphatic, (: 3-10 carbocyclyl, 3-14 membered heterocyclyl, (:6_14) An aryl group and a 5-14 membered heteroaryl group, or two RB12 groups are bonded to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring; the RC is selected from the group consisting of -OH, -ORcl, _〇n (RC2) 2. -N(RC2)2, -C(=0)Rcl, -CHO, _C02Rc丨, -C(=〇)n(RC2)2, _C(=NRC2)〇Rcl, -c(=nrC2)n (rC2)2, -so2R^, _s(=0)rC1, _Si( RC1)3, Ci i 〇 基, (: 〖-10 full halogen base, (: 2.10 alkenyl, (: 2-10 alkynyl, 3-14 member heteroaliphatic, Cm carbocyclyl, 3- The 14-membered heterocyclic group, the c6.14 aryl group and the 5-14 membered heteroaryl group have the restriction that Rc is not _CH3; in each case, the RC1 is independently selected from a Cl lQ alkyl group, a Ci iQ perhalogen. Base, 匚2-1()alkenyl, (:2.1()alkynyl, 3-14 membered heteroaliphatic, (:3-1() carbocyclyl, 3-14 membered heterocyclyl, c6_14 aryl) And 5-14 membered heteroaryl; and in each case R is independently selected from the group consisting of hydrogen, -OH, -〇Rcl, -N(RC3)2, _CN, -C(=0)RC1, _c(=〇 N(RC3)2, c〇2rC1, -S02RCi . -C(=NRC3)〇rci . -C(=NRC3)N(RC3)2 . -S〇2N(RC3)2, -S〇2RC3,- S〇2〇rC3, _s〇rC1, 156069.doc •13- 201144296, .c(=〇)SR. , c (4) srG3, p (= 〇) 2RCi, -P (=0) (RC1W (= Q) 2N (R, _P (= C)) (10) alkyl, ~ 〇 all g base, C2.1 〇 dilute , c(9)alkynyl, Μ&quot; heterocyclic group, C3-1G carbocyclic group, 3-14 membered heterocyclic group, fluorene 16-U or two RC2 groups are bonded to form a 3-14 member heterocyclic ring. aryl and 5- A 14-membered heteroaryl group, a cyclic group or a 5-14 membered heteroaryl group R8, R9 and R10 to 18. The compound of claim 17, wherein one of R6 and R is the group _re. a compound of formula (I), Ο R\ N--RB wherein: a carbocyclyl, an anthracenyl, a aryl and a 5-rB are selected from the group consisting of an alkyl group, a c-enemidine, a 2-1G alkenyl group C2, an alkynyl group, and a 3-14 member. With ethnic violence, 0:3_丨〇 carbocyclic group, 3_14 member Fang, ',, base, C6-h aryl and 5-14 member hetero-rC are selected from hydrogen, -OH ' -Orc!, cr- 0, RC1 shop (rC2) 2, Na, 2, (_〇) R, _CH0, -_c, 々 = 0_%, -C (four) Μ, _C (杳2) n (rC2) 2, for, (4) 156069. Doc 201144296 -Si(Rcl)3, Cmo, Ke, perhaloalkyl, c2.10 alkenyl, c2_10 alkynyl, 3-14 membered heteroaliphatic, c3, carbocyclyl, 3-14 heterocyclyl, Aryl and 5-14 membered heteroaryl; in each case the RC1 is independently selected from the group consisting of Ci iQ alkyl, Ci iq all-tooth alkyl, C2.1Q alkenyl, Cm alkynyl, 3-14 heteroaliphatic,丨Q carbocyclic group, 3-14 membered heterocyclic group, C6 l4 aryl group and 5-14 membered heteroaryl group; and in each case, RC2 is independently selected from hydrogen, 〇H, -〇rC1 -N(RC3)2, -CN, -C(=〇)Rcl, •S02RC1, -C(=NRC3)〇rCi -S02N(RC3)2 , _s〇2RC3 , -c(=o)n(rC3) 2. -co2Rcl, , -C(=NRC3)N(RC3)2, -S〇2〇RC3, _S0RC1, -C(=S)N(R ">2, _c(=〇)srC3, _c(=s ) srC3 p(=〇)2RCi, -P( 0)(R )2, _P(=〇)2N(RC3)2, _p(=〇)(NRC3h, Ci i. Institute base, Ci-io Wang Halane a group, a c2 l〇 dilute group, a C2 i decynyl group, a 3_i4 member heteroaliphatic group, a C3-indenyl group, a 3-14 membered heterocyclic group, a C6·丨* aryl group, and a heteroaryl group. Or two R &amp; groups are joined to form a 3-14 membered heterocyclic group or a 5.14 membered heteroaryl ring; or a RB and Rc are attached to each of the 5-14 membered rings. And the at least one pharmaceutically acceptable form of the compound of formula (I) according to claim 1; or a pharmaceutically acceptable form thereof; excipient. 21. The pharmaceutical composition comprising at least one of formula (1) as claimed in claim 19. Or a pharmaceutically acceptable form thereof; and at least one pharmaceutically acceptable excipient. 156069.doc • 15· 201144296 22. The use of a compound as claimed in the manufacture of a medicament for the treatment of a FASN-mediated disorder selected from the group consisting of a hyperproliferative disorder, an inflammatory condition, an obesity-related disorder, Type II diabetes, fatty liver disease, microbial infection, viral infection, bacterial infection, fungal infection, parasitic infection and protozoal infection. 23. The use of a compound as claimed in the present invention for the manufacture of a medicament for the treatment of a hyperproliferative disorder. 24. The use of claim 23 wherein the hyperproliferative disorder is cancer. 25. The use of claim 24, wherein the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, endometrial cancer, gastric cancer, gastrointestinal stromal tumor, renal cancer, liver cancer, lung cancer, mesothelium. Tumor, multiple myeloma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, paget's disease, retinoblastoma, soft tissue sarcoma, skin cancer or thyroid cancer. 26. The use of claim 24, wherein the cancer is selected from the group consisting of mesothelioma, multiple myeloma, neuroblastoma, Paget's disease, retinoblastoma, leukemia, myelodysplastic syndrome, and soft tissue sarcoma. 27. The use of claim 24 wherein the agent is used in combination with one or more anticancer agents. 28. The use of a compound of claim 1 for the manufacture of a medicament for the treatment of an inflammatory condition. 29. The use of claim 28, wherein the inflammatory condition is selected from the group consisting of anemia, asthma, arteritis, arthritis, chronic obstructive pulmonary disease, dermatitis, gastroesophageal reflux disease, Crohn's disease, inflammatory Intestinal syndrome, 156069.doc • 16· 201144296 Multiple sclerosis, psoriasis and autoimmune diseases. 30. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a condition associated with obesity. 3. The use of claim 30, wherein the obesity-related disorder is selected from the group consisting of type II diabetes, hypertension, high cholesterol, ischemic heart disease, arterial vascular disease, colic, myocardial infarction, stroke, migraine, Congestive heart failure, deep vein thrombosis, pulmonary embolism, gallstones, gastroesophageal reflux disease, obstructive sleep apnea, obesity insufficiency syndrome, asthma, gout, dysmotility, back pain, erectile dysfunction, urine Incontinence, liver damage and chronic renal failure. 3. 2. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of type 2 diabetes. 33. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of fatty liver disease. 34. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a microbial infection. 3. The use of claim 34, wherein the microbial infection is a viral infection. 36. The use of claim 35, wherein the viral infection is an enveloped virus or a picornavirus infection. 37. The use of claim 35, wherein the viral infection is selected from the group consisting of HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, HHV-8, HMCV, CVB3, influenza A virus, influenza B Virus, RSV, PIV, measles virus, rhinovirus, adenovirus, HMPV, SARS virus, vaccinia virus, vaccinia virus, ectomelia virus, monkeypox virus, rabbit disease 156069.doc •17· 201144296 virus, HBV , HCV, papilloma virus, BK virus, VEE virus, Rift Valley fever virus, Tavaribe virus, yellow fever virus, West Nile virus, dengue fever Dengue virus, ρτν or Pichinde virus ° 3 8. The use of claim 37, wherein the viral infection is HCV or dengue virus infection. 39. The use of claim 34, wherein the agent is used in combination with one or more other anti-virus agents. 40. The use of claim 39, wherein the additional antiviral agent is an interferon, a protease inhibitor, an integrase inhibitor, a reverse transcriptase inhibitor, or a combination thereof. 41. The use of claim 39, wherein the other antiviral agent is an interferon, a ribavirin, or a combination thereof. 42. The use of claim 41, wherein the interferon is m-type interferon, π-type interferon type I interferon, peginterferon a-2a (peginterferon alfa-2a), and pegylated interferon a2b (peginterfer〇n aifa2b), standard interferon a-2a, standard interferon a_2b, complex interferon (c_ensus interferon), complex a interferon aifac〇nl), ALBUFER0N, omega interferon, interferon gamma-lb, lymphoblast Cell-like interferon tau or a combination thereof. 43. The use of claim 34, wherein the microbial infection is a bacterial infection. 44. The use of claim 43, wherein the bacterial infection is selected from the group consisting of Helicobacter pylori (Helicobacter pyl〇rid snail, spinel 7〇reHa, Legionella vulgaris plus/Μpneumophilia), tuberculosis 156069.doc 201144296 Mycobacterium, Mycobacterium avium (Μ. &lt;aW«w), Mycobacterium intracellulare (M., Kansas branch Bacillus (Μ. Α:α«·5ίπ7), M. gordowae, Staphylococcus aureus (*Siap/z; v/ococcws awrews), Neisseria gonorrhoeae (iVWwerza goworr/zoeae) , NeVebierk meningitidis, Listeria monocytogenes wowoc^ogewe·?), Pichia sphaeroides (“SYre/^ococcws p less 〇ge«ej”), no lactococcus ( iSYre/^ococcM·? agfl/aciiae), Staphylococcus aureus ((Sirepioccjccw·? Wr/i/aw·?), Staphylococcus aureus (“Sirepiococcwi /aeca/i·?”), Streptococcus bovis (•SYrepiococcws 6oWs) ), Streptococcus pneumoniae (*Sire/?iococcM5 pnewmow/ae), Haemophilus influenzae (i/aewop/n7wi z&gt;z//Me«Zi3e), Bacillus anthracis (5α£?ζ7/«·5 awirac/ί ), Coryne bacterium diphtheriae (Erysipelothrhr rhusiopathiae), Clostridium perfringers, Clostridium ieiam·, Enterobacteriaceae (five to roiacier, pneumonia) Klebsiella pneumoniae (A7eZ^k//a pwewwom'fle), Pasteurella multocida {Pasturella mw/iodda), Fusobacterium nucleatum (FwsoZiac^e) Www nucleatum), Arepioftacz·//!^ moniliformis, Treponema pallidium, perioid (periewwe), Leptospira, rickettsia (and sputum), Israel Actinomycetes or a combination thereof. 45. The use of claim 44, wherein the bacterial infection is M. tuberculosis 156069.doc -19- 201144296. 46. The use of claim 34, wherein the microbial infection is a fungal infection. 47. The use of claim 46, wherein the fungal infection is an infection: aspergilli〇sis, crytococcosis, sporotrichosis, coccidioidomycosis, Brazil Paracoccidioidomycosis, histoplasmosis, blastomycosis, zygomycosis or candidiasis 〇48. The use of claim 34, wherein the microorganism The infection is a parasite or protozoal infection. 49. The use of claim 48 wherein the parasite or protozoal infection is caused by the following infections: malignant cancer protozoa (_Ρ· yij/czybrz'MW), ovate 遽原愚(/&gt;. σνα/e ), Plasmodium vivax (ρ·νζ·νβχ), Plasmodium vivax (p, Dussian Leishman body (£·, baby Leishman body (Z, Ethiopian Leishman body (I., huge Z. wayor, tropical Leishman body (Z 叩z.ca), Mexican Leishman body (I. mexzcawa), Brazilian Leishman body, Gangdishishman body (71· Go« Mountain 7), tiny cariworms (where wz.crc> 〖z·), B. divergens, large intestine coke, B. coli, human 螽 螽 ^ h〇minis), Cryptosporidium parvum (C*. ;?arvMw), Cayetta Cyclospora (cc noisy ei (10), fragile dual-core amoeba (D), E. histolytica (£·, Bayesian, etc. (/heart, Schistosoma mansoni (S. Egyptian schistosomiasis (s; ^ said as 〇6~), Trypanosoma ssp, T螽慝x〇piasma ssp, Iris green 156069.doc -20- 201144296 ((9. vo/vm/w·?), cattle worm hoWs), dog Cocci (Βαέαία cam\s), C. cerevisiae (5(10)eha GAiom), Besnoitia daflingi, Cytauxzoon felis, Eimeria ssp., Hajd It is a genus (Hammondia ssp.), a large bow worm (Γ. ca«b), a locust (Cesioda), a Tyler prototheon (TTzd/eWa •^P) or a combination thereof. 50. The use of claim 48, wherein the parasite or protozoal infection causes malaria, babesiosis, trypanosomiasis, American trypanosomiasis, leishmaniasis ), toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isosporiasis, Cyclosporiasis, microsporidiosis, ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis, Trichinosis, lymphatic filariasis, onchocerciasis, filariasis, schistosomiasis (8〇11丨31〇30111丨33丨3) or by The dermatitis caused by the suction of the animal. 51. The use of claim 50, wherein the parasite or protozoal infection causes malaria. 52. The use of claim 50, wherein the parasite or protozoal infection results in leishmaniasis, caribe, toxoplasmosis or trypanosomiasis. 156069.doc -21 -